CN1214039A - 姆替林的氨基甲酰氧基衍生物及其抗菌素用途 - Google Patents

姆替林的氨基甲酰氧基衍生物及其抗菌素用途 Download PDF

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CN1214039A
CN1214039A CN96180177A CN96180177A CN1214039A CN 1214039 A CN1214039 A CN 1214039A CN 96180177 A CN96180177 A CN 96180177A CN 96180177 A CN96180177 A CN 96180177A CN 1214039 A CN1214039 A CN 1214039A
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woods
nurse
deoxidation
formic acid
methoxyl group
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杰里米·D·欣克斯
安德鲁·K·塔克尔
埃里克·亨特
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Priority claimed from GBGB9600048.4A external-priority patent/GB9600048D0/en
Priority claimed from GBGB9616305.0A external-priority patent/GB9616305D0/en
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Publication of CN1214039A publication Critical patent/CN1214039A/zh
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Abstract

通式(1A)的姆替林衍生物及其可药用的盐和衍生物治疗细菌感染的药物组合物的应用,其中R1是乙基或乙烯基,Y是氨基甲酰氧基,N－原子是未取代或者是一取代或二取代的。

Description

姆替林的氨基甲酰氧基 衍生物及其抗菌素用途
本发明涉及新化合物，其制备方法，含有它们的药物组合物以及医疗特别是抗菌治疗的用途。
通式(1)化合物截短侧耳素是天然存在的抗菌素，它有抗支原体活性和一般抗菌活性。已表明在其14位置用R-X-CH2CO2-替代二醇酯部分就能改良抗微生物活性，其中R是脂族或芳族部分且X是O、S或NR’(见H Egger和H Reinshagen，抗菌素杂志，1976,29,923)。通式(2)化合物铁木林，一般用作兽药抗菌素，是这种类型的衍生物(G Hogenauer，见抗菌素，V卷，1部，F E Hahn,Springer-Verlag出版，1979,p.344)。
Figure A9618017700051
在本申请中，使用(G Hogenauer,loc.cit.)文献中通常使用的非常规计数体系。
我们发现，截短侧耳素类似物含有14-氧-氨基甲酰基也有改良的抗微生物活性。
因此，广义上讲，本发明提供一种姆替林(mutilin)或19,20-二氢姆替林的14-氧-氨基甲酰基衍生物，其中氨基甲酰基的N-原子是未取代、一取代或二取代的。
更具体地，本发明提供一种通式(3)的化合物：其中，R1是乙烯基或乙基；R2和R3是相同或不同的基团，选自
氢；
直链或支链，饱和或不饱和，任选取代的C1-C6烃基；
饱和或不饱和，任选取代的C3-C8环烃基；
任选取代的杂环基；
任选取代的芳基；
或一起形成有3-8环原子的任选取代的环基，任选地含有一个选自N、O和S的另外的杂原子，和任选地稠合到烃环、杂环或芳上；或者
R2是上述单价基团之一且R3是一种选自SO2R4、COR5、OR5和NR6R7的基团，其中
R4选自直链或支链，饱和或不饱和，任选取代的C1-C6烃基；饱和或不饱和，任选取代的C3-C8环烃基；任选取代的杂环基；任选取代的芳基；任选取代的C1-C6烷基氨基；和任选取代的芳基氨基；
R5选自氢；直链或支链，饱和或不饱和，任选取代的C1-C6烃基；饱和或不饱和，任选取代的C3-C8环烃基；任选取代的杂环基；任选取代的芳基；
R6和R7是相同或不同的基团，选自氢；直链或支链，饱和或不饱和，任选取代的C1-C6烃基；饱和或不饱和，任选取代的C3-C8环烃基；任选取代的杂环基；任选取代的芳基；或一起形成有3-8环原子的任选取代的环基，任选地含有一个选自N、O和S的另外的杂原子，和任选地稠合到烃环、杂环或芳基上。
合适的C1-C6烃基包括含有1-6碳原子的直链或支链烷基，例如甲基，乙基，正丙基和异丙基，优选甲基。
合适的C3-C8环烃基包括环丙基，环戊基和环己基。
(C1-6)烷基和(C3-8)环烷基合适的任选取代基包括卤素，羟基，(C1-6)烷氧基，芳氧基，羧基及其盐，(C1-6)烷氧基羰基，氨基甲酰基，一-或二(C1-6)烷基氨基甲酰基，氨磺酰基，一-和二(C1-6)烷基氨磺酰基，氨基，一-和二取代(C1-6)烷氨基，(C1-6)酰氨基，脲基，(C1-6)烷氧羰基氨基，芳基，杂环基，氧桥，羟基亚氨基，酰基，(C1-6)烷硫基，芳硫基，(C1-6)链烷烃-亚磺酰基，芳基亚磺酰基，(C1-6)链烷磺酰基，芳基磺酰基。
本文所用术语“芳基”包括苯基和萘基。合适的芳基，包括苯基和萘基，任选地被最多五个、优选三个取代基取代。合适的取代基包括卤素，(C1-6)烷基，芳基(C1-4)烷基，(C1-6)烷氧基，(C1-6)烷氧基(C1-6)烷基，卤代(C1-6)烷基，羟基，硝基，氨基，一-和二-N-(C1-6)烷氨基，酰氨基，酰氧基，羧基，羧酸盐，羧酸酯，氨基甲酰基，一-和二-N-(C1-6)烷基氨基甲酰基，(C1-6)烷氧基羰基，芳氧基羰基，脲基，胍基，磺酰氨基，氨磺酰基，(C1-6)烷硫基，(C1-6)烷基亚磺酰基(C1-6)烷基磺酰基，杂环基和杂环(C1-4)烷基。另外，两个相邻的环碳原子可用(C3-5)亚烷基链连在一起成碳环。
本文所用术语“杂芳基”包括芳族单环和稠环且每个环最多有四个杂原子，选自O、N和S，环是未取代或者被最多三个取代基取代。每个杂芳环适宜有5或6个环原子。稠合的杂环包括碳环和必需包括唯一的杂环。
除非另有规定，本文所用术语“杂环”适宜包括芳族和非芳族、单环和稠环，每个环最多有四个杂原子，选自O、N和S，环是未取代或者被最多三个取代基取代。每个杂芳环适宜有4-7个、5-6个环原子。稠合的杂环包括碳环和必需包括唯一的杂环。
杂芳基或杂环基合适的取代基选自卤素，(C1-6)烷基，芳基(C1-4)烷基，(C1-6)烷氧基，(C1-6)烷氧基(C1-6)烷基，卤代(C1-6)烷基，羟基，硝基，氨基，一-和二-N-(C1-6)烷氨基，酰氨基，羧酸盐，羧酸酯，氨基甲酰基，一-和二-N-(C1-6)烷基羰基，芳氧基羰基，(C1-6)烷氧基羰基(C1-6)烷基，芳基，氧桥，脲基，胍基，磺酰氨基，氨磺酰基，(C1-6)烷硫基，(C1-6)烷基亚磺酰基，(C1-6)烷基磺酰基，杂环基和杂环(C1-4)烷基。
R2和R3特别合适的基团是氢，羟基，甲氧基，苯基，甲基，异丙基，苯基磺酰基，甲氧基苯基，硝基苯基，三氯乙酰基，苄基，羟基亚氨基苄基，苄氨基-磺酰基，二氯吡啶基，羟乙基，2-苯基乙基，1-(R)-苯基-2-羟乙基，2-(甲氧羰基)乙基，2-羧乙基，二甲氨基，二甲氨基丙基，甲磺酰氨基，甲磺酰基，苯甲酰氨基，任选地用以下基团取代的苯甲酰基：三氟甲基，羧基，甲氧基，羟基，乙酸基，氨基或硝基，糠酰基，烟酰基，异烟酰基，乙酰基，苯乙酰基，和苯氧基。对环基R2R3N特别合适的基团是吲哚代和吗啉代。
本发明另一方面提供一种本发明化合物的制备方法，包括将通式(4)或(5)的化合物与合适取代的氨甲酸酯型试剂反应，通式(4)中的X是氢或带例如乙酰基保护基的羟基。
制备氨甲酸酯的一般方法已公开，例如见AF Hegarty文章，综合有机化学，2卷，IO Sutherland,Pergamon Press出版，1979,p.1083。一般步骤是与异氰酸酯或甲氨酰氯反应，或与光气或光气等效物反应随后与胺反应。
本发明特别涉及的一个方面是提供一种通式(3)化合物的制备方法，包括通式(4)化合物与以下化合物反应，通式(4)中X是氢或羟基的保护基，
(a)R2NCO化合物，
(b)R2R3NCOCl化合物，或
(c)光气或氯代甲酸酯或碳酸酯随后与R2R3NH化合物反应，
其中R2和R3如上定义，并且被合适地保护，和必要时在11位置将X脱保护产生羟基，脱保护被护的R2和R3，将一个R2或R3基团转换成另一个R2或R3基团，或者氢化12位置的乙烯基形成乙基。
尽管原则上能够以公知姆替林化合物(通式(4)中X=H)通过在14-羟基的反应制备通式(3)化合物，实际上使用一种其中11-羟基被保护的中间体是合乎要求的。
合适的通式(4)化合物是11-氧-酰基姆替林衍生物(通式(4)中X=乙酰基)(见A J Brich,C W Holzapfel,R W Richards文章，四面体(suppl.),1966,8,Ⅱ部，359)。形成14-氧-氨基甲酰基衍生物后，选择合适的水解(例如用甲醇中的氢氧化钠)去除14-氧-酰基。
本发明另一方面，提供一种通式(3)化合物的制备方法，将通式(5)化合物与以下化合物反应，
(a)R2NCO化合物，
(b)R2R3NCOCl化合物，或
(c)光气或或氯代甲酸酯或碳酸酯随后与R2R3NH化合物反应。
其中R2和R3如上定义并且被合适地保护，用酸处理产物，脱保护被护的基团R2和R3，将一个R2或R3基团转换成另一个R2或R3基团，或者氢化12位的乙烯基形成乙基。
通式(5)是(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表-姆替林(通式(4)中X=乙酰基)(见H Berner,G Schulz和H Schneider文章，四面体(suppl.),1980,36,1807)。形成14-氨基甲酰酯后，在二噁烷中用浓盐酸或卢卡斯试剂处理中间体就转换成(3)。
关于19,20-二氢类似物的制备(其中R1=乙基的通式(3)化合物)，在甲氨酰化之前或之后通式(4)或(5)的化合物在溶剂中将其R1乙烯基用载钯催化剂(例如10％钯/碳)氢化还原，溶剂例如乙酸乙酯，乙醇，二噁烷或四氢呋喃。
如下在14位形成甲氨酸酯：
(1)14-羟基与异氰酸酯(R2N=C=O)在惰性溶剂(例如二氯甲烷，三氯甲烷，四氢呋喃，乙醚，二噁烷)中的反应，任选地在一种有机或无机碱(例如N,N-二异丙基乙胺，碳酸钾)的存在下进行。这将在14位得到R2NHCO2-基团。制备异氰酸酯的方法已公开，例如见J March文辛“高级有机化学”1992第4版，Wiley,New York出版，p.1290。
(2)14-羟基与N,N-二取代氨基甲酰氯(R2R3NCOCl)在有机溶剂(例如二氯甲烷，三氯甲烷，四氢呋喃，乙醚，二噁烷)中在一种位阻叔碱(例如2,6-二甲基吡啶，N,N-二异丙基乙胺)存在下进行。这将在14位置得到R2R3NHCO2-基团。制备氨基甲酰氯的方法已公开，例如见A FHegarty,loc.cit,p.1088。
(3)14-羟基与光气或等效试剂(例如氯甲酸三氯甲酯，碳酸双(三氯甲酯))在一种有机碱(例如吡啶，2,6-二甲基吡啶，N,N-二异丙基乙胺)存在下反应，所得14-氯甲酸酯与伯胺或仲胺(R2NH2或R2R3NH)反应。
合适的羟基、羧基和氨基的保护基是本领域熟知的，它们可在常规条件下去除而并不断裂分子的其余部分。保护羟基、羧基和氨基方式和断裂所得被护衍生物方法的综述，例如见“有机化学中的保护基”(作者T.W.Greene,Wiley-Interscience,New York,1991，第二版)。特别合适的羟基保护基包括，例如三烷基甲硅烷基的三有机甲硅烷基类，和有机羰基以及有机氧羰基，如乙酰基，烯丙氧基羰基，4-甲氧基苄氧基羰基和4-硝基苄氧基羰基。特别合适的羧基保护基包括烷基和芳基，例如甲基，乙基和苯基。特别合适的氨基保护基包括烷氧基羰基，4-甲氧基苄氧基羰基和4-硝基苯氧基羰基。
在使用通式(4)中间体(例如X=乙酰基)情况下，在X基团脱保护的同时可方便地去除不稳定碱保护基。在使用通式(5)的中间体情况下，在化合物(5)转换成化合物(3)的同时可方便地去除不稳定酸的保护基。
本发明方法中形成的中间体化合物，例如通式(5)化合物的14-氯甲酸酯衍生物和14-氧-氨基甲酰基衍生物，这也是本发明的新颖部分。
本发明化合物可以是结晶或非结晶形式，如果结晶，任选地水合或溶剂合。当让本发明一些化合物从有机溶剂中结晶或再结晶时，结晶产物中可存在结晶溶剂。这种溶剂化物也在本发明范围内。同样，本发明一些化合物也可从含水溶剂中结晶或再结晶。在这种情况下，结晶产物中存在水合作用的水。化学计量水合物以及含有通过诸如冷冻干燥法产生的可变量水的化合物也在本发明范围内。
以基本纯的形式提供本发明化合物是合适的，例如纯度至少50％，合适的纯度至少60％，有益的纯度至少75％，优选纯度至少85％，更优选纯度至少95％，甚至纯度至少98％，所有百分比都以重量/重量计。不纯或纯度较低形式的本发明化合物，例如可用来制备适合药物用途的更纯形式的同样化合物或相关化合物(例如相应的衍生物)。
本发明还包括本发明化合物的可药用的盐或衍生物。当一个取代基带有酸性或碱性基团时就可形成盐。可通过常规方式的盐交换制备这种盐。
本发明化合物及其可药用的盐或衍生物具有抗微生物性质，并可用来处理动物特别是哺乳动物包括人类特别是人和家养动物(包括田间动物)的微生物感染。该化合物还可处理由例如革兰氏阳性和阴性细菌和支原体造成的感染，例如金黄色葡萄球菌属，粪肠球菌属，生浓链球菌属，无乳链球菌属，肺炎链球菌属，嗜血杆菌属种，萘瑟氏菌属种，军团菌属种，肺支原体和鸡败血支原体。
本发明提供一种药物组合物，包括通式(3)化合物或其可药用的盐或其衍生物以及与其一起的可药用的载体或赋性剂。
本发明还提供一种治疗动物、特别是人类或家养哺乳动物的微生物感染的方法，包括将通式(3)化合物或其可药用盐或其衍生物，或本发明的组合物给予待治的病人。
本发明还提供一种以医疗组合物制剂形式的本发明化合物或其可药用的盐或衍生物的用途，用于治疗微生物感染。
可将本发明化合物和组合物配制成方便给药的形式，用于人类或兽类医疗，从其它抗生素类推。
可以任何给药途径配制本发明化合物和组合物，例如口服、外用或经肠给药。例如可将组合物制成片剂，胶囊剂，粉剂，粒剂，锭剂，膏剂，糖浆，或液体制剂如溶液或悬浮液，亦即配制口服应用或经肠注射或注入的灭菌液形式。
片剂和胶囊剂的口服给药可以是单剂型，可含有的常规赋形剂，包括例如粘合剂如糖浆，阿拉伯胶，明胶，山梨醇，黄耆胶或聚乙烯基吡咯烷酮；填充剂如乳糖，蔗糖，玉米淀粉，磷酸钙，山梨醇或甘氨酸；压片润滑剂如硬脂酸镁，滑石，聚乙二醇或硅石；崩解剂如土豆淀粉；和可药用的湿润剂如月桂基硫酸钠。片剂可用常规药学实践的公知方法包衣。
口服液体制剂的形式为例如水性或油性悬浮液，溶液，乳液，糖浆或酏剂，或者以干粉制品存在、使用前用水或其他合适的载体复制。这种液体制品可含有常规添加剂，包括例如悬浮剂如山梨醇，甲基纤维素，葡萄糖糖浆，明胶，羟乙基纤维素，羧甲基纤维素，硬脂酸铝胶或氢化食用脂肪；乳化剂如卵磷脂，一油酸脱水山梨醇酯或阿拉伯胶；非水载体(可包括食用油)如杏仁油，油状酯(如甘油)，丙二醇或乙醇；防腐剂如对羟基苯甲酸或山梨酸的甲酯或丙酯；并且如果需要还有常规矫味剂和着色剂。
本发明组合物打算外用的形式可以是例如软膏，膏剂，洗剂，眼膏，滴眼剂，滴耳剂，滴鼻剂，喷鼻剂，浸渍贴皮剂和气溶胶，并且可以含有合适的常规添加剂，包括例如防腐剂，辅助药物渗透的溶剂，和在软膏和膏剂中的润肤剂。这种外用制剂也可含有相容的常规载体如膏剂或软膏的基质，洗剂用的乙醇或油醇。这类载体可占组合物重量的约1％～98％，更通常约占组合物重量高达80％。
本发明组合物还可配制成栓剂，它含有常规栓剂基质如可可脂或其他甘油酯。
打算经肠给药的本发明组合物可以是方便的流体单剂型，利用化合物和灭菌载体优选水来制备。根据所用的载体和浓度，该化合物可悬浮或可溶于载体。制备溶液时，化合物溶于注射用水并且在装入合适的小瓶或安瓿瓶之前进行灭菌过滤，然后密封。包括例如局部麻醉剂、防腐剂和缓冲剂的常规添加剂优选溶于载体。为了增强溶液的稳定性，组合物可在填入小瓶后冷冻，并在真空下除水；然后所得干燥的冷冻粉末密封在小瓶内，而且可同时供应注射用水小瓶以在使用前复制液体。以基本同样的方式可制备非经肠给药的悬浮液，除了化合物不是溶解而是悬浮在载体中，而且灭菌不能通过过滤完成。相反化合物可以通过悬浮在灭菌载体之前在环氧乙烷中暴露而灭菌。为促使化合物均匀分布，这种悬浮液优选包括表面活性剂或湿润剂。
本发明化合物或组合物适合以抗菌有效量向病人给药。
根据给药方式，本发明组合物适合含有的本发明化合物量为0.1wt％(重量％)，优选10-60wt％(基于组合物总重)。
适合向病人给药本发明组合物的日剂量为1.0-50mg/kg体重。对成年人(大约70kg体重)，每天给药本发明组合物的量从50-3000mg，例如大约1500mg。成年人每天适合的剂量是5-20mg/kg。但是这些剂量可更高或更低一些，取决于正常的临床实践。
本发明组合物以单剂型存在时，每单剂型适合包括25-1000mg、优选50-500mg本发明化合物。
以下实施例进一步说明本发明。
实施例1．14-(N-苯基氨甲酸)姆替林
步骤1．14-(N-苯基氨甲酸)的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(H Berner,GSchulz和H schneider，四面体，1980,36,1807)(170mg)在干二氯甲烷(3ml)中用异氰酸苯酯(0.12ml)和N,N-二异丙基乙胺(1滴)处理，排除湿气室温保持溶液7天。用乙酸乙酯(50ml)稀释溶液并用稀盐酸(20ml)、水(20ml)和饱和碳酸氢钠溶液(20ml)洗涤。用硫酸钠干燥溶液，减压蒸发去除溶剂得到一种无色油。该无色油进行硅胶色谱分离，用1∶4乙酸乙酯-己烷洗脱得到14-(N-苯基氨甲酸)的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林无色胶(190mg)；υ最大(CHCl3)3435,1724,1695,1603和1523cm-1。
步骤2．14-(N-苯基氨甲酸)姆替林
14-(N-苯基氨甲酸)的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(160mg)在二噁烷(3ml)中用浓盐酸中的饱和氯化锌溶液(1.2ml)中处理，室温搅拌所得溶液3.5小时。用乙酸乙酯(50ml)稀释混合物并用饱和氯化钠(20ml)和饱和碳酸氢钠(20ml)洗涤。用硫酸钠干燥溶液，减压蒸发去除溶剂得到无色油。在硅胶上色谱分离该油，用1∶3乙酸乙酯-己烷洗脱得14-(N-苯基氨甲酸)姆替林无色(145mg)；二氯甲烷-己烷结晶得到无色棱晶(130mg)，熔点211-212℃；λ最大(乙醇)236nm((19000)；υ最大(CHCl3)3630,3562,3435,1726,1602和1523cm-1；MS(EI)m/z439(M+)。
实施例2．14-(N-甲基氨甲酸)姆替林
步骤1．14-(N-甲基氨甲酸)的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(335mg,1.0mmol)在干二氯甲烷(5ml)中与异氰酸甲酯(0.12ml,2.0mmol)和N,N-二异丙基乙胺(1滴)反应，如同实施例1的步骤1，得到标题化合物(145mg,37％)；υ最大(CH2Cl2)3459,1711，和1516cm-1；
1H NMR(CDCl3)6.79(1H,dd,J17.5,10.5Hz)5.65(1H,d,J9.9Hz)5.31(1H,
d,J10.9Hz)5.01(1H,d,17.6Hz)4.55(1H,br)3.46(1H,m)3.23(3H,s)2.95
(1H,q,J6.4Hz)2.83(3H,br d,J4.8Hz)2.40(1H,dd,J15.3,9.8Hz)2.20(1H,
m)2.02(2H,m)1.65(3H,m)1.47(1H,m)1.30-1.07(4H,m)1.20(6H,s)0.99
(3H,d,J6.4Hz)0.85(3H,br d,J6.9Hz)；MS(EI)m/z 391(M+).
步骤2．14-(N-甲基氨甲酸)姆替林
步骤1的产物(135mg,0.34mmol)在二噁烷(2ml)中用浓盐酸中的饱和氯化锌溶液(0.5ml)中处理，如同实施例1的步骤2，得到标题化合物(89mg,69％)；υ最大(CH2Cl2)3460,1732和1714cm-1；
        1H NMR(CDCl3)6.61(1H,dd,J17.4,11.0Hz)5.64(1H,d,J8.4Hz)5.37
(1H,br d,J11.0Hz)5.21(1H,dd,J17.4,1.6Hz)4.47(1H,br)3.34(1H,dd,J
11.0,6.7Hz)2.78(3H,br d,J4.8Hz)2.37(1H,五重峰,J6.8Hz)2.21(4H,m)
2.02(2H,m)1.70(4H,m)1.42(6H,m)1.23(3H,s)0.86(3H,d,J7.0Hz)0.76
(3H,d,J6Hz)；MS(EI)m/z 377(M+).
实施例3．14-(N-异丙基氨甲酸)姆替林
步骤1．14-(N-异丙基氨甲酸)的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(335mg,1.0mmol)在二氯甲烷(5ml)中与异氰酸异丙酯(0.2ml,2.0mmol)和N,N-二异丙基乙胺(1滴)反应，如同实施例1的步骤1，得到标题化合物(367mg,87％)；υ最大(CH2Cl2)3435,1700cm-1；1H NMR
(CDCl3)6.77(1H,dd,J17.5,10.6Hz)5.64(1H,d,J9.8Hz)5.30(1H,d,J
10.6Hz)5.00(1H,d,J17.5Hz)4.44(1H,d,J7.8Hz)3.83(1H,m)3.45(1H,m)
3.22(3H,s)2.94(1H,q,J6.4Hz)2.39(1H,dd,15.1,9.9Hz)2.18(1H,m)2.00
(2H,m)1.65(4H,m)1.46(1H,m)1.29-1.05(5H,m)0.98(3H,d,J6.4Hz)0.84
(3H,d,J6.8Hz)；MS(EI)m/z 419(M+).
步骤2．14-(N-异丙基氨甲酸)姆替林
步骤1产物(324mg,0.77mmol)在二噁烷(10ml)中用浓盐酸中的饱和氯化锌溶液(2ml)中处理，如同实施例1的步骤2，得到标题化合物(102mg,33％)；υ最大(CH2Cl2)3436,1733,1710和1505cm-1；
    1H NMR(CDCl3)6.60(1H,dd,J17.4,11.0Hz)5.64(1H,d,J
8.4Hz)5.36(1H,dd,J11.0,1.6Hz)5.20(1H,dd,J17.5,1.6Hz)4.36(1H,br)
3.79(1H,m)3.34(1H,dd,J11.0,6.6Hz)2.38(1H,m)2.21(2H,m)2.02(2H,
m)1.81-1.59(4H,m)1.49-1.26(7H,m)1.14(10H,m)0.86(3H,d,J7.1Hz)
0.76(3H,br d,J5.8Hz)；MS(NH3 DCI)m/z 406(MH+).
实施例4．14-(N-苯磺酰基氨甲酸)姆替林
步骤1．14-(N-苯磺酰基氨甲酸)的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(335mg,1.0mmol)在二氯甲烷(5ml)中与异氰酸苯磺酰酯(0.27ml,2.0mmol)和N,N-二异丙基乙胺(1滴)反应，如同实施例1的步骤1，得到标题化合物(365mg,71％)；υ最大(CH2Cl2)3361,1745,1698,1450和1354cm-1；1H NMR(CDCl3)8.05(2H,d,J7.1Hz)7.68(1H,t,J7.3Hz)7.57(2H,m)6.42(1H,dd,J17.5,10.7Hz)5.67(1H,d,J10.0Hz)5.25(1H,d,J10.7Hz)4.96(1H,d,J17.5Hz)3.37(1H,ddd,.J11.1,8.3,5.1Hz)3.21(3H,s)2.77(1H,q,J6.4Hz)2.32(1H,dd,J15.3,10.0Hz)2.16(1H,m)1.99(2H,m)1.67(1H,d,J11.3Hz)1.48-1.02(7H,m)1.15(3H,s)1.10(3H,s)0.95(3H,d,J
    6.4Hz)0.62(3H,d,J6.9Hz)；MS(EI)m/z 517(M+)，测定值：517.2504,
    C22H39NO6S：理论值：517.2498.
步骤2．14-(N-苯磺酰基氨甲酸)姆替林
步骤1产物(340mg,0.66mmol)在二噁烷(5ml)中用浓盐酸中的饱和氯化锌溶液(1ml)中处理，如同实施例1的步骤2，得到标题化合物(291mg,88％)；熔点125-7℃；(最大(CH2Cl2)3364,1736,1450,1420和1353cm-1；
                        1H NMR(CDCl3)8.00(2H,d,J7.4Hz)7.65(1H,
t,J7.4Hz)7.54(2H,t,J7.5Hz)6.26(1H,dd,J17.4,11.0Hz)5.61(1H,d,J
8.4Hz)5.23(1H,dd,J11.0,1.3Hz)5.07(1H,dd,J17.5,1.3Hz)3.18(1H,dd,J
10.1,6.7Hz)2.19(3H,m)1.95(2H,m)1.75-1.23(8H,m)1.33(3H,s)1.08(1H,
m)1.07(3H,s)0.85(3H,d,J7.0Hz)0.51(3H,d,J6.7Hz)；MS(EI)m/z 503
(M+)，测定值：503.2348,C27H37NO6S理论值503.2342.
实施例5．14-(N-4-甲氧基苯基氨甲酸)姆替林
步骤1．14-(N-4-甲氧基苯基氨甲酸)的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(1.0g,2.97mmol)在干二氯甲烷(10ml)中与异氰酸4-甲氧基苯基酯(0.77ml,5.95mmol)和N,N-二异丙基乙胺(5滴)反应，排除湿气室温保持溶液8天。用二氯甲烷稀释溶液并用水洗涤，随后用盐水洗涤。用硫酸镁干燥，减压蒸发去除溶剂。用乙酸乙酯/己烷研制残留物，在减压下将母液的体积减少之前过滤去除所得固体。在硅胶上色谱纯化，用1∶4乙酸乙酯-己烷洗脱。分离出泡沫状标题化合物(1.37g,95％)；υ最大(CH2Cl2)3428,2932,1722,1697和1597cm-1；1H NMR
(CDCl3)0.89(3H,d,J6.1Hz),0.99(3H,d,J6.4Hz),1.20(6H,s)叠加在
1.07-1.29(5H,m)上,1.34-1.37(1H,m),1.70(1H,d,J15.3Hz),1.73(1H,d,J
11.3Hz),194-2.05(2H,m).2.15-2.24(1H,m),2.46(1H,dd,J15.2,10.0Hz),
2.96(1H,q,J6.4Hz),3.23(3H,s),3.47(1H,m),3.80(3H,s),5.01(1H,d,J
17.4Hz),5.31(1H,d,J10.7Hz),5.77(1H,d,J9.9Hz),6.43(1H,宽s),6.75
(1H,dd,J17.5,10.6Hz),6.86(2H,d,J8.9Hz),7.31(2H,宽d)；MS(ESI-ve
离子)m/z 482((M-H)-).
步骤2．14-(N-4-甲氧基苯基氨甲酸酯)姆替林
将14-(N-4-甲氧基苯基氨甲酸酯)的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(483mg,1.0mmol)在二噁烷(5ml)中用浓盐酸中的饱和氯化锌溶液(1ml)中处理，如同实施例1的步骤2，分离得到结晶固体状的标题化合物(400mg,86％)；熔点(二氯甲烷/己烷)192-194℃；υ最大(CH2Cl2)3625,3563,2937,1725,1597和1519cm-1；
               1H NMR(CDCl3)0.79(3H，宽d),0.87(3H,d,J
7.0Hz),1.18(6H,s),1.14-1.82(13H,m),2.04-2.26(3H,m),2.37(1H五重峰,J
6.9Hz),3.36(1H,dd,J10.9,6.7Hz),3.78(3H,s),4.81(1H,dd,J17.4,1.6Hz),
5.36(1H,dd,J10.9,1.4Hz),5.73(1H,d,J8.3Hz),6.39(1H,宽s),6.59(1H,
dd,J17.4,10.9Hz),6.85(2H,d,J8.9Hz),7.26(2H,宽d)；MS(EI)m/z 469
(M+).C28H39NO5理论值469.2828,测定值：469.2830.
实施例6．14-(N-4-硝基苯基氨甲酸)姆替林
步骤1．14-(N-4-硝基苯基氨甲酸)的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(1.0g,2.97mmol)与异氰酸4-硝基苯酯(731mg,4.5mmol)和N,N-二异丙基乙胺(5滴)溶于干二氯甲烷(10ml)中,如同实施例5的步骤1，得到标题化合物(702mg)；υ最大(CH2Cl2)3415,2981,1733,1698和1599cm-1；
          1H NMR(CDCl3)0.87(3H,d,J6.9Hz),1.01(3H,d,J6.4Hz),1.21
(3H,s)和1.26(3H,s)叠加在1.10-1.90(6H,m)上,1.68(1H,d,J
15.4Hz),1.75(1H,d,J11.5Hz),1.94-2.06(2H,m),2.16-2.25(1H,m),2.51(1H,
dd,J15.2,10.1Hz),2.94(1H,q,J6.3Hz),3.23(3H,s),3.47-3.49(1H,m),5.04
(1H,d,J17.5Hz),5.32(1H,d,J10.7Hz),5.82(1H,d,J9.9Hz),6.70(1H,dd,J
17.5,10.6Hz),6.93(1H.宽s),7.61(2H,d,J9.1Hz),8.22(2H,d,J9.1Hz)；
MS(NH3DCI)m/z 499(MH+),m/z 516(MNH4 +).
步骤2．14-(N-4-硝基苯基氨甲酸)姆替林
步骤1产物(203mg,0.41mmol)在二噁烷(5ml)中用浓盐酸中的饱和氯化锌溶液(0.5ml)处理，如同实施例1的步骤2。分离得到结晶固体状的标题化合物(163mg,82％)；熔点(二氯甲烷/己烷)208-210℃；(0.5ml)最大(CH2Cl2)3562,3314,2939,1733,1598和1536cm-1；1H NMR(CDCl3)0.78(3H,d,J6.5Hz),0.92(3H,d,J
7.0Hz),1.20(3H,s)和1.46(3H,s)叠加在1.20-1.84(10H,m)上，
2.09-2.28(3H,m),2.39(1H,五重峰,J7.0Hz),3.38(1H,dd,J10.7,6.6Hz),5.23
(1H,dd,J17.5,1.4Hz),5.39(1H,dd,J10.9,1.4Hz),5.80(1H,d,J9.3Hz),6.56
(1H,dd,J17.4,10.9Hz),6.88(1H,宽s),7.56(2H,d,J9.2Hz),8.20(2H,d,J
9.2Hz)；MS(EI)m/z 484(M+).C27H36N2O6理论值484.2573,测定值：
484.2571.
实施例7．14-氨甲酸姆替林
步骤1．14-(N-三氯乙酰基氨甲酸)的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(1.0g,2.97mmol)与异氰酸三氯乙酰酯(0.389ml,3.3mmol)和N,N-二异丙基乙胺(5滴)溶于干二氯甲烷(10ml)中，如同实施例5的步骤1，得到标题化合物(1.80g)；υ最大(CH2Cl2)3510,3396,1737,1698和1583cm-1；1H NMR(d6-丙酮)0.85-.91(3H,m),1.02(3H,d,J6.4Hz),1.11-1.79(14H,m),1.90-2.23(3H,m),2.42-2.63(1H,m),3.01(1H,q,J6.4Hz),3.18-3.27(5H,m),3.50-3.59(1H,m),4.04-4.18(2H,m),4.99(1H,d,J17.6Hz),5.30(1H,d,J10.8Hz),5.83-5.87(1H,m),6.82-6.99(m),7.16-7,23(m),7.88-7.91(m)(总共4H)；MS(NH3DCI)m/z 521(MH+),m/z 539(MNH4 +).
步骤2．14-(N-三氯乙酰基氨甲酸)姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(1.8g,2.97mmol)在二噁烷(10ml)中用浓盐酸中的饱和氯化锌溶液(2.0ml)处理,如同实施例1的步骤2,分离得到固体状的标题化合物(901mg,60％)；υ最大(CH2Cl2)3406,1803和1736cm-1；
                              1H NMR(d6-丙酮)0.89(3H,d,J
6.8Hz),1.01(3H,d,J6.4Hz),1.11-2.22(17H,m),2.55(1H,dd,J15.4,10.1Hz),
2.91-2.96(1H,m),3.19(3H,s),3.45-3.55(1H,m),5.00(1H,d,J17.6Hz),5.31
(1H,d,J10.7Hz),5.88(1H,d,J10.0Hz),6.74(1H,dd,J17.5,10.7Hz),10.59
(1H宽s)；MS(ESI-ve离子)m/z 506((M-H)-)
步骤3．14-氨甲酸姆替林
将14-(N-三氯乙酰基氨甲酸)姆替林(300mg)在用碳酸钾(122mg,0.9mmol)处理之前溶于二氯甲烷(2ml)和甲醇(2ml)中。在用二氯甲烷稀释之前，室温搅拌反应4小时。有机相用水(两次)洗涤，随后用饱和食盐水溶液洗涤，减压去除溶剂。研制残留物得到白色固体状的标题化合物(179mg,85％)；υ最大(CH2Cl2)3538,3421,1725和1582cm-1；
                                           1H NMR(CDCl3)
0.79(3H,d,J6.4Hz),0.86(3H,d,J7.0Hz),1.17(3H,s),1.39(3H,s)
叠加在1.38-1.79(10H-m)上,2.02-2.25(1H,d,J8.6Hz),2.09(1H,宽
s),2.17-2.31(2H,m),2.36(1H,五重峰,J6.9Hz),3.35(1H,宽t),4.52(2H,
宽s),5.21(1H,dd,J17.4,1.5Hz),5.36(1H,dd,J11.0,1.5Hz),5.62(1H,d,
J8.5Hz)6.57(1H,dd,J17.4,10.9Hz)；MS(NH3DCI)m/z 364(MH+),m/z 381
(MNH4 +).
实施例8．14-(N-苄基氨甲酸)姆替林
步骤1．14-(N-苄基氨甲酸)的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
将(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(336mg,1.0mmol)溶于干二氯甲烷(5ml)中，用异氰酸苄酯(0.16ml,1.3mmol)和N,N-二异丙基乙胺(5滴)处理，如同实施例5的步骤1反应。分离出白色泡沫状的标题化合物(432mg,95％)；υ最大(CH2Cl2)3444,2930,1711,1698和1456cm-1；
                1H NMR(CDCl3)0.87(3H,d,J6.8Hz),0.98(3H,d,J6.4Hz),1.18
(3H,s)和1.19(3H,s)叠加在1.02-1.54(6H.m)上,1.67(1H,d,J
15.2Hz),1.70(1H,d,J11.3Hz),1.93-2.04(2H,m),2.15-2.23(1H,m),2.42(1H,
dd,J15.1,10.0Hz),2.95(1H,q,J6.4Hz),3.22(3H,s),3.42-3.51(1H,m),4.32
(1H,dd,J14.9,5.5Hz),4.52(1H,dd,J14.9,6.4Hz),4.95(1H,宽s),5.01
(1H,d,J17.6Hz),5.32(1H,d,J10.7Hz),5.69(1H,d,J9.8Hz),6.79(1H,dd,J
17.5,10.6Hz),7.26-7.37(5H,m).
步骤2．14-(N-苄基氨甲酸)姆替林
14-(N-苄基氨甲酸)的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(400mg,0.85mmol)在二噁烷(5ml)中用浓盐酸中的饱和氯化锌溶液(1.0ml)处理，如同实施例1的步骤2，分离出泡沫状标题化合物(329mg,82％)；υ最大(CH2Cl2)3626,3563,2934,1718,1581和1510cm-1；                             1H NMR(CDCl3)0.77
(3H,d,J5.9Hz),0.86(3H,d,J7.0Hz),1.17(3H,s)和1.39(1H,s)
叠加在1.08-1.80(8H)上,1.99-2.07(3H,m),2.17-2.24(2H,m),2.39
(1H,五重峰,J6.9Hz),3.35(1H,dd,J10.8,6.7Hz),4.31(1H,dd,J5.9Hz),4.41
(1H,dd,J16.0,6.2Hz),4.90(1H,宽t),5.20(1H,d,J17.3Hz),5.36(1H,d,J
10.9Hz),5.69(1H,d,J8.4Hz),6.61(1H,dd,J17.4,11.0Hz),7.24-7.43(5H,m)；
MS(EI)m/z 391(M+)；MS(NH3DCI)m/z 392(MH+)
实施例9．14-[N-(苄基氨磺酰基)氨甲酸]姆替林
步骤1．14-[N-(氯磺酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(1.0g,2.97mmol)用异氰酸氯磺酰酯(0.284ml,3.3mmol)处理并如实施例5的步骤1进行反应。分离出白色泡沫状标题化合物(1.03g,75％)；υ最大(CH2Cl2)3331,2929,1765,1698和1441cm-1；
                                     1H NMR(CDCl3)0.93(3H,
d,J6.9Hz),1.02(3H,d,J6.4Hz),1.20(3H,s)和1.26(3H,s)和1.82(1H,d,
J15.2Hz)叠加在1.22-2.26(3H,s)上.,2.60(1H,dd,J15.4,10.2Hz),
2.95(1H,q,J6.4Hz),2.97(3H,s),3.46-3.55(1H,m),5.02(1H,d,J17.5Hz),
5.33(1H,d,J10.7Hz),5.88(1H,d,J10.1Hz),6.68(1H,dd,J17.5,10.7Hz).
步骤2．14-[N-(苄基氨磺酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
14-[N-(氯磺酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(300mg,0.65mmol)在氩气氛下溶于干二氯甲烷中。溶液用苄胺(0.077ml,0.71mmol)随后用三乙胺(0.1ml,0.71mmol)处理。室温搅拌12小时后用二氯甲烷稀释反应，并用水和饱和食盐水溶液洗涤。硫酸镁干燥后硅胶色谱纯化粗产物，用1∶4乙酸乙酯-己烷洗脱。分离出泡沫状标题化合物(233mg,65％)；υ最大(CH2Cl2)3370,2981,2930,1734,1698和1456cm-1；
1H NMR(CDCl3)0.88(3H,d,J6.8Hz),0.99(3H,d,J6.4Hz),1.19
(3H,s),1.21(3H,s),1.54(1H,d,J15.4Hz),1.72(1H.d,J11.3Hz),1.07-1.74
(6H,m),1.93-2.02(2H,m),2.14-2.23(1H,m),2.44(1H,dd,J15.2,10.2Hz),
2.84(1H,q,J6.5Hz),3.21(3H,s),3.38-3.47(1H,m),4.19(1H,dd,J13.6,
5.3Hz),4.30(1H,dd,J13.7,6.9Hz),5.02(1H,d,J17.5Hz),5.30(1H,d,J
10.7Hz),5.40(1H,宽t,J～5.7Hz)5.74(1H,d,J10.0Hz),6.56(1H,dd,J
17.5,10.7Hz),7.35(5H,宽s),7.50(1H,宽s)；MS(NH3DCI)m/z 564
(MNH4 +)；MS(EI)m/z 546(M+).C29H42N2O6S理论值546.2764,测定值：
546.2764.
步骤3．14-[N-(苄基氨磺酰基)氨甲酸]姆替林
14-[N-(苄基氨磺酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(233mg,0.43mmol)在二噁烷(4ml)中用浓盐酸中的饱和氯化锌溶液(0.5ml)中处理，如同实施例1的步骤2。分离出泡沫状标题化合物(169mg,82％)；υ最大(CH2Cl2)3562,3372,2934和1734cm-1；1H NMR(CDCl3)
0.79(3H,d,J6.8Hz),0.88(3H,d,J7.0Hz),1.20(3H,s),1.40(1H,s),1.47(1H,
d,J10.7Hz),1.10-1.81(10H,m),2.08-2.32(5H,m),3.36(1H,dd,J10.3,
6.7Hz),4,19(1H,s),4.20(1H,s),5.26(1H,dd,J17.3,1.4Hz),5.37(1H,dd,J
10.9,1.3Hz),534-5.39(1H,m),5.72(1H,d,J8.5Hz),6.46(1H,dd,J17.4,
11.0Hz),7.28-7.37(5H,m)；MS(NH3DCI)m/z 550(MNH4 +).
实施例10．14-[N-(2,6-二氯吡啶-4-基)氨甲酸]姆替林
步骤1．14-[N-(2,6-二氯吡啶-4-基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(336mg,1.0mmol)溶于干二氯甲烷(5ml)中并用异氰酸2,6-二氯吡啶-4-基酯(283mg,1.5mmol)和N,N-二异丙基乙胺(5滴)处理，如实施例5步骤1进行反应。分离出白色泡沫状标题化合物(589mg，定量)；υ最大(CH2Cl2)3407,3295,2981,1734,1698,1575和1502cm-1；
                                          1H NMR(CDCl3)0.83(3H,d,J
6.9Hz),1.01(3H,d,J6.4Hz),1.20(3H,s),1.21(3H,s),1.08-1.56(6H,m)1.64
(1H,d,J15.3Hz),1.74(1H,d,J11.3Hz),1.94-2.05(2H,m),2.16-2.30(1H,m),
2.50(1H,dd,J12.7,6.4Hz),2.91(1H,q,J6.2Hz),3.23(3H,s),3.41-3.48(1H,
m),5.04(1H,d,J17.5Hz),5.36(1H.d,J10.7Hz),5.80(1H,d,J9.9Hz),6.65
(1H,dd,J17.6,10.7Hz),7.07(1H,宽s),7.34(1H,s),7.44(1H,s)；MS
(NH3DCI)m/z 523(MH+).
步骤2．14-[N-2,6-二氯吡啶-4-基)氨甲酸]姆替林
14-[N-(2,6-二氯吡啶-4-基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(569mg,1.0mmol)在二噁烷(5ml)中用浓盐酸中的饱和氯化锌溶液(1.5ml)处理，如同实施例1的步骤2，分离出泡沫状产物，用乙酸乙酯/己烷结晶得标题化合物(266mg,52％)；熔点(乙酸乙酯/己烷)237℃；υ最大(CH2Cl2)3404,2926,1739,1719,1579和1507cm-1；
                                                   1H NMR
(CDCl3)0.61(3H,d,J6.2Hz),0.77(3H.d,J7.0Hz),0.96-1.08(4H,m),0.96-
1.08(10H,m),1.90-2.27(6H,m),3 20-3.26(2H,m),5.07(1H,dd,J17.4,
1.4Hz),5.22(1H,dd,J10.9.1.3Hz),5.58(1H,d,J8.3Hz),6.34(1H,dd,J17.4,
11.0Hz),7.34(2H,s)；MS(EI)m/z 508(M+)；MS(NH3DCI)m/z 509(MH+).
实施例11．14-(N,N-二甲基氨甲酸)姆替林
步骤1．14-(N,N-二甲基氨甲酸)的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(336mg,1.0mmol)溶于吡啶(10ml)后,用N,N-二甲基氨基甲酰氯(0.12ml,1.3mmol)处理。氩气氛下加热反应至回流。反应期间以5天的间隔周期向反应添加另一部分的N,N-二甲基氨基甲酰氯(0.12ml,1.3mmol)。回流14天后让反应冷却，然后在乙酸乙酯和1.0M盐酸之间分配。分离有机相并用水随后用饱和食盐水洗涤。硫酸镁干燥后，硅胶色谱纯化粗产物，装载甲苯，并用1∶9乙酸乙酯-己烷洗脱。分离出白色固体状的标题化合物(158mg,40％)；υ最大(CH2Cl2)2931,1693和1456cm-1；
                  1H NMR(CDCl3)0.87(3H,d,J6.7Hz),0.98(3H,d,J
6.4Hz),1.20(3H,s)和1.26(3H,s)叠加在1.07-1.74(6H,m)上,
1.99-2.04(2H,m),2.16-2.24(1H,m),2.82和2.92(3H,s+s),2.92(1H,m),
3.21和3.23(3H,s+s),3.46-3.56(1H,m),4.28和4.76(ABq,J15.2Hz)以及
4.32和4.76(ABq.J15.7Hz)(总共2H),5.01(1H,d,J17.6Hz),5.32(1H,d,J
10.2Hz),5.72(1H,d,J9.9Hz),6.79-6.90(1H,m),7.22-7.31(5H,m).
步骤2．14-(N,N-二甲基氨甲酸)姆替林
14-(N,N-二甲基氨甲酸)的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(158mg,0.40mmol)在二噁烷(3ml)中用浓盐酸中的饱和氯化锌溶液(0.5ml)处理，如同实施例1的步骤2，分离得到固体状标题化合物(74mg,49％)；υ最大(CH2Cl2)3564,2933,1734,1692和1454cm-1；
                                     1H NMR(CDCl3)0.73(3H,
d,J6.4Hz),0.84(3H,d,J7.1Hz),1.16(3H,s)和1.36(1H,d,J16.0Hz)和
1.45(3H,s)叠加在108-1.80(5H,m)上,2.00-2.10(2H,m),2.18-2.26
(2H,m),2.37(1H,五重峰,J6.9Hz),2.86(3H,s),2.90(3H,s),3.34(1H,dd,J
11.3,6.6Hz),5.20(1H,dd,J17.4,1.7Hz),5.36(1H,dd,J11.0,1.6Hz),5.67
(1H,d,J8.4Hz),6.65(1H,dd,J17.4,11.0Hz):MS(EI)m/z 391(M+)；MS
(NH3DCI)m/z 392(MH+).
实施例12．14-氧-(二氢吲哚基羰基)姆替林
步骤1．14-氯甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
方法1
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(1.0g,2.97mmol)在氩气氛下溶于干四氢呋喃(10ml)中。反应冷却到0℃用氯甲酸三氯甲酯(0.215ml,1.48mmol)随后用三乙胺(0.495ml,3.56mmol)处理。室温搅拌非均相混和物2小时，然后进一步用氯甲酸三氯甲酯(0.215ml,1.48mmol)和三乙胺(0.495ml,3.56mmol)处理。再2小时后，加入更多的氯甲酸三氯甲酯(0.108ml,0.74mmol)和三乙胺(0.250ml,1.78mmol)。用四氢呋喃(30ml)和甲苯(10ml)稀释反应。用饱和食盐水洗涤后，分离有机相并用硫酸镁干燥。去除溶剂得到黄色油，静置结晶得到标题物(1.42g，定量)。将该固体部分进行硅胶色谱纯化，装载并用1∶19乙酸乙酯-己烷洗脱。分离出白色结晶固体状的标题化合物(145mg,62％)；υ最大(CH2Cl2)1765,1732,1699和1458cm-1；1H NMR(d6-丙酮)0.94(3H,d,J6.8Hz),1.00(3H,d,J6.4Hz),{1.21(3H,s)1.27(3H,s),1.78(1H,d,J11.3Hz),1.91(1H,d,J15.7Hz)}均叠加在1.11-2.26(9H,m)上,2.63(1H,dd,J15.6,10.3Hz),2.82(1H,q,被HOD遮蔽),3.14(3H,s),3.49-3.53(1H,m),5.02(1H,d,J17.6Hz),5.35(1H,d,J10.7Hz),5.83(1H,d,J10.2Hz),6.52(1H,dd,J17.6,10.7Hz).
方法2．
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(1.0g,2.97mmol)在氩气氛下溶于甲苯。溶液冷却到0℃，并用光气(2.82ml的12.5％w/w甲苯溶液，3.56mmol)处理，随后用吡啶(0.24ml,2.97mmol)处理。室温搅拌均匀的反应混和物。在2和12小时间隔后加入等量的光气和吡啶。然后用甲苯(40ml)稀释反应混合物并且用饱和食盐溶液洗涤，加入足够量的水完全溶解水相中所有固体。硫酸镁干燥后，硅胶色谱纯化，得到结晶固体状的标题化合物(926mg,78％)。
步骤2．(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-14-氧-(二氢吲哚基羰基)-4-表姆替林
14-氯甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(300mg,0.75mmol)在氩气氛下溶于干二氯甲烷中。溶液用二氢吲哚(268mg,2.2mmol)处理并室温搅拌反应物15分钟。用二氯甲烷稀释混和物接着用1.0M盐酸随后用水和饱和食盐溶液顺次洗涤。用硫酸镁干燥有机相，减压蒸发去除溶剂。硅胶色谱纯化，装载并用1∶9乙酸乙酯-己烷洗脱。分离出泡沫状标题化合物(308mg,86％)；υ最大(CH2Cl2)2930,1731,1696和1602cm-1；1HNMR(d6-丙酮)0.85-
0.91(3H,m),1.02(3H,d,J6.4Hz),1.11-1.79(14H,m),1.90-2.23(3H,m),2.42-
2.63(1H,m),3.01(1H,q,J6.4Hz),3.18-3.27(5H,m),3.50-3.59(1H,m),4.04-
4.18(2H,m),4.99(1H,d,J17.6Hz),5.30(1H,d,J10.8Hz),5.83-5.87(1H,m),
6.82-6.99(m),7.16-7,23(m),7.88-7.91(m)(总共4H)；MS(EI)m/z 479(M+),
(NH3DCI)m/z 480(MH+).
步骤3．14-氧-(二氢吲哚基羰基)姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-14-氧-(二氢吲哚基羰基)-4-表姆替林(260mg,0.54mmol)在二噁烷(5ml)中用浓盐酸中的饱和氯化锌溶液(0.5ml)处理，如同实施例1的步骤2，分离出固体状的从二氯甲烷-己烷结晶的标题化合物(195mg,77％)；υ最大(CH2Cl2)3627,3563,2934,1734,1697,1602,1487和1407cm-1；
1H NMR(CDCl3)0.76(3H,m),0.89(3H,d,J7.1Hz),
1.06-1.83(16H.m),2.14-2.29(4H,m),2.44(1H，五重峰，J6.9Hz),3.12(2H,t,J
8.6Hz),3.38(1H,m),3.94-4.04(1H,m),5.22(1H,dd,J17.5,1.5Hz),5.38(1H,
dd,J11.0,1.5Hz),5.72-5.86(1H,m),6.58-6.64(1H,m),6.92-6.98(m),7.19-
7.22(m),7.89-7.92(m)(总共4H)；MS(EI)m/z 465(M+).C29H39NO4理论值
465.2879，测定值：465.2885。
实施例13．14-[N-(2-羟乙基)氨甲酸]姆替林
步骤1．14-[N-(2-羟乙基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
14-氯甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(300mg,0.75mmol)(如实施例12方法2的步骤1制备)溶于干二氯甲烷(5ml)中，用乙醇胺(0.137ml,2.25mmol)处理并按实施例步骤1所述反应。分离出泡沫状标题化合物(323mg,定量)；υ最大(CH2Cl2)3616,3446,2931,1699和1513cm-1；
           1HNMR(CDCl3)0.85(3H,d,J6.9Hz),0.98(3H,
d,J6.4Hz),1.23(6H,s),1.61(1H,d,在D2O交换 叠加在0.95-1.72(7H,m)上
            ,1.93-2.04(2H,m),2.14-2.36(1H,m),2.41(1H,dd,J15.2,
10.1Hz),2.93(1H,q,J6.4Hz),3.22(3H,s),3.37-3.48(3H,m),3.72(2H,m,
在D2O中分解为三重峰(t),J5.0Hz),5.00(1H,d,J17.6Hz)
叠加在5.04(1H,宽)5 29(1H,d,J10 8Hz)上,5.69(1H,d,J9.9Hz),6.73(1H,dd,J17.5,
10.6Hz)；MS(NH3DCI)m/z 422(MH+),m/z 439(MNH4 +).
步骤2．14-[N-(2-羟乙基)氨甲酸]姆替林
14-[N-(2-羟乙基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(300mg,0.56mmol)在二噁烷(5ml)中用浓盐酸中的饱和氯化锌溶液(0.5ml)处理，如同实施例1的步骤2，分离得固体状的从乙酸乙酯/己烷结晶的标题化合物(108mg,47％)；υ最大(CH2Cl2)3620,3564,3446,2937,1733,1712,1512和1455cm-1；1H NMR(CDCl3)0.76(3H,d,J
6.4Hz),0.86(3H,d,J7.0Hz),1.08-1.81(16H,m)(包括1.16(3H,s),1.40
(3H,s)},2.08(1H,宽s)叠加在1.98-2.13(1H,m)上,2.18-2.24(2H,
m),2.39(1H,五重峰,J6.9Hz),3.31-3.38(3H,m),3.68(2H,m,在D2O中分解为三重峰(t),J5.0Hz),4.98(1H,宽t),5.20(1H,dd,J17.5,1.5Hz),5.35(1H,dd,J
11.3,1.5Hz),5.64(1H,d,J8.3Hz),6.56(1H,dd,J17.4,11.0Hz)；MS(EI)m/z
484(M+).C23H37NO5理论值407.2762,测定值：407.2670.
实施例14．14-(N-甲基-N-苄基氨甲酸)姆替林
步骤1．14-(N-甲基-N-苄基氨甲酸)的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
14-氯甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(300mg,0.75mmol)(实施例12方法2的步骤1制备)溶于干二氯甲烷(5ml)中并用N-甲基苄基胺(0.293ml,2.25mmol)处理并如实施例步骤1进行反应。分离出泡沫状标题化合物(323mg,90％)；υ最大(CH2Cl2)2981,2929,1698和1454cm-1；1H NMR(CDCl3)0.87(3H,d,J6.7Hz),0.98
(3H,d,J6.4Hz),1.20(3H,s)和1.26(3H,s)均叠加在1.07-1.74(12H,m)上,1.99-2.04(2H,m),2.16-2.24(1H,m),2.82和2.92(3H,s+s),2.92
(1H,m),3.21和3.23(3H,s+s),3 46-3.56(1H,m),4.28和4.76(ABq,J
15.2Hz)以及4.32和4.76(ABq,J15.7Hz)(总共2H)5.01(1H,d,J17.6Hz),
5.32(1H,d,J10.2Hz),5.72(1H,d,J9.9Hz),6 79-6.90(1H,m),7.22-7.31(5H,
m)；MS(NH3DCI)m/z 482(MH+),m/z 499(MNH4 +)；MS(EI)m/z 481(M+)
C30H43NO4理论值481.3192,测定值：481.3199.
步骤2．14-(N-甲基-N-苄基氨甲酸)姆替林
14-(N-甲基-N-苄基氨甲酸)的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(270mg,0.56mmol)在二噁烷(5ml)中用浓盐酸中的饱和氯化锌溶液(0.5ml)处理，如同实施例1的步骤2，分离得固体状标题化合物(187mg,72％)；υ最大(CH2Cl2)3656,3564,2932,1734,1688和1453cm-1；                                      1H NMR(CDCl3)0.76
(3H,d,J5.9Hz),0.86(3H,d,J7.0Hz),1.41-1.81(15H,m),1.97-2.42(5H,m),
2.78和2.89(3H,s+s),3.32-3.38(1H,m),4.24和4.34(1H,d+d,J15.8Hz),
4.61(1H,d,J15.3Hz),5.32(1H,d,J17.5Hz),5.38(1H,d,J10.8Hz),5.75(1H,
d,J8.3Hz),6.56-6.73(1H,m),7.20-7.31(5H,m)；MS(EI)m/z 467(M+)；MS
(NH3DCI)m/z 468(MH+).
实施例15．14-氧-(吗啉代羰基)姆替林
步骤1．(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-14-氧-(码啉代羰基)-4-表姆替林
向CH2Cl2(5ml)中的14-氯甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(300mg,0.75mmol)(实施例12方法2的步骤1制备)在氩气氛下加入吗啉(0.2ml,2.29mmol)。两天后用二氯甲烷稀释反应物并用1M盐酸洗涤。硫酸镁干燥有机相，去除溶剂得到粗产物。硅胶色谱得到标题化合物(193mg,57％)；υ最大(CH2Cl2)1691cm-1；
                                                1H NMR(CDCl3)
6.79(1H,dd,J17.6,10.7Hz),5.86(1H,d,J9.9Hz),5.31(1H,d,J10.7Hz),
5.01(1H,d,J17.6Hz),3.66(4H,m),3.49(5H,m),3.22(3H,s),2.93(1H,q,J
6.4Hz),2.43(1H,dd,J15.2,10.0Hz),2.20(1H,m),1.99(2H,m),1.72(1H,d,J
11.3Hz),1.63(1H,d,J15.2Hz),1.52-1.20(5H,m),1.23(3H,s),1.20(3H,s),
1.09(1H,m),0.98(3H,d,J6.4Hz),0.89(3H,d,J6.9Hz),MS(EI),m/z 447(M+)
测定值：447.2990.C26H41NO5理论值447.2985.
步骤2．14-氧-(码啉代羰基)姆替林
步骤1产物(153mg,034mmol)在二噁烷(5ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，如同实施例1的步骤2，得标题化合物(81mg,55％)；υ最大(CH2Cl2)3563,1733和1689cm-1；
    1H NMR(CDCl3)6.62(1H,dd,J17.4,11.0Hz),5.70(1H,d,J8.4Hz),
5.37(1H,dd,J11.0,1.6Hz),5.21(1H,dd,J17.4,1.6Hz),3.62(4H,m),3.43
(4H,m),3.35(1H,d,J11.2,6.6Hz),2.36(1H,五重峰,J7.0Hz),2.22(2H,m),
2.10(1H,br),2.04(1H,m),1.81-1.57(4H,m),1.54-1.34(4H,m),1.43(3H,s),
1.19(1H,m),1.17(3H,s),0.86(3H,d,J7.0Hz),0.74(3H,d,J6.5Hz),MS(EI)
m/z 433(M+)测定值：433.2834,C25H39NO5理论值433.2828.
实施例16．14-(N-甲基-N-苯基氨甲酸)姆替林
步骤1．14-(N-甲基-N-苯基氨甲酸)的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
将N-甲基苯胺(0.3ml,2.32mmol)与CH2Cl2(5ml)中的14-氯甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(300mg,0.75mmol)(实施例12方法2的步骤1制备)，并如实施例12步骤2进行反应。得到标题化合物(287mg,81％)；υ最大(CH2Cl2)1693cm-1；
                                                     1H NMR
(CDCl3)7.37(2H,m),7.24(3H,m),6.83(1H,m),5.69(1H,m),5.30(1H,d,J
10.7Hz),5.00(1H,d,J17.5Hz),3.45(1H,m),3.32(3H,s),3.19(3H,s),2.92
(1H,m),2.41(1H,m),2.18(1H,m),1.99(2H,m),1.74-1.58(3H,m),1.38-1.02
(11H,m),0.97(3H,d,J6.4Hz),0.82(3H,m)；MS(EI)m/z 467(M+)测定值：
467.3040,C29H41NO4理论值467.3036.
步骤2．14-(N-甲基-N-苯基氨甲酸)姆替林
步骤1产物(270mg,0.58mmol)在二噁烷(5ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，如同实施例1的步骤2，得标题化合物(172mg,66％)；υ最大(CH2Cl2)3562,1734和1691cm-1；
            1H NMR(CDCl3)7.34(2H,m),7.20(3H,m),6.64(1H,dd,J17.3,
11.0Hz),5.71(1H,m),5.38(1H,d,J10.7Hz),5.23(1H,d,J17.6Hz),3.33(1H,
dd,J11.2,6.7Hz),3.28(3H,s),2.38-2.05(5H,m),1.78-1.07(9H,m),1.58(3H,
s),1.18(3H,s),0.85(3H,d,J7.0Hz),0.74(3H,m),MS(EI)m/z 453(M+)
测定值：453.2884,C28H39NO4理论值453.2879.
实施例17．14-[N-(3-二甲基氨丙基)氨甲酸]姆替林
步骤1．14-[N-(3-二甲基氨丙基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
14-氯甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(170mg,0.43mmol)与3-二甲基氨丙基胺在二氯甲烷(3ml)中反应，如实施例12步骤2所述；得到标题化合物(147mg,74％)；υ最大(CH2Cl2)3447和1698cm-1；1H NMR
(CDCl3)6.78(1H,dd,J17.5,10.7Hz),5.62(1H,dd,J9.9Hz),5.52(1H,m),
5.29(1H,d,J10.7Hz),4.99(1H,d,J17.5Hz),3.48-3.15(3H,m),3.21(3H,s),
2.94(1H,q,J6.4Hz),2.42(1H,m),2.33(2H,t,J6.7Hz),2.21(6H,s),2.16(1H,
m),1.98(2H,m),1.83(1H,br),1.67(5H,m),1.47(1H,m),1.30-1.05(3H,m),
1.18(6H,s),0.97(3H,d,J6.4Hz),0.85(3H,d,J6.9Hz),MS(EI)m/z 462(M+)
测定值：462.3457,C27H46N2O4理论值462.3458
步骤2．14-[N-(3-二甲基氨丙基)氨甲酸]姆替林
步骤1产物(141mg,0.3mmol)在二噁烷(3ml)中用浓盐酸(1ml)处理，室温搅拌24小时。仔细将反应物在乙酸乙酯和饱和碳酸氢钠之间分配，水相用乙酸乙酯再提取。硫酸镁干燥合并的有机相并浓缩得到标题化合物(123mg,90％)；υ最大(CH2Cl2)3447,1733和1708cm-1；
                                   1H NMR(CDCl3)6.61
(1H,dd,J17.4,11.0Hz),5.63(1H,d,J8.4Hz),5.35(2H,包括1H,dd,J
11.0,1.5Hz),5.19(1H,dd,J17.4,1.6Hz),3.22(3H,m),2.35(4H,m),2.19(6H,
s),2.00(2H,m),1.68(7H,m),1.42(7H,m),1.16(3H,s),1.15(1H,m),0.85
(3H,d,J7.0Hz),0.76(3H,d,J6.0Hz):MS(EI)m/z 448(M+)测定值：448.3302,
C26H44N2O4理论值448.3301.
实施例18．14-(N-羟基氨甲酸)姆替林
步骤1．14-(N-羟基氨甲酸)的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
将盐酸羟胺(50mg,0.72mmol)与14-氯甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(50mg,0.72mmol)和二异丙基乙胺(0.2ml,1.15mmol)在二氯甲烷(3ml)中进行反应，反应如实施例12的步骤2进行，得到标题化合物(80mg,54％)；υ最大(CH2Cl2)3534,1720和1698cm-1；                    1H NMR(CDCl3)7.18(1H,s),6.67(2H
包括1H,dd,J17.5,10.6Hz),5.73(1H,d,J9.9Hz),5.29(1H,d,J10.7Hz),
5.02(1H,d,17.5Hz),3.44(1H,ddd,J11.2,8.0,5.4Hz),3.21(3H,s),2.89(1H,
q,J6.4Hz),2.45(1H,dd,J15.2,10.1Hz),2.19(1H,m),1.99(2H,m),1.72(1H,
d,J11.3Hz),1.62(1H,d,J15.2Hz),1.49(2H,m),1.35-1.03(4H,m),1.19(6H,
s),0.99(3H,d,J6.4Hz),0.84(3H,d,J6.9Hz),MS(3NOBA钠) m/z 416
(MNa+).
步骤2．14-(N-羟基氨甲酸)姆替林
步骤1产物(72mg,0.18mmol)在二噁烷(3ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，如同实施例1的步骤2，得标题化合物(47mg,68％)；υ最大(KBr盘)3418和1728cm-1；                            1H
NMR(CDCl3)9.38(1H,s),8.59(1H,s),6.24(1H,dd,J17.7,11.1Hz),5.46
(1H,d,J8.0Hz),5.11(1H,dd,J17.7,1.8Hz),5.04(1H,dd,J11.2,1.9Hz),4.46
(1H,d,J6.1Hz),3.40(1H,m,),2.36(1H,br s),2.09(4H,m),1.65(2H,m),1.49
(2H,m),1.33(3H,s),1.26(3H,m),1.06(4H,包括3H,s),0.81(3H,d,J
6.8Hz),0.67(3H,br d,J5.7Hz)；MS(CI)m/z 397(MNH4 +).
实施例19．14-(N-甲氧基氨甲酸)姆替林
步骤1．14-(N-甲氧基氨甲酸)的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
将盐酸甲氧胺(70mg,0.84mmol)与14-氯甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(167mg,0.42mmol)和二异丙基乙胺(0.22ml,1.26mmol)在二氯甲烷(3ml)中反应，如实施例12步骤2进行。得到标题化合物(164mg,96％)；υ最大(CH2Cl2)3379,1742和1698cm-1；
                                  1H NMR(CDCl3)7.39(1H,s),6.70
(1H,dd,J17.5,10.7Hz),5.73(1H,d,J10.0Hz),5.29(1H,d,J10.7Hz),5.00
(1H,d,17.5Hz),3.75(3H,s),3.46(1H.ddd,J11.2,4.9,2.9Hz),3.21(3H,s),
2.90(1H,q,J6.4Hz),2.46(1H,dd,J15.3,10.1Hz),2.19(1H,m),2.00(2H,m),
1.72(1H,d,J11.3Hz),1.65(1H,d,J15.3Hz),1.57(2H,m),1.36-1.06(4H,m),
1.21(3H,s),1.19(3H,s),0.99(3H,d,J6.4Hz),0.86(3H,d,J6.9Hz)；MS(EI)
m/z 407(M+)测定值：407.2670,C23H37NO5理论值407.2672.
步骤2．14-(N-甲氧基氨甲酸)姆替林
步骤1产物(144mg,0.35mmol)在二噁烷(3ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，如同实施例1的步骤2，得到标题化合物(98mg,70％)；υ最大(CH2Cl2)3379和1735cm-1；                            1H
NMR(CDCl3)7.28(1H,s),6.54(1H,dd,J17.4,11.0Hz),5.71(1H,d,J8.5Hz),
5.37(1H,dd,J11.0,1.5Hz),5.22(1H,dd,J17.4,1.5Hz),3.71(3H,s),3.35(1H,
dd,J10.8,6.7Hz),2.34(1H,五重峰,J6.9Hz),2.23(2H,m),2.08(2H,m),1.71
(4H,m),1.46-1.38(4H,m),1.42(3H,s),1.18(3H,s),1.15(1H,m),0.88(3H,d,
J7.1Hz),0.78(3H,d,J6.6Hz),MS(CI)m/z 411(MNH4 +),394(MH+)
实施例20．14-(N-二甲氨基氨甲酸)姆替林
步骤1．14-(N-二甲氨基氨甲酸)的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
将14-氯甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(167mg,0.42mmol)与二异丙基乙胺(0.15ml,0.86mmol)在二氯甲烷(3ml)中与1,1-二甲基肼(0.04ml,0.52mmol)反应，如实施例12步骤2进行。得到标题化合物(130mg,73％)；υ最大(CH2Cl2)3330,1729和1696cm-1；
                            1H NMR(CDCl3)6.78(1H,dd,J17.5,
10.7Hz),5.66(1H,d,J9.9Hz),5.54(1H,br s),5.26(1H,d,J10.7Hz),4.98(1H,
d,17.5Hz),3.46(1H,ddd,J11.2,4.7,2.9Hz),3.21(3H,s),2.92(1H,q,J
6.4Hz),2.58(6H,s),2.40(1H,dd,J14.9,10.2Hz),2.18(1H,m),1.98(2H,m),
1.64(3H,m),1.53-1.05(5H,m),1.18(6H,s),0.98(3H,d,J6.4Hz),0.84(3H,d,
J6.9Hz)；MS(EI)m/z 420(M+)测定值：420.2994,C24H40N2O4理论值
420.2988.
步骤2．14-(N-二甲氨基氨甲酸)姆替林
步骤1产物(114mg,0.27mmol)在二噁烷(3ml)中用浓盐酸(1ml)处理，如同实施例17的步骤2，得标题化合物(98mg,89％)；υ最大(CH2Cl2)3330和1732cm-1；
                                      1H NMR(CDCl3)6.60(1H,dd,
J17.4,11.0Hz),5.65(1H,d,J8.4Hz),5.41(1H,br s),5.34(1H,dd,J11.0,
1.5Hz),5.19(1H,dd,J17.4,1.5Hz),3.34(1H,dd,J10.9,6.6Hz),2.55(6H,s),
2.36(1H,五重峰,J6.9Hz),2.22(2H,m),2.03(2H,m),1.81-1.59(4H,m),1.42
(7H,m),1.16(3H,s),1.12(1H,m),0.87(3H,d,J7.0Hz),0.76(3H,d,J6.2Hz)；
MS(EI)m/z 406(M+)测定值：406.2838,C23H38N2O4理论值406.2832.
实施例21．14-[N-(甲磺酰氨基)氨甲酸]姆替林
步骤1．14-[N-(甲磺酰氨基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
将14-氯甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(170mg,0.43mmol)、二异丙基乙胺(0.19ml,1.09mmol)和4-二甲氨基吡啶(催化剂量)在二氯甲烷(3ml)中与甲磺酰基肼(94mg,0.85mmol)反应，如实施例12步骤2所述；得到标题化合物(179mg,89％)；υ最大(CH2Cl2)3372,1716和1698cm-1；
                    1H NMR(CDCl3)6.63(1H,dd,J17.5,10.7Hz),5.85
(1H,d,J10.1Hz),5.31(1H,d,J10.7Hz),5.03(1H,d,17.5Hz),4.32(2H,s),
3.47(1H,ddd,J11.3,8.1.5.3Hz),3.33(3H,s),3.22(3H,s),2.87(1H,q,J
6.4Hz),2.57(1H,dd,J15.3,10.1Hz),2.21(1H,m),2.00(2H,m),1.76(1H,d,J
11.3Hz),1.67(1H,d,J15.3Hz),1.54-1.05(6H,m),1.33(3H,s),1.21(3H,s),
1.00(3H,d,J6.4Hz),0.87(3H,d,J6.9Hz)；MS(EI)m/z 470(M+).
步骤2．14-[N-(甲磺酰氨基)氨甲酸]姆替林
步骤1产物(124mg,0.26mmol)在二噁烷(3ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，如实施例1的步骤2所述，得到标题化合物(102mg,85％)；υ最大(CH2Cl2)3371和1733cm-1；1H
NMR(CDCl3)6.48(1H,dd,J17.4,11.0Hz),5.81(1H,d,J8.6Hz),5.37(1H,
dd,J11.0,1.4Hz),5.23(1H,dd,J17.4,1.4Hz),4.28(2H,s),3.37(1H,dd,J
10.6,6.7Hz),3.29(3H,s),2.24(4H,m),2.12(1H,br s),1.81-1.41(8H,m),1.59
(3H,s),1.19(3H,s),1.17(1H,m),0.89(3H,d,J7.0Hz),0.77(3H,d,J6.8Hz)；
MS(CI)m/z 474(MNH4 +).
实施例22．14-(N-甲磺酰基氨甲酸)姆替林
步骤1．14-(N-甲磺酰基氨甲酸)的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
14-氯甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(170mg,0.43mmol)、二异丙乙胺(0.19ml,1.09mmol)和4-二甲氨基吡啶(催化剂量)在二氯甲烷(3ml)中与DMF(3ml)中的甲磺酰胺(80mg,0.84mmol)反应，如实施例12步骤2所述；得到标题化合物(191mg,98％)；υ最大(CH2Cl2)3364,1742和1698cm-1；
                      1H NMR(CDCl3)6.59(1H,dd,J17.5,10.7Hz),5.80
(1H,d,J10.0Hz),5.31(1H,d,J10.7Hz),5.07(1H,d,17.5Hz),3.44(1H,ddd,J
11.2,8.2,5.5Hz),3.32(3H,s),3.22(3H,s),2.86(1H,q,J6.4Hz),2.52(1H,dd,
J15.4,10.1Hz),2.20(1H,m),1.99(2H,m),1.74(1H,d,J11.3Hz),1.66(1H,d,
J15.4Hz),1.55-1.05(6H,m),1.23(3H,s),1.21(3H,s),1.03(3H,d,J6.4Hz),
0.88(3H,d,J6.9Hz)；MS(EI)m/z 455(M+).
步骤2．14-(N-甲磺酰基氨甲酸)姆替林
步骤1产物(144mg,0.32mmol)在二噁烷(3ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，如实施例1的步骤2所述，得到标题化合物(113mg,81％)；υ最大(CH2Cl2)3366和1737cm-1；
                                                            1H
NMR(CDCl3)6.45(1H,dd,J17.4,11.0Hz),5.75(1H,d,J8.5Hz),5.37(1H,
dd,J11.0,1.3Hz),5.23(1H,dd,J17.4,1.4Hz),3.36(1H,dd,J10.4,6.7Hz),
3.27(3H,s),2.24(4H,m),2.09(1H,br s),1.81-1.40(8H,m),1.43(3H,s),1.20
(3H,s),1.19(1H,m),0.89(3H,d,J7.0Hz),0.78(3H,d,J6.8Hz)；MS(CI)m/2
459(MNH4 +).
实施例23．14-(N-苯甲酰氨基氨甲酸)姆替林
步骤1．14-(N-苯甲酰氨基氨甲酸)的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
苯甲酰肼(90mg,0.66mmol)与14-氯甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(130mg,0.33mmol)和二异丙基乙胺(0.17ml,0.98mmol)在二氯甲烷(3ml)中反应，如实施例步骤1所述；得到标题化合物(163mg,100％)；υ最大(CH2Cl2)3403,1729和1696cm-1；
                    1H NMR(CDCl3)8.12(1H,br),7.82(2H,d,J7.3Hz),
7.56(1H,t,J7.3Hz),7.45(2H,t,J7.4Hz),6.84(1H,br),6.68(1H,dd,J17.5,
10.7Hz),5.73(1H,d,J9.9Hz),5.26(1H,d,J10.7Hz),5.00(1H,d,17.5Hz),
3.44(1H,m),3.22(3H,s),2.89(1H,q,J6.4Hz),2.47(1H,dd,J15.2,10.0Hz),
2.19(1H,m),2.01(2H,m),1.75-1.20(13H,m),1.12(1H,m),0.98(3H,d,J
6.4Hz),0.94(3H,br d,J6.5Hz)；MS(EI)m/z 496(M+).
步骤2．14-(N-苯甲酰氨基氨甲酸)姆替林
步骤1产物(153mg,0.31mmol)在二噁烷(3ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，如实施例1的步骤2所述，得到标题化合物(110mg,67％)；υ最大(CH2Cl2)3405,1734和1691cm-1；
    1H NMR(CDCl3)8.14(1H,br),7.79(2H,d,J7.2Hz),7.54(1H,t,J
7.3Hz),7.43(2H,t,J7.4Hz),6.80(1H,br),6.52(1H,dd,J17.4,11.1Hz),5.69
(1H,d,J8.5Hz),5.34(1H,dd,J11.3Hz),5.23(1H,dd,J17.4Hz),3.36(1H,dd,
J10.7,6.5Hz),2.27(3H,m),2.07(2H,m),1.80-1.43(8H,m),1.61(3H,s),1.19
(3H,s),1.18(1H,m),0.87(6H,d,J6.9Hz)；MS(EI)m/z 482(M+).
实施例24．14-(N-苯甲酰基氨甲酸)姆替林
步骤1．14-(N-苯甲酰基氨甲酸)的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(335mg,1.0mmol)与异氰酸苯甲酰基酯(0.25ml,2.0mmol)在二氯甲烷(5ml)中反应，如实施例1步骤1所述；得到标题化合物(478mg,99％)；υ最大(CH2Cl2)3423,1777,1714和1698cm-1；
                            1H NMR(CDCl3)7.99(1H,br s),7.83
(2H,d,J7.0Hz),7.61(1H,t,J7.3Hz),7.50(2H,m),6.73(1H,dd,J17.4,
10.6Hz),5.85(1H,d,J9.9Hz),5.30(1H,d,J10.7Hz),5.02(1H,d,17.5Hz),
3.47(1H,ddd,J11.2,8.3,5.3Hz),3.23(3H,s),2.91(1H,q,J6.4Hz),2.54(1H,
dd,J15.3.10.1Hz),2.21(1H,m),2.01(2H,m),1.75(1H,d,J11.2Hz),1.73
(1H,d,J15.3Hz),1.62-1.08(6H,m),1.32(3H,s),1.21(3H,s),1.01(3H,d,J
6.4Hz),0.91(3H,d,J6.9Hz)；MS(EI)m/z 481(M+)测定值：481.2823,
C29H39NO5理论值481.2828.
步骤2．14-(N-苯甲酰基氨甲酸)姆替林
步骤1产物(370mg,0.77mmol)在二噁烷(3ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理,如实施例1的步骤2所述,得到标题化合物(208mg,58％)；υ最大(CH2Cl2)3429,1779和1733cm-1；
    1H NMR(CDCl3)7.96(1H,s),7.80(2H,d,J7.1Hz),7.59(1H,t,J
7.3Hz),7.48(2H,t,J7.4Hz),6.56(1H,dd,J17.4,11.0Hz),5.84(1H,d,J
8.5Hz),5.38(1H,dd,J11.0,1.5Hz),5.24(1H,dd,J17.4,1.5Hz),3.77(1H,dd,
J10.9,6.6Hz),2.35(1H,五重峰,J7.0Hz),2.19(4H,m),1.82-1.30(8H,m),1.52
(3H,s),1.20(3H,s),1.13(1H,m),0.89(3H,d,J7.0Hz),0.81(3H,d,J=6.6
Hz)；MS(CI)m/z 485(MNH4 +).
实施例25．抗菌活性
下面的表说明代表性14-氨甲酸衍生物与铁木林相比较的抗菌活性。活性以最小抑制浓度(10-6g/ml)给出，并用标准的肉汤稀释方法以微量滴定测定。
有机物 铁木林 14-氨甲酸姆替林(实施例7) 14-(N-羟基)氨甲酸姆替林(实施例18) 14-(N-苯甲酰基)氨甲酸姆替林(实施例24)
 B.fE.c.H.i.M.c.E.fS.a.S.e.S.ag.S.pn.S.p.     1162＜0.06＞640.250.125＜0.06＜0.06＜0.06     0.2522＜0.0640.50.1250.50.50.25     10.51＜0.06＞640.50.50.2511     ＜0.060.5＜0.06＞640.125＜0.06＜0.06＜0.06＜0.06
B.f.=B70脆弱类杆菌属；E.c.=大肠DC2埃希氏菌属；H.i.=Q1流感嗜血菌属；M.c.=1502粘膜炎莫拉氏菌属；E.f.=Ⅰ型粪肠球菌属；S.a.=牛津金黄色葡萄球菌属；S.e.=PHLN20表皮葡萄球菌属；S.ag.=Hester无乳链球菌属；S.pn.=1761肺炎链球菌属；S.p.=CN10生浓链球菌属。
实施例26．14-[N-(2-苯乙基)氨甲酸]姆替林
步骤1．14-[N-(2-苯乙基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
14-氯甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(170mg,0.43mmol)在二氯甲烷(5ml)中与苯乙胺(0.16ml,1.29mmol)反应，如实施例12步骤2所述；得到标题化合物(200mg,97％)；υ最大(CH2Cl2)2902,2254,1794,1703,1644和1465cm-1；
         1H NMR(CDCl3)0.84(3H,d,J6.9Hz),0.97(3H,d,J6.4Hz),1.05-
2.27(12H,m)包括1.14(3H,s)和1.18(3H,s),2.38(1H,dd,J15.3,
10.0Hz),2.82(1H,dd,J13.2,6.9Hz),2.94(1H,q,J6.4Hz),3.21(3H,s),3.37-
3.61(3H,m),4.65(1H,宽t),5.00(1H,d,J17.5Hz),5.31(1H,d,J10.6Hz),
5.64(1H,d,J9.8Hz),6.75(1H,dd,J17.8,10.7Hz),7.18-7.34(5H,m)；MS
(NH3DCI)m/z 482(MH+)
步骤2．14-[N-(2-苯乙基)氨甲酸]姆替林
步骤1产物(200mg,0.42mmol)在二噁烷(5ml)中用浓盐酸中的饱和氯化锌溶液(0.5ml)处理，如实施例1的步骤2所述，得到标题化合物(75mg,39％)；υ最大(CH2Cl2)3445,1733,1712和1635cm-1；
              1H NMR(CDCl3)0.75(3H,宽s),0.86(3H,d,J7.0Hz),
1.06-2.23(18H,m)包括1.16(3H,s)和1.35(3H,s),2.37(1H,五重峰,J
6.6Hz),2.77(1H,q,J6.5Hz),3.30-3.51(3H,m),4.11(2H,q,J7.2Hz),4.66
(1H,宽s),5.21(1H,dd,J17.3,1.2Hz),5.35(1H,d,J10.8Hz),5.64(1H,d,J
8.3Hz),6.58(1H,dd,J17.4,10.9Hz),7.14-7.31(5H,m)；MS(EI)m/z 467(M+),
MS(NH3DCI)m/z 468(MH+).
实施例27．14-[N-(1-(R)-苯基-2-羟基)乙基氨甲酸]姆替林
步骤1．14-[N-(1-(R)-苯基-2-羟基)乙基氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
14-氯甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(170mg,0.43mmol)在二氯甲烷(5ml)中与(R)-2-苯基甘氨醇(phenylglycinol)(177mg,1.29mmol)反应，如实施例12步骤2所述；得到标题化合物(220mg，定量)；υ最大(CH2Cl2)3600,3433,2931,1698和1503cm-1；
1H NMR(CDCl3)0.82(3H,d,J6.6Hz),0.95(3H,d,J6.4Hz),0.98-2.22
(18H,m),2.43(1H,dd,J15.3,10.0Hz),2.87(1H,q,J6.5Hz),3.23(3H,s),3.46
(1H,s),3.89(2H,m),4.13(2H,dd,J14.3,7.1Hz),4.87(1H,宽s),4.99(1H,
d,J17.5Hz),5.27(1H,d,J7.3Hz),5.64(1H,d,J9.9Hz),6.66(1H,dd,J17.4,
10.6Hz),7.27-7.37(5H,m).
步骤2．14-[N-(1-(R)-苯基-2-羟基)乙基氨甲酸]姆替林
步骤1产物(212mg,0.42mmol)在二噁烷(5ml)中用浓盐酸中的饱和氯化锌溶液(0.5ml)处理，如实施例1的步骤2所述，得到标题化合物(81mg,39％)；υ最大(CH2Cl2)3565,3433,2961,1732,1713和1503cm-1；
                         1H NMR(CDCl3)0.73(3H,宽d),0.84(3H,d,J
7.0Hz),0.97-1.76(18H,m),1.93-2.30(3H,m),2.32(1H,五重峰,J6.6Hz),3.25-
3.40(1H,m),3.70-3.95(2H,m),4.75-4.87(1H,宽s),5.15-5.35(3H,m),
5.62(1H,d,J8.3Hz),7.27-7.37(5H,m)；MS(EI)m/z 483(M+),(NH3DCI)m/z
484(MH+).
实施例28．14-[N-2-(甲氧基羰基)乙基氨甲酸]姆替林
步骤1．14-[N-2-(甲氧基羰基)乙基氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
14-氯甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(1 70mg,0.43mmol)和N,N-二异丙基乙胺(0.150ml,0.86mmol)在二氯甲烷(5ml)中与β-氨基丙酸甲基酯盐酸盐(120mg,0.43mmol)反应，如实施例12步骤2所述；得到标题化合物(185mg,93％)；υ最大(CH2Cl2)3446,2930,1733,1709,1509和1456cm-1；1H NMR(CDCl3)0.81(3H,d,J6.9Hz),0.97(3H,d,J6.4Hz),
1.04-1.71(14H,m),1.92-2.04(2H,m),2.13-2.22(1H,m),2.39(1H,dd,J15.2,
10.0Hz),2.55(2H,t,J5.7Hz),2.92(1H,q,J6.4Hz),3.21(3H,s),3.41-3.54
(3H,m),3.69(3H,s),4.99(1H,d,J17.6Hz),5.13(1H,t,J6.0Hz),5.28(1H,d,
J10.7Hz),5.63(1H,d,J9.9Hz),6.74(1H,dd,J17.5,10.7Hz)；MS(NH3DCI)
m/z 464(MH+),m/z 481(MNH4 +)
步骤2．14-[N-2-(甲氧基羰基)乙基氨甲酸]姆替林
步骤1产物(200mg,0.42mmol)在二噁烷(5ml)中用浓盐酸中的饱和氯化锌溶液(0.5ml)处理，室温搅拌反应过夜。溶液倾入乙酸乙酯和饱和氯化钠溶液。水相用乙酸乙酯再提取，合并的有机相用饱和碳酸氢钠溶液洗涤(两次)。最终用饱和氯化钠溶液洗涤，硫酸镁干燥。硅胶色谱纯化，装载二氯甲烷中并用乙酸乙酯与己烷的混合物洗脱。分离出泡沫状标题化合物(21mg,12％)；υ最大(CH2Cl2)3564,3446,1734,1713和1509cm-1；
1H NMR(CDCl3)0.71(3H,宽d,J6.0Hz),0.85(3H,d,J7.0Hz),1.07-1.79
(15H,m)包括1.13(3H,s)和1.37(3H,s),1.96-2.23(4H,m),2.35(IH,
五重峰,J6.9Hz),2.52(2H,t,J5.9Hz),3.30-3.50(3H,m),3.67(3H,s),5.06(1H,
宽t),5.26(1H,dd,J17.5,1.5Hz),5.34(1H,dd,J11.0,1.5Hz),5.62(1H,d,J
8.4Hz),6.56(1H,dd,J17.4,11.0Hz)；MS(EI)m/z 449(M+),(NH3DCI)m/z 450
(MH+).
实施例29．14-[N-羧乙基氨甲酸]姆替林
步骤1．14-[N-2-羧乙基氨甲酸]姆替林
从实施例28的步骤2取碳酸氢钠溶液用盐酸(5M)酸化，所得溶液用乙酸乙酯提取(两次)。有机相用饱和氯化钠溶液洗涤后硫酸镁干燥，真空蒸发去除溶剂，得到白色固体状的标题化合物(43mg,24％)；υ最大(CH2Cl2)3446,2961,1730,1714和1509cm-1；
                                     1H NMR(CDCl3)0.72(3H,
宽d,J5.7Hz),0.86(3H,d,J7.0Hz),0.97-1.79(15H,m),1.96-2.23(5H,m),
2.55-2.60(2H,m),3.34-3.46(3H,m),5.07-5.38(3H,m),5.61-5.68(1H,m),
6.50-6.52(1H,m)；MS(EI)m/z 435(M+)；MS(NH3DCI)m/z 436(MH+),m/z
453(MNH4 +).
实施例30．14-[N-(羟基亚氨基苄基)氨甲酸]姆替林
步骤1．14-[N-(羟基亚氨基苄基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
14-氯甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(170mg,0.43mmol)在二氯甲烷(3ml)中与苄胺肟(129mg,0.94mmol)反应，如实施例12步骤2所述；得到标题化合物(180mg,84％)；υ最大(CH2Cl2)3519,3414,2930,1759,1697,1640,1586和1457cm-1；1H NMR(CDCl3)0.93(3H,d,J6.9Hz),1.00(3H,d,J
6.4Hz),1.07-1.60(13H,m)包括1.20(3H,s)和1.30(3H,s),1.74(1H,d,
J11.2Hz),1.77(1H,d,J15.3Hz),1.94-2.04(2H,m),2.15-2.24(1H,m),2.52
(1H,dd,J15.2.10.2Hz),2.88(1H,q,J6.4Hz),3.23(3H,s),3.43-3.54(1H,m),
4.99(1H,d,J17.4Hz),5.09(1H,宽s),5.27(1H,d,J10.8Hz),5.70(1H,d,J
10.0Hz),6.75(1H,dd,J17.5,10.7Hz),7.38-7.52(3H,m),7.69-7.73(2H,m)；
MS(NH3DCI)m/z 497(MH+).
步骤2．14-[N-(羟基亚氨基苄基)氨甲酸]姆替林
步骤1产物(160mg,0.33mmol)在二噁烷(4ml)中用浓盐酸中的饱和氯化锌溶液(0.8ml)处理，如实施例1的步骤2所述，得到标题化合物(114mg,72％)；υ最大(CH2Cl2)3520,3414,2932,1761,1733,1710,1640和1587cm-1；
                                1H NMR(CDCl3)0.84(3H,d.J
6.7Hz),0.88(3H,d,J7.1Hz),0.99-1.82(16H,m)包括1.19(3H,s)和
1.50(3H,s),2.08-2.34(4H,m)包括2.32(1H,五重峰,J6.8Hz),3.36(1H,
dd,J10.5,6.6Hz),5.06(2H,宽s),5.23(1H,dd,J17.3,1.5Hz),5.37(1H,dd,
J11.2,1.4Hz),5.69(1H,d,J8.6Hz),6.57(1H,dd,J17.3,11.0Hz),7.26-7.51
(3H,m),7.67-7.71(2H,m)；MS(NH3DCI)m/z 483(MH+).
实施例31．14[N-(4-甲氧基苯甲酰基)氨甲酸]姆替林
步骤1．4-甲氧基苯甲酰基异氰酸酯
氰酸银(689mg,4.6mmol)在氩气氛下悬浮于干二氯甲烷(5ml)中。加入4-甲氧基苯甲酰氯(682mg,4.0mmol)的二氯甲烷(5ml)溶液，按照Arcus等人的方法(美国化学会志.1954.4018)在避光下回流搅拌该非均相混和物。一个小时后让反应冷却并通过Kieselguhr过滤。溶液立即进行下一个反应。υ最大(CH2Cl2)2246cm-1。
步骤2．14-[N-(4-甲氧基苯甲酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤1的产物冷却到0℃，与(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(335mg,1.0mmol)反应并搅拌1小时。混和物用二氯甲烷稀释，用1.0M盐酸随后用水和饱和氯化钠溶液洗涤。硫酸镁干燥后硅胶色谱纯化粗物料，装载二氯甲烷，己烷中20％乙酸乙酯洗脱。真空蒸发溶剂得到标题化合物(488mg,95％)；熔点(二氯甲烷/己烷)168℃；υ最大(CH2Cl2)3427,3300,2931,1774,1697,1605和1479cm-1；1H NMR(CDCl3)0.90
(3H,d,J6.9Hz),1.00(3H,d,J6.4Hz),1.07-1.56(12H,m)包括1.20(3H,
s)和1.32(3H,s),1.72(1H,d,J15.3Hz),1.74(1H,d,J11.2Hz).1.94-2.04
(2H,m),2.16-2.24(1H,m),2.53(1H,dd,J15.2,10.1Hz),2.91(1H,q,J6.2Hz),
3.23(3H,s),3.42-3.50(1H,m),3.87(3H,s),5.00(1H,d,J17.5Hz),5.29(1H,d,
J10.7Hz),5.84(1H,d,J9.9Hz),6.73(1H,dd,J17.4,10.6Hz),6.97(2H,d,J
8.9Hz)，7.81(2H,d,J8.9Hz)；MS(EI)m/z511(MH+)；(NH3DCI)m/z512
(MH+)；(测定值：C,70.38；H,8.21；N,2.91.C30H41NO6理论值C,70.42；H,
8.08；N,2.74)
步骤3．14-[N-(4-甲氧基苯甲酰基)氨甲酸]姆替林
步骤2产物(440mg,0.85mmol)在二噁烷(5ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，如实施例1的步骤2所述，得到标题化合物(140mg,33％)；熔点(二氯甲烷/己烷)108℃(分解)；υ最大(CH2Cl2)3564,3429,2961,1776,1733,1710,1607和1479cm-1；
    1H NMR(CDCl3)0.81(3H,d,J6.6Hz),0.88(3H,d,J7.0Hz),1.10-1.81
(15H,m)包括1.15(3H,s)和1.51(3H,s),2.12(1H,bs)叠加在2.09-2.26(2H,m)上
           ,2.35(1H,五重峰,J6.9Hz),3.36(1H,dd,J11.0,6.6Hz),3.86
(3H,s),5.22(1H,dd,J17.3,1.5Hz),5.37(1H,dd,J11.0,1.4Hz),5.83(1H,d,J
8.5Hz),6.56(1H,dd,J17.3,11.0Hz),6.95(2H,d,J8.8Hz),7.77(2H,d,J
8.8Hz),7.88(1H,bs)；MS(NH3DCI)m/z 498(MH+)；(测定值：C,69.88；H,
7.67；N,2.93.C29H39NO6理论值C,70.00；H,7.90；N,2.81)
实施例32．14-[N-(4-硝基苯甲酰基)氨甲酸]姆替林
步骤1．4-硝基苯甲酰基异氰酸酯
氰酸银(689mg,4.6mmol)在氩气氛下悬浮于干二氯甲烷(5ml)中。加入4-硝基苯甲酰氯(682mg,4.0mmol)的二氯甲烷(5ml)溶液，按照实施例31的步骤1进行反应。溶液立即用于下一个反应。
步骤2．14-[N-(4-硝基苯甲酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤1的溶液冷却到0℃，与(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(335mg,1.0mmol)反应并搅拌1小时。如实施例31步骤2的同样步骤分离标题化合物(480mg,91％)；υ最大(CH2Cl2)3406,2959,1780,1733,1698,1607和1531cm-1；
                    1H NMR(CDCl3)0.90(3H,d,J
6.8Hz),1.03(3H,d,J6.4Hz),1.08-1.59(12H,m)包括1.20(3H,s)和
1.31(3H,s),1.69(1H,d,J15.5Hz),1.75(1H,d,J11.6Hz),1.93-2.05(2H,m),
2.15-2.25(1H,m),2.54(1H,dd,J15.2,10.1Hz),2.89(1H,q,J6.4Hz),3.22
(3H,s),3.41-350(1H,m),5.01(1H,d,J17.5Hz),5.28(1H,d,J10.7Hz),5.84
(1H,d,J9.9Hz),6.64(1H,dd,J17.4,10.7Hz),8.00(2H,d,J8.7Hz),8.22(1H,
bs),8.35(2H,d,J8.9Hz)；MS(NH3DCI)m/z 544(MNH4 +).
步骤3．14-[N-(4-硝基苯甲酰基)氨甲酸]姆替林
步骤2产物(440mg,0.83mmol)在二噁烷(10ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，如实施例1的步骤2所述，得到标题化合物(282mg,66％)；υ最大(CH2Cl2)3551,3412,2959,1786,1734,1699,1607和1531cm-1；                     1H NMR(CDCl3)0.80(3H,d,J
6.8Hz),0.88(3H,d,J7.0Hz),1.10-1.23(4H,m),1.41-1.82(12H,m)包括
1.50(3H,s),2.11(1H,bs),2.14-2.34(3H,m),3.37(1H,dd,J10.7,6.6Hz),5.24
(1H,dd,J17.3,1.4Hz),5.36(1H,dd,J10.9,1.3Hz),5.81(1H,d,J8.5Hz),6.49
(1H,dd,J17.3,11.0Hz),7.94(2H,d,J8.8Hz),8.04(1H,bs),8.33(2H,d,J
8.8Hz)
实施例33．14-[N-(3-硝基苯甲酰基)氨甲酸]姆替林
步骤1．3-硝基苯甲酰基异氰酸酯
氰酸银(689mg,4.6mmol)在氩气氛下悬浮于干二氯甲烷(5ml)。加入3-硝基苯甲酰氯(682mg,4.0mmol)的二氯乙烷(5ml)溶液并按照实施例31的步骤1处理之前搅拌回流反应4小时。溶液立即用于下一个反应。υ最大(CH2Cl2)2247cm-1。
步骤2．14-[N-(3-硝基苯甲酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤1的溶液冷却到0℃，与(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(335mg,1.0mmol)反应并搅拌1小时。如实施例31步骤2的同样步骤分离标题化合物(523mg，定量)；υ最大(CH2Cl2)3406,2930,1781,1720,1698,1618和1537cm-1；
                                 1H NMR(CDCl3)0.91(3H,d,J
6.8Hz),1.00(3H,d,J6 4Hz),1.08-1.60(12H,m)包括1.20(3H,s)和
1.30(3H,s),1.67-1.77(2H,m),2.00-2.05(2H,m),2.15-2.25(1H,m),2.55(1H,
dd,J15.3,10.1Hz),2.89(1H,q,J6.3Hz),3.22(3H,s),3.41-3.50(1H,m),5.01
(1H,d,J17.5Hz),5.24(1H,d,J10.7Hz),5.86(1H,d,J10.0Hz),6.62(1H,dd,J
17.4,10.6Hz),7.73(1H,t,J8.0Hz),8.20(1H,d,J7.9Hz),8.23(1H,s),8.46
(1H,dd,J7.8,1.0Hz),8 67(1H,m):MS(NH3DCI)m/z 544(MNH4 +).
步骤3．14-[N-(3-硝基苯甲酰基)氨甲酸]姆替林
步骤2产物(483mg,0.92mmol)在二噁烷(10ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，如实施例1的步骤2所述，得到标题化合物(280mg,66％)；熔点(二氯甲烷/己烷)121℃；υ最大(CH2Cl2)3564,3418,2940,1782,1733,1617和1537cm-1；
                                                          1H NMR
(CDCl3)0.80(3H,d,J6.7Hz),0.88(3H,d,J6.9Hz),1.09-1.23(4H,m),1.40-
1.81(12H,m),2.11(1H,bs),2.14-2.33(3H,m),3.36(1H,dd,J10.7,6.7Hz),
5.23(1H,dd,J17.4,1.4Hz),5.31(1H,dd,J10.9,1.2Hz).5.81(1H,d,J8.0Hz),
6.49(1H,dd,J17.3,11.0Hz),7.71(1H,t,J8.0Hz),8.17(1H,dt,J7.9,1.3Hz),
8.29(1H,bs),8.43(1H,dt,J8.0,1.1Hz),8.64(1H,t,J1.9Hz)；MS(NH3DCI)
m/z 530(MNH4 +)；(测定值：C,65.95；H,7.23；N,5.35.C28H36N2O7理论值
C,65.61；H,7.08；N,5.46).
实施例34．14-[N-(4-氨基苯甲酰基)氨甲酸]姆替林
14-[N-(4-硝基苯甲酰基)氨甲酸]姆替林(79mg,0.15mmol)悬浮于乙醇(10ml)中。加入乙酸乙酯(2ml)完全溶解。加入氯化锡(Ⅱ)(146mg,0.75mmol)并同时在氩气氛下加热回流。1小时后让反应冷却，倾入乙酸乙酯/水，然后用碳酸氢钠中和。硫酸镁干燥有机相，硅胶色谱纯化，用50％乙酸乙酯的己烷液洗脱。分离得到无色泡沫状标题化合物(44mg,61％)；υ最大(CH2Cl2)3684,3405,2933,1782,1773,1733,1605和1473cm-1；
   1H NMR(CDCl3)0.80(3H,d,J6.5Hz),0.88(3H,d,J7.0Hz),1.09-1.26
(4H,m),1.40-1.81(12H,m),2.04-2.37(4H,m),3.36(1H,dd,J10.6,6.6Hz),
4.13(2H,bs),5.22(1H,dd,J17.4,1.5Hz),5.36(1H,dd,J11.0,1.3Hz),5.78
(1H,d,J8.4Hz),6.56(1H,dd,J17.4,11.0Hz),6.65(2H,d,J8.7Hz),7.64(2H,
d,J8.7Hz),7.83(1H,bs)；MS(NH3DCl)m/z 483(MH+).
实施例35．14-[N-(3-氨基苯甲酰基)氨甲酸]姆替林
14-[N-(3-硝基苯甲酰基)氨甲酸]姆替林(100mg,0.19mmol)悬浮于乙醇(10ml)中。加入乙酸乙酯(2ml)完全溶解。加入氯化锡(Ⅱ)(185g,1.0mmol)并如实施例34所述处理反应。分离得到无色泡沫状标题化合物(55mg,60％)；υ最大(CH2Cl2)3395,2932,1778,1733,1716,1624和1479cm-1；
                 1H NMR(CDCl3)0.80(3H,d,J6.6Hz),0.88(3H,d,J
7.0Hz),1.10-1.82(16H,m,包括1.19(3H,s)和1.51(3H,s)),2.09-2.37
(4H,m),3.37(1H,dd,J10.8,6.6Hz),3.86(2H,bs),5.23(1H,dd,J17.4,
1.5Hz),5.39(1H,dd,J11.0,1.4Hz),5.82(1H,d,J8.5Hz),6.58(1H,dd,J17.3,
11.0Hz),6.86(1H,dd,J7.8,2.4Hz),7.06(1H,d,J7.8Hz),7.13(1H,t,J2.0Hz),
7.23(1H,t,J7.8Hz),7.88(1H,bs)；MS(ESI,-ve离子)m/z 481(M-H-).
实施例36．14-[N-(2-羟基苯甲酰基)氨甲酸]姆替林
步骤1．2-乙酰氧基苯甲酰基异氰酸酯
氰酸银(689mg,4.6mmol)和氧-乙酰基水杨酰(salicoyl)氯(794mg,4.0mmol)在二氯乙烷(10ml)按实施例33步骤1所述进行反应。标题化合物立即用于下一个反应。
步骤2．14-[N-(2-乙酰氧基苯甲酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤1的溶液冷却到0℃，用(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(335mg,1.0mmol)处理并搅拌反应物1小时。如实施例31步骤2的同样步骤分离得到标题化合物(385mg,70％)；υ最大(CH2Cl2)3411,2981,2931,1778,1732,1698,1606和1480cm-1；1H NMR(CDCl3)
0.89(3H,d,J6.8Hz),1.00(3H,d,J6.4Hz),1.08-1.60(12H,m)包括1.20
(3H,s)和1.26(3H,s),1.67-1.76(2H,m),1.95-2.05(2H,m),2.15-2.25(1H,
m),2.38(3H,s),2.50(1H,dd,J15.3,10.1Hz),2.88(1H,q,J6.3Hz),3.22(3H,
s),3.42-3.48(1H,m),5.00(1H,d,J17.5Hz),5.30(1H,d,J10.7Hz),5.81(1H,
d,J10.0Hz),6.72(1H,dd,J17.4,10.6Hz),7.21-7.42(2H,m),7.68(1H,dt,J
7.8,1.4Hz),8.09(1H,dd,J7.9,1.6Hz),8.36(1H,bs),8.46(1H,dd,J7.8,
1.0Hz),8.67(1H,m)；MS(EI)m/z 539(MH+)；(NH3DCI)m/z 540(MH+).
步骤3．14-[N-(3-羟基苯甲酰基)氨甲酸]姆替林
步骤2产物(385mg,0.50mmol纯度80％的材料)在二噁烷(10ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，如实施例1的步骤2所述。将粗物料溶于乙醇(2ml)并用1.0M氢氧化钠室温处理1小时。溶液倾入乙酸乙酯的己烷溶液和水。饱和氯化钠洗涤有机相，硫酸镁干燥；硅胶色谱纯化，用甲苯中10％的丙酮洗脱。分离得到白色固体状的标题化合物(115mg,47％)；熔点(二氯甲烷/己烷)170℃；υ最大(CH2Cl2)3566,3434,2960,1775,1733,1673和1493cm-1；
             1H NMR(CDCl3)0.79(3H,d,J6.7Hz),0.89(3H,d,J6.9Hz),
1.09-1.25(4H,m),1.37-1.81(12H,m),2.11-2.33(4H,m),3.37(1H,dd,J10.2,
6.6Hz),5.22(1H,dd,J17.4,1.3Hz),5.35(1H,dd,J10.9,1.1Hz),5.81(1H,d,J
8.5Hz),6.52(1H,dd,J17.3,11.0Hz),6.90(1H,td,J7.5,0.8Hz),7.02(1H,dd,J
8.3,0.9Hz),7.18-7.28(1H,m),7.95(1H,d,J7.6Hz),8.45(1H,bs),11.31(1H,
bs)；MS(ESI-ve离子)m/z 482(M-H-).
实施例37．14-[N-(4-乙酰氧基苯甲酰基)氨甲酸]姆替林
步骤1．4-乙酰氧基苯甲酰基异氰酸酯
氰酸银(950mg,6.3mmol)和4-乙酰氧基苯甲酰氯(1.09g,5.5mmol)在二氯乙烷(10ml)中按实施例34步骤1所述进行反应。标题化合物立即用于下一个反应。υ最大(CH2Cl2)2240cm-1。
步骤2．14-[N-(4-乙酰氧基苯甲酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤1的溶液冷却到0℃，用(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(446mg,1.27mmol)处理并搅拌1小时。如实施例31步骤2的同样步骤分离得到标题化合物(620mg,91％)；υ最大(CH2Cl2)3420,2930,1777,1762,1731,1714,1698,1604和1478cm-1；
                                            1H NMR(CDCl3)0.89
(3H,d,J6.8Hz),1.00(3H,d,J6.4Hz),1.07-1.56(12H,m),1.72(1H,d,J
15.4Hz),1.74(1H,d,J11.2Hz),1.94-2.10(2H,m),2.15-2.48(1H,m),2.33(3H,
s),2.53(1H,dd,J15.2,10.0Hz),2.90(1H,q,J6.4Hz),3.22(3H,s),3.42-3.50
(1H,m),5.02(1H,d,J17.5Hz),5.29(1H,d,J10.7Hz),5.85(1H,d,J9.9Hz),
6.72(1H,dd,J17.5,10.7Hz),7.24(2H,d,J8.7Hz),7.86(2H,d,J8.7Hz),8.02
(1H,bs).
步骤3．14-[N-(4-羟基苯甲酰基)氨甲酸]姆替林
步骤2产物(570mg,1.05mmol)在二噁烷(10ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，如实施例1的步骤2所述，得到标题化合物(56mg,11％)；υ最大(CH2Cl2)3563,3419,2960,1778,1761,1733,1718,1604和1479cm-1；1H NMR(CDCl3)0.40(3H,d,J
6.6Hz),0.88(3H.d,J7.0Hz),1.10-1.28(4H,m),1.38-1.82(13H,m),2.12-2.37
(6H,m),3.37(1H,dd,J10.8,6.6Hz),5.24(1H,dd,J17.3,1.4Hz),5.38(1H,dd,
J11.1,1.4Hz),5.83(1H,d,J8.7Hz),6.56(1H,dd,J17.4,11.0Hz),7.22(2H,d,
J8.7Hz),,7.83(2H,d,J8.7Hz),8.22(1H,bs)；MS(FAB,NOBA/Na)m/z 548
(MNa+).
实施例38．14-[N-(4-羟基苯甲酰基)氨甲酸]姆替林
从实施例37步骤3所述反应物中分离得到标题化合物(134mg,27％)；υ最大(KBr片)1764,1730和1690cm-1；
                                                  1HNMR(CDCl3+
CD3OD)0.76(3H,d,J6.4Hz),0.84(3H,d,J6.9Hz),1.05-1.21(4H,m),1.37-
1.78(11H,m),2.00-2.34(4H,m),3.32(1H,d,J6.5Hz),5.19(1H,dd,J17.4,
1.4Hz),5.32(1H,d,J11.0Hz),5.77(1H,d,J8.7Hz),6.51(1H,dd,J17.4,
11.0Hz),6.82(2H,d,J8.7Hz),,7.66(2H,d,J8.7Hz)；MS(FAB,NOBA/Na)
m/z 506(MH+)m/z 548(MNa+).
实施例39．14-[N-(3-甲氧基苯甲酰基)氨甲酸]姆替林
步骤1．3-甲氧基苯甲酰基异氰酸酯
氰酸银(689mg,4.6mmol)和3-甲氧基苯甲酰氯(563ml,4.0mmol)在干二氯甲烷(10ml)按实施例31步骤1所述进行反应。含有标题化合物的溶液立即用于下一个反应。
步骤2．14-[N-(3-甲氧基苯甲酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤1的溶液冷却到0℃，用(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(336mg,1.00mmol)处理并搅拌反应1小时。如实施例31步骤2的同样步骤分离标题化合物(430mg,84％)；熔点(二氯甲烷/己烷)110-112℃；υ最大(CH2Cl2)3419,2931,1770,1714,1697,1601和1585cm-1；
                                                             1H
NMR(CDCl3)0.89(3H,d,J6.9Hz),1.00(3H,d,J6.4Hz),1.07-1.56(12H,m)
包括1.20(3H,s)and 1.32(3H,s),1.72(1H,d,J15.4Hz),1.75(1H,d,J
11.3Hz),1.94-2.06(2H,m),2.16-2.25(1H,m),2.53(1H,dd,J15.2,10.1Hz),
2.90(1H,q,J6.5Hz),3.23(3H,s),3.42-3.50(1H,m),3.86(3H,s),5.01(1H,d,
J17.4Hz),5.30(1H,d,J10.8Hz),5.85(1H,d,J9.9Hz),6.73(1H,dd,J17.5,
10.7Hz),7.13(1H,ddd,J6.8,2.6,1.0Hz),7.31-7.43(3H,m),7.99(1H,bs)；MS
(NH3DCI)m/z 512(MH+)；(测定值：C,70.38；H,8.28；N,2.91.C30H41NO6
理论值C,70.42,H,8.08；N,2.74)
步骤3．14-[N-(3-甲氧基苯甲酰基)氨甲酸]姆替林
步骤2产物(440mg,0.85mmol)在二噁烷(5ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，如实施例1的步骤2所述。得到标题化合物(170mg,45％)；熔点(二氯甲烷/己烷)117℃(分解)；υ最大(CH2Cl2)3556,3423,2961,1779,1733和1479cm-1；
                                                       1H NMR
(CDCl3)0.80(3H,d,J6.6Hz),0.88(3H,d,J6.9Hz),1.10-1.81(16H,m)
包括1.23(3H,s)和1.52(3H,s),2.04-2.37(4H,m),3.36(1H,dd,J10.9,
6.5Hz),3.85(3H,s),5.23(1H,dd,J17.3,1.5Hz),5.37(1H,dd,J10.9,1.4Hz),
5.83(1H,d,J8.5Hz),6.56(1H,dd,J17.3,10.9Hz),7.11(1H,ddd,J8.0,2.4,
1.3Hz),7.28-7.41(3H,m),7.98(1H,bs)；MS(NH3DCI)m/z 498(MH+),m/z
515(MNH4 +).
实施例40．14-[N-(2-甲氧基苯甲酰基)氨甲酸]姆替林
步骤1．2-甲氧基苯甲酰基异氰酸酯
氰酸银(689mg,4.6mmol)和3-甲氧基苯甲酰氯(593ml,4.0mmol)在干二氯甲烷(10ml)按实施例31步骤1所述进行反应。含有标题化合物的溶液立即用于下一个反应。υ最大(CH2Cl2)2250cm-1。
步骤2．14-[N-(2-甲氧基苯甲酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤1的溶液冷却到0℃，用(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(336mg,1.00mmol)处理并搅拌反应1小时。如实施例31步骤2的同样步骤分离得到标题化合物(500mg,98％)；υ最大(CH2Cl2)3344,2981,2931,1772,1732,1698,1602和1509cm-1；
                                    1H NMR(CDCl3)0.90(3H,d,J
6.8Hz),1.01(3H,d,J6.4Hz),1.07-1.59(12H,m)包括1.20(3H,s)和
1.33(3H,s),1.75(1H,d,J11.2Hz),1.77(1H,d,J15.4Hz),1.95-2.04(2H,m),
2.16-2.25(1H,m),2.50(1H,dd,J15.2,10.1Hz),2.91(1H,q,J6.3Hz),3.23
(3H,s),3.44-3.51(1H,m),4.(0)4(3H,s),5.00(1H,d,J17.5Hz),5.30(1H,d,J
10.7Hz),5.78(1H,d,J9.9Hz),6.82(1H,dd,J17.5,10,7Hz),7.02(1H,d,J
8.0Hz),7.10(1H,td,J7.5,0.7Hz),7.54(1H,td,J7.8,1.8Hz),8.24(1H,dd,J
7.8,1.8Hz),10.00(1H,bs)；MS(ESI,-veion)m/2 510(M-H-).
步骤3．14-[N-(2-甲氧基苯甲酰基)氨甲酸]姆替林
步骤2产物(430mg,0.83mmol)在二噁烷(5ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理,如实施例1的步骤2所述。得到标题化合物(208mg,49％)；熔点(二氯甲烷/己烷)142-145℃；υ最大(CH2Cl2)3626,3563,3346,2953,1773,1733,1701和1609cm-1；1H
NMR(CDCl3)0.81(3H,d,J6.6Hz),0.88(3H,d,J7.0Hz),1.15-1.81(16H,m)
包括1.22(3H,s)和1.52(3H,s),2.04-2.38(4H,m),3.36(1H,dd,J11.1,
6.5Hz),4.01(3H,s),5.23(1H,dd,J17.3,1.5Hz),5.39(1H,dd,J10.9,1.4Hz),
5.78(1H,d,J8.5Hz),6.62(1H,dd,J17.4,11.0Hz),7.11(1H,t,J7.6Hz),7.52
(1H,td,J7.8,1.8Hz),8.20(1H,dd,J7.8,1.8Hz),9.89(1H,bs)；MS(ESI,+ve
离子)m/z 520(MNa+).
实施例41．14-[N-(苯乙酰基)氨甲酸]姆替林
步骤1．异氰酸苯乙酰基酯
氰酸银(689mg,4.6mmol)和苯乙酰氯(0.563ml,4.0mmol)在干二氯甲烷(10ml)按实施例31步骤1所述进行反应。含有标题化合物的溶液立即用于下一个反应。
步骤2．14-[N-(苯乙酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤1的溶液冷却到0℃，用(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(336mg,1.00mmol)处理并搅拌反应1小时。如实施例31步骤2的同样工序分离得到标题化合物(500mg，定量)；熔点(二氯甲烷/己烷)187-8℃；υ最大(CH2Cl2)3383,2930,1784,1751,1698和1479cm-1；
                                                    1H NMR(CDCl3)0.78(3H,d,J6.9Hz),1.00(3H,d,J6.4Hz),1.00-1.61(13H,m),1.72(1H,d,J11.3Hz),1.92-2.05(2H,m),2.14-2.23(1H,m),2.46(1H,dd,J15.3,10.1Hz),2.88(1H,q,J6.5Hz),3.21(3H,s),3.38-3.48(1H,m),4.10(2H,s),5.03(1H,d,J17.4Hz),5.32(1H,d,J10,7Hz),5.72(1H,d,J9.9Hz),6.63(1H,dd,J17.5,10.7Hz),7.24-7.38(5H,m),7.50(1H,bs)；MS(NH3DCI)m/z 496(MH+),m/z 513(MNH4 +).
步骤3．14-[N-(苯乙酰基)氨甲酸]姆替林
步骤2产物(460mg,0.93mmol)在二噁烷(10ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，如实施例1的步骤2所述。得到标题化合物(202mg,45％)；熔点(二氯甲烷/己烷)187℃；υ最大(CH2Cl2)3564,3386,2941,1784,1752,1733和1477cm-1；1H NMR
(CDCl3)0.68(3H,d,J6.7Hz),0.89(3H,d,J7.0Hz),1.09-1.82(15H,m)
包括1.22(3H,s)和1.40(3H,s),2.00-2.38(5H,m),3.36(1H,dd,J10.4,
6.7Hz),4.02和4.12(2H,ABq,J15.7Hz),5.23(1H,dd,J17.5,1.4Hz),5.38
(1H,dd,J10.9,1.3Hz),5.71(1H,d,J8.4Hz),6.57(1H,dd,J17.3,11.1Hz),
7.24-7.35(5H,m),7.51(1H,bs)；MS(NH3DCI)m/z 482(MH+),m/z 499
(MNH4 +).
实施例42．14-[N-(4-羧基苯甲酰基)氨甲酸]姆替林
步骤1．14-[N-(4-甲酰基苯甲酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(680mg,2.0mmol)与4-甲酰基苯甲酰氯(1.68g,10.0mmol)、氰酸银(1.50g,10.0mmol)和四(三苯膦)钯(0)(25mg)在干二氯甲烷(25ml)中结合，在氩气氛下避光室温搅拌反应6小时。混和物通过Kieselguhr过滤，过滤物用1.0M盐酸随后用水和食盐水洗涤。硫酸镁干燥后硅胶色谱纯化，装载二氯甲烷，用乙酸乙酯和己烷混和物洗脱。分离得到结晶固体状的标题化合物(700mg,70％)；υ最大(CH2Cl2)3406,2930,1778,1707,1576和1480cm-1；
              1H NMR(CDCl3)0.90(3H,d,J6.8Hz),1.00(3H,d,J
6.4Hz),1.04-1.62(12H,m),1.73-1.77(2H,m),1.94-2.24(2H,m),2.15-2.25
(1H,m),2.54(1H,dd,J15.2,10.0Hz),2.88(1H,q,J6.3Hz),3.22(3H,s),3.41-
3.48(1H,m),5.02(1H,d,J17.5Hz),5.28(1H,d,J10.7Hz),5.85(1H,d,J
10.0Hz),6.67(1H,dd,J17.5,10.0Hz),7.95-8.03(5H,m),8.13(1H,bs),10.11
(1H,s)；MS(NH3DCI)m/z 527(MNH4 +).(测定值：C,70.46；H,8.03；N,2.55.
C30H39NO6  理论值C,70.70；H,7.71；N,2.75).
步骤2．14-[N-(4-羧基苯甲酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
14-[N-(4-甲酰基苯甲酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(200mg,0.4mmol)溶于丙酮(5ml)并用琼斯试剂(0.05ml的[O]的8M溶液，0.4mmol)处理，室温搅拌反应5分钟。加入更多的琼斯试剂(0.05ml)并继续在室温搅拌。反应混和物用异丙醇(1ml)处理，然后在乙酸乙酯和水中分配。用水和食盐水洗涤后硫酸镁干燥。真空去除溶剂得到泡沫状标题化合物(182mg,87％)。υ最大(CH2Cl2)3434,3273,2927,1732和1699cm-1；
                                                        1H
NMR(CDCl3,CD3OD))0.84(3H,d,J6.8Hz),0.93(3H,d,J6.3Hz),1.01-1.54
(13H,m),1.62-1.69(2H,m),2.08-2,17(2H,m),2.44(1H,dd,J15.2,10.0Hz),
2.85(1H,q,J6.3Hz),3.16(3H,s),3.36-3.41(1H,m),4.94(1H,d,J17.4Hz),
5.23(1H,d,J10.8Hz),5.78(1H,d,J9.8Hz),6.65(1H,dd,J17.5,10.7Hz),7.84
(2H,d,J8.5Hz),8.05(2H,d,J8.5Hz)；MS(NH3DCl)m/z543(MNH4 +).
步骤3．14-[N-(4-羧基苯甲酰基)氨甲酸]姆替林
步骤2产物(600mg,1.14mmol)在二噁烷(15ml)中用浓盐酸的饱和氯化锌溶液(3.5ml)处理，如实施例1的步骤2所述，得到标题化合物(280mg,68％)；υ最大(KBr片)1766,1740和1709cm-1；
        1H NMR(d6-丙酮)0.82(3H,d,J6.3Hz),0.96(3H,d,J7.0Hz),
1.19-1.25(4H,m),1.39-1.84(10H,m),2.07-2.36(5H,m),3.36(1H,bs，在D2O中
分解为双重峰,J6.0Hz),5.19(1H,dd,J11.2,1.8Hz),5.27(1H,dd,J17.7,1.6Hz),
5.79(1H,d,J8.5Hz),6.45(1H,dd,J17.6,11.2Hz),8.01(1H,d,J8.5Hz),8.14
(1H,d,J8.1Hz),10.04(1H,s,D2O交换)；MS(ESI,+ve离子)m/z 534
(MNa+).
实施例43．14-(N-苯氧基氨甲酸)姆替林
步骤1．14-(N-苯氧基氨甲酸)的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
14-氯甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(150mg,0.38mmol)和二异丙基乙胺(0.33ml,1.9mmol)在二氯甲烷(3ml)中与氧-苯基羟胺盐酸盐(165mg,1.13mmol)反应，如实施例12步骤2，得到标题化合物粗产物(150mg)无需纯化用于下一个反应；υ最大(CH2Cl2)3368,1753和1698cm-1；
                          1H NMR特别(CDCl3)0.87(3H,d,
J6.9Hz),0.98(3H,d,J6.4Hz)1.13(3H,s),1.20(3H,s),1.05-1.30(4H,m),
1.52(2H,m),1.69(1H,d,J15.4Hz),171(1H,d,J11.2Hz),1,98(2H,m),2.18
(1H,m),2.48(1H,dd,J15.3,10.1Hz),2.88(1H,q,J6.4Hz),3.20(3H,s),3.44
(1H,m),5.01(1H,d,17.5Hz),5.28(1H,d,J10.6Hz),5.76(1H,d,J10.0Hz),
6.69(1H,dd,J17.4,10.6Hz),7.08(3H,m),7.31(2H,m),7.63(1H,s)；MS(CI)
m/z 487(MNH4 +).
步骤2．14-(N-苯氧基氨甲酸)姆替林
步骤1产物(112mg)在二噁烷(3ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，如实施例1的步骤2所述，得到标题化合物(11.5mg)；υ最大(二氯甲烷)3562和1735cm-1；
                                                    1H NMR
(CDCl3)0.68(3H,br),0.86(3H,d,J6.9Hz),1.06-1.79(9H,m),1.16(3H,s),
1.29(3H,s),2.05(2H,m),2.23(3H,m),3.33(1H,m,),5.21(1H,dd,J17.2,
1.3Hz),5.36(1H,d,J11.1Hz),5.75(1H,d,J8.3Hz),6.46(1H,dd,J17.3,
11.0Hz),6.91(1H,d,J7.9Hz),7.06(1H,t,J7.3Hz),7.28(2H,m)；MS(EI)m/z
456(M+)测定值：455.2677,C27H37NO5理论值455.2672
实施例44．14-[N-(4-三氟甲基苯甲酰基)氨甲酸]姆替林
步骤1．4-三氟甲基苯甲酰基异氰酸酯
氰酸银(690mg,4.6mmol)与4-三氟甲基苯甲酰氯(0.6g,4.0mmol)在干二氯甲烷(5ml)中反应，如实施例31步骤1方法所述进行。含有标题化合物的溶液立即用于下一个反应；υ最大(CH2Cl2)2246cm-1。
步骤2．14-[N-(4-三氟甲基苯甲酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤1溶液用(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(335mg,1.00mmol)处理，搅拌反应1.5小时。如实施例31步骤2同样工序，分离得到标题化合物(405mg,74％)。υ最大(CH2Cl2)3416,1780,1718和1698cm-1；
                                                           1H NMR
(CDCl3)0.85(1H,m),0.90(3H,d,J6.9Hz),1.01(3H,d,J6.4Hz),1.08-1.31
(3H,m),1.21(3H,s),1.31(3H,s),1.52(2H,m),1.74(2H,m),2.03(2H,m),
2.21(1H,m),2.54(1H,dd,J15.2,10.1Hz),2.89(1H,q,J6.4Hz),3.23(3H,s),
3.46(1H,m),5.02(1H,d,J17.4Hz),5.30(1H,d,J10.6Hz),5.85(1H,d,J
10.0Hz),6.68(1H,dd,J17.4,10.6Hz),7.77(1H,d,J8.3Hz),7.94(1H,d,J
8.2Hz),8.02(1H,s)；MS(EI)m/z549(M+)测定值：549.2703,C30H38F3NO5
理论值549.2702.
步骤3．14-[N-(4-三氟甲基苯甲酰基)氨甲酸]姆替林
步骤2产物(385mg,0.7mmol)在二噁烷(6ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，如实施例1的步骤2所述，得到标题化合物(148mg,40％)；υ最大(二氯甲烷)3421,1781和1734cm-1；
        1H NMR(CDCl3)0.80(3H,d,J6.7Hz),0.89(3H,d,J7.0Hz),1.18
(1H,m)1.20(3H,s)1.51(3H,s),1.41-1.82(8H,m),2.04-2.36(5H,m),3.37
(1H,dd,J10.7,6.6Hz),5.24(1H,dd,J17.4,1.4Hz),5.37(1H,dd,J11.0,
1.3Hz),5.82(1H,d,J8.5Hz),6.53(1H,dd,J17.3,11.0Hz),7.75(2H,d,J
8.3Hz),7.90(1H,d,J8.2Hz),7.98(1H,bs)；MS(CI)m/z 553(MNH4 +).
实施例45．14-[N-(3-三氟甲基苯甲酰基)氨甲酸]姆替林
步骤1．3-三氟甲基苯甲酰基异氰酸酯
氰酸银(690mg,4.6mmol)与3-三氟甲基苯甲酰氯(0.6ml,3.98mmol)在干二氯甲烷(5ml)中如实施例31步骤1方法进行反应。含有标题化合物的溶液立即用于下一个反应；υ最大(CH2Cl2)2250cm-1。
步骤2．14-[N-(3-三氟甲基苯甲酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤1溶液用(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(335mg,1.0mmol)处理，搅拌反应1.5小时。如实施例31步骤2同样工序，分离得到标题化合物(480mg,87％)。υ最大(CH2Cl2)3414,1780,1718和1698cm-1；
                                                         1H NMR
(CDCl3)0.90(3H,d,J6.8Hz),1.00(3H,d,J6.4Hz),1.05-1.43(4H,m),1.21
(3H,s),1.30(3H,s),1.53(2H,m),1.71(1H,d,J15.3Hz),1.75(1H,d,J
11.2Hz),2.00(2H,m),2.20(1H,m),2.55(1H,dd,J15.2,10.1Hz),2.89(1H,q,
J6.4Hz),3.22(3H,s),3.46(1H,ddd,J11.2,5.3,2.9Hz),5.02(1H,d,J17.5Hz),
5.28(1H,d,J10.7Hz),5.86(1H,d,J10.0Hz),6.67(1H,dd,J17.5,10.7Hz),
7.65(1H,t,J7.8Hz),7.86(1H,d,J7.9Hz),8.01(1H,d,J7.9Hz),8.09(2H,
brs)；MS(CI)m/z567(MNH4 +)(测定值：C,65.50；H,6.90；N,2.71.
C30H38F3NO5理论值C,65.56；H,6.97；N,2.55).
步骤3．14-[N-(3-三氟甲基苯甲酰基)氨甲酸]姆替林
步骤2产物(350mg,0.64mmol)在二噁烷(5ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，如实施例1的步骤2所述，得到标题化合物(184mg,54％)；υ最大(二氯甲烷)3411,1781和1734cm-1；
    1H NMR(CDCl3)0.80(3H,d,J6.7Hz),0.89(3H,d,J6.9Hz),1.15(1H,m)1.20(3H,s)1.51(3H,s),1.41-1.81(8H,m),2.11-2.35(5H,m),3.37(1H,dd,J10.9,6.6Hz),5.23(1H,dd,J17.3,1.4Hz),5.35(1H,dd,J11.0,1.3Hz),5.82(1H,d,J8.5Hz),6.52(1H,dd,J17.3,11.0Hz),7.63(1H,t,J
7.8Hz),7.84(1H,d,J7.8Hz),7.98(1H,d,J7.8Hz)8.06(1H,s),8.12(1H,s)；
MS(电喷)m/z558(MNa+)
实施例46．14-[N-(2-三氟甲基苯甲酰基)氨甲酸]姆替林
步骤1．2-三氟甲基苯甲酰基异氰酸酯
氰酸银(690mg,4.6mmol)与2-三氟甲基苯甲酰氯(0.5ml,3.4mmol)在干二氯甲烷(5ml)中如实施例31步骤1方法所述反应3小时。含有标题化合物的溶液立即用于下一个反应；υ最大(CH2Cl2)2254cm-1。
步骤2．14-[N-(2-三氟甲基苯甲酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤1溶液用(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(335mg,1.0mmol)处理，搅拌反应0.5小时。如实施例31步骤2同样工序，分离得到标题化合物(231mg,42％)。υ最大(CH2Cl2)3384,1782,1760和1698cm-1；
                                                         1H NMR
(CDCl3)0.85(3H,d,J6.8Hz),0.95(3H,d,J6.4Hz),1.05-1.36(4H,m),1.19
(6H,s),1.50(2H,m),1.62(1H,d,J15.4Hz),1.71(1H,d,J11.3Hz),1.98(2H,
m),2.17(1H,m),2.48(1H,dd,J15.3,10.1Hz),2.81(1H,q,J6.4Hz),3.21(3H,
s),3.43(1H,m),4.98(1H,d,J17.5Hz),5.23(1H,d,J10.7Hz),5.72(1H,d,J
10.0Hz),6.50(1H,dd,J17.4,10.6Hz),7.50(1H,m,),7.64(2H,m),7.76(2H,
m)；MS(CI)m/z567(MNH4 +).
步骤3．14-[N-(2-三氟甲基苯甲酰基)氨甲酸]姆替林
步骤2产物(207mg,0.38mmol)在二噁烷(3ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，如实施例1的步骤2所述，得到标题化合物(149mg,74％)；υ最大(二氯甲烷)3390,1784,1763,1734和1705cm-1；
           1H NMR(CDCl3)0.76(3H.d,J6.9Hz),0.83(3H,d,J7.0Hz),
1.16(1H,m)1.18(3H,s)1.38(3H,s),1.36-1.49(4H,m),1.55-1.76(4H,m),
2.04-2.28(5H,m),3.33(1H,dd,J10.6,6.7Hz),5.19(1H,dd,J17.3,1.3Hz),
5.28(1H,d.J11.0Hz),5.67(1H,d,J8.4Hz),6.36(1H,dd,J17.2,11.0Hz),7.44
(1H,m),7.62(2H,m),7.72(2H,m)；MS(CI)m/z553(MNH4 +)
实施例47．14-[N-异烟酰基氨甲酸]姆替林
步骤1．14-[N-异烟酰基氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
氰酸银(690mg,4.6mmol)、异烟酰氯盐酸盐(535mg,3.0mmol)、四(三苯膦)钯(0)(18.5mg,0.016mmol)和(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(335mg,1.0mmol)的混合物在二氯甲烷(15ml)中避光保护，并在氩气氛下室温搅拌66小时。然后加入二异丙基乙胺(1ml)，用Kieselguhr过滤反应混和物。浓缩得到粗产物，硅胶色谱纯化，用50-75％乙酸乙酯/己烷混合物洗脱，得到标题化合物(212mg,44％)。υ最大(CH2Cl2)3406,1781,1721和1698cm-1；
1H NMR(CDCl3)0.89(3H,d,J6.9Hz),1.01(3H,d,J6.4Hz),1.03-1.62(6H,
m),1.21(3H,s),1.31(3H,s),1.70(1H,d,J15.5Hz),1.75(1H,d,J11.5Hz),
2.00(2H,m),2.21(1H,m),2.54(1H,dd,J15.2,10.1Hz),2.88(1H,q,J6.3Hz),
3.22(3H,s),3.46(1H,ddd,J11.2,8.3.5.3Hz),5.02(1H,d,J17.5Hz),5.29(1H,
d,J10.7Hz),5.85(1H,d,J10.0Hz),6.66(1H,dd,J17.5,10.7Hz),7.64(2H,dd,
J4.4,1.6Hz),8.11(1H,s),8.84(2H,dd,J4.4,1.5Hz)；MS(CI)m/z483
(MNH4 +)
步骤2．14-[N-异烟酰基氨甲酸]姆替林
步骤1产物(177mg,0.37mmol)在二噁烷(2ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，如实施例1的步骤2所述，得到标题化合物(29.6mg,17％)；υ最大(二氯甲烷)3400,1783和1734cm-1；
    1H NMR(CDCl3)0.79(3H,d,J6.8Hz),0.89(3H,d,J7.0Hz),1.16
(1H,m)1.20(3H,s)1.50(3H,s),1.44-1.82(8H,m),2.11-2.35(5H,m),3.37
(1H,dd,J10.7,6.6Hz),5.23(1H,dd,J17.3,1.4Hz),5.36(1H,dd,J10.9,
1.3Hz),5.82(1H,d,J8.5Hz),6.51(1H,dd,J17.3,11.0Hz),7.62(1H,dd,J4.5,
1.5Hz),8.20(1H,s),8.79(2H,dd,J4.5,1.7Hz)；MS(CI)m/z469(MH+).
实施例48．14-[N-烟酰基氨甲酸]姆替林
步骤1．14-[N-烟酰基氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
氰酸银(690mg,4.6mmol)、烟酰氯盐酸盐(712mg,4.0mmol)、四(三苯膦)钯(0)(14mg,0.012mmol)、二异丙基乙胺(0.7ml,4.0mmol)和(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(335mg,1.0mmol)的混合物在二氯甲烷(14ml)中避光保护，并在氩气氛下室温搅拌50分钟。用Kieselguhr过滤反应混和物并浓缩，粗产物硅胶色谱纯化得到标题化合物(177mg,37％)。υ最大(CH2Cl2)3410,1779,1717和1698cm-1；
                     1H NMR(CDCl3)0.90(3H,d,J6.8Hz),1.00(3H,
d,J6.4Hz),1.08-1.56(6H,m),1.21(3H,s),1.30(3H,s),1.71(1H,d,J
15.3Hz),1.75(1H,d,J11.2Hz),2.00(2H,m),2.21(1H,m),2.54(1H,dd,J
15.3,10.1Hz),2.89(1H,q,J6.4Hz),3.22(3H,s),3.46(1H,ddd,J11.2,8.1,
5.4Hz),5.02(1H,d,J17.4Hz),5.28(1H,d,J10.7Hz),5.85(1H,d,J10.0Hz),
6.67(1H,dd,J17.5,10.7Hz),7.46(1H,dd,J7.6,4.9Hz),8.16(2H,m),8.81
(1H,dd,J4.9,1.5Hz)9.02(1H,d,J2.3Hz)；MS(CI)m/z483(MNH4 +).
步骤2．14-[N-烟酰基氨甲酸]姆替林
步骤1产物(153mg,0.32mmol)在二噁烷(2ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，如实施例1的步骤2所述，得到标题化合物(95mg,64％)；υ最大(二氯甲烷)3410,1781和1734cm-1；
        1H NMR(CDCl3)0.81(3H,d,J6.7Hz),0.89(3H,d,J6.9Hz),1.18
(1H,m)1.20(3H,s)1.50(3H,s),1.44-1.82(8H,m),2.11-2.35(5H,m),3.37
(1H,dd,J10.6,6.7Hz),5.23(1H,d,J17.4Hz),5.36(1H,d,J11.1Hz),5.82(1H,
d,J8.4Hz),6.52(1H,dd,J17.3,11.0Hz),7.44(1H,dd,J7.8,4.9Hz),8.12(2H,
br),8.80(1H,d,J3.4Hz),8.99(1H,d,J1.7Hz)；MS(EI)m/z469(MH+).
测定值：469.2704,C27H37N2O5(MH+)理论值469.2702.
实施例49．14-[N-2-糠酰基氨甲酸]姆替林
步骤1．14-[N-2-糠酰基氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
氰酸银(690mg,4.6mmol)、2-糠酰氯(0.4ml,3.0mmol)、四(三苯膦)钯(0)(17mg,0.015mmol)和(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(335mg,1.0mmol)的混合物在二氯乙烷(10ml)中避光保护，并在氩气氛下室温搅拌41小时。用Kieselguhr过滤反应混和物并浓缩得到粗产物，硅胶色谱纯化，得到标题化合物(468mg,99％)。υ最大(CH2Cl2)3415,1777,1714和1699cm-1；
                1H NMR(CDCl3)0.89(3H,d,J6.9Hz),1.00(3H,
d,J6.4Hz),1.07-1.42(4H,m),1.20(3H,s),1.33(3H,s),1.53(2H,m),1.71
(1H,d,J15.3Hz),1.75(1H,d,J11.3Hz),2.02(2H,m),2.20(1H,m),2.53(1H,
dd,J15.4,10.1Hz),2.90(1H,q,J6.4Hz),3.23(3H,s),3.47(1H,ddd,J11.2,
8.3,5.3Hz),5.01(1H,d,J17.4Hz),5.30(1H,d,J10.7Hz),5.84(1H,d,J
9.9Hz),6.59(1H,dd,J3.5,1.7Hz),6.73(1H,dd,J17.4,10.6Hz),7.34(1H,d,J
3.3Hz),7.54(1H,s),8.20(1H,s)；MS(CI)m/z471(M+).
步骤2．14-[N-2-糠酰基氨甲酸]姆替林
步骤2产物(200mg,0.42mmol)在二噁烷(2ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，如实施例1的步骤2所述，得到标题化合物(129mg,67％)；υ最大(二氯甲烷)3412,1777,1733和1716cm-1；
        1H NMR(CDCl3)0.80(3H,d,J6.7Hz),0.89(3H,d,J7.0Hz),1.18
(1H,m)1.19(3H,s)1.54(3H,s),1.37-1.82(8H,m),2.10-2.38(5H,m),3.37
(1H,dd,J11.0,6.6Hz),5.23(1H,dd,J17.3,1.5Hz),5.38(1H,dd,J11.0,
1.5Hz),5.83(1H,d,J8.5Hz),6.56(1H,dd,J17.3,11.0Hz),6.57(1H,dd,J3.5,
1.8Hz),7.32(1H,d,J3.3Hz),7.52(1H,d,J2.1Hz),8.15(1H,s)；MS(CI)m/z
475(MNH4 +).
实施例50．14-[N-乙酰基氨甲酸]姆替林
步骤1．乙酰基异氰酸酯
氰酸银(690mg,4.6mmol)与乙酰氯(0.28ml,3.94mmol)在干二氯甲烷(5ml)中如实施例31步骤1方法所述反应1.75小时。含有标题化合物的溶液立即用于下一个反应；υ最大(CH2Cl2)2257cm-1。
步骤2．14-[N-乙酰基氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤1溶液用(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(335mg,1.0mmol)处理，搅拌反应10分钟。如实施例31步骤2同样工序，分离得到标题化合物(420mg,100％)。υ最大(CH2Cl2)3388,1753和1713cm-1；
                                                        1H NMR
(CDCl3)0.83(3H,d,J6.gHz),1.00(3H,d,J6.4Hz),1.07-1.54(6H,m),1.21
(6H,s),1.62(1H,d,J15.7Hz),1.73(1H,d,J11.3Hz),1.99(2H,m),2.20(1H,
m),2.48(3H,s),2.49(1H,dd,J15.4,10.0Hz),2.88(1H,q,J6.4Hz),3.22(3H,
s),3.45(1H,ddd,J11.2,8.1,5.3Hz),5.03(1H,d,J17.5Hz),5.33(1H,d,J
10.7Hz),5.72(1H,d,J10.0Hz),6.63(1H,dd,J17.5,10.7Hz),7.45(1H,s)；MS
(EI)m/z419(M+)，测定值：419.2674,C24H37NO5理论值419.2672.
步骤3．14-[N-乙酰基氨甲酸]姆替林
步骤2产物(284mg,0.68mmol)在二噁烷(3ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，如实施例1的步骤2所述，得到标题化合物(190mg,69％)；υ最大(二氯甲烷)3392,1755,1734和1714cm-1；
         1H NMR(CDCl3)0.74(3H,d,J6.7Hz),0.89(3H,d,J7.0Hz),1.16
(1H,m)1.19(3H,s)1.43(3H,s),1.37-1.55(5H,m),1.59-1.85(3H,m),2.05-
2.38(5H,m),2.42(3H,s),3.37(1H,dd,J10.6,6.6Hz),5.23(1H,dd,J17.4,
1.3Hz),5.37(1H,dd,J11.0,1.3Hz),5.72(1H,d,J8.4Hz),6.49(1H,dd,J17.4,
11.0Hz),7.51(1H,s)；MS(CI)m/z423(MNH4 +).
实施例51．14-[N-(4-氯代苯磺酰基)氨甲酸]姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(500mg)在干二氯甲烷(7ml)中用4-氯代苯磺酰胺(265mg)、二异丙基乙胺(0.5ml)和4-二甲氨基吡啶(10ml)处理，室温搅拌溶液30分钟。用乙酸乙酯(50ml)稀释溶液，并用稀盐酸(30ml)、水(30ml)和饱和食盐水(30ml)洗涤。硫酸钠干燥，减压蒸发去除溶剂得到白色泡沫状产物(780mg)。
泡沫溶于1,4-二噁烷(8ml)并用浓盐酸中的饱和氯化锌溶液(2.5ml)处理，室温搅拌溶液2.5小时，乙酸乙酯(50ml)稀释，水洗涤三次。硫酸钠干燥，减压蒸发去除溶剂得到粉红色泡沫。二氯甲烷-己烷结晶得到无色晶体状的标题化合物(555mg)；熔点216-218℃；λ最大(乙醇)230nm(ε12,100)υ最大(三氯甲烷)3380,1735和1210cm-1；
                                δH(CDCl3)7.94(2H,d,J5
Hz),7.52(2H,d,J5Hz),6.27(1H,dd,J17.4和11Hz),5.61(1H,d,J8.4
Hz),5.24(1H,dd,J11和1.2Hz),5.10(1H,dd,J17.4和1.2Hz),3.30(1H,
dd,J10.1和6.7),2.20(3H,m),1.95(2H,m),1.8-1.0(重叠的多重峰)，
         1.34(3H,s),1.09(3H,s),0.83(3H,d.J7Hz),和0.52(3H,d,J6.8
Hz)；MS(CI)m/z555(M.NH4 +).
实施例52．14-[N-(4-氟苯磺酰基)氨甲酸]姆替林
步骤1．14-[N-(4-氟苯磺酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(200mg)在干二氯甲烷(3ml)中用4-氟苯磺酰胺(180mg)、二异丙基乙胺(0.2ml)和4-二甲氨基吡啶(2mg)处理，并在室温搅拌溶液30分钟。溶液用乙酸乙酯(50ml)稀释，并用稀盐酸(20ml)、水(20ml)和饱和食盐水(20ml)洗涤。用硫酸钠干燥溶液，减压蒸发去除溶剂得到无色胶体，硅胶色谱纯化，用乙酸乙酯-己烷洗脱得到无色胶体的标题化合物(240mg)。(最大(CHCl3)3379,1737,1697和1594cm-1；MS(EI)m/z535(M+)(测定值；M+,535.2408.C28H38NO6FS理论值M,535.2404)。
步骤2．14-[N-(4-氟苯磺酰基)氨甲酸]姆替林
14-[N-(4-氟代苯磺酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(200mg)在1,4-二噁烷(4ml)中用浓盐酸中的饱和氯化锌溶液(1.5ml)处理，室温保持溶液1.5小时。溶液用乙酸乙酯(50ml)稀释并用水洗涤三次(每份20ml)。用硫酸钠干燥溶液，减压蒸发去除溶剂得无色胶体。硅胶色谱纯化，用乙酸乙酯-己烷洗脱得到无色晶体状的标题化合物(140mg)。二氯甲烷-己烷再结晶得无色针状体，熔点228-229℃；υ最大(乙醇)217nm(ε11660)；
                                   δH(CDCl3)8.01(2H,dd,J9和5
Hz),7.20(2H,t.J9Hz),6.27(1H,dd,J17.5和11Hz),5.58(1H,d.J8.3Hz),
5.20(1H,dd,J11和1.2Hz),5.06(1H,dd,J17.5和1.2Hz),3.20(1H,d,J
6.2Hz),2.22(2H,m),1.97(2H,m),1.8-1.0(重叠的多重峰),1.35(3H,
s),1.09(3H,s),0.85(3H,d,J7Hz),0.51(3H,d,J6.7Hz)；MS(CI)m/z539
(M.NH4 +).
实施例53．14-[N-(4-正丙基苯磺酰基)氨甲酸]姆替林
步骤1．14-[N-(4-正丙基苯磺酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
使用实施例52步骤1所述方法，将14-氯甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(200mg)和4-正丙基苯磺酰胺(150mg)转换成无色胶体状的标题化合物(220mg)；MS(CI)m/z557(M.NH4 +)。
步骤2．14-[N-(4-正丙基苯磺酰基)氨甲酸]姆替林
使用实施例52步骤2的方法，将14-[N-(4-正丙基苯磺酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(190mg)转换成标题化合物(150mg)。υ最大(三氯甲烷)3565,3384,1735,1598和1421cm-1；
δH(CDC13)7.85(2H,d,J8.5Hz),7.32(2H,d,J8.5Hz),6.28(1H,dd,J17.3
和11Hz),5.61(1H,d,J8.3Hz),5.23(1H,dd,J11和1.3Hz),5.08(1H,dd,
J17和1.3Hz),3.29(1H,dd,J10.2和6.6Hz),2.67(2H,t,J7.3Hz),2.20
(2H,m),1.95(2H,m),1.8-0.8(重叠的多重峰),0.49(3H,d,J6.7Hz)；
MS(CI)m/z563(M.NH4 +).
实施例54．14-[N-(4-羟基苯磺酰基)氨甲酸]姆替林
14-氯代甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(300mg)在干二氯甲烷(5ml)中用4-羟基苯磺酰胺(170mg)、二异丙基乙胺(0.35ml)和4-二甲氨基吡啶(8mg)处理，并在室温搅拌30分钟。溶液用乙酸乙酯(50ml)稀释，并用稀盐酸(20ml)、水(20ml)和饱和食盐水(20ml)洗涤。用硫酸钠干燥溶液，减压蒸发去除溶剂得到无色胶体。硅胶色谱纯化，乙酸乙酯-己烷洗脱得到白色泡沫状产物(410mg)。
上述产物溶于1,4-二噁烷(8ml)中，用浓盐酸中的饱和氯化锌溶液(3ml)处理，室温保持溶液3.5小时。溶液用乙酸乙酯(50ml)稀释并用水洗涤三次(每份20ml)。用硫酸钠干燥溶液，减压蒸发去除溶剂得浅黄色胶体。硅胶色谱纯化，乙酸乙酯-己烷洗脱得到白色泡沫状产物(180mg)。这个产物的NMR谱表示它含有两个不同的姆替林部分，暗示通过氯甲酸的4-表姆替林分子与羟基和4-羟基苯磺酰胺的4-磺酰氨基两者同时反应衍生的：
[姆替林]-O2COC6H4SO2NHCO2-[姆替林]
上述产物溶于甲醇(8ml)，溶液用1M氢氧化钠(1ml)处理并室温保持6小时。乙酸乙酯(50ml)稀释溶液，稀盐酸(20ml)和饱和食盐水(20ml)洗涤。硫酸钠干燥，减压蒸发去除溶剂得到黄色胶体。硅胶色谱纯化，乙酸乙酯-己烷洗脱得到白色固体状的标题化合物(170mg)；λ最大(乙醇)239nm(ε12340)；υ最大(三氯甲烷)3690,3583,3382,1734,1602,1418和1157cm-1；
                                           δH(CDCl3-d4-
甲醇)7.77(2H,d,J7Hz),6.84(2H,d,J7Hz),6.28(1H,dd.J17.3和11
Hz),5.56(1H,d,J8.3Hz),5.21(1H,d,J11Hz),5.07(1H,d,J17.3Hz),3.26
(1H,d,J6.4Hz),2.5-1.0(重叠的多重峰),0.82(3H,d,J7Hz),0.51
(3H,d,J6.5Hz)；MS(CI)m/z537(M.NH4 +),519.(M+)
实施例55．14-[N-(3,4-二甲氧基苯甲酰基)氨甲酸]姆替林
步骤1．3,4-二甲氧基苯甲酰基异氰酸酯
氰酸银(690mg,4.6mmol)与3,4-二甲氧基苯甲酰氯(800mg,4.0mmol)在干二氯甲烷(5ml)中如实施例31步骤1方法所述进行反应，含有标题化合物的溶液立即用于下一个反应；υ最大(CH2Cl2)2238cm-1。
步骤2．14-[N-(3,4-二甲氧基苯甲酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤1溶液用(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(335mg,1.0mmol)处理，搅拌反应40分钟。如实施例31步骤2同样工序，分离得到标题化合物(392mg,72％)。υ最大(CH2Cl2)3430,1774和1698cm-1；
                                                         1H NMR
(CDCl3)0.91(3H,d,J6.8Hz),1.00(3H,d,J6.4Hz),1.05-1.57(6H,m),1.21
(3H,s),1.34(3H,s),1.73(1H,d,J15.3Hz),1.75(1H,d,J10.5Hz),2.02(2H,
m),2.20(1H,m),2.54(1H,dd,J15.2,10.1Hz),2.91(1H,q,J6.2Hz),3.23(3H,
s),3.47(1H,m),3.95(6H,s),5.02(1H,d,J17.5Hz),5.30(1H,d,J10.7Hz),
5.85(1H,d,J9.9Hz),6.79(1H,dd,J17.5,10.7Hz),6.90(1H,d,J8.4Hz),7.34
(1H,dd,J8.4,2.0Hz),7.46(1H,d,J2.0Hz),7.94(1H.s)；MS(CI)m/z542
(MH+).
步骤3．14-[N-(3,4-二甲氧基苯甲酰基)氨甲酸]姆替林
步骤2产物(275mg,0.51mmol)在二噁烷(2ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，如实施例1的步骤2所述，得到标题化合物(75mg,28％)；υ最大(KBr片)3305,1768,1730和1687cm-1；
        1H NMR(CDCl3)0.82(3H,d,J6.6Hz),0.89(3H,d,J6.9Hz),1.20
(1H,m),1.23(3H,s),1.54(3H,s),1.44-1.82(8H,m),2.12-2.38(5H,m),3.38
(1H,dd,J10.7,6.6Hz),3.94(6H,s),5.24(1H,dd,J17.4,1.4Hz),5.38(1H,dd,
J10.9,1.4Hz),5.84(1H,d,J8.5Hz),6.58(1H,dd,J17.3,11.0Hz),6.88(1H,d,
J8.4Hz),7.30(1H,dd,J8.4,2.0Hz),7.43(1H,d,J2.1Hz),7.86(1H,s)；MS
(EI)m/z527(M+)，测定值：527.2884,C30H41NO7理论值527.2883.
实施例56．14-[N-(3,4-亚甲基二氧苯甲酰基)]姆替林
步骤1．3,4-亚甲基二氧苯甲酰基异氰酸酯
氰酸银(690mg,4.6mmol)与胡椒基酰氯(738mg,4.0mmol)在干二氯甲烷(5ml)中反应，如实施例31步骤1方法所述。含有标题化合物的溶液立即用于下一个反应；υ最大(CH2Cl2)2238cm-1。
步骤2．14-[N-(3,4-亚甲基二氧苯甲酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤1溶液用(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(335mg,1.0mmol)处理，搅拌反应40分钟。如实施例31步骤2同样工序，分离得到标题化合物(283mg,54％)。υ最大(CH2Cl2)3428,1755和1698cm-1；                                    1H NMR
(CDCl3)0.90(3H,d,J6.9Hz),1.00(3H,d,J6.4Hz),1.07-1.56(6H,m),1.20
(3H,s),1.31(3H,s),1.71(1H,d,J15.3Hz),1.75(1H,d,J11.2Hz),1.99(2H,
m),2.20(1H,m),2.52(1H,dd,J15.2,10.1Hz),2.90(1H,q,J6.5Hz),3.23(3H,
s),3.46(1H,ddd,J11.2,8.2,5.3Hz),5.01(1H,d,J17.4Hz),5.29(1H,d,J
10.7Hz),5.84(1H,d,J10.0Hz).6.07(2H,s).6.72(1H,dd,J17.5,10.7Hz),6.87
(1H,d,J8.0Hz),7.32(1H,d,J1.5Hz),7.36(1H,dd,J7.9,1.8Hz),7.89(1H,s)；
MS(CI)m/z543(MNH4 +),526(MH+).
步骤3．14-[N-(3,4-亚甲基二氧苯甲酰基)氨甲酸]姆替林
步骤2产物(237mg,0.45mmol)在二噁烷(2ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，如实施例1的步骤2所述，得到标题化合物(151mg,65％)；υ最大(二氯甲烷)3432,1777,1733和1712cm-1；
       1H NMR(CDCl3)0.80(3H,d,J6.6Hz),0.89(3H,d,J7.0Hz),1.18
(1H,m),1.19(3H,s),1.38-1.83(8H,m),1.51(3H,s),2.09-2.37(5H,m),3.37
(1H,dd,J10.9,6.6Hz),5.23(1H,dd,J17.4,1.5Hz),5.38(1H,dd,J11.0,
1.5Hz),5.82(1H,d,J8.5Hz),6.06(2H,s),6.56(1H,dd,J17.4,11.0Hz),6.85
(1H,d,J8.0Hz),7.29(1H,d,J1.6Hz),7.32(1H,dd,J8.1,1.8Hz),7.81(1H,s)；
MS(EI)m/z511(M+),测定值：511.2566,C29H37NO7理论值511.2570。
实施例57．14-(N-对甲氧基磺酰基氨甲酸)姆替林
步骤1．11-二氯乙酸姆替林
姆替林(1.0g,3.12mmol)在氩气氛下溶于干四氢呋喃(10ml)，并用吡啶(0.33ml,4.06mmol)、四氢呋喃(2ml)中的二氯乙酐(820mg,3.42mmol)和N,N-4-二甲氨基吡啶(5mg)处理。反应24小时后反应用乙酸乙酯稀释，用1M盐酸、饱和碳酸氢钠和饱和氯化钠溶液洗涤。硫酸镁干燥溶液并浓缩，得到粗产物(1.5g)；硅胶色谱纯化(15-25％乙酸乙酯/己烷)得到标题化合物(925mg,69％)；υ最大(CH2Cl2)3635,1756和1735cm-1；
                    1H NMR(CDCl3)0.86(3H,d,J7.1Hz),0.97
(3H,d,J7.0Hz),1.06(3H,s),1.15(1H,m),1.32-1.50(4H,m),1.39(3H,s),
1.63-2.02(5H,m),2.10(1H,s),2.22(2H,m),2.37(1H,五重峰,J7.0Hz),4.31
(1H,t,J6.4Hz),4.91(1H,d,J6.9Hz),5.32(1H,dd,J11.2,0.7Hz),5.48(1H,
dd,J17.7,0.8Hz),6.00(1H,s),6.12(1H,dd,J18.0,11.2Hz)；MS(CI)m/z448
/450/452(MNH4 +).
步骤2．14-氯甲酸-11-二氯乙酸姆替林
步骤1产物(882mg,2.04mmol)氩气氛下溶于干四氢呋喃(15ml)中，冰浴冷却，用氯甲酸三氯甲酯(0.25ml,2.07mmol)和吡啶(0.21ml,2.6mmol)处理。迅速搅拌所得非均相混和物1小时，乙酸乙酯稀释，用饱和氯化钠溶液洗涤。硫酸镁干燥溶液并浓缩，得到可不需纯化而使用的标题化合物(982mg,97％)。υ最大(CH2Cl2)1760和1737cm-1；
          1H NMR(CDCl3)0.83(3H,d,J7.1Hz),0.88(3H,d,J7.1Hz),1.13
(3H,s),1.16(1H,m),1.37-1.54(3H,m),1.48(3H,s).1.61-1.92(4H,m),2.13-
2.37(4H,m),2.46(1H,五重峰,J7.0Hz),4.93(1H,t,J6.8Hz),5.31(1H,d,J
17.2Hz),5.37(1H,d,J10.7Hz),5.61(1H,d,J8.4Hz),5.99(1H,s),6.25(1H,
dd,J17.5,11.2Hz)；MS(EI)m/z498-492(M+).
步骤3．11-二氯乙酸-14-(N-对甲氧基磺酰基氨甲酸)姆替林
步骤2产物(250mg,0.51mmol)氩气氛下溶于二氯甲烷(5ml)，并用DMF(0.5ml)中的对甲氧基磺酰胺(187mg,1.0mmol)、N,N-二异丙基乙胺(0.2ml,1.15mmol)和N,N-4-二甲氨基吡啶(5mg)处理。室温搅拌溶液3小时后，用二氯甲烷稀释溶液并用1M盐酸洗涤。硫酸镁干燥并浓缩溶液得到粗产物(746mg)。硅胶色谱纯化(50％乙酸乙酯/己烷)得到标题化合物(294mg,90％)；υ最大(二氯甲烷)3368和1736cm-1；
            1H NMR(CDCl3)0.53(3H,d,J6.7Hz),0.83(3H,d,J7.0Hz),
0.99(3H,s),1.06-1.89(8H,m),1.35(3H,s),1.94-2.29(4H,m),2.45(1H,m),
3.88(3H,s),4.86(1H,d,J6.8Hz),5.09(1H,d,J17.6Hz),5.19(1H,d,J
11.2Hz),5.52(1H,d,J8.0Hz),5.96(1H,s),6.16(1H,dd,J17.6,11.2Hz),6.99
(2H,d,J8.9Hz),7.94(2H,d,J8.9Hz)；MS(CI)m/z665/663/661(MNH4 +).
步骤4．14-(N-对甲氧基磺酰基氨甲酸)姆替林
步骤3产物(262mg,0.41mmol)溶于四氢呋喃(3ml)和甲醇(1ml)中，并用1M氢氧化钠(1ml,1.0mmol)处理。1小时后用乙酸乙酯稀释溶液并用1M盐酸和水洗涤。硫酸镁干燥并浓缩得到粗产物(260mg)。硅胶色谱纯化(50％乙酸乙酯/己烷)得到标题化合物(206mg,95％)；υ最大(二氯甲烷)3367和1736cm-1；
                                 1H NMR(CDCl3)0.53(3H,d,J
6.7Hz),0.83(3H,d,J7.0Hz),1.08(1H,m),1.10(3H,s),1.25-1.75(8H,m),
1.35(3H,s),1.97(2H,m),2.20(3H,m),3.29(1H,dd,J10.2,6.6Hz),3.88(3H,
s),5.09(1H,dd,J17.4,1.3Hz),5.24(1H,d,J11.0,1.2Hz),5.61(1H,d,J
8.4Hz),6.28(1H,dd,J17.4,11.0Hz),6.98(2H,d,J9.0Hz),7.43(1H,s),7.93
(2H,d,J9.0Hz)；MS(CI)m/z551(MNH4 +)；(测定值：C,63.13；H,7.54；N,
2.61.C28H39NO7S理论值C,63.02；H,7.37；N,2.62).
实施例58．14-[N-(4-羟基苯甲酰基)氨甲酸]姆替林
步骤1．11-氧-二氯乙酰基姆替林
姆替林(4.0g,12.5mmol)溶于干四氢呋喃(20ml)中，并用吡啶(1.31ml,16.2mmol)、二氯乙酐(3.29g,13.7mmol)和N,N-4-二甲氨基吡啶(20mg)处理。氩气氛下室温搅拌反应2小时。在乙酸乙酯和水之间分配反应混和物。有机相用1M盐酸、水和饱和氯化钠溶液洗涤，硫酸镁干燥。硅胶色谱纯化，分离得到结晶固体状的标题化合物(3.57g,66％)；υ最大(CH2Cl2)3635,2936,1756,1735和1463cm-1；
1H NMR(CDCl3)0.86(3H,d,J7.1Hz),0.97(3H,d,J7.0Hz),1.06(3H,s),1.15
(1H,m)1.39(3H,s),1.32-1.50(4H,m),1.63-2.02(5H,m),2.10(1H,s),2.22
(2H,m),2.37(1H,五重峰,J6.5Hz),4.31(1H,t,J6.4Hz),4.91(1H,d,J6.9Hz),
5.32(1H,dd,J11.2,0.7Hz),5.48(1H,dd,J17.7,0.7Hz),6.00(1H,s),6.12(1H,
dd,J1 8.0,11.2Hz)；MS(NH3DCI)m/z 448.450,452(MNH4 +).
步骤2．11-氧-二氯乙酰基姆替林-14-[N-(4-乙酰氧基苯甲酰基)氨甲酸]
4-乙酰氧基苯甲酰基异氰酸酯(6mmol)的二氯甲烷(20ml)溶液(实施例33步骤1所述制备)用11-氧-二氯乙酰基姆替林(650mg,1.5mmol)处理，如实施例31步骤2所述分离得到标题化合物(716mg,72％)。υ最大(CH2Cl2)3420,2943,1779,1734,1604和1479cm-1；
                   1H NMR(CDCl3)0.80(3H,d,J6.5Hz),0.87(3H,
d,J7.0Hz),1.11-1.23(4H,m),1.38-1.93(11H,m),2.14-2.32(5H,m),2.56-2.62
(1H,m),4.96(1H,d,J6.7Hz),,5.33(1H,d,J17.6Hz),5.36(1H,dd,J11.1Hz),
5.75(1H,d,J8.1Hz),5.99(1H,s),6 44(1H,dd,J17.3,11.3Hz),7.22(2H,d,J
8.7Hz),),7.84(2H,d,J8.7Hz),7.89(1H,bs)；MS(ESI,+ve离子)m/z 653
(MNH4 +)；(测定值：C,60.34:H,6.42；N,2.13.C32H39Cl2NOx理论值C,60.38；
H,6.18；N,2.20)
步骤3．14-[N-(4-羟基苯甲酰基)氨甲酸]姆替林
11-氧-二氯乙酰基姆替林-14-[N-(4-乙酰氧基苯甲酰基)氨甲酸](671mg,1.05mmol)溶于四氢呋喃(5ml)和甲醇(1.0ml)，后用1.0M氢氧化钠(3.2ml,3.2mmol)处理。室温搅拌反应1小时。在乙酸乙酯和1.0M盐酸之间分配反应物，有机相用水、碳酸氢钠溶液最终用食盐水洗涤。硫酸镁干燥后粗产物用硅胶色谱纯化，装载和用己烷中的50％乙酸乙酯随后乙酸乙酯洗脱。分离得到固体状的标题化合物(409mg,80％)。
实施例59．14-[N-(4-羟甲基苯甲酰基)氨甲酸]姆替林
步骤1．14-[N-(4-羟甲基苯甲酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
将14-[N-(4-甲酰基苯甲酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(250mg,0.49mmol)(实施例42步骤2制备)溶于干四氢呋喃(2.5ml)并用二异丁基铝氢化物(0.54ml的1.0M甲苯溶液，0.8mmol)处理。室温搅拌15分钟后，反应在乙酸乙酯和水之间分配。有机相用水、饱和碳酸氢钠溶液和食盐水洗涤后，硫酸镁干燥溶液。硅胶色谱纯化，用乙酸乙酯和己烷的混和物洗脱，分离得到泡沫状标题化合物(184mg,73％)；υ最大(CH2Cl2)3605,3426,2930,1776,1731,1698,1613和1479cm-1；
                 1H NMR(CDCl3)1.00(3H,d,J6.4Hz),1.31
(3H,d,J6.8Hz),1.07-1.60(12H,m),1.69-1.73(2H,m),1.91-2.04(2H,m),
2.15-2.24(1H,m),2.53(1H,dd,J15.2,10.1Hz),2.90(1H,q,J6.3Hz),3.22
(3H,s),3.42-3.50(1H,m),4,79和4.81(2H,s+s),5.00(1H,d,J17.4Hz),5.30
(1H,d,J10.7Hz),5.85(1H,d,J9.9Hz),6.72(1H,dd,J17.4,10.7Hz),7.49(2H,
d,J8.2Hz),7.82(1H,d,J8.3Hz),8.00(1H,bs)；MS(NH3DCI)m/z 512(MH+),
m/z 529(MNH4 +)
步骤2．14-[N-(4-羟甲基苯甲酰基)氨甲酸]姆替林
步骤1产物(164mg,0.32mmol)在二噁烷(2.0ml)中用浓盐酸中的饱和氯化锌溶液(0.5ml)处理，如实施例1的步骤2所述，得到标题化合物(52mg,33％)；υ最大(二氯甲烷)3604,3431,1778,1733,1714和1613cm-1；
1H NMR(CDCl3)0.81(3H,d,J6.6Hz),0.88(3H,d,
J7.0Hz),1.19-1.81(16H,m),1.86(1H,bs),2.10-2.37(4H,m),3.37(1H,dd,J
10.5,6.5Hz),4.79(2H,bs),5.23(1H,dd,J17.4,1.4Hz),5.38(1H,dd,J11.0,
1.4Hz),5.83(1H,d,J8.5Hz),6.55(1H,dd,J17.3,11.0Hz),7.50(1H,d,J
8.2Hz),7.80(1H,d,J8.3Hz),7.96(1H,bs)；MS(NH3DCI)m/z 498(MH+),m/z
515(MNH4 +).
实施例60．14-[N-(4-甲磺酰氨基苯甲酰基)氨甲酸]姆替林
步骤1．14-[N-(4-氨基苯甲酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
14-[N-(4-硝基苯甲酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(460mg,0.87mmol)按照实施例34方法转换成标题化合物(268mg,64％)。υ最大(CH2Cl2)3405,2930,1771,1698,1623和1477cm-1；
                                               1H NMR(CDCl3)0.89
(3H,d,J6.9Hz),1.00(3H,d,J6.4Hz),1.07-1.61(12H,m),1.69-1.76(2H,m),
1.94-2.04(2H,m),2.15-2.24(1H,m),2.52(1H,dd,J15.2,10.1Hz),2.91(1H,q,
J6.4Hz),3.22(3H,s),3.42-3.50(1H,m),4.15(2H,bs),5.00(1H,d,J17.5Hz),
5.29(1H,d,J10.7Hz),5.83(1H,d,J9.9Hz),6.64-6.80(3H,m),7.66(2H,d,J
8.6Hz),7.86(1H,bs)；MS(NH3DCI)m/z 497(MH+)
步骤2．14-[N-(4-甲磺酰氨基苯甲酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
14-[N-(4-氨基苯甲酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(248mg,0.50mmol)室温氩气氛下溶于干二氯甲烷(5ml)中。用吡啶(0.132ml,1.65mmol)和甲磺酰氯(0.126ml,1.65mmol)分三份在3小时内加入反应中。二氯甲烷稀释反应，用饱和碳酸氢钠、1.0M盐酸、水和饱和氯化钠溶液洗涤，硫酸镁干燥。粗产物用己烷研制得到固体状标题化合物(236mg,82％)。υ最大(KBr片)1762,1695和1603cm-1；
                1H NMR(d6-丙酮)0.94(3H,d,J6.9Hz),1.01(3H,d,J
6.4Hz),1.0-1.97(12H,m),2.04-2.10(m,被溶剂峰遮蔽),2.53(1H,dd,J
15.6,10.5Hz),2.80-3.00(m,被溶剂峰遮蔽),3.11(3H,s),3.21(3H,s),
3.46-3.52(1H,m),4.99(1H,d,J17.5Hz),5.30(1H,d,J10.7Hz),5.80(1H,d,J
9.9Hz),6.82(1H,dd,J17.5,10.7Hz),7.43(2H,d,J8.8Hz),7.94(2H,d,J
8.7Hz),9.11(1H,bs),9.91(1H,s).
步骤3．14-[N-(4-甲磺酰氨基苯甲酰基)氨甲酸]姆替林
14-[N-(4-甲磺酰氨基苯甲酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(208mg,0.36mmol)溶于二噁烷(2.0ml)中并用浓盐酸中的饱和氯化锌溶液(0.5ml)处理，如实施例1步骤2所述得到标题化合物(72mg,36％)；υ最大(KBr片)1733和1608cm-1；
                          1H NMR(d6-丙酮)0.67(3H,d,J
6.3Hz),0.82(3H,d,J7.1Hz),0.91-1.71(15H,m),1.96-2.05(1H,m),2.19(1H,
五重峰,J6.8Hz),2.26(1H,bs),2.96(3H,s),3.30(1H,d,J7.3Hz,D2O交换),
3.50(1H,m在D2O中分解为双重峰,J5.9Hz),5.05(1H,dd,J11.0,1.7Hz),5.11
(1H,dd,J17.7,1.7Hz),5.64(1H,d,J8.3Hz),6.32(1H,dd,J17.7,11.1Hz),
7.26(1H,d,J8.8Hz),7.80(1H,d,J8.7Hz),9.72(1H,bs,D2O交换)；MS
(NH3DCI)m/z 561(MH+),m/z 578(MNH4 +).
实施例61．14-[N-(4-氨磺酰苯基)氨甲酸]姆替林
步骤1．14-[N-(4-氨磺酰苯基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(336mg,1.0mmol)在干二氯甲烷(7.5ml)中用异氰酸4-氯磺酰苯基酯(283mg,1.3mmol)和N,N-二异丙基乙胺(1滴)处理，排除湿气室温保持两天，然后在冰箱内放70小时。用旋转蒸发器去除溶剂再用四氢呋喃(7.5ml)代替。0.880S.G.加入氨水(0.5ml)，搅拌混合物1.5小时。用乙酸乙酯(50ml)稀释溶液并用食盐水洗涤。水层用乙酸乙酯(50ml)再提取，合并的乙酸乙酯溶液用1M盐酸(5ml)/食盐水(5ml)洗涤。硫酸镁干燥，减压蒸发去除溶剂得到无色泡沫。硅胶色谱纯化泡沫，用4∶6随后用1∶1再后用7∶3的乙酸乙酯-己烷洗脱，得到无色固态泡沫状的14-[N-(4-氨磺酰苯基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(460mg,86％)；υ最大(CH2Cl2)3420,3335,2980,2930,1731,1698,1592,1218和1163cm-1；
                                             1H NMR(CDCl3)0.87
(3H,d,J6.9 Hz),1.00(3H,d,J6.37Hz),1.01-1.8(ca 14H,m),1.9-21.(2H,
m),2.1-2.3(1H,m),2.50(1H,dd,J10.0,15.2Hz),2.94(1H,q,J6.4Hz),3.23
(3H,s),3.4-3.6(1H,m),4.84(2H,s),5.03(1H,d,J17.5Hz),5.34(1H,d,J
10.7Hz),5.81(1H,d,J9.8Hz),6.70(1H,dd,J10.6,17.5Hz),6.88(1H,s),
7.59(2H,d,J8.7Hz),7.88(2H,d,J8.8Hz)；MS(CI)m/z 550(MNH4)+.
步骤2．14-(N-4-氨磺酰苯基氨甲酸)姆替林
14-[N-(4-氨磺酰苯基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(410mg,0.77mmol)在二噁烷(7.5ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，室温搅拌溶液5小时。在反应未进行完全时，加入更多的饱和氯化锌的浓盐酸液(2ml)，继续搅拌2小时。乙酸乙酯(50ml)稀释混合物，用饱和氯化钠溶液(20ml)和饱和碳酸氢钠溶液(20ml)洗涤。硫酸镁干燥，减压蒸发去除溶剂得到无色固体。硅胶色谱纯化，装入二氯甲烷/含有微量乙酸乙酯的甲苯，先后以1∶1的乙酸乙酯-己烷随后以3∶7、6∶4和1∶1乙酸乙酯-甲苯的混合物洗脱得到无色固体状的标题化合物(281mg,70％)；υ最大(KBr)1725,1595,1530,1337,1317,1228和1160cm-1；
1H NMR[(CD3)2SO]0.90(3H,d,J6.8Hz),1.00(3H,d,J6.3Hz),1.0-
1.8(14H,m,包括1.08和1.43处的单峰),2.04-2.27(4H,m),2.42(1h,
br s),3.45(1H,brt,J ca.5.8Hz；d,J5.5Hz在D2O交换后),4.52(1H,d,J6.1
Hz,D2O交换)，5.05-5.15(2H,m),5.38(1H,brd,J7.8 Hz),6.27(1H,dd,J
11.1,17.7Hz),7.21(2H,s,D2O交换),7.59(2H,d,J8.8Hz),7.71(2H,d,J8.8
Hz),9.82(1H,s)；MS(CI)m/z 536(M+NH4 +).
实施例62．14-{N-[4-([2R]-2,3-二羟基丙氧基)苯甲酰基]}氨甲酸姆替林
步骤1．14-[N-(4-羟基苯甲酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
14-[N-(4-乙酰氧基苯甲酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(实施例37步骤2)(809mg,1.5mmol)溶于干1,4-二噁烷(10ml)中，用1M氢氧化钠(4.5ml)水溶液处理，搅拌混合物2.5小时。加入乙酸乙酯(100ml)和1M盐酸水溶液(10ml)，随后加入水(50ml)。分离水层后，用乙酸乙酯洗涤。合并的乙酸乙酯层用硫酸镁干燥并蒸发。残留物硅胶色谱纯化，装入二氯甲烷，先后用1∶1、6∶4、7∶3和8∶2的乙酸乙酯/己烷混合物洗脱，得到无色固体状的标题化合物(677mg,90％)；υ最大(CH2Cl2)3565,3417,2930,1774,1729,1698,1608,1478,1187和1167cm-1；
                         1H NMR(CDCl3)0.90(3H,d,J
6.8Hz),1.00(3H,d,J6.3Hz),1.0-1.8(14H,m，包括1.20处的s和131处的s
),1.99(2H,m),2.21(1H,dt,J10.0,2.7Hz),2.52(1h,dd,J10.1,15.2Hz),
2.91(1H,q,J6.4Hz),3.23(3H,s),3.46(1H,m),5.01(1H,d,J17.5Hz),5.28
(1H,d,J10.8Hz),5.84(1H,d,J9.9Hz),6.71(1H,dd,J10.7,17.5Hz),6.94
(2H,d,J8.7Hz),7.75(2H,d,J8.7Hz),7.96(1H,s)；MS(CI)m/z 498(MH+),
515(MNH4 +).
步骤2．14-{N-[4-([2R]-2,3-二羟基丙氧基)-苯甲酰基]}氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
14-[N-(4-羟基苯甲酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(497mg,1mmol)氩气氛下在叔丁醇(5ml)中加热溶解，然后用氢化钠(40mg的60％油中分散体，1mmol)处理。当停止起泡时(约30分钟)，加入二氯甲烷(2.5ml)中的(R)-(+)-缩水甘油(0.06ml,74mg,1mmol)，然后加入异丙氧钛(Ⅳ)(0.36ml,341mg,1.2mmol)。氩气氛下搅拌混合物18小时，再加热回流(50℃油浴)6.5小时。加入乙酸乙酯(50ml)/1MHCl(25ml)分层。水层用乙酸乙酯再提取，合并的乙酸乙酯层用食盐水洗涤，硫酸镁干燥。去除溶剂后硅胶色谱纯化粗产物，装载二氯甲烷，先后以1∶1、6∶4、7∶3和8∶4的乙酸乙酯/己烷混合物洗脱。合并含有产物的馏份并蒸发，得到泡沫状固体的标题化合物(297mg,52％)；υ最大(CH2Cl2)3585,2931,1774,1729,1698,1605,1478和1171cm-1；
                                      1H NMR(CDCl3)0.90(3H,d,J
6.8Hz),1.00(3H,d,J6.3Hz),1.0-1.6(12H,m,包括1.20处的s和1.30处的s)
1.70(1H,d,J9.9Hz),1.70(1H,d,J5.7Hz),1.9-2.3(4H,m；1H D2O交换),
2.53(1H,dd,J10.1,15.2Hz),2.60(1H,br s,D2O交换),2.90(1H,q,J6.4Hz),
3.22(3H,s),3.41-3.50(1H,m),3,7-4.0(2H,m,在D2O交换信号加强
),4.07-4.16(3H,m),5.01(1H,d,J17.4Hz),5.29(1H,d,J17.4Hz),5.29
(1H,J10.8Hz),5.84(1H,dJ9.9Hz),6.71(1H,dd,J10.6,17.4Hz),6.97(2H,
d,J8.8Hz),7.79(2H,d,J8.8Hz),8.00(1H,s)；MS(电喷)m/z 572
(MH+),1143(2M+H)+.
步骤3．14{N-[4-([2R]-2,3-二羟基丙氧基)-苯甲酰基]}-氨甲酸姆替林
步骤2产物(256mg,0.45mmol)在二噁烷(3ml)中用浓盐酸中的饱和氯化锌溶液(1.0ml)处理，如实施例1步骤2，得到标题化合物(105mg,42％)；υ最大(KBr片)1761,1732,1605,1497,1255,1204和1174cm-1；
              1H NMR(CDCl3+CD3OH)0.77(3H,d,J6.4Hz)
0.85(3H,d,J6.9Hz),1.0-2.4(19H,m，包括1.15处的s和1.48处的s)，3.33
(1h,d,J6.5Hz),3.60-3.83 92h,m),3.9-4.2(3H,m),5.19(1H,dd,J1.4,
17.4Hz),5.33(1H,dd,J1.3,11.0Hz),5.78(1H,d,J8.3Hz),6.51(1h,dd,J
11.0,17.3Hz),6.92(2H,d,J8.8Hz),7.74(2H,d,J8.8Hz)；MS(电喷)
m/z 558(MH+),1115(2M+H+).
实施例63．14-(N-氯代乙酰基)-氨甲酸姆替林
步骤1．14-(N-氯代乙酰基)氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(335mg,1.5mmol)和氰酸银(225mg,1.5mmol)在CH2Cl2(5ml)中氩气氛下在铝箔包住的烧瓶中用氯代乙酰氯(0.12ml,169mg,1.5mmol)处理，将混合物搅拌1小时。混合物通过Kieselguhr过滤并蒸发。加入甲苯然后去除。残留物进行硅胶色谱，装载二氯甲烷，用2∶8然后以3∶7的乙酸乙酯/己烷混合物洗脱，得到标题化合物(456mg，定量)；υ最大(CH2Cl2)3381,2981,1787,1754,1728,1698,1489,1459和1198cm-1；
                                            1H NMR(CDCl3)0.83
(3H,d,J6.8Hz),1.00(3H,d,J6.4Hz),1.01-1.40(10H,m,包括1.20处的s
和1.30处的s),1.40-1.56(2H,m),1.62(1H,d,J1523Hz),1.73(1H,d,J11.3
Hz),1.8-2.1(2H,m),2.20(1H,dt,J2.8,12.7Hz),2.51(1H,dd,J10.1,15.3
Hz),2.86(1H,q,J6.3Hz),3.22(3H,s),3.35-3.50(1H,m),4.51(2H,s),5.03
(1H,d,J17.5Hz),5.32(1H,d,J10.7Hz),5.75(1H,d,J10.0Hz)6.60(1H,dd,
J10.7,17.5Hz),7.88(1H,s,D2O交换)；MS(CI)m/z 471(MNH4 +).
步骤2．14-(N-氯代乙酰基)-氨甲酸姆替林
步骤2产物(400mg,0.88mmol)在二噁烷(4.5ml)中用浓盐酸中的饱和氯化锌溶液(1.5ml)处理，如实施例1步骤2，得到标题化合物(185mg,52％)；υ最大(二氯甲烷)3564,3388,2960,2895,1783,1755,1732,1605和1478cm-1；
                                        1H NMR(CDCl3)0.74
(3H,d,J6.8Hz),0.89(3H,d,J7.1Hz),1.0-1.3(4H,m,包括1.19处的s),
1.3-1.9(12H,m，包括1.44处的s),2.0-2.4(4H,m),3.37(1H,dd,J6.6,
10.7Hz；d,J6.5Hz在D2O交换后),4.47(2H,s),5.23(1H,dd,J1.4,17.4Hz),
5.38(1H,dd,J1.3,10.9Hz),5.72(1H,d,J8.5Hz),6.47(1H,dd,J11.0,17.4
Hz),7.81(1H,D2O交换)；MS(CI)m/z 457(MNH4 +).
实施例64．14-[N-(4-羟基苯甲酰基)-氨甲酸]的19,20-二氢姆替林
14-[N-(4-羟基苯甲酰基)]-氨甲酸姆替林(130mg)加入含有10％钯/碳(44mg)的乙酸乙酯(10ml)中，混合物在大气压力下氢化30分钟。Kieselguhr过滤混合物并去除乙酸乙酯；然后加入氯仿/甲醇，再去除；加入氯仿再去除，留下泡沫状固体的标题化合物(131mg)；υ最大(溴化钾)1781,1725,1697,1609,1459,1299和1201cm-1；
        1H NMR(CDCl3+CD3OD+D2O)0.7-1.27(15H,m),1.27-1.90
(10H,m，包括1.46处的s)，1.9-2.5(5H,m),3.39(1h,d,J5.4Hz),5.65(1H,
d,J7.9Hz),6.84(2H,d,J8.7Hz),7.69 2H,d,J8.7Hz)；MS(CI)m/z 486
(MH+)503(MNH4 +)；MS(电喷)503(MNH4 +)544(MNH4 ++MeCN).
实施例65．14-[N-(3-氨基-1,2,4-三唑基硫代乙酰基)-氨甲酸姆替林
14-(N-氯代乙酰基氨甲酸)姆替林(100mg,0.23mmol)在N,N-二甲基甲酰胺(2.5ml)中用3-氨基-5-巯基-1,2,4-三唑(29mg,0.25mmol)随后用N,N-二异丙基乙胺(0.043ml,32mg,0.25mmol)处理。混合物搅拌4.5小时然后加入乙酸乙酯(25ml)和水(15ml)将混合物分相。水相用乙酸乙酯再提取，合并的有机层用食盐水洗涤，硫酸镁干燥并蒸发。残留的油被吸收在二氯甲烷中并装载在硅胶色谱柱上。先后用乙酸乙酯/己烷(1∶1)、乙酸乙酯、乙酸乙酯/乙醇洗脱，得到被很少DMF沾污的标题化合物。将该物质被乙酸乙酯吸收并用水随后用食盐水洗涤，硫酸镁干燥并蒸发。残留物用乙醚研制得到标题化合物(102mg,85％)；
               1H NMR(CDCl3+CD3OD+D2O)特别0.63(3H,d,J6.4
Hz),0.81(3H,d,J6.9Hz),0.9.1.8(14H,m，包括1.04处的s和1.32处的s),
1.9-2.3(5H,m),3.65和3.72(2H,ABq,J15.2Hz),5.08(1H,dd,J1.4,17.3
Hz),5.22(1H,dd,J1.3,11.1Hz),5.55(1H,d,J8.4Hz),6.35(1H,dd,J11.0,
17.4Hz)；MS(CI)520(MH+).
实施例66．14-[N-(2-N,N-二乙胺基乙硫基乙酰基)]-氨甲酸姆替林
14-(N-氯代乙酰基)-氨甲酸姆替林(100mg,0.23mmol)在四氢呋喃(2ml)中用N,N-二乙氨基乙烷硫醇盐酸盐(39mg,0.23mmol)随后用1M氢氧化钠水溶液(0.5ml)处理。搅拌4.5小时后加入乙酸乙酯(25ml)和水(20ml)分层。水层用乙酸乙酯再提取，将合并的提取物硫酸镁干燥并蒸发；硅胶色谱残留物，用95∶4.5∶0.5随后是90∶9∶1的二氯甲烷/甲醇/0.880氢氧化铵混合物洗脱，得到标题化合物(20mg)；
                             1H NMR(CDCl3+CD3OD+D2O)
0.73(3H,d,J6.4Hz),0.85(3H,d,J6.9Hz),1.00(6H,t,J7.1Hz),1.1-1.25
(4H,s叠加在m上),1.25-1.9(11H,m，包括1.42处的s),2.0-2.4
(6H,m),2.53(4H,q,J7.1Hz),2.65(4H,br.s),3.33(1H,d,J6.3Hz),5.19(1H,
d,J17.2Hz),5.33(1H,d J11.0Hz),5.70(1H,d,J8.3Hz),6.46(1H,dd,J
11.0,17.4Hz).
实施例67．14-[N-(4-硝基苯磺酰基)]-氨甲酸姆替林
步骤1．14-[N-(4-硝基苯磺酰基)-氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
14-氯甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(500mg)在干二氯甲烷(10ml)中用4-硝基苯磺酰胺(508mg)、二异丙基乙胺(0.5ml)和4-二甲氨基吡啶(5mg)处理，室温搅拌溶液2小时。溶液用乙酸乙酯(100ml)稀释，稀盐酸(100ml)、水(100ml)和饱和食盐水(100ml)洗涤。硫酸镁干燥溶液，减压蒸发去除溶剂得到无色胶体状粗产物。
步骤2．14-[N-(4-硝基苯磺酰基)]-氨甲酸姆替林
步骤1的14-[N-(4-硝基苯磺酰基)-氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林粗产物溶于1,4-二噁烷(12ml)中用浓盐酸中的饱和氯化锌溶液(4ml)处理。室温保持溶液4小时，用乙酸乙酯(150ml)稀释，水洗涤三次(每次100ml)。溶液用硫酸钠干燥，减压蒸发去除溶剂得到无色胶体。硅胶色谱纯化，用乙酸乙酯/己烷混合物洗脱得到白色固体状的标题化合物(272mg)；υ最大(CH2Cl2)3624,3353,1736，和1608cm-1；
                                 δH(CDCl3)8.32(2H,d,J8.5Hz),
8.18(2H,d,J8.5Hz),6.27(1H,dd,J17.5和11Hz),5.60(1H,d,J8.3Hz),
5.22(1H,d,J11Hz),5.09(1H,d,J17.5Hz),3.30(1H,dd,J6.5 and 10Hz),
2.22(2H,m),2.00(2H,m),1,8-1.0(重叠的多重峰),1.35(3H,s),1.09
(3H,s),0.85(3H,d,J6.9 Hz),0.51(3H,d,J6.7Hz)；MS(CI)m/z 566
(M.NH4 +).
实施例68．14-[N-(4-氰基苯磺酰基)]-氨甲酸姆替林
步骤1．14-[N-(4-氰基苯磺酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
14-氯甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(400mg)在干二氯甲烷(20ml)中用4-氰基苯磺酰胺(273mg)、二异丙基乙胺(0.4ml)和4-二甲氨基吡啶(4mg)处理，室温搅拌溶液16小时。用乙酸乙酯(100ml)稀释溶液，稀盐酸(100ml)、水(100ml)和饱和食盐水(100ml)洗涤。硫酸钠干燥，减压蒸发去除溶剂得到无色胶体粗产物。
步骤2．14-[N-(4-氰基苯磺酰基)]-氨甲酸姆替林
步骤1的14-[N-(4-氰基苯磺酰基)-氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林粗产物溶于1,4-二噁烷(12ml)中并用浓盐酸中的饱和氯化锌溶液(4ml)处理。室温保持溶液4小时，用乙酸乙酯(150ml)稀释，水洗涤三次(每次100ml)。硫酸钠干燥溶液，减压蒸发去除溶剂得到无色胶体。硅胶色谱纯化，用乙酸乙酯/己烷混合物洗脱得到白色泡沫状的标题化合物(185mg)；υ最大(CH2Cl2)3627,3348和1735cm-1；
                           δH(CDCl3)8.12(2H,d,J8.5Hz),7.82
(2H,d,J8.5Hz),6.27(1H,dd,J17.5和11Hz),5.60(1H,d,J8.4Hz),5.21
(1H,d,J10.5 Hz),5.10(1H,d,J17.5Hz),3.30(1H,dd,J6.5和10Hz),2.21
(2H,m),2.00(2H,m),1.8-1.0(重叠的多重峰),1.33(3H,s),1.10(3H,
s),0.86(3H,d,J6.9Hz),0.51(3H,d,J6.9Hz)；MS(CI)m/z 546(M.NH4 +).
实施例69．14-[N-(4-氨基苯磺酰基)]-氨甲酸姆替林
14-[N-(4-硝基苯磺酰基)]-氨甲酸姆替林(265mg)溶于乙醇(30ml)和乙酸乙酯(5ml)中并在氩气氛下用氯化锡(Ⅱ)(458mg)轻轻回流加热5小时。冷却后蒸发溶剂，残留物硅胶色谱，用乙酸乙酯-己烷混合物洗脱，得到白色固体状的标题化合物(80mg)；υ最大(CH2Cl2)3407,1735,1624和1596cm-1；
δH(d6-
DMSO)11.23(1H,s，在D2O中交换)，7.44(2H,d,J8.8Hz),6.90(1H,s,
在D2O中交换),6.59(2H,d,J8.8Hz),6.10(1H,s,在D2O中交换),
6.10(1H,dd,J17.7和11.2Hz),5.32(1H,d,J7.6Hz),4.87(1H,dd,J11.2
和1.4Hz),4.78(1H,dd,J17.8和1.4Hz),4.51(1H,d,J6.0Hz,在D2O
中交换),3.30(1H,d),2.3-1.0(重叠的多重峰),1.30(3H,s),0.98(3H,
s),0.78(3H,d,J6.9Hz),0.48(3H,d,J6.3Hz)；MS(CI)m/z 536(M.NH4 +).
实施例70．14-[N-(6-乙氧基苯并噻唑基-2-磺酰基)]-氨甲酸姆替林
步骤1．14-[N-(6-乙氧基苯并噻唑基-2-磺酰基)]-氨甲酸的11-氧-二氯乙酰基-姆替林
14-氯甲酸-11-二氯乙酸姆替林(246mg,0.5mmol)的二氯甲烷(1ml)溶液中加入冰冷却的6-乙氧基苯并噻唑基-2-磺酰胺(130mg,0.5mmol)和N,N-二异丙基乙胺(0.092ml,1.05当量)的二氯甲烷(2ml)-DMF(0.5ml)溶液。移去冷却浴，室温搅拌溶液3天。用乙酸乙酯稀释溶液，用稀盐酸、水和食盐水洗涤，硫酸镁干燥和蒸发得到泡沫(大约350mg)，硅胶色谱纯化，用5％甲醇-氯仿洗脱得到白色固体产物(142mg)；υ最大(CHCl3)3500,3368,1734,1740(肩峰)和1601cm-1。
步骤2．14-[N-(6-乙氧基苯并噻唑基-2-磺酰基)]-氨甲酸姆替林
步骤1的产物(130mg,0.18mmol)溶于甲醇(2ml)，加入1N氢氧化钠(0.18ml)。搅拌1小时后再加入一份1N氢氧化钠(0.18ml)。总计3小时后，加入2N盐酸(0.2ml)酸化混和物，用乙酸乙酯提取。食盐水洗涤提取物，硫酸镁干燥溶液，蒸发得到胶体(140mg)。硅胶色谱纯化，用10％甲醇/氯仿洗脱得到白色固体状的标题化合物(96mg,87％)；υ最大(CHCl3)3370,1737和1602cm-1；
1H NMR(CDCl3)0.59(3H,d,J6.7),0.82(3H,d,J6.9),0.94(3H,s),0.9-1.1
(ca 12H,m),1.25-1.7(约15H,m)1.8-2.25(约4H,m),3.24(1H,dd,J9,7
分解为d,J6 D2O交换),4.13(2H,q,J7),5.00(1H,d,J17),5.11(1H,d,J
11),5.62(1H,d,J8),6.2(1H,br,分解为dd,J17,11 D2O交换),7.2 1H,ddJ
2.2,9),7.35(1H,d,J2.3),8.0(1H,d,J9)；MS(NH3DCI)m/z 605(MH+),622
(MNH4 +)
实施例71．14-[N-(2,4-二甲基噻唑基-5-磺酰基)]-氨甲酸姆替林
步骤1．14-[N-(2,4-二甲基噻唑基-5-磺酰基)]-氨甲酸的11-氧-二氯乙酰基-姆替林
14-氯甲酸-11-二氯乙酸姆替林(493mg,1mmol)的二氯甲烷(4ml)溶液中加入冰冷却的2,4-二甲基噻唑-5-磺酰胺(192mg,1mmol)和N,N-二异丙基乙胺(0.175ml,1mmol)的二氯甲烷(5ml)-DMF(0.5ml)溶液。移去冷却浴，室温搅拌溶液过夜，回流5小时后再次室温过夜。tlc(薄层色谱)检验表明差不多反应完全。蒸发溶剂后硅胶色谱，用2％甲醇-氯仿洗脱得到不纯产物，进一步硅胶色谱，用1∶1乙酸乙酯-己烷洗脱得到白色固体状产物(188mg)；υ最大(CHCl3)3378和1735cm-1。
                     1H NMR(CDCl3)特别2.70(3H,s),4.89(1H,
d,J7),5.17(1H,d,J17),5.24(1H,d,J11),5.58(1H,d,J8),5.98(1H,s),
6.21(1H,dd J17,11),7.5-7.8(1H,br)；MS(NH3DCI)m/z 649/651(MH+).
步骤2．14-[N-(2,4-二甲基噻唑基-5-磺酰基)]-氨甲酸姆替林
步骤1的产物(175mg,0.27mmol)溶于甲醇(5ml)-四氢呋喃(2ml)中，加入1N氢氧化钠(0.50ml,1.85当量)。室温搅拌3小时后加入2N盐酸(0.25ml)酸化混和物，用乙酸乙酯(50ml)提取。用水和食盐水洗涤提取物，硫酸镁干燥溶液，蒸发得到胶体(140mg)。硅胶色谱纯化，用1∶1乙酸乙酯/己烷洗脱得到白色泡沫状的标题化合物(85mg)；υ最大(CHCl3)3694,3562和1736cm-1；
                                 1H NMR(CDCl3)0.61
(3H,d,J6.8),0.86(3H,d,J7),1.1-1.8(约15H,m),2.0-2.25(约5H,m),2.64
(3H,s),2.70(3H,s),3.32(1H,d,J6.5),5.14(1H,dd,J17,1.3),5.30(1H,dd,J
10,1.3),5.66(1H,d,J8),6.32(1H,dd,J17.11),7.71(1H,br,D2O交换)；MS
(EI)m/z 538(M+).测定值：538.2171,C26H38N2O6S2理论值538.2172.
实施例72．14-[N-(噻吩-2-磺酰基)]-氨甲酸姆替林
步骤1．14-[N-(噻吩-2-磺酰基)]-氨甲酸的11-氧-二氯乙酰基-姆替林
14-氯甲酸-11-二氯乙酸姆替林(370mg,0.75mmol)的二氯甲烷(1ml)溶液中加入冰冷却的噻吩-2-磺酰胺(122mg,0.75mmol)和N,N-二异丙基乙胺(0.13ml)和4-二甲氨基吡啶(2mg)的二氯甲烷(3ml)-DMF(0.4ml)溶液。移去冷却浴，室温搅拌溶液过夜。用乙酸乙酯稀释溶液，稀盐酸和食盐水洗涤。硫酸镁干燥和蒸发溶液得到胶体，硅胶色谱纯化，用5％丙酮-甲苯洗脱得到白色泡沫状产物(280mg)；υ最大(CHCl3)3381和1736cm-1；
                                         1H NMR(CDCl3)特别
4.88(1H,d,J6.9),5.15(1H,d,J17),5.24(1H,d,J11),5.58(1H,d,J8),
5.97(1H,s),6.21(1H,dd,J17,11),7.12(1H,dd,J5,3.8),7.70(1H,dd,J5,
1.4),7.85(1H,dd,J3.8,1.4)；MS(NH3DCI)m/z 637/639(MNH4 +).
步骤2．14-[N-(噻吩-2-磺酰基)]-氨甲酸姆替林
步骤1的产物(248mg,0.4mmol)溶于甲醇(4ml),加入1N氢氧化钠(0.8ml,2当量)。在4小时后加入2N盐酸酸化混和物，用乙酸乙酯提取。食盐水洗涤提取物，硫酸镁干燥并蒸发得到胶体，硅胶色谱纯化，用1∶1乙酸乙酯/己烷洗脱得到白色固体状的标题化合物(155mg)；υ最大(CHCl3)3380和1736cm-1；
                                               1H
NMR(CDCl3)0.57(3H,d,J6.8),0.85(3H,d,J7),1.11(3H,s),1.38(3H,s),
1.2-1.75(约11H,m),1.92-2.05(2H,m),2.22(2H,q,J8),3.31(1H,dd,J10,
6.8),5.12(1H,dd J17,1.4),5.28(1H,dd,J11,1.4),5.67(1H,d,J8.4),7.11
(1H,dd,J5,4),7.69(1H,dd J5,1.2),7.84(1H,dd,J4,1.2),7.5(1H,br)；MS
(NH3DCI)m/z 527(MNH4 +).
实施例73．14-[N-(5-乙酰氨基-1,3,4-噻唑基-2-磺酰基)-氨甲酸姆替林
步骤1．14-[N-(5-乙酰氨基-1,3,4-噻唑基-2-磺酰基)]-氨甲酸的11-氧-二氯乙酰基-姆替林
14-氯甲酸-11-二氯乙酸姆替林(246mg,0.5mmol)的DMF(1ml)溶液中加入5-乙酰氨基-1,3,4-噻二唑基-2-磺酰胺(111mg,0.5mmol)、N,N-二异丙基乙胺(0.09ml,1.05当量)和4-二甲氨基吡啶(催化剂)的DMF(1ml)溶液。室温搅拌溶液过夜，用乙酸乙酯稀释溶液，用稀盐酸和食盐水洗涤，硫酸镁干燥和蒸发溶液得到胶体，硅胶色谱纯化，用10％甲醇-氯仿洗脱得到白色固体状产物(97mg)。
步骤2．14-[N-(5-乙酰氨基-1,3,4-噻二唑基-2-磺酰基)]-氨甲酸姆替林
步骤1的产物(95mg)溶于THF(0.5ml)和甲醇(1.5ml)中,加入1N氢氧化钠(0.28ml,2当量)。让溶液室温保持大约24小时，其期间再加入一份1N氢氧化钠(0.14ml)。用2N盐酸酸化混和物，用乙酸乙酯提取。用食盐水洗涤提取物，硫酸镁干燥溶液，蒸发得到胶体，硅胶色谱纯化，10％甲醇/氯仿洗脱，用乙酸乙酯再次色谱得到白色固体状的标题化合物(19mg,24％)；                                1H NMR(d6-丙酮-
D2O)特别2.36(3H,s),3.54(1H,dJ6),5.0-5.1(约2H,m),5.58(1H,d,J
8),6.18(1H,dd,J17,11)；MS(电喷)m/z 569(MH+).
实施例74．14-[N-(3-氨基-4-甲氧基苯甲酰基)-氨甲酸姆替林
步骤1．4-甲氧基-3-硝基苯甲酰基异氰酸酯
氰酸银(967mg,6.5mmol)在氩气氛下悬浮于二氯甲烷(6ml)中。加入4-甲氧基-3-硝基苯甲酰氯(1.29g,6.0mmol)的二氯甲烷(4ml)溶液，避光回流搅拌非均相混和物。40分钟后让反应冷却，用Kieselguhr过滤。溶液立即用于下一个反应。υ最大(CH2Cl2)2337cm-1。
步骤2．14-[N-(4-甲氧基-3-硝基苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤1的溶液冷却到0℃，用(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(500mg,1.5mmol)处理，搅拌反应1小时。混和物用二氯甲烷稀释，用1M盐酸、水和饱和食盐水洗涤混和物。硫酸镁干燥后粗产物硅胶色谱纯化，用40％乙酸乙酯/己烷洗脱得到标题化合物(770mg,92％)；熔点178-180℃；υ最大(CH2Cl2)3300,2980,1777,1697,1619和1476cm-1；
                                 1H NMR(CDCl3)0.90(3H,d,J6.8Hz),
0.99(3H,d,J6.4Hz),1.07-1.58(12H,m)包括1.21(3H,s)和1.31(3H,
s),1.68-1.76(2H,m),1.94-2.04(2H,m),2.20(1H,m),2.54(1H,dd,J15.3,
10.0Hz),2.90(1H,q,J6.2Hz),3.24(3H,s),3.48(1H,m),4.05(3H,s),5.01
(1H,d,J17.4Hz),5.26(1H,d,J10.7Hz),5.86(1H,d,J9.9Hz),6.67(1H,dd,J
17.4,10.7Hz),7.20(1H,d,J8.9Hz),8.09(1H,s),8.12(1H,dd,J8.9,2.4Hz)；
8.33(1H,d,J2.4Hz)；MS(电喷)m/z 574(MNH4 +)；(测定值：C,64.33；
H,7.48；N,4.68.C30H40N2O8理论值C,64.73；H,7.24；N,5.03).
步骤3．14-[N-(3-氨基-4-甲氧基苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
14-[N-(4-甲氧基-3-硝基苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(720mg,1.29mmol)悬浮于乙醇(30ml)。加入乙酸乙酯(6ml)使其完全溶解。加入氯化锡(Ⅱ)(1.26g,6.65mmol)，氩气氛下加热回流。3小时后使反应冷却，倾入乙酸乙酯和水，然后用碳酸氢钠中和。硫酸镁干燥有机相，硅胶色谱纯化，用40％乙酸乙酯/己烷洗脱得到无色泡沫状的标题化合物(297mg,44％)；υ最大(CH2Cl2)3393,2981,1773,1698,1605和1474cm-1；
                              1H NMR(CDCl3)0.90(3H,d,J
6.6Hz),0.99(3H,d,J6.4Hz),1.05-1.55(12H,m)包括1.21(3H,s)和
1.34(3H,s),1.70-1.79(2H,m),1.94-2.08(2H,m),2.21(1H,m),2.53(1H,dd,J
15.3,10.0Hz),2.92(1H,q,J6.1Hz),3.26(3H,s),3.48(1H,m),3.93(3H,s),
3.99(2H,bs),5.03(1H,d,J17.5Hz),5.30(1H,d,J10.8Hz),5.84(1H,d,J
9.9Hz),6.73(1H,dd,J17.5,10.8Hz),6.82(1H,d,J 8.6Hz),7.18(1H,dd,J8.6,
2.3Hz),7.23(1H,d,J2.3Hz),7.90(1H,s)；MS(电喷)m/z 527(MH+).
步骤4．14-[N-(3-氨基-4-甲氧基苯甲酰基)]-氨甲酸姆替林
步骤3的产物(100mg,0.19mmol)在二噁烷(1ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，室温搅拌反应物30分钟。溶液倾入乙酸乙酯和饱和碳酸氢钠溶液，水相用乙酸乙酯再提取，合并的有机相用饱和氯化钠溶液洗涤。硫酸镁干燥有机相，硅胶色谱纯化，70％乙酸乙酯/己烷混合物洗脱得到无色泡沫状的标题化合物(53mg,54％)；υ最大(CH2Cl2)3393,2939,1774,1733,1615和1476cm-1；
                                     1H NMR(CDCl3)0.80(3H,d,J
6.6Hz),0.88(3H,d,J7.0Hz),1.12-1.80(16H,m)包括1.19(3H,s)和1.51
(3H,s),2.08-2.40(4H,m),3.37(1H,dd.J11.0,6.6Hz),3.91(3H,s),3.93(2H,
bs),5.22(1H,dd,J17.4,1.4Hz),5.39(1H,dd,J10.9,1.4Hz),5.81(1H,d,J
8.5Hz),6.59(1H,dd,J17.4,10.9Hz),6.89(1H,d,J8.4Hz),7.11-7.20(2H,m),
7.80(1H,bs)；MS(电喷)m/z 513(MH+)
实施例75．14-[N-(3-甲磺酰氨基-4-甲氧基苯甲酰基)]-氨甲酸姆替林
步骤1．14-[N-(3-甲磺酰氨基-4-甲氧基苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
14-[N-(3-氨基-4-甲氧基苯甲酰基)氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(158mg,0.30mmol)溶于二氯甲烷(5ml)并用吡啶(81(1,1.05mmol)随后用甲磺酰氯(81(1,1.05mmol)处理。搅拌3小时后，反应混和物用二氯甲烷稀释，顺次以0.5M盐酸、饱和碳酸氢钠水溶液、水和食盐水洗涤反应混和物。硫酸镁干燥后真空浓缩。残留物硅胶色谱纯化，用70％乙酸乙酯的己烷溶液洗脱得到无色泡沫状标题化合物(159mg,88％)；υ最大(CH2Cl2)3338,2981,1775,1697,1607和1476cm-1；
                                      1H NMR(CDCl3)0.90
(3H,d,J6.8Hz),1.02(3H,d,J6.4Hz),1.05-1.59(12H,m)包括1.20(3H,
s)和1.31(3H,s),1.70-1.78(2H,m),1.96-2.07(2H,m),2.22(1H,m),2.55
(1H,dd,J15.2,10.1Hz),2.91(1H,q,J6.4Hz),3.02(3H,s),3.23(3H,s),3.48
(1H,m),3.99(3H,s),5.01(1H,d,J17.5Hz),5.30(1H,d,J10.8Hz),5.83(1H,
d,J9.9Hz),6.72(1H,dd,J17.5,10.8Hz),6.86(1H,bs),7.02(1H,d,J8.6Hz),
7.72(1H,dd,J8.6,2.2Hz),733(1H,d,J2.2Hz),7.99(1H,s).
步骤2．14-[N-(3-甲磺酰氨基-4-甲氧基苯甲酰基)]-氨甲酸姆替林
步骤1的产物(128mg,0.21mmol)在二噁烷(1ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，室温搅拌溶液30分钟。溶液倾入乙酸乙酯和饱和碳酸氢钠溶液，水相用乙酸乙酯再提取，合并的有机相用饱和氯化钠溶液洗涤。硫酸镁干燥有机相，硅胶色谱纯化，用70％乙酸乙酯的己烷溶液洗脱得到无色泡沫状的标题化合物(46mg,37％)；υ最大(CH2Cl2)3340,2941,1776,1733,1607和1477cm-1；
                         1H NMR(CDCl3)0.81(3H,d,J
6.6Hz),0.89(3H,d,J6.9Hz),1.10-1.82(16H,m)包括1.21(3H,s)和
1.52(3H,s),2.10-2.38(4H,m),2.99(3H,s),3.38(1H,dd,J10.8,6.5Hz),3.96
(3H,s),5.22(1H,dd,J17.4,1.4Hz),5.38(1H,dd,J11.1,1.4Hz),5.82(1H,d,J
8.4Hz),6.54(1H,dd,J17.4,11.1Hz),6.84(1H,bs),6.99(1H,d,J8.6Hz),7.70
(1H,dd,J8.6,2.3Hz),7.88(1H,d,J2.3Hz),7.95(1H,bs).
实施例76．14-[N-(异噁唑-5-基)]-氨甲酸姆替林
步骤1．14-[N-(异噁唑-5-基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(633mg,1.89mmol)在干二氯甲烷(15ml)中与异噁唑-5-碳酰氯(1.0g,7.60mmol),氰酸银(1.22g,8.14mmol)和四(三苯膦)钯(0)(32mg)结合，氩气氛下避光于室温搅拌反应30分钟。通过Kieselguhr过滤混合物，顺次以饱和碳酸氢钠(2次)水溶液和食盐水洗涤混和物。硫酸镁干燥后硅胶色谱纯化，用30％乙酸乙酯的己烷溶液洗脱。分离出无色泡沫状标题化合物(850mg,95％)；υ最大(CH2Cl2)3393,2929,1783,1726,1597和1496cm-1；
                                      1H NMR(CDCl3)
0.88(3H,d,J6.8Hz),1.01(3H,d,J6.4Hz),1.08-1.59(12H,m)包括1.20
(3H,s)和1.31(3H,s),1.69-1.77(2H,m),1.93-2.07(2H,m),2.21(1H,m),
2.56(1H,dd,J15.3,10.1Hz),2.89(1H,q,J6.3Hz),3.22(3H,s),3.48(1H,m),
5.02(1H,d,J17.5Hz),5.31(1H,d,J10.7Hz),5.86(1H,d,J10.0Hz),6.68(1H,
dd,J17.5,10.7Hz),7.03(1H,d,J1.8Hz),8.39(1H,bs),8.43(1H,d,J1.8Hz)；
MS(CI)m/z 490(MNH4 +).
步骤2．14-[N-(异噁唑-5-基)]-氨甲酸姆替林
步骤1的产物(810mg,1.71mmol)在二噁烷(6ml)中用浓盐酸中的饱和氯化锌溶液(3ml)处理，室温搅拌溶液30分钟。溶液倾入乙酸乙酯和饱和碳酸氢钠溶液中。水相用乙酸乙酯再提取，合并的有机相用饱和氯化钠溶液洗涤。硫酸镁干燥有机相，硅胶色谱纯化，用50％乙酸乙酯的己烷溶液洗脱得到标题化合物(540mg,69％)；υ最大(CH2Cl2)3395,2959,1785,1731和1496cm-1；
1H NMR(CDC13)0.79(3H,d,J6.8Hz),0.90(3H,d,J7.0Hz),1.10-
1.83(16H,m)包括1.20(3H,s)和1.50(3H,s),2.10-2.37(4H,m),3.38
(1H,dd,J10.8,6.6Hz),5.23(1H,dd,J17.3,1.4Hz),5.40(1H,dd,J10.9,
1.4Hz),5.85(1H,d,J8.5Hz),6.53(1H,dd,J17.3,10.9Hz),7.10(1H,d,J
1.9Hz),8.36(1H,bs),8.41(1H,d,J1.9Hz)；MS(CI)m/z 476(MNH4 +).
实施例77．14-[N-(甲氧基乙酰基)]-氨甲酸姆替林
步骤1．14-[N-(甲氧基乙酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(500mg,1.50mmol)在干二氯甲烷(15ml)中与甲氧基乙酰氯(547(1,6.0mmol)和氰酸银(965mg,6.40mmol)相结合，氩气氛下室温避光搅拌反应10分钟。通过Kieselguhr过滤混合物，滤液用饱和碳酸氢钠(2次)溶液和食盐水洗涤。硫酸镁干燥后硅胶色谱纯化，用30％乙酸乙酯/己烷洗脱。分离得到无色泡沫状标题化合物(630mg,94％)；υ最大(CH2Cl2)3388,2932,1786,1722和1488cm-1；
1H NMR(CDCl3)0.85(3H,d,J6.9Hz),1.00(3H,d,J6.4Hz),1.08-
1.58(12H,m)包括1.19(3H,s)和1.28(3H,s),1.64-1.77(2H,m),1.94-
2.06(2H,m),2.21(1H,m),2.51(1H,dd,J15.3,10.1Hz),2.88(1H,q,J6.4Hz),
3.21(3H,s),3.42(1H,m),3.49(3H,s),4.08(2H,s),5.01(1H,d,J17.6Hz),
5.30(1H,d,J10.7Hz),5.77(1H,d,J10.0Hz),6.69(1H,dd,J17.6,10.7Hz),
8.26(1H,bs).
步骤2．14-[N-(甲氧基乙酰基)]-氨甲酸姆替林
步骤1的产物(600mg,1.34mmol)在二噁烷(6ml)中用浓盐酸中的饱和氯化锌溶液(3ml)处理，室温搅拌溶液2小时。溶液倾入乙酸乙酯和饱和碳酸氢钠溶液中，水相用乙酸乙酯再提取，合并的有机相用饱和氯化钠溶液洗涤。硫酸镁干燥有机相，硅胶色谱纯化，用40％乙酸乙酯/己烷混合物洗脱得到无色泡沫状的标题化合物(210mg,36％)；υ最大(CH2Cl2)3388,2941,1787,1726和1488cm-1；
                     1H NMR(CDCl3)0.74(3H,d,J6.7Hz),0.90
(3H,d,J7.0Hz),1.10-1.85(16H,m)包括1.17(3H,s)和1.48(3H,s),
2.04-2.37(4H,m),3.35(1H,dd,J10.9,6.6Hz),3.45(3H,s),4.06(2H,s),5.22
(1H,dd,J17.4,1.5Hz),5.38(1H,dd,J11.0,1.5Hz),5.75(1H,d,J8.5Hz),6.52
(1H,dd,J17.4,11.0Hz),8.20(1H,bs)；MS(CI)m/z 453(MNH4 +).
实施例78．14-[N-(6-甲氧基烟酰基)]-氨甲酸姆替林
步骤1．14-[N-(6-甲氧基烟酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(500mg,1.50mmol)在干二氯甲烷(20ml)中与6-甲氧基烟酰氯(430mg,2.5mmol)和氰酸银(400mg,2.67mmol)相结合，氩气氛下室温遮光搅拌反应4.5小时。通过Kieselguhr过滤混合物，用饱和碳酸氢钠(2次)溶液和食盐水洗涤滤液。硫酸镁干燥后硅胶色谱纯化，用30％乙酸乙酯/己烷洗脱。分离得到无色泡沫状标题化合物(750mg,98％)；υ最大(CH2Cl2)3423,2930,1776,1729,1603和1477cm-1；
1H NMR(CDCl3)0.91(3H,d,J6.8Hz),1.01(3H,d,
J6.4Hz),1.10-1.59(12H,m)包括1.27(3H,s)和11.36(3H,s),1.68-1.78
(2H,m),1.96-2.04(2H,m),2.21(1H,m),2.52(1H,dd,J15.3,10.1Hz),2.91
(1H,q,J6.4Hz),3.23(3H,s),3.49(1H,m),4.02(3H,s),5.03(1H,d,J17.4Hz),
5.30(1H,d,J10.8Hz),5.84(1H,d,J10.0Hz),6.69(1H,dd,J17.4,10.8Hz),
6.83(1H,d,J8.8Hz),7.91(1H,bs),8.05(1H,dd,J8.8,2.6Hz),8.63(1H,d,J
2.6Hz)；MS(CI)m/z 513(MH+).
步骤2．14-[N-(6-甲氧基乙酰基)]-氨甲酸姆替林
步骤1的产物(720mg,1.41mmol)在二噁烷(5ml)中用浓盐酸中的饱和氯化锌溶液(3ml)处理，搅拌反应物2小时。溶液倾入乙酸乙酯和饱和碳酸氢钠溶液中，水相用乙酸乙酯再提取，合并的有机相用饱和氯化钠溶液洗涤。硫酸镁干燥有机相，硅胶色谱纯化，用50％乙酸乙酯/己烷混合物洗脱得到无色泡沫状的标题化合物(600mg,85％)；υ最大(CH2Cl2)3423,2949,1777,1733,1603和1475cm-1；
                     1H NMR(CDCl3)0.82(3H,d,J6.7Hz),
0.89(3H,d,J7.0Hz),1.10-1.82(16H,m)包括1.20(3H,s)和1.49(3H,
s),2.06-2.37(4H,m),3.36(1H,dd,J10.9,6.5Hz),3.99(3H,s),5.24(1H,dd,J
17.4,1.4Hz),5.39(1H,dd,J11.0,1.4Hz),5.82(1H,d,J8.5Hz),6.54(1H,dd,J
17.4,11.0Hz),6.81(1H,d.J8.8Hz),7.92(1H,bs),8.01(1H,dd,J8.8,2.5Hz),
8.62(1H,d,J2.5Hz)；MS(CI)m/z 499(MH+)
实施例79．14-[N-(吡嗪-2-酰基)]-氨甲酸姆替林
步骤1．14-[N-(吡嗪-2-酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(500mg,1.50mmol)在干二氯甲烷(15ml)中与吡嗪-2-酰氯(1.14g,8.0mmol)和氰酸银(1.20g,8.0mmol)相结合，氩气氛下室温避光搅拌反应10分钟。通过Kieselguhr过滤混合物，用饱和碳酸氢钠(2次)溶液和食盐水洗涤滤液。硫酸镁干燥后硅胶色谱纯化，用40％乙酸乙酯/己烷洗脱。分离得到无色泡沫状标题化合物(498mg,69％)；υ最大(CH2Cl2)3364,2931,1781,1720,1697和1490cm-1；
         1H NMR(CDCl3)0.90(3H,d,J6.8Hz),1.01(3H,d,J6.4Hz),
1.09-1.61(12H,m)包括1.20(3H,s)和1.38(3H,s),1.69-1.79(2H,m),
1.94-2.06(2H,m),2.21(1H,m),2.56(1H,dd,J15.3.10.1Hz),2.92(1H,q,J
6.4Hz),3.24(3H,s),3.50(1H,m),5.03(1H,d,J17.4Hz),5.32(1H,d,J
10.7Hz),5.89(1H,d,J9.9Hz),6.75(1H,dd,J17.4,10.7Hz),8.62(1H,d,J
2.5Hz),8.88(1H,d,J2.5Hz),9.51(1H,d,J1.5Hz),9.76(1H,bs).
步骤2．14-[N-(吡嗪-2-酰基)]-氨甲酸姆替林
步骤1的产物(450mg,0.93mmol)在二噁烷(2ml)中用浓盐酸中的饱和氯化锌溶液(2ml)处理，室温搅拌反应物1小时。溶液倾入乙酸乙酯和饱和碳酸氢钠溶液中。水相用乙酸乙酯再提取，合并的有机相用饱和氯化钠溶液洗涤。硫酸镁干燥有机相，硅胶色谱纯化，用50％乙酸乙酯/己烷混合物洗脱得到无色泡沫状的标题化合物(420mg,96％)；υ最大(CH2Cl2)3364,2939,1782,1734和1491cm-1；
                    1H NMR(CDCl3)0.79(3H,d,J6.7Hz),0.91
(3H,d,J7.0Hz),1.10-1.85(16H,m)包括1.20(3H,s)和1.58(3H,s),
2.10-2.43(4H,m),3.39(1H,dd,J10.9,6.6Hz),5.24(1H,dd,J17.4,1.5Hz),
5.40(1H,dd,J10.9,1.4Hz),5.85(1H,d,J8.5Hz),6.59(1H,dd,J17.4,
10.9Hz),8.60(1H,d,J2.3Hz),8.84(1H,d,J2.5Hz),9.45(1H,d,J2.3Hz),9.72
(1H,bs)；MS(CI)m/z 487(MNH4 +).
实施例80．14-(N-噻吩-2-酰基)-氨甲酸姆替林
步骤1．14-(N-噻吩-2-酰基)-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
将氰酸银在二氯甲烷(10ml)中的悬浮液用2-噻吩碳酰氯处理，混合物回流加热45分钟。通过Kieselguhr过滤得到一种浅黄色溶液。向该溶液加入(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(500mg)。20分钟后，用稀盐酸、饱和氯化钠溶液洗涤。用无水硫酸镁干燥。真空去除溶剂后得到白色固体状的产物，硅胶色谱纯化，用二氯甲烷然后用1％和2％丙酮/二氯甲烷洗脱，得到白色固体状标题化合物(686mg,94％)；υ最大(CH2Cl2)3422,1773,1726(w),1698,1521和1481cm-1；
                                       1HNMR(CDCl3)
0.89(3H,d,J6.8Hz),1.01(3H,d,J6.4Hz),1.07-1.78(8H,m),1.20(3H,s),1.34
(3H,s),1.99(2H,m),2.21(1H,m),2.55(1H,dd,J10.1,15.3Hz),2.90(1H,q,
J6.4Hz),3.22(3H,s),3.46(1H,m),5.01(1H,d,J17.5),5.28(1H,d,J10.7Hz),
5.86(1H,d,J10.0Hz),6.70(1H,d,J10.7,17.5Hz),7.13(1H,m),7.66(2H,m)
和8.03(1H,s):MS(NH3DCI)m/z 488(MH+)和505(MNH4 +).
步骤2．14-[N-(噻吩-2-酰基)]-氨甲酸姆替林
步骤1的产物(450mg)在二噁烷(1.5ml)中用卢卡斯试剂(饱和氯化锌/浓盐酸；1.5ml)于室温处理。反应混和物变暗变暖。5分钟后，t.l.c.分析表明不存在原料。反应混合物用乙酸乙酯稀释且用水洗涤溶液；乙酸乙酯提取有机相，将合并的有机相用饱和碳酸氢钠、饱和氯化钠溶液洗涤，干燥浓缩得一种桔色胶体。硅胶色谱纯化，用乙酸乙酯/己烷洗脱得到白色固体状的标题化合物(173mg,40％)；υ最大(CH2Cl2)3564,3424,1775,1733,1705,1521和1482cm-1；
       1H NMR(CDCl3)0.80(3H,d,J6.7Hz),0.89(3H,d,7.0Hz),
1.14(1H,m),1.19(3H,s),1.37-1.82(9H,m),1.54(3H,s),2.12-2.37(4H,m),
3.37(1H,dd,J6.6,10.6Hz),5.23(1h,dd,J1.5,17.4Hz),5.36(1H,dd,
J1.5,11.1Hz),5.83(1H,d,J8.5Hz),6.54(1H,J,11.0,17.4Hz),7.12(1H,m),7.63
(2H,m)和7.95(1H,s)；MS(NH3 DCI)m/z 474(MH+)和491(MNH4 +).
实施例81．14-[(S)-四氢呋喃-2-酰基]-氨甲酸姆替林
步骤1．14-[(S)-四氢呋喃-2-酰基]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(S)-(-)-四氢糠酸(0.464g)在二氯甲烷(3ml)中于室温用草酰氯(0.635g)和一滴DMF处理1小时。IR分析表明完全转化成酰氯。真空去除溶剂和多余的草酰氯，残留物再溶于干二氯甲烷中。
该酰氯与氰酸银(0.645g)和(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(322mg)如实施例80步骤1所述进行反应。硅胶色谱纯化后分离得到无色泡沫状产物(430mg,91％)；υ最大(CH2Cl2)3381,1783,1744,1717和1698cm-1；
                    1H NMR(CDCl3)0.83(3H,d,J6.9Hz),0.99
(3H,d,J6.4Hz),1.06-1.75(9H,m),1.19(3H,s),1.29(3H,s),1.87-2.38(7H,m),
2.50(1H,dd,J10.1,15.3Hz),2.88(1H,q,J6.4Hz),3.22(3H,s),3.46(1H,m),
3.96(2H,m),4.43(1H,dd,J5.7,8.4Hz),5.00(1H,d,J17.4Hz),5.29(1H,d,
J10.7Hz),6.71(1H,dd,J10.7,17.5Hz)和8.59(1H,s)；MS(NH4 DCI)m/z 494
(MNH4 +).
步骤2．14-[(S)-四氢呋喃-2-酰基]-氨甲酸姆替林
步骤1的产物(388mg)在二噁烷(1ml)中用卢卡斯试剂如实施例80步骤2所述处理。硅胶色谱纯化后分离得到无色泡沫状的产物(242mg,64％)；υ最大(CH2Cl2)3562,3381,1784,1733和1480cm-1；
                                   1H NMR(CDCl3)0.75
(3H,d,J6.7Hz),0.89(3H,d,J7.1Hz),1.15(1H,m),1.18(3H,s),1.42-2.35
(19H,m),1.50(3H,s),3.36(1H,dd,J6.7,10.9Hz),3.94(2H,m),4.40(1H,dd,
J5.8,8.4Hz),5.22(1H,dd,J1.5,17.4Hz),5.37(1H,dd,J1.5,10.9Hz),5.77(1H,d,
J8.5Hz),6.54(1H,dd,J11.0,17.4Hz)和8.51(1H,s)；MS(NH4DCI)m/z 479
(MNH4 +).
实施例82．14-[(R)-四氢呋喃-2-酰基]-氨甲酸姆替林
步骤1．14-[(R)-四氢呋喃-2-酰基]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(R)-(+)-四氢糠酸(0.464g)和(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(322mg)如实施例80步骤1所述转换成标题化合物。硅胶色谱纯化后得到无色泡沫状标题化合物(432mg,91％)；υ最大(CH2Cl2)3383,1782,1718,1698和1474cm-1；
                                          1H NMR(CDCl3)
0.86(3H,d,J6.9Hz),1.00(3H,d,J6.4Hz),1.06-1.75(9H,m),1.17(3H,s),1.28
(3H,s),1.87-2.38(7H,m),2.50(1H,dd,J10.1,15.3Hz),2.88(1H,q,J6.4Hz),
3.22(3H,s),3.46(1H,m),3.88-4.06(2H,m),4.43(1H,dd,J5.7,8.4Hz),5.00
(1H,d,J17.4Hz),5.29(1H,d,J10.7Hz),6.71(1H,dd,J10.7,17.5Hz)和8.59
(1H,s)；MS(NH3 DCI)m/z 494(MNH4 +).
步骤2．14-[(R)-四氢呋喃-2-酰基]-氨甲酸姆替林
步骤1的产物(380mg)在二噁烷(1ml)中用卢卡斯试剂如实施例80步骤2所述处理。硅胶色谱纯化后，分离得到无色泡沫状产物(195mg,53％)；υ最大(CH2Cl2)3560,3382,1783,1733和1480cm-1；
                                             1H NMR(CDCl3)0.76
(3H,d,J6.7Hz),0.88(3H,d,J7.1Hz),1.15(1H,m),1.18(3H,s),1.42-2.35
(19H,m),1.48(3H,s),3.36(1H,dd,J6.7,10.9Hz),3.86-4.05(2H,m),4.40(1H,
dd,J5.8,8.4Hz),5.22(1H,dd,J1.5,17.4Hz),5.37(1H,dd,J1.5,10.9Hz),5.77
(1H,d,J8.5Hz),6.54(1H,dd,J11.0,17.4Hz)和8.51(1H,s)；MS(NH4 DCI)
m/z 479(MNH4 +).
实施例83．14-[N-(2,4-二氟苯甲酰基)]-氨甲酸姆替林
步骤1．14-[N-(2,4-二氟苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(200mg)、2,4-二氟苯甲酰氯(212mg)和氰酸银(180mg)在二氯甲烷(5ml)中于室温搅拌2小时。用乙酸乙酯(100ml)稀释混合物并过滤。滤液用水(2×30ml)和饱和碳酸氢钠溶液(30ml)洗涤，硫酸钠干燥溶液，减压蒸发去除溶剂得到无色胶体的标题化合物(400mg)；                                                1H NMR(CDCl3)特别
3.23(3H,s),3.46(1H,m),5.00(1H,d,J17.5Hz),5.30(1H,d,J10.5Hz),5.81
(1H,d,J10Hz),6.72(1H,dd,J17.5,10.5Hz),6.90(1H,m),7.03(1H,m),8.10
(1H,m),8.40(1H,d,J13Hz).
步骤2．14-[N-(2,4-二氟苯甲酰基)]-氨甲酸姆替林
步骤1的产物(400mg)在二噁烷(5ml)中用浓盐酸中的饱和氯化锌溶液(2ml)处理，室温保持3小时。乙酸乙酯(50ml)稀释，水(2×30ml)和饱和碳酸氢钠溶液(30ml)洗涤；硫酸钠干燥溶液，减压蒸发去除溶剂得到浅黄色胶体。硅胶色谱纯化，用1∶4-2∶3的乙酸乙酯/己烷洗脱得到白色泡沫状的标题化合物。从二氯甲烷/己烷结晶得到无色晶体(250mg)，熔点178-180℃；
                                               1H NMR(CDCl3)
特别3.37(1H,dd,J11,6.6Hz),5.23(1H,dd,J17.3,1.4Hz),5.38(1H,dd,
J11,1.4Hz),5.80(1H,d,J8.5 Hz),6.55(1H,dd,J17.3,11Hz),6.91(1H,m),
7.03(1H,m),8.10(1H,m),8.30(1H,d,J13Hz).
实施例84．14-[N-(3,4-二氟苯甲酰基)]-氨甲酸姆替林
用实施例83所述方法将(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(250mg)和3,4-二氟苯甲酰氯(210mg)转换成14-[N-(3,4-二氟苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林[MS(EI)m/z517(M+)]，由此转化标题化合物，得到无色晶体(120mg)；熔点144-146℃(二氯甲烷/己烷)；
                         1H NMR(CDCl3)特别3.37(1H,dd,J10.7,
6.6Hz),5.23(1H,dd,J17.3,1.4Hz),5.32(1H,dd,J11,1.3Hz),5.82(1H,d,J
8.5Hz),6.50(1H,dd,J17.3,11Hz),7.30(1H,m),7.60(1H,m),7.70(1H,m),
8.13(1H,s).
实施例85．14-[N-(1-叔丁氧基羰基-氮杂环丁烷-3-酰基)-氨甲酸姆替林
步骤1．1-叔丁氧基羰基-氮杂环丁烷-3-羧酸
3-氮杂环丁烷羧酸(250mg)在水(2ml)中用二碳酸二叔丁酯(650mg)的1,4-二噁烷(3ml)的溶液处理，室温搅拌混合物17小时。加入几滴1M盐酸酸化混合物，用水(10ml)稀释，用乙酸乙酯(2×20ml)提取。有机提取物用水(2×10ml)洗涤。硫酸钠干燥，减压蒸发去除溶剂得到无色胶体。从乙醚/戊烷结晶得到无色晶体的标题化合物(470mg)，熔点102.5-104℃；
   1H NMR(CDCl3)1.44(9H,s),3.38(1H,quin,J7.4Hz),4.13(4H,d,J7.4
Hz).
步骤2．11-三氟乙酸姆替林
姆替林(960mg)在干四氢呋喃(12ml)中用吡啶(0.3ml)处理，溶液冷却到0℃。在3分钟内向搅拌溶液中滴加三氟乙酐(0.48ml)。溶液在0℃保持2小时，然后用乙酸乙酯(100ml)稀释，水(2×30ml)、饱和碳酸氢钠溶液(30ml)和饱和氯化钠溶液(30ml)洗涤。硫酸钠干燥，减压蒸发去除溶剂得到无色胶体。产物用硅胶色谱纯化，用1∶9-1∶4的乙酸乙酯/己烷洗脱得到无色晶体状的标题化合物(570mg)；二氯甲烷/己烷再结晶得到无色条棒，熔点170-171℃；υ最大(CHCl3)3636,1777和1736cm-1；MS(EI)m/z416(M+)。
步骤3．14-[N-(1-叔丁氧基羰基-氮杂环丁烷-3-酰基)]-氨甲酸11-三氟乙酸姆替林
1-叔丁氧基羰基-氮杂环丁烷-3-羧酸(345mg)在干二氯甲烷(10ml)中用草酰氯(254mg,0.175ml)和N,N-二甲基甲酰胺(一滴)处理。溶液搅拌1.5小时，之后减压蒸发去除溶剂。残留物溶于甲苯(10ml)，减压蒸发去除甲苯得到1-叔丁氧基羰基-氮杂环丁烷-3-碳酰氯的无色油。
该油溶于二氯甲烷(6ml)，溶液用氰酸银(525mg)处理。混合物搅拌10分钟后加入CH2Cl2(9ml)中的11-三氟乙酸姆替林(535mg)。混合物搅拌20小时。加入乙酸乙酯(50ml)，过滤混合物。滤液用饱和碳酸氢钠溶液(20ml)和饱和氯化钠溶液(20ml)洗涤。用硫酸钠干燥溶液，减压蒸发去除溶剂得到无色胶体。硅胶色谱纯化，用1∶4-1∶2的乙酸乙酯/己烷洗脱得到无色胶体的标题化合物(485mg)；1HNMR(CDCl3)特别1.43(9H,s),3.93(1H,quin,J7.2Hz),4.98(1H,d,J6.9Hz),4.14(4H,m),5.23(1H,d,J17.5Hz),5.29(1H,(d,J11.2Hz),5.58(1H,d,J8Hz),6.31(1H,dd,J17.5,11.2Hz),7.57(1H,s).
步骤4．14-[N-(1-叔丁氧羰基-氮杂环丁烷-3-酰基)]-氨甲酸姆替林
14-[N-(1-叔丁氧基羰基-氮杂环丁烷-3-酰基)]-氨甲酸11-三氟乙酸姆替林(450mg)溶于四氢呋喃(10ml)/水(2ml)，用0.5M氢氧化钠(1.5ml)处理。混合物搅拌4.5小时，用乙酸乙酯(50ml)稀释，用水(2×30ml)洗涤。用硫酸钠干燥溶液，减压蒸发去除溶剂得到白色泡沫状的标题化合物(380mg)；υ最大(CHCl3)3551,3396和1706cm-1；
1H NMR(CDCl3)特别1.43(9H,s),3.35(1H,m),3.94(1H,五重峰,J7.5
Hz),4.10(4H,m),5.22(1H,d,J17.3Hz),.5.33(1H,d,J11Hz),5.65(1H,d,J
8.4 Hz),6.42(1H,dd,J17.3,11Hz),7.26(1H,s).
实施例86．14-(N-氮杂环丁烷-3-酰基)-氨甲酸姆替林
14-[N-(1-叔丁氧基羰基-氮杂环丁烷-3-酰基)]-氨甲酸姆替林(350mg)在二氯甲烷(8ml)中用三氟乙酸(0.5ml)处理，室温保持溶液5小时。减压蒸发去除溶剂，残留物溶于乙酸乙酯(20ml)。用稀盐酸(10ml)提取溶液，提取物用乙酸乙酯(10ml)洗涤。用碳酸氢钾使水溶液碱化(pH10)，然后用乙酸乙酯(3×30ml)提取。有机提取物用饱和氯化钠洗涤，硫酸钠干燥。减压去除溶剂得白色蜡状固体(125mg)。硅胶色谱该固体，用1∶9∶90的氨溶液(35％)/甲醇/二氯甲烷洗脱得到白色泡沫状标题化合物(100mg)；
1H NMR(1∶9 CD3OD∶CDCl3)特别3.33(1H,d,
J6.3Hz),4.01(4H,m),5.20(1H,d,J17.4Hz),5.32(1H,d,J11.2Hz),5.64
(1H,d,J8.3Hz),6.41(1H,dd,J17.4,11.2Hz)；MS(ES)m/z 447(MH+).
实施例87．14-[N-(1-乙基-哌啶-4-酰基)]-氨甲酸姆替林
步骤1．1-乙基异哌啶甲酸乙酯
异哌啶甲酸乙酯(6.28g)在乙醇(35ml)中用乙基碘(6.86g)和碳酸钾粉末(10g)处理。搅拌并回流加热混和物20小时。混和物冷却到室温，过滤去除固体并用乙醇(2×10ml)洗涤。减压蒸发去除滤液中的乙醇，所得残留物在氯仿(100ml)和水(50ml)之间分相。分离有机层，用饱和氯化钠溶液洗涤，硫酸钠干燥。减压蒸发去除溶剂得到黄色油的标题化合物(6.62g)；MS(EI)m/zl85(M+)。
步骤2．1-乙基-异哌啶甲酸盐酸盐
1-乙基异哌啶甲酸乙酯(5.5g)溶于水(22ml)/浓盐酸(39ml)，溶液回流加热4小时。减压蒸发去除溶剂，残留物溶于水(30ml)，减压蒸发去除水。残留物用甲苯(50ml)研制，减压蒸发去除甲苯得到一种固体，真空干燥18小时。得到白色固体状的标题化合物(5.4g)；MS(EI)m/z157(M+)。
步骤3．14-[N-(1-乙基-哌啶-4-酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
1-乙基异哌啶甲酸盐酸盐(950mg)悬浮于亚硫酰氯(8ml)中，搅拌并回流加热混和物3小时得到亮黄色溶液。减压蒸发去除亚硫酰氯，所得残留物悬浮于甲苯(5ml)中，再减压蒸发去除甲苯得到白色固体状的1-乙基-异哌啶甲酰氯盐酸盐。将该酰氯悬浮于干二氯甲烷(20ml)，加入氰酸银(1.5g)。搅拌并回流加热混合物1小时，将混合物冷却到室温，加入(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(1g)和三乙胺(0.5g)。混和物室温搅拌16小时，用乙酸乙酯(50ml)稀释，过滤去除固体。用饱和碳酸氢钠溶液和饱和氯化钠溶液洗涤滤液。硫酸钠干燥溶液，减压蒸发去除溶剂得到黄色胶体。产物硅胶色谱纯化，用1∶3的乙酸乙酯/氯仿和1∶9∶90的氨溶液(35％)/甲醇/二氯甲烷洗脱得到无色胶体的标题化合物(134mg)；1H NMR(CDCl3)特别2.88(2H,q,J6.5
Hz),3.08(3H,m),3.22(3H,s),3.42(1H,m),5.04(1H,d,J17.5Hz),5.33(1H,
d,J10.7Hz),5.74(1H,d,J9.9Hz),6.63(1H,dd,J17.5,10.7Hz),7.47(1H,s).
步骤4．14-[N-(1-乙基-哌啶-4-酰基)]-氨甲酸姆替林
14-[N-(1-乙基-哌啶-4-酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(110mg)在1,4-二噁烷(0.7ml)中用浓盐酸(0.7ml)处理，室温保持溶液2.5小时。用水(10ml)稀释溶液，二氯甲烷(10ml)洗涤。仔细加入固体碳酸钾碱化水相，所得混和物用氯仿(3×10ml)提取，硫酸钠干燥有机提取物，减压蒸发去除溶剂得到白色固体状的标题化合物(80mg)；
1H NMR(CDCl3)特别1.12(3H,t,J7.1Hz),2.48
(2H,q,J7.1Hz),2.97(3H,m),3.37(1H,dd,J10.3,6.6Hz),5.24(1H,d,J17.5
Hz),5.37(1H,d,J11Hz),5.70(1H,d,J8.4Hz),6.50(1H,dd,J17.5,11Hz),
7.35(1H,s)；MS(EI)m/z 502(M+).
实施例88．14-{N-[1-(1-甲基-乙基)-哌啶基-4-酰基]}-氨甲酸姆替林
步骤1．1-(1-甲基-乙基)异哌啶甲酸乙酯
使用实施例87步骤1的方法，将异哌啶甲酸乙酯(6.28g)和2-碘代-丙烷(7.48g)转换成标题化合物，得到黄色油(7.17g)；MS(EI)m/z199(M+)。
步骤2．1-(1-甲基-乙基)-异哌啶甲酸盐酸盐
使用实施例87步骤2的方法，将1-(1-甲基-乙基)-异哌啶甲酸乙酯(6g)转换成标题化合物，得到白色粉末(6.1g)；MS(EI)m/z171(M+)。
步骤3．14-{N-[1-(1-甲基-乙基-哌啶)-4-酰基]}-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
使用实施例87步骤3的方法，将1-(1-甲基-乙基)异哌啶甲酸盐酸盐(0.96g)和(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(1g)转换成标题化合物，得到浅黄色胶体(195mg)；MS(EI)m/z530(M+)。
步骤4．14-{N-[1-(1-甲基-乙基)-哌啶-4-酰基]}-氨甲酸姆替林
使用实施例87步骤4的方法，将14-{N-[1-(1-甲基-乙基)-哌啶-4-酰基]}-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(170mg)转换成白色固体状的标题化合物(110mg)；
1H NMR(CDCl3)特别1.01(6H,d,J6.5Hz),
2.74(1H,m),2.92(3H,m),3.37(1H,dd,J10.5,6.6Hz),5.23(1H,d,J17.4
Hz),5.36(1H,d,J11Hz),5.71(1H,d,J8.4Hz),6.50(1H,dd,J17.4,11Hz),
7.32(1H,s)；MS(EI)m/z 516(M+).
实施例89．14-{N-[1-(2-甲氧基-乙基)-哌啶基-4-酰基]}-氨甲酸姆替林
步骤1．1-(2-甲氧基-乙基)异哌啶甲酸乙酯
使用实施例87步骤1的方法，将异哌啶甲酸乙酯(6.28g)和2-溴乙基-甲醚(6.12g)转换成标题化合物，得到黄色油(8.47g)；MS(EI)m/z216(MH+)；测定值：216.1601,C11H22NO3理论值：216.1599。
步骤2．1-(2-甲氧基-乙基)-异哌啶甲酸盐酸盐
使用实施例87步骤2的方法，将1-(2-甲氧基-乙基)-异哌啶甲酸乙酯(7.3g)转换成标题化合物，得到黄色胶体(7.1g)；MS(EI)m/z187(M+)。
步骤3．14-{N-[1-(2-甲氧基-乙基)-哌啶-4-酰基]}-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
使用实施例87步骤3的方法，将1-(2-甲氧基-乙基)异哌啶甲酸盐酸盐(0.98g)和(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(1g)转换成标题化合物，得到浅黄色固体(80mg)；MS(EI)m/z546(M+)。
步骤4．14-{N-[1-(2-甲氧基-乙基)-哌啶-4-酰基]}-氨甲酸姆替林
使用实施例87步骤4的方法，将14-{N-[1-(2-甲氧基-乙基)-哌啶-4-酰基]}-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(65mg)转换成白色固体状的标题化合物(50mg)；1H NMR(CDCl3)特别2.58(2H,t,5.7Hz),3.00
(3H,m),3.36(4H,s覆盖),3.51(2H,t,J5.7Hz),5.24(1H,d,J17.3
Hz),5.37(1H,d,J11Hz),5.70(1H,d,J8.4Hz),6.50(1H,dd,J17.3,11Hz),
7.31(1H,s)；MS(EI)m/z 532(M+)；测定值：532.3523.C30H48N2O6理论值
532.3512.
实施例90．14-[N-(1-丙基-哌啶基-4-酰基)]}-氨甲酸姆替林
步骤1．1-丙基-异哌啶甲酸乙酯
使用实施例87步骤1的方法，将异哌啶甲酸乙酯(4.2g)和丙基碘(5g)转换成标题化合物，得到浅黄色油(4.39g)；MS(EI)m/z199(M+)。
步骤2．1-丙基-异哌啶甲酸盐酸盐
使用实施例87步骤2的方法，将1-丙基-异哌啶甲酸乙酯(4.3g)转换成标题化合物，得到灰白色固体(4.4g)；MS(EI)m/z171(M+)。
步骤3．14-[N-(1-丙基-哌啶-4-酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
使用实施例87步骤3的方法，将1-丙基-异哌啶甲酸盐酸盐(0.5g)和(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(0.5g)转换成标题化合物，得到浅黄色胶体(65mg)；MS(EI)m/z530(M+)。
步骤4．14-[N-(1-丙基-哌啶-4-酰基)]-氨甲酸姆替林
使用实施例87步骤4的方法，将14-[N-(1-丙基-哌啶-4-酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(50mg)转换成白色固体状的标题化合物(37mg)；
1H NMR(CDCl3)特别3.00(3H,m),3.36(1H,dd,J10.6.6Hz),
5.24(1H,d,J17.3Hz),5.36(1H,d,J11Hz),5.70(1H,d,J8.6Hz),6.48(1H,
dd,J17.3,11Hz),7.34(1H,s)；MS(EI)m/z 516(M+).
实施例91．14-[N-(奎宁环-4-酰基)]-氨甲酸姆替林
步骤1．14-[N-(奎宁环-4-酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
使用实施例87步骤3的方法，将4-羧酸奎宁环盐酸盐(helveticaChimica Acta,1974,57,2332)(230mg)和(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(330mg)转换成标题化合物，得到白色泡沫(160mg)；
                                              1H NMR
(CDCl3)特别1.90(6H,dd,J8,7.4Hz),3.10(6H,dd,J8,7.4Hz)),3.21
(3H,s),5.00(1H,d,J17.5Hz),5.27(1H,d,J10.7Hz),5.77(1H,d,J10Hz),
6.68(1H,dd,J17.5,10.7Hz),7.85(1H,宽s)；MS(ES)m/z 515(MH+).
步骤2．14-[N-(奎宁环-4-酰基)]-氨甲酸姆替林
使用实施例87步骤4的方法，将14-[N-(奎宁环-4-酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(140mg)转换成白色固体状的标题化合物(86mg)；
1H NMR(CDCl3)特别0.73(3H,d,J6.7Hz),0.87(3H,d,J7Hz),
1.17(3H,s),1.49(3H,s),1.68(6H,dd,J8,7.3z),2.93(6H,dd,J8,7.3Hz),
3.34(1H,dd,J10,6.6Hz),5.22(1H,d,J17.3Hz),5.36(1H,d,J11Hz),5.76
(1H,d,J8.5Hz),6.54(1H,dd,J17.3,11Hz)；MS(ES)m/z 501(MH+).
实施例92．14-[N-(奎宁环-4-酰基)]-氨甲酸姆替林盐酸盐
14-[N-(奎宁环-4-酰基)]-氨甲酸姆替林(71mg)溶于乙酸乙酯(5ml)/1,4-二噁烷(2ml)并加入4M盐酸的二噁烷溶液(0.2ml)。通过减压蒸发溶剂使溶液浓缩到大约1ml，加入甲苯(5ml)得到白色沉淀物。通过过滤收集沉淀，用甲苯(2ml)洗涤，真空干燥得到白色固体状的标题化合物(79mg)；
                                          1H NMR(D2O)特别
     0.69(3H,d,J6Hz),0.92(3H,d,J6.8Hz),1.15(3H,s),1.39(3H,s),2.16
(6H,dd,J8.2,7.5Hz),3.42(6H,dd,J8.2,7.5Hz),3.58(1H,d,J6Hz),5.20
(1H,d,J17.5Hz),5.28(1H,d,J11.1Hz),5.68(1H,d,J8.1Hz),6.36(1H,dd,
J17.5,11.1Hz).
实施例93．14-{N-(1-氮杂双环[2.2.1]庚烷-4-酰基)}-氨甲酸姆替林
步骤1．14-{N-(1-氮杂双环[2.2.1]庚烷-4-酰基)}-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
使用实施例87步骤3的方法，将1-氮杂双环[2.2.1]庚烷4-羧酸盐酸盐(Chemical Abstracts,1989,110,95016)(700mg)和(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(1g)转换成白色固体状的标题化合物(330mg)；
1H NMR(CDCl3)特别2.05(4H,m),2.72(4H,m),3.08(2H,m),3.22(3H,
s),3.44(1H,m),5.02(1H,d,J17.5Hz),5.30(1H,d,J11.6Hz),5.80(1H,d,J
9.9Hz),6.69(1H,dd,J17.5,11.6Hz).7.48(1H,s)；MS(ES)m/z 501(MH+).
步骤2．14-(N-(1-氮杂双环[2.2.1]庚烷-4-酰基)}-氨甲酸姆替林
使用实施例87步骤4的方法，将14-{N-(1-氮杂双环[2.2.1]庚烷-4-酰基)}-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(300mg)转换成白色固体状的标题化合物(250mg)；
                1H NMR(CDCl3)特别2.28(4H,m),3.06(2H,
m),3.37(1H,宽s),5.24(1H,dd,J17,3,1.4Hz),5.38(1H,dd,J11,1.4Hz),
5.78(1H,d,J8.5 Hz),6.64(1H,dd,J17.3,11Hz),7.38(1H,s)；MS(EI)m/z
486(M+)；测定值：486.3085,C28H42N2O5理论值486.3094.
实施例94．14-[N-(N,N-二甲基氨基甲酰基)]-氨甲酸姆替林
步骤1．14-[N-(N,N-二甲基氨基甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(270mg,0.80mmol)在干二氯甲烷(15ml)中与二甲基氨基甲酰氯(0.088ml,0.96mmol)和氰酸银(197mg,1.31mmol)相结合，在氩气氛下避光室温搅拌反应3天。通过Kieselguhr过滤混合物，用饱和碳酸氢钠溶液(×2)和食盐水洗涤滤液。硫酸镁干燥后硅胶色谱纯化，用40％乙酸乙酯的己烷溶液洗脱，分离得到无色泡沫状的标题化合物(135mg,38％)；υ最大(CH2Cl2)3052,2981,1771,1695,1490和1459cm-1；MS(CI)m/z449(MH+),466(MNH4 +)。
步骤2．14-[N-(N,N-二甲基氨基甲酰基)]-氨甲酸姆替林
步骤1的产物(110mg,0.25mmol)在二噁烷(2ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，室温搅拌反应30分钟。溶液倾入乙酸乙酯和饱和碳酸氢钠溶液中。用乙酸乙酯提取水相，合并的有机相用饱和氯化钠溶液洗涤。硫酸镁干燥有机相后硅胶色谱纯化，用70％乙酸乙酯的己烷溶液洗脱得到标题化合物(90mg,83％)；υ最大(CH2Cl2)3402,2935,1774,1735,1686和1489cm-1；
             1H NMR(CDCl3)0.78(3H,d,J6.6Hz),0.89(3H,d,
J7.0Hz),1.10-1.83(16H,m)包括1.19(3H,s)和1.43(3H,s),2.06-2.37
(4H,m),2.99(6H,s),3.37(1H,dd,J10.8,6.7Hz),5.20(1H,dd,J17.3,1.5Hz),
5.36(1H,dd,J11.1,1.5Hz),5.71(1H,d,J8.4Hz),6.53(1H,dd,J17.3,
11.1Hz),6.54(1H,bs)；MS(Cl)m/z 435(MH+).
实施例95．14-[N-(1-甲基(6H)-6-氧代吡啶-3-羰基)]-氨甲酸姆替林
步骤1．14-[N-(1-甲基(6H)-6-氧代吡啶-3-羰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(500mg,1.50mmol)在干二氯甲烷(30ml)中与1-甲基(6H)-6-氧代吡啶-3-碳酰氯(600mg,3.50mmol)和氰酸银(539mg,3.59mmol)相结合，氩气氛下反应避光室温搅拌20小时。通过Kieselguhr过滤混合物，用饱和碳酸氢钠溶液(×2)和食盐水洗涤滤液。硫酸镁干燥后硅胶色谱纯化，用80％乙酸乙酯的己烷溶液洗脱，分离得到无色泡沫状的标题化合物(559mg,73％)；υ最大(CH2Cl2)3382,2959,1779,1735,1704和1473cm-1；MS(CI)m/z513(MH+),530(MNH4 +)。
步骤2．14-[N-(1-甲基(6H)-6-氧代吡啶-3羰基)]-氨甲酸姆替林
步骤1的产物(550mg,1.07mmol)在二噁烷(5ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，室温搅拌反应2小时。溶液倾入乙酸乙酯和饱和碳酸氢钠溶液。用乙酸乙酯再提取水相，将合并的有机相用饱和氯化钠溶液洗涤。硫酸镁干燥有机相后硅胶色谱纯化，用乙酸乙酯洗脱得到标题化合物(360mg,67％)；υ最大(CH2Cl2)3427,2935,1778,1734,1662和1479cm-1；
1H NMR(CDCl3)0.78(3H,d,J6.6Hz),0.87(3H,d,J7.0Hz),
1.08-1.83(16H,m)including 1.18(3H,s)和1.48(3H,s),2.08-2.34(4H,m),
3.36(1H,dd,J10.8,6.6Hz),3.59(3H,s),5.22(1H,dd,J17.3,1.5Hz),5.38(1H,
dd,J11.1,1.5Hz),5.79(1H,d,J8.5Hz),6.52(1H,dd,J17.3,11.1Hz),6.54
(1H,d,J9.5Hz),7.62(1H,dd,J9.5,2.6Hz),7.87(1H,bs),8.16(1H,d,J
2.6Hz)；MS(EI)m/z 498(M+).测定值：498.2741,C28H38N2O6理论值
498.2730.
实施例96．14-[N-(6-氯代烟酰基)]-氨甲酸姆替林
步骤1．14-[N-(6-氯代烟酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(250mg,0.75mmol)在干二氯甲烷(15ml)中与6-氯代烟酰氯(1.21g,7.0mmol)和氰酸银(100mg,6.67mmol)相结合，氩气氛下混合物避光室温搅拌10分钟。通过Kieselguhr过滤混合物，用饱和碳酸氢钠溶液(×2)和食盐水洗涤滤液。硫酸镁干燥后硅胶色谱纯化，用20％乙酸乙酯的乙烷溶液洗脱，分离得到无色泡沫状的标题化合物(311mg,80％)；υ最大(CH2Cl2)3413,2930,1780,1719,1697和1488cm-1；MS(CI)m/z517(MH+),534(MNH4 +)。
步骤2．14-[N-(6-氯代烟酰基)]-氨甲酸姆替林
步骤1的产物(300mg,0.58mmol)在二噁烷(2ml)中用浓盐酸中的饱和氯化锌溶液(2ml)处理，室温搅拌溶液2小时。溶液倾入乙酸乙酯和饱和碳酸氢钠溶液。用乙酸乙酯提取水相，合并的有机相用饱和氯化钠溶液洗涤。将有机相用硫酸镁干燥并用硅胶色谱纯化，用己烷中50％乙酸乙酯洗脱得到标题化合物(85mg,29％)；υ最大(CH2Cl2)3413,2939,1782,1735,1697,1586和1489cm-1：
                 1H NMR(CDCl3)0.78(3H,d,J6.6Hz),0.89
(3H,d,J7.0Hz),1.07-1.82(16H,m)包括1.18(3H,s)和1.50(3H,s),
2.08-2.33(4H,m),3.36(1H,dd,J10.7,6.6Hz),5.21(1H,dd,J17.3,1.5Hz),
5(1H,dd,J11.1,1.5Hz,5.79(1H,d,J8.5Hz),6.49(1H,dd,J17.3,
11.1Hz),7.45(1H,d,J8.3Hz),8.07(1H,dd,J8.3,2.3Hz),8.08(1H,bs),8.74
(1H,d,J2.3Hz)；6Hz)；MS(EI)m/z 512(M+).测定值：512.2882,C29H40N2O6
理论值512.2886.
实施例97．14-[N-(2-甲氧基异烟酰基)]-氨甲酸姆替林
步骤1．14-[N-(2-甲氧基异烟酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(500mg,1.50mmol)在干二氯甲烷(20ml)中与2-甲氧基异烟酰氯(600mg,3.2mmol)和氰酸银(500mg,3.30mmol)相结合，氩气氛下避光室温搅拌反应3小时。通过Kieselguhr过滤混合物，用饱和碳酸氢钠溶液(×2)和食盐水洗涤滤液。将有机硫酸镁干燥后硅胶色谱纯化，用己烷中30％乙酸乙酯洗脱，分离得到无色泡沫状的标题化合物(598mg,78％)；υ最大(CH2Cl2)3410,2931,1781,1720,1698,1559和1473cm-1；MS(CI)m/z517(MH+),534(MNH4 +)。
步骤2．14-[N-(2-甲氧基异烟酰基)]-氨甲酸姆替林
步骤1的产物(560mg,1.09mmol)在二噁烷(4ml)中用浓盐酸中的饱和氯化锌溶液(4ml)处理，室温搅拌反应2小时。溶液倾入乙酸乙酯和饱和碳酸氢钠溶液中。用乙酸乙酯再提取水相，合并的有机相用饱和氯化钠溶液洗涤。将有机相用硫酸镁干燥并用硅胶色谱纯化，用己烷中50％乙酸乙酯洗脱得到标题化合物(374mg,69％)；υ最大(CH2Cl2)3412,2946,1782,1735,1610,1559和1474cm-1；
           1H NMR(CDCl3)0.78(3H,d,J6.6Hz),0.89
(3H,d,J7.0Hz),1.08-1.84(16H,m)包括1.20(3H,s)和1.49(3H,s),
2.10-2.37(4H,m),3.38(1H,dd,J10.6,6.7Hz),3.99(3H,s),5.24(1H,dd,J
17.3,1.5Hz),5.39(1H,dd,J11.1,1.5Hz),5.72(1H,d,J8.5Hz),6.53(1H,dd,J
17.3,11.1Hz),7.05(1H,d,J1.1Hz),7.18(1H,dd,J5.2,1.1Hz),7.92(1H,bs),
8.31(1H,d,J5.2Hz)；MS(EI)m/z 498(M+).测定值：498.2726,C28H29N2O6
理论值498.2730.
实施例98．14-[N-(吗啉-4-基羰基)]-氨甲酸姆替林
步骤1．14-[N-(吗啉-4-基羰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(1000mg,3.0mmol)在干二氯甲烷(45ml)中与4-吗啉碳酰氯(1.40ml,12.0mmol)和氰酸银(2.0g,13.3mmol)相结合，氩气氛下避光室温搅拌反应17天。通过Kieselguhr过滤混合物，用饱和碳酸氢钠溶液(×2)和食盐水洗涤滤液。硫酸镁干燥后硅胶色谱纯化，用己烷中50％乙酸乙酯洗脱，分离得到无色泡沫状的标题化合物(990mg,67％)；υ最大(CH2Cl2)3394,2985,1771,1736,1695和1421cm-1；MS(CI)m/z491(MH+)。
步骤2．14-[N-(吗啉-4-基羰基)]-氨甲酸姆替林
步骤1的产物(500mg,1.02mmol)在二噁烷(5ml)中用浓盐酸中的饱和氯化锌溶液(5ml)处理，室温搅拌反应2小时。溶液倾入乙酸乙酯和饱和碳酸氢钠溶液。用乙酸乙酯再提取水相，合并的有机相用饱和氯化钠溶液洗涤。将有机相用硫酸镁干燥并用硅胶色谱纯化，用己烷中70％乙酸乙酯洗脱得到标题化合物(180mg,37％)；υ最大(CH2Cl2)3391,2928,1773,1735,1684,1488和1458cm-1；
                  1H NMR(CDCl3)0.78(3H,d,J6.6Hz),0.85
(3H,d,J7.0Hz),1.06-1.82(16H,m)包括1.18(3H,s)和1.42(3H,s),
2.04-2.38(4H,m),3.33(1H,dd,J10.4,6.6Hz),3.45(4H,m),3.70(4H,m),5.20
(1H,dd,J17.3,1.5Hz),5.32(1H,dd,J11.1,1.5Hz),5.69(1H,d,J8.4Hz),6.51
(1H,dd,J17.3,11.1Hz),6.68(1H,bs)；MS(CI)m/z 477(MH+).
实施例99．14-[N-(硫代吗啉-4-基羰基)]-氨甲酸姆替林
步骤1．14-[N-(硫代吗啉-4-基羰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(250mg,0.75mmol)在乙醚(5ml)中在氩气氛下于-50℃加入N-(氯代羰基)-异氰酸酯(0.060ml,0.75mmol)的乙醚(5ml)溶液中。经过1.5小时将温度升高到0℃，然后滴加硫代吗啉(0.075ml,0.75mmol)和三乙胺(0.079ml,0.75mmol)的乙醚(5ml)溶液。将反应混合物室温搅拌2小时，然后在0.5M盐酸和乙酸乙酯之间分配。食盐水洗涤有机层。硫酸镁干燥后硅胶色谱纯化，用己烷中30％乙酸乙酯洗脱，分离得到无色泡沫状的标题化合物(144mg,38％)；υ最大(CH2Cl2)3393,2928,1771,1739,1682和1458cm-1；MS(电喷)m/z505(M-H)+。
步骤2．14-[N-(硫代吗啉-4-基羰基)]-氨甲酸姆替林
步骤1的产物(170mg,0.34mmol)在二噁烷(1.5ml)中用浓盐酸中的饱和氯化锌溶液(1.5ml)处理，室温搅拌反应1小时。溶液倾入乙酸乙酯和饱和碳酸氢钠溶液中。乙酸乙酯再提取水相，合并的有机相用饱和氯化钠溶液洗涤。将有机相用硫酸镁干燥并用硅胶色谱纯化，用己烷中50％乙酸乙酯洗脱得到标题化合物(115mg,69％)；υ最大(CH2Cl2)3393,2930,1772,1736,1682,1458和1426cm-1；
                 1H NMR(CDCl3)0.75(3H,d,J6.6Hz),0.89
(3H,d,J7.0Hz),1.09-1.83(16H,m)包括1.18(3H,s)和1.45(3H,s),
2.04-2.35(4H,m),2.69(4H,m),3.34(1H,dd,J10.6,6.6Hz),3.73(4H,m),5.20
(1H,dd,J17.3,1.5Hz),5.33(1H,dd,J11.1,1.5Hz),5.69(1H,d,J8.7Hz),6.50
(1H,dd,J17.3,11.1Hz),6.65(1H,bs)；MS(CI)m/z 493(MH+).
实施例100．14-[N-(硫代吗啉-4-基羰基-1,1-二氧化物)]-氨甲酸姆替林
步骤1．14-[N-(硫代吗啉-4-基羰基-1,1-二氧化物)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(120mg,0.24mmol)在甲醇(2ml)中冷却到0℃，用过硫酸氢钾制剂(442mg,0.72mmol)的水(2ml)溶液处理。室温搅拌反应混和物1小时，然后在水和二氯甲烷之间分配。用水和食盐水洗涤有机层。硫酸镁干燥后硅胶色谱纯化，用己烷中50％乙酸乙酯洗脱，分离得到无色泡沫状的标题化合物(73mg,57％)；υ最大(CH2Cl2)3387,2931,1775,1742,1694和1461cm-1；MS(CI)m/z539(MH+)。
步骤2．14-[N-(硫代吗啉-4-基羰基-1,1-二氧化物)]-氨甲酸姆替林
步骤1的产物(220mg,0.40mmol)在二噁烷(2ml)中用浓盐酸中的饱和氯化锌溶液(2ml)处理，室温搅拌溶液2小时。溶液倾入乙酸乙酯和饱和碳酸氢钠溶液中。用乙酸乙酯再提取水相，合并的有机相用饱和氯化钠溶液洗涤。将有机相用硫酸镁干燥并用硅胶色谱纯化，用己烷中80％乙酸乙酯洗脱得到标题化合物(120mg,57％)；υ最大(CH2Cl2)3388,2938,1776,1736,1692,1465和1426cm-1；
1HNMR(CDCl3)0.72(3H,d,J6.6Hz),0.90
(3H,d,J7.0Hz),1.09-1.83(16H,m)包括1.18(3H,s)和1.42(3H,s),
2.07-2.34(4H,m),3.18(4H,m),3.37(1H,dd,J10.6,6.5Hz),3.92(4H,m),5.22
(1H,dd,J17.3,1.5Hz),5.33(1H,dd,J11.1,1.5Hz),5.67(1H,d,J8.4Hz),6.46
(1H,dd,J17.3,11.1Hz),6.80(1H,bs；MS(CI)m/z542(MNH4 +).
实施例101.14-[N-(1-甲基哌嗪-4-基羰基)]-氨甲酸姆替林
步骤1．14-[N-(1-甲基哌嗪-4-基羰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(500mg,1.5mmol)在乙醚(10ml)中氩气氛下于-50℃加入N-(氯代羰基)异氰酸酯(0.12ml,1.5mmol)的乙醚(10ml)液。经过1.5小时温度升高到0℃，然后滴加1-甲基哌嗪(0.16ml,1.5mmol)和三乙胺(0.16ml,1.5mmol)的乙醚(10ml)溶液。室温搅拌反应混合物2小时，之后在0.5M盐酸和乙酸乙酯之间分配。用食盐水洗涤有机层，硫酸镁干燥后硅胶色谱纯化，用乙酸乙酯中20％甲醇洗脱，分离得到无色泡沫状的标题化合物(170mg,23％)；υ最大(CH2Cl2)3394,2942,1769,1740,1684和1458cm-1；MS(CI)m/z504(MH+)。
步骤2．14-[N-(1-甲基哌嗪-4-基羰基)]-氨甲酸姆替林
步骤1的产物(165mg,0.32mmol)在二噁烷(2ml)中用浓盐酸中的饱和氯化锌溶液(2ml)处理，室温搅拌溶液3小时。溶液倾入乙酸乙酯和饱和碳酸氢钠溶液。用乙酸乙酯再提取水相，合并的有机相用饱和氯化钠溶液洗涤。将有机相用硫酸镁干燥并用硅胶色谱纯化，用乙酸乙酯中30％甲醇洗脱得到标题化合物(81 mg,52％)；υ最大(CH2Cl2)3392,2941,1771,1736,1683,1488和1458cm-1；
                     1H NMR(CDCl3)0.75(3H,d,J6.6Hz),
0.86(3H,d,J7.0Hz),1.00-1.80(16H,m)包括1.12(3H,s)和1.38(3H,
s),2.02-2.25(4H,m),2.30(3H,s),2.41(4H,m),3.35(1H,m),3.45(4H,m),
5.20(1H,dd,J17.3,1.5Hz),5.35(1H,dd,J11.1,1.5Hz),5.70(1H,d,J8.4Hz),
6.50(1H,dd,J17.3,11.1Hz),6.60(1H,bs)；MS(CI)m/z 490(MH+).
实施例102．14-[N-(4-{4-(2-吗啉代乙氧基)}-苯甲酰基)]-氨甲酸姆替林
步骤1．14-[N-(4-乙酰氧基苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(1.0g,3.0mmol)在干二氯甲烷(30ml)中与4-乙酰氧苯甲酰氯(2.3g,11.0mmol)和氰酸银(1.7g,11.3mmol)相结合，氩气氛下室温避光搅拌反应3小时。通过Kieselguhr过滤混合物，滤液用饱和碳酸氢钠溶液(×2)和食盐水洗涤。硫酸镁干燥后硅胶色谱纯化，用己烷中40％乙酸乙酯洗脱，分离得到无色泡沫状的标题化合物(1.5g,93％)；
                     1H NMR(CDCl3)0.90(3H,d,J6.6Hz),1.02
(3H,d,J7.0Hz),1.10-1.77(12H,m)包括1.22(3H,s)和1.30(3H,s),
1.69-1.76(2H,m),1.95-2.05(2H,m),2.22(1H,m),2.32(3H,s),2.53(1H,dd,J
15.3,10.1Hz),2.90(1H,q,J6.5Hz),3.20(3H,s),3.47(1H,m),5.02(1H,d,J
17.5Hz),5.30(1H,d,J10.7Hz),5.87(1H,d,J10.0Hz),6.72(1H,dd,J17.5,
10.7Hz),7.20(2H,d,J8.7Hz),7.88(2H,d,J8.7Hz),7.95(1H,bs).
步骤2．14-[N-(4-羟基苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤1的产物(1.50g,2.78mmol)在二噁烷(20ml)中用1M氢氧化钠水溶液(9ml)处理，氩气氛下室温搅拌反应混合物30分钟。用乙酸乙酯和稀盐酸水溶液稀释混合物，分离水层，用食盐水洗涤有机相。硫酸镁干燥后硅胶色谱纯化，用己烷中50％乙酸乙酯洗脱。分离得到无色泡沫状的标题化合物(1.30g,94％)；
1H NMR(CDCl3)0.89(3H,d,J6.6Hz),1.00(3H,d,J7.0Hz),
1.09-1.70(12H,m)包括1.20(3H,s)和1.30(3H,s),1.70-1.79(2H,m),
1.97-2.03(2H,m),2.20(1H,m),2.53(1H,dd,J15.3,10.1Hz),2.92(1H,q,J
6.5Hz),3.23(3H,s),3.49(1H,m),5.01(1H,d,J17.5Hz),5.29(1H,d,J
10.7Hz),5.85(1H,d,J10.0Hz),6.12(1H，交换),6.70(1H,dd,J17.5,10.7Hz),
6.94(2H,d,J8.7Hz),7.74(2H,d,J8.7Hz),7.94(1H,bs)
步骤3．14-[N-(4-{4-(2-吗啉代乙氧基)}苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤2的产物(700mg,1.41mmol)在丙酮(14ml)中用碳酸钾(389mg,2.82mmol)和4-(2-氯乙基)吗啉盐酸盐(262mg,1.41mmol)处理。氩气氛下将反应混合物加热至回流16小时。用乙酸乙酯和水稀释混合物并分层，硫酸镁干燥后硅胶色谱纯化，用乙酸乙酯中5％乙醇洗脱。分离得到无色泡沫状的标题化合物(275mg,32％)；υ最大(CH2Cl2)3421,2932,1774,1726,1698,1605和1474cm-1；MS(电喷)m/z611(MH+)。
步骤4．14-[N-(4-{4-(2-吗啉代乙氧基))苯甲酰基)]-氨甲酸姆替林
步骤3的产物(265mg,0.43mmol)在二噁烷(2ml)中用浓盐酸中的饱和氯化锌溶液(2ml)处理，室温搅拌反应1小时。将溶液倾入乙酸乙酯和饱和碳酸氢钠溶液中。用乙酸乙酯再提取水相，合并的有机相用饱和氯化钠溶液洗涤。将有机相用硫酸镁干燥并用硅胶色谱纯化，用己烷中70％乙酸乙酯洗脱得到标题化合物(160mg,62％)；υ最大(CH2Cl2)3418,2939,1775,1732,1605和1476cm-1；
                1H NMR(CDCl3)0.79(3H,d,J6.6Hz),0.86(3H,d,
J7.0Hz),1.10-1.82(16H,m)包括1.15(3H,s)和1.49(3H,s),2.08-2.39
(4H,m),2.54(4H,m),2.80(2H,t,J5.7Hz),3.36(1H,dd,J10.8,6.5Hz),3.72
(4H,m),4.13(2H,t,J5.7Hz),5.21(1H,dd,J17.3,1.5Hz),5.37(1H,dd,J11.1,
1.5Hz),5.82(1H,d,J8.4Hz),6.55(1H,dd,J17.3,11.1Hz),6.92(2H,d,J
8.9Hz),7.78(2H,d,J8.9Hz),7.83(1H,bs)；MS(CI)m/z 597(MH+).
实施例103．14-[N-(3-(2-二甲氨基乙氧基)-苯甲酰基)]-氨甲酸姆替林
步骤1．14-[N-(3-乙酰氧基苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(1.0mg,3.0mmol)在干二氯甲烷(30ml)中与3-乙酰氧苯甲酰氯(1.8g,8.4mmol)和氰酸银(1.31g,8.7mmol)相结合，氩气氛下室温避光搅拌反应2小时。通过Kieselguhr过滤混合物，滤液用饱和碳酸氢钠水溶液(×2)和食盐水洗涤。硫酸镁干燥后硅胶色谱纯化，用二氯甲烷中5％乙酸乙酯洗脱，得到标题化合物(960mg,59％)；υ最大(CH2Cl2)3414,2929,1775,1715,1698和1475cm-1；MS(EI)m/z539(M+)。测定值：539.2883,C31H41NO7理论值：539.2883。
步骤2．14-[N-(3-羟基苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤1的产物(940mg,1.74mmol)在二噁烷(14ml)中用1M氢氧化钠水溶液(5.6ml)处理，氩气氛下室温搅拌反应混合物30分钟。用乙酸乙酯和稀盐酸水溶液稀释混合物，分离水层，食盐水洗涤有机相。硫酸镁干燥后硅胶色谱纯化，用己烷中50％乙酸乙酯洗脱得到标题化合物(629mg,73％)；υ最大(CH2Cl2)3575,3414,2929,1776,1713,1697和1479cm-1；MS(CI)m/z498(MH+),515(MNH4 +)。
步骤3．14-[N-(3-(2-二甲氨基乙氧基)苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤2的产物(590mg,1.19mmol)在丙酮(10ml)中用碳酸钾(328mg,2.38mmol)和2-二甲氨基乙基氯盐酸盐(171mg,1.19mmol)处理。氩气氛下将反应混合物加热至回流16小时。乙酸乙酯和水稀释并分层。硫酸镁干燥后硅胶色谱纯化，用乙酸乙酯中10％乙醇洗脱得到标题化合物(138mg,20％)；υ最大(CH2Cl2)3419,2943,1776,1713,1698,1583和1477cm-1；MS(EI)m/z568(MH+)。测定值：568.3516,C33H48N2O6理论值：568.3512。
步骤4．14-[N-(3-(2-二甲氨基乙氧基)苯甲酰基)]-氨甲酸姆替林
步骤3的产物(120mg,0.21mmol)在二噁烷(2ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，室温搅拌反应2小时。溶液倾入乙酸乙酯和饱和碳酸氢钠溶液。用乙酸乙酯再提取水相，合并的有机相用饱和氯化钠溶液洗涤。将有机相用硫酸镁干燥并用硅胶色谱纯化，用二氯甲烷中3％(9∶1的甲醇∶(35％)氨)洗脱得到标题化合物(69mg,59％)；υ最大(CH2Cl2)3412,2961,1778,1732,1706和1479cm-1；
                                  1H NMR(CDCl3)0.80(3H,d,J6.6Hz),0.89(3H,d,J7.0Hz),1.15-1.83(16H,m)包括1.19(3H,s)和1.52(3H,s),2.03-2.28(4H,m),2.34(6H,s),2.74(2H,t,J5.6Hz),3.39(1H,m),4.10(2H,t,J5.6Hz),5.22(1H,dd,J17.3,1.5Hz),5.39(1H,dd,J11.1,1.5Hz),5.83(1H,d,J8.4Hz),6.56(1H,dd,J17.3,11.1Hz),7.12(1H,m),7.28-7.40(3H,m),7.92(1H,bs)；MS(EI)m/z 554(M+).测定值：554.3368,C32H48N2O6理论值554.3356.
实施例104．14-[N-(4-(3-二甲氨基丙基)-苯甲酰基)]-氨甲酸姆替林
步骤1．14-[N-(4-(3-二甲氨基丙基)苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
14-[N-(4-羟基-苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(370mg,0.74mmol)在丙酮(10ml)中用碳酸钾(207mg,1.50mmol)和3-二甲氨基丙基氯盐酸盐(118mg,0.75mmol)处理。氩气氛下将反应混合物加热至回流16小时。用乙酸乙酯和水稀释并分层，硫酸镁干燥后硅胶色谱纯化，用二氯甲烷中5％(9∶1的甲醇∶(35％)氨)洗脱得到标题化合物(170mg,39％)；υ最大(CH2Cl2)3425,2943,1774,1697,1605和1468cm-1；MS(EI)m/z582(M+)。测定值：582.3675,C34H50N2O6理论值582.3669。
步骤2．14-[N-(4-(3-二甲氨基丙基)苯甲酰基)]-氨甲酸姆替林
步骤1的产物(152mg,0.26mmol)在二噁烷(1ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理，室温搅拌反应1.5小时。溶液倾入乙酸乙酯和饱和碳酸氢钠溶液。用乙酸乙酯再提取水相，合并的有机相用饱和氯化钠溶液洗涤。将有机相用硫酸镁干燥并用硅胶色谱纯化，用二氯甲烷中5％(9∶1的甲醇∶(35％)氨)洗脱得到标题化合物(80mg,54％)；υ最大(CH2Cl2)3418,2956,1775,1732,1605和1477cm-1；
                               1H NMR(CDCl3)0.78
(3H,d,J6.6Hz),0.87(3H,d,J7.0Hz),1.05-1.85(16H,m)包括1.18(3H,
s)和1.50(3H,s),1.95-2.30(6H,m),2.34(6H,s),2.55(2H,t,J7.1Hz),3.42
(1H,m),4.08(2H,t,J6.3Hz),5.21(1H,dd,J17.3,1.5Hz),5.37(1H,dd,J11.1,
1.5Hz),5.82(1H,d,J8.4Hz),6.56(1H,dd,J17.3,11.1Hz),6.93(2H,d,J
8.8Hz),7.74(2H,d,J8.8Hz),7.85(1H,bs)；MS(EI)m/z 568(M+).测定值：
568.3499,C33H48N2O6理论值568.3512.
实施例105．14-[N-(4-[2-吡咯烷-1-基乙氧基)-苯甲酰基])-氨甲酸姆替林
步骤1．14-[N-(4-[2-吡咯烷-1-基乙氧基)苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
14-[N-(4-羟基苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(600mg,1.21mmol)在丙酮(10ml)中用碳酸钾(333mg,2.41mmol)和1-(2-氯乙基)吡咯烷盐酸盐(205mg,1.21mmol)处理。氩气氛下将反应混合物加热至回流16小时。用乙酸乙酯和水稀释混合物并分层，硫酸镁干燥后硅胶色谱纯化，用二氯甲烷中3％(9∶1的甲醇∶(35％)氨)洗脱得到标题化合物(302mg,42％)；υ最大(CH2Cl2)3053,2985,1774,1697,1605和1421cm-1；MS(CI)m/z595(MH+)。
步骤2．14-[N-(4-[2-吡咯烷-1-基乙氧基)苯甲酰基)]-氨甲酸姆替林
步骤1的产物(280mg,0.47mmol)在二噁烷(2ml)中用浓盐酸中的饱和氯化锌溶液(2ml)处理，室温搅拌反应2小时。溶液倾入乙酸乙酯和饱和碳酸氢钠溶液中。用乙酸乙酯再提取水相，合并的有机相用饱和氯化钠溶液洗涤。将有机相用硫酸镁干燥并用硅胶色谱纯化，用二氯甲烷中4％(9∶1的甲醇∶(35％)氨)洗脱得到标题化合物(52mg,19％)；υ最大(CH2Cl2)3427,1775,1732,1711,1606和1478cm-1；
                                    1H NMR(CDCl3)0.79
(3H,d,J6.6Hz),0.89(3H,d,J7.0Hz),1.10-1.85(20H,m)包括1.18(3H,
s)和1.52(3H,s),2.09-2.40(4H,m),2.62(4H,m),2.92(2H,t,J5.8Hz),3.46
(1H,m),4.12(2H,t,J5.8Hz),5.22(1H,dd,J17.3,1.5Hz),5.38(1H,dd,J11.1.
1.5Hz),5.82(1H,d,J8 4Hz),6.58(1H,dd,J17.3,11.1Hz),6.97(2H,d,J
8.8Hz),7.75(2H,d,J8.8Hz),7.80(1H,bs)；MS(CI)m/z 581(MH+).
实施例106．14-[N-(4-[3-(4-甲基哌嗪-1-基)-丙氧基]-苯甲酰基)]-氨甲酸姆替林
步骤1．14-[N-(4-[3-(4-甲基哌嗪-1-基)-丙氧基]苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
14-[N-(4-羟基苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(600mg,1.21mmol)在丙酮(10ml)中用碳酸钾(480mg,3.47mmol)和1-(3-氯丙基)-4-甲基哌嗪二盐酸盐(302mg,1.21mmol)处理。氩气氛下将反应混合物加热至回流16小时。用乙酸乙酯和水稀释并分层，硫酸镁干燥后硅胶色谱纯化，用二氯甲烷中5％(9∶1的甲醇∶(35％)氨)洗脱得到标题化合物(230mg,30％)；υ最大(CH2Cl2)3420,2941,1774,1697,1605和1467cm-1；MS(EI)m/z637(M+)。测定值：637.4085,C37H55N3O6理论值637.4091。
步骤2．14-[N-(4-[3-(4-甲基哌嗪-1-基)-丙氧基]苯甲酰基)]-氨甲酸姆替林
步骤1的产物(200mg,0.31mmol)在二噁烷(2ml)中用浓盐酸中的饱和氯化锌溶液(2ml)处理，室温搅拌反应2小时。溶液倾入乙酸乙酯和饱和碳酸氢钠溶液。用乙酸乙酯再提取水相，合并的有机相用饱和氯化钠溶液洗涤。将有机相用硫酸镁干燥并用硅胶色谱纯化，用二氯甲烷中5％(9∶1的甲醇∶(35％)氨)洗脱得到标题化合物(80mg,41％)；υ最大(KBr)3427,2924,1753,1727,1689,1605和1465cm-1；
                                 1H NMR(CDCl3)
0.80(3H,d,J6.6Hz),0.87(3H,d,J7.0Hz),1.14-2.52(35H,m)包括1.18
(3H,s),1.52(3H,s)和2.29(3H,s),3.36(1H,m),4.08(2H,t,J6.3Hz),5.21
(1H,dd,J17.3,1.5Hz),5.38(1H,dd,J11.1,1.5Hz),5.82(1H,d,J8.4Hz),6.57
(1H,dd,J17.3,11.1Hz),6.94(2H,d,J8.8Hz),7.73(2H,d,J8.8Hz),7.81(1H,
bs)；MS(EI)m/z 623(M+).测定值：623.3921,C36H53N2O6理论值623.3921.
实施例107．14-[N-(3-氟-4-羟基苯甲酰基)]-氨甲酸姆替林
步骤1．14-[N-(4-乙酰氧基-3-氟苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(1.0mg,3.0mmol)在干二氯甲烷(30ml)中与4-乙酰氧基-3-氟苯甲酰氯(1.7g,7.5mmol)和氰酸银(1.20mg,8.0mmol)相结合，氩气氛下反应避光室温搅拌2小时。通过Kieselguhr过滤混合物，滤液用饱和碳酸氢钠溶液(×2)和食盐水洗涤。硫酸镁干燥后，硅胶色谱纯化，用二氯甲烷中5％乙酸乙酯洗脱得到标题化合物(1.61g,96％)；υ最大(CH2Cl2)3413,2930,1777,1716,1697和1479cm-1；MS(CI)m/z575(MNH4 +)。
步骤2．14-[N-(3-氟-4-羟基苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤1的产物(1.59g,2.85mmol)在二噁烷(20ml)中用1M氢氧化钠溶液(9ml)处理。氩气氛下室温搅拌反应混合物30分钟。用乙酸乙酯和稀盐酸溶液稀释，分离水层，食盐水洗涤有机相。硫酸镁干燥后硅胶色谱纯化，用己烷中40％乙酸乙酯洗脱得到标题化合物(1.42g,96％)；υ最大(CH2Cl2)3547,3417,2930,1776,1713,1618和1479cm-1；MS(电喷)m/z514(M-H)-。
步骤3．14-[N-(3-氟-4-羟基苯甲酰基)]-氨甲酸姆替林
步骤2的产物(200mg,0.39mmol)在二噁烷(1ml)中用浓盐酸中的饱和氯化锌溶液(2ml)处理，室温搅拌反应1.5小时。溶液倾入乙酸乙酯和饱和碳酸氢钠溶液。乙酸乙酯再提取水相，合并的有机相用饱和氯化钠溶液洗涤。硫酸镁干燥后硅胶色谱纯化，用己烷中60％乙酸乙酯洗脱得到标题化合物(110mg,56％)；υ最大(KBr)3307,2931,1731,1690,1618,1504和1457cm-1；
                 1H NMR(CDCl3+d6DMSO)0.72(3H,d,J6.6Hz),
0.83(3H,d,J7.0Hz),1.05-1.76(16H,m)包括1.10(3H,s)和1.42(3H,
s),1.85-2.34(5H,m),3.39(1H,dd,J10.1,6.6Hz),5.13(1H,dd,J17.3,1.5Hz),
5.26(1H,dd,J11.1,1.5Hz),5.72(1H,d,J8.4Hz),6.50(1H,dd,J17.3,
11.1Hz),6.92(1H,m),7.45(1H,m),7.58(1H,m),8.99(1H,bs)；MS(CI)m/z
519(MNH4 +).
实施例108．14-[N-(4-[2-二甲氨基乙氧基]-3-氟苯甲酰基)]-氨甲酸姆替林
步骤1．14-[N-(4-[2-二甲氨基乙氧基]-3-氟苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
14-[N-(3-氟-4-羟基苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(613mg,1.19mmol)在丙酮(10ml)中用碳酸钾(328mg,2.38mmol)和2-二甲氨基乙基氯盐酸盐(171mg,1.19mmol)处理。氩气氛下将反应加热至回流16小时。用乙酸乙酯和水稀释混合物并分层。硫酸镁干燥后硅胶色谱纯化，用二氯甲烷中2％(9∶1甲醇∶(35％)氨)洗脱得到标题化合物(360mg,52％)；υ最大(CH2Cl2)3419,2943,1776,1697,1615和1497cm-1；MS(CI)m/z587(MH+)。
步骤2．14-[N-(4-[二甲氨基乙氧基]3-苯甲酰基)]-氨甲酸姆替林
步骤1的产物(350mg,0.59mmol)在二噁烷(2ml)中用浓盐酸中的饱和氯化锌溶液(2ml)处理，室温搅拌溶液2小时。溶液倾入乙酸乙酯和饱和碳酸氢钠溶液。用乙酸乙酯再提取水相，合并的有机相用饱和氯化钠溶液洗涤。硫酸镁干燥后硅胶色谱纯化，用二氯甲烷中5％(9∶1的甲醇∶(35％)氨)洗脱得到标题化合物(203mg,60％)；υ最大(二氯甲烷)3414,2944,1777,1732,1713,1615和1479cm-1；
                               1H NMR
(CDCl3)0.80(3H,d,J6.6Hz),0.89(3H,d,J7.0Hz),1.16-1.83(16H,m)
包括1.18(3H,s)和1.49(3H,s),2.10-2.29(4H,m),2.33(6H,s),2.79
(2H,t,J5.7Hz),3.36(1H,m),4.17(2H,t,J5.7Hz),5.21(1H,dd,J17.3,
1.5Hz),5.38(1H,dd,J11.1,1.5Hz),5.82(1H,d,J8.4Hz),6.54(1H,dd,J17.3,
11.1Hz),7.01(1H,m),7.52-7.60(2H,m),7.82(1H,bs)；MS(CI)m/z 573,
(MH+).
实施例109.14-[N-(4-[2-二甲氨基乙氧基]-3-甲氧基苯甲酰基)]-氨甲酸姆替林
步骤1．14-[N-(4-乙酰氧基-3-甲氧基苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(1.0mg,3.0mmol)在干二氯甲烷(30ml)中与4-乙酰氧基-3-甲氧基苯甲酰氯(820mg,4.75mmol)和氰酸银(715mg,4.75mmol)相结合，氩气氛下室温避光搅拌反应2小时。通过Kieselguhr过滤混合物，滤液用饱和碳酸氢钠溶液(×2)和食盐水洗涤。硫酸镁干燥后硅胶色谱纯化，用二氯甲烷中50％乙酸乙酯洗脱，得到标题化合物(1.37g,80％)；υ最大(CH2Cl2)3417,2931,1775,1713,1698,1604和1479cm-1；MS(EI)m/z569(M+)。测定值：569.2991,C32H43NO8理论值569.2989。
步骤2．14-[N-(4-羟基-3-甲氧基苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤1的产物(1.30mg,2.28mmol)在二噁烷(20ml)中用1M氢氧化钠水溶液(7.3ml)处理。在氩气氛下室温搅拌反应混合物2小时。用乙酸乙酯和稀盐酸水溶液稀释混合物，分离水层，食盐水洗涤有机相。硫酸镁干燥后硅胶色谱纯化，用二氯甲烷中20％乙酸乙酯洗脱得到标题化合物(1.08g,90％)；υ最大(CH2Cl2)3519,3424,2930,1773,1697和1479cm-1；MS(EI)m/z527(M+)。测定值：527.2889,C30H41NO7理论值527.2883。
步骤3.14-[N-4-(2-二甲氨基乙氧基)-3-甲氧基苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤2的产物(1.04g,1.97mmol)在丙酮(20ml)中用碳酸钾(545mg,3.95mmol)和2-二甲氨基乙基氯盐酸盐(284mg,1.97mmol)处理。氩气氛下将反应混合物加热至回流16小时。用乙酸乙酯和水稀释混合物并分层，硫酸镁干燥后硅胶色谱纯化，用二氯甲烷中4％(9∶1甲醇∶(35％)氨)洗脱得到标题化合物(185mg,16％)；υ最大(CH2Cl2)3421,2941,1773,1697,1599和1477cm-1；MS(CI)m/z598(MH+)。
步骤4．14-[N-4-(2-二甲氨基乙氧基)-3-甲氧基苯甲酰基)]-氨甲酸姆替林
步骤3的产物(160mg,0.27mmol)在二噁烷(1.5ml)中用浓盐酸中的饱和氯化锌溶液(1.5ml)处理，室温搅拌溶液2小时。溶液倾入乙酸乙酯和饱和碳酸氢钠溶液。用乙酸乙酯再提取水相，合并的有机相用饱和氯化钠溶液洗涤。将有机相用硫酸镁干燥并用硅胶色谱纯化，用二氯甲烷中4％(9∶1的甲醇∶(35％)氨)洗脱得到标题化合物(65mg,41％)；υ最大(CH2Cl2)3418,2962,1776,1732,1600和1478cm-1；
                        1H NMR(CDCl3)0.80
(3H,d,J6.6Hz),0.89(3H,d,J7.0Hz),1.12-1.90(16H,m)包括1.19(3H,
s)和1.52(3H,s),2.05-2.30(4H,m),2.35(6H,s),2.80(2H,t,J6.0Hz),3.39
(1H,m),3.90(3H,s),4.12(2H,t,J6.0Hz),5.23(1H,dd,J17.3,1.5Hz),5.39(1H,dd,J11.1,1.5Hz),5.85(1H,d,J8.4Hz),6.58(1H,dd,J17.3,11.1Hz),6.90(1H,m),7.29-7.42(2H,m),7.85(1H,bs)；MS(EI)m/z 584(M+).测定值：584.3474,C33H48N2O7理论值584.3474.
实施例110．14-{N-[(3S,4R)-1-氮杂双环[2.2.1]庚烷-3-基羰基]}-氨甲酸姆替林
步骤1．14-{N-[(3S,4R)-1-氮杂双环[2.2.1]庚烷-3-基羰基]}-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(490mg,1.46mmol)在干二氯甲烷(20ml)中与(3S,4R)-1-氮杂双环[2.2.1]庚烷-3-基碳酰氯(280mg,1.46mmol)和氰酸银(550mg,3.67mmol)相结合。加入三乙胺(0.2ml,1.46mmol)，氩气氛下反应避光室温搅拌16小时。通过Kieselguhr过滤混和物且滤液用饱和碳酸氢钠水溶液(×2)和食盐水洗涤。硫酸镁干燥后硅胶色谱纯化，用二氯甲烷中4％(9∶1的甲醇∶(35％)氨)洗脱得到标题化合物(276mg,38％)；υ最大(CH2Cl2)3383,2981,1780,1749,1698,1460和1374cm-1；MS(EI)m/z500(M+)。测定值：500.3248,C29H44N2O5理论值500.3250。
步骤2．14-{N-[(3S,4R)-1-氮杂双环[2.2.1]庚烷-3-基羰基]}-氨甲酸姆替林
步骤1的产物(260mg,0.52mmol)在二噁烷(3ml)中用浓盐酸中的饱和氯化锌溶液(3ml)处理，室温搅拌溶液30分钟。溶液用水稀释并用二氯甲烷(×2)洗涤。水相用饱和碳酸氢钠溶液碱化并用二氯甲烷提取。将有机相硫酸镁干燥并浓缩得到标题化合物(187mg,74％)；υ最大(二氯甲烷)3386,2962,1782,1735,1699和1467cm-1；
                     1H NMR(d6-DMSO)0.63(3H,d,
J6.6Hz),0.81(3H,d,J7.0Hz),1.05-3.12(29H,m)包括1.09(3H,s)和
1.42(3H,s),4.52(1H,d,J6.0Hz，交换),5.03-5.12(2H,m),5.51(1H,d,J
7.8Hz),6.21(1H,dd,J17.7,11.1Hz),1040(1H,bs)；MS(CI)m/z 487(MH+).
实施例111．11-(哌啶-4-酰基)-氨甲酸姆替林
步骤1．11-二氯乙酰基-14-(1-叔丁氧羰基哌啶-4-酰基)-氨甲酸姆替林
1-叔丁氧羰基哌啶-4-羧酸[J.Med.Chem.,(1996)39(10)1943-5](229mg)在二氯甲烷中用草酰氯(152mg,0.105mmol)和一滴DMF转换成酰氯。向反应混和物中加入氰酸银(300mg)并回流混和物1小时。冷却后，加入11-二氯乙酸姆替林(216mg)和四(三苯膦)钯(0)(5mg)，继续室温搅拌反应混和物16小时。硅藻土过滤混和物，真空下去除滤液中的溶剂，硅胶色谱纯化后得到无色泡沫状的标题化合物(154mg,45％)；υ最大(CH2Cl2)3382,1786,1754,1736,1686和1473cm-1；MS(CI)m/z702(M+NH4)+。
步骤2．14-(1-叔丁氧羰基哌啶-4-酰基)-氨甲酸姆替林
11-二氯乙酸-14-(1-叔丁氧羰基哌啶-4-酰基)-氨甲酸姆替林(150mg)在四氢呋喃(1ml)中用1M氢氧化钠水溶液(1.5ml)处理，室温剧烈搅拌1.5小时。用乙酸乙酯稀释反应混和物，用5％柠檬酸、食盐水洗涤，无水硫酸镁干燥并浓缩。硅胶色谱纯化后，得到无色固体状标题化合物(47mg,37％)；υ最大(CH2Cl2)3385,1784,1735,1699和1686cm-1；MS(CI)m/z575(M+H)+。
步骤3．14-(哌啶-4-酰基)-氨甲酸姆替林
14-(1-叔丁氧羰基哌啶-4-酰基)-氨甲酸姆替林(45mg)在二氯甲烷中用三氟乙酸(90mg,0.06mmol)处理，室温保持溶液16小时。真空浓缩溶液并干燥得到无色固体(36mg,97％)，丙酮/己烷结晶得到无色棱晶状标题化合物，熔点190-195℃；υ最大(CH2Cl2)3382,1780,1735,1704和1677cm-1；
                                          1H NMR(CDCl3)特别
0.73(3H,d,J6.6Hz),0.90(3H,d,J6.8Hz),1.19(3H,s),1.43(3H,s),2.87(2H,
t,J11.6Hz),3.32(3H,m),5.23(1H,d,J18.6Hz),5.35(1H,d,J11.1Hz),5.69
(1H,d,J8.4Hz),6.48(1H,dd,J11.1,18.6Hz)和7.90(1H,vbr s)；MS(CI)m/z
475(M+H)+.
实施例112．14-(2,3-二氢咪唑[2,1-b]噻唑-6-酰基)-氨甲酸姆替林
步骤1．2,3-二氢咪唑[1,2-b]噻唑-6-羧酸
2,3-二氢咪唑[1,2-b]噻唑-6-羧酸乙酯(WO94/10178专利，1994年5月11日)(760mg)在乙醇(5ml)中用氢氧化钠水溶液于60℃水解3小时。真空去除溶剂，残留物再溶于水并用5M盐酸酸化到pH=3，没有沉淀形成。冷冻干燥水溶液，固体残留物用热乙醇提取。过滤后去除溶剂得到黄色非晶形固体状的标题化合物(621mg，定量)；1HNMR(CDCl3)3.93(2H,t,J7.0Hz),4.25(2H,t,J7.6Hz)和7.93(1H,s)。
步骤2．14-(2,3-二氢咪唑[2,1-b]噻唑-6-酰基)-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
2,3-二氢咪唑[1,2-b]噻唑-6-羧酸(316mg)在干二氯甲烷(3ml)中的悬浮液用草酰氯(381mg,0.26mmol)处理3小时。将形成的浆料真空浓缩去除过量的草酰氯，固体残留物再悬浮于干二氯甲烷中。冰浴冷却反应混和物，缓慢加入三乙胺(202mg,0.28ml)。浅黄色溶液/固体暖热到室温，加入氰酸银(600mg)。室温搅拌混和物16小时；加入(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(334mg)。搅拌反应混和物2小时，通过硅藻土过滤混合物。然后用水和饱和碳酸氢钠水溶液洗涤滤液，无水硫酸镁干燥并浓缩。硅胶色谱纯化，用己烷中80％，然后是90％乙酸乙酯洗脱得到无色泡沫状标题化合物(113mg,21％)；υ最大(CH2Cl2)3374,1769,1728,1698,1543,1945和1468cm-1；MS(CI)m/z530(M+H)+。
步骤3．14-(2,3-二氢咪唑[2,1-b]噻唑-6-酰基)-氨甲酸姆替林
14-(2,3-二氢咪唑[2,1-b]噻唑-6-酰基)-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(214mg)在二噁烷(1ml)中用卢卡斯试剂(1ml)室温处理。反应放热并变暗。1小时后t.l.c.分析表明完全转换成产物。用乙酸乙酯稀释反应混合物，用饱和碳酸氢钠溶液中和。用乙酸乙酯提取水相，合并的有机相用盐水洗涤。无水硫酸镁干燥后浓缩得到无色固体。用二氯甲烷研制，过滤得到白色非晶形固体状的标题化合物(97mg,47％)；υ最大(KBr)1762,1732,1637,1543,1509和1464cm-1；
        1HNMR(CDCl3)特别0.63(3H,d,J6.0Hz),0.81(3H,d,J
6.7Hz),1.05(3H,s),1.39(3H,s),3.41(1H,d,J5.5Hz),3.90(2H,t,J7.0Hz)
4.24(2H,t,J7.0Hz),5.09(2H,m),5.53(7.8Hz),6.20(1H,dd,J11.2,17.6Hz),
7.98(1H,s)和9.66(1H,s在D2O中交换)；MS(ES)m/z 516(M+H)+.
实施例113．14-(2,3-二氢咪唑[2,1-b]噻唑-5-酰基)-氨甲酸姆替林
步骤1．2,3-二氢咪唑[1,2-b]噻唑-5-羧酸
2,3-二氢咪唑[1,2-b]噻唑-5-羧酸乙酯(实施例112制备噻唑-6-羧酸的副产物)(3.84g)如实施例112步骤1所述，用氢氧化钠水溶液(50ml)水解成酸。酸化后形成白色沉淀。滤出后用水洗涤并真空干燥过夜，得到白色固体状标题化合物(2.86g,93％)；1HNMR(d6-DMSO)3.96(2H,t,J7.3Hz),4.37(2H,t,J7.3Hz),7.51(1H,s)和12.89(1H,vbrs)。
步骤2．14-(2,3-二氢咪唑[2,1-b]噻唑-5-酰基)-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
用实施例112步骤2所述方法，将2,3-二氢咪唑并[1,2-b]噻唑-5-羧酸(316mg)转换成酰氯，并偶合到同样规模的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林上。硅胶色谱纯化，用己烷中50％然后60％的乙酸乙酯洗脱得到无色固体状的标题化合物(353mg,67％)；υ最大(CH2Cl2)3419,1769,1723,1697,1520和1484cm-1；MS(EI)m/z529(M+)。
步骤3．14-(2,3-二氢咪唑并[2,1-b]噻唑-5-酰基)-氨甲酸姆替林
1 4-(2,3-二氢咪唑[2,1-b]噻唑-5-酰基)-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(324mg)在二噁烷(2ml)中用浓盐酸(1ml)室温处理2天。如实施例113步骤3所述加工反应混合物。所得无色泡沫加入二氯甲烷结晶，得到无色结晶固体状的标题化合物(206mg,65％)；υ最大(KBr)1735,1712,1527和1433cm-1；
                            1HNMR(d6-DMSO)特别0.67
(3H,d,J5.9Hz),0.83(3H,d,J6.8Hz),1.08(3H,s)1.45(3H,s),3.45(1H,t,J
5.5Hz),3.95(2H,d,J7.8Hz),4.54(1H,d,J6.0Hz),5.09(2H,m),5.60(1H,d,J
7.9Hz),7.87(1H,s)和10.5(1H,s)；MS(CI)m/z 515(M+)；测定值：515.2458,
C27H37N3O5S理论值515.2452.
实施例114．14-(1-甲基哌啶-4-酰基)-氨甲酸姆替林
步骤1．14-(1-甲基哌啶-4-酰基)-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
1-甲基哌啶-4-羧酸(500mg)用亚硫酰氯[J.Med.Chem.,(1990),33(6),1599]转换成相应的酰氯。将该酰氯在干二氯甲烷(5ml)中的悬浮物用氰酸银(1.04g)处理并回流反应混和物1小时。冷却后加入(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(334mg)，随后在10分钟之后加入三乙胺(281mg,0.39ml)。硅藻土过滤反应混和物，且滤液用饱和碳酸氢钠溶液洗涤；硅胶色谱纯化得到无色泡沫状的标题化合物(426mg,85％)；(最大(CH2Cl2)3381,1781,1749,1698和1474cm-1；MS(EI)m/z502(M+)。测定值：500.3411,C29H46N2O5理论值502.3407。
步骤2．14-(1-甲基哌啶-4-酰基)-氨甲酸姆替林
步骤1的产物(1.08g)在二噁烷(8ml)中用浓盐酸(4ml)室温处理5小时。t.l.c.分析表明完全转换成产物。真空去除溶剂，残留物溶于水，用二氯甲烷提取。用饱和碳酸氢钠水溶液碱化水溶液到pH=8，再用二氯甲烷提取(三次)。合并的有机相随后用食盐水洗涤，无水硫酸镁干燥并浓缩得到无色非晶形固体状的标题化合物(574mg,55％)；υ最大(二氯甲烷)3385,1782,1736,1704和1474cm-1；
1HNMR(CDCl3)特别0.73(3H,d,J6.7Hz),0.89(3H,d,J7.0Hz),1.18
(3H,s),1.42(3H,s),2.28(3H,s),3.36(1H,dd,J6.7,10.2Hz),5.22(1H,d,J
17.5Hz),5.36(1H,d,J11.0Hz),5.70(1H,d,J8.4Hz),6.49(1H,dd,J
11.0,17.3Hz)和7.43(1H,s)；MS(EI)m/z 488(M+)，测定值：488.3225,
C28H44N2O5理论值488.3250.
实施例115．14-(1-甲基哌啶-4-酰基)-氨甲酸姆替林盐酸盐
14-(1-甲基哌啶-4-酰基)-氨甲酸姆替林(350mg)在乙酸乙酯(5ml)中室温下用4M盐酸的二噁烷溶液滴加处理，直至不再形成沉淀为止。过滤去除白色固体，用乙酸乙酯洗涤并用真空干燥，得到非晶形白色固体状的标题化合物(300mg,80％)；
                                                     1H NMR
(D2O)特别0.69(3H,d,J5.8Hz),0.92(3H,d,J6.8Hz),1.14(3H,s),1.38
(3H,s),2.89(3H,s),3.05(2H,t,J12.7Hz),5.19(1H,d,J17.5Hz),5.26(1H.d,
J11.1Hz),5.61(1H,d,J8.1Hz)和6.35(1H,d,J11.1,17.5Hz).
实施例116．14-(2-氯丙酰基)-氨甲酸姆替林
步骤1．14-(2-氯丙酰基)-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(668mg)、3-氯丙酰氯(889mg,0.67ml)和氰酸银(2.05g)在二氯甲烷(10ml)中室温反应3天。硅藻土过滤混和物，用饱和碳酸氢钠水溶液洗涤，无水硫酸镁干燥并浓缩，得到一种胶体。硅胶色谱纯化，得到松脆白色泡沫状的标题化合物(909mg,97％)；υ最大(CH2Cl2)3382,1785,1752,1711,1699,和1473cm-1；MS(CI)m/z485(M+NH4)+。
步骤2．14-(2-氯丙酰基)-氨甲酸姆替林
步骤1的产物(300mg)在二噁烷(2ml)中冷却到0-5℃用卢卡斯试剂(2ml)处理，让其暖热到室温。2小时后用二氯甲烷稀释反应混和物，用水、饱和碳酸氢钠水溶液和食盐水洗涤；无水硫酸镁干燥，硅胶色谱纯化得到无色泡沫状的标题化合物(223mg,77％)；υ最大(二氯甲烷)3624,3564,3384,1786,1754,1734,1710和1473cm-1；
                                     1H NMR(CDCl3)特别0.74(3H,d,J6.8Hz),0.89(3H,d,J7.0Hz),1.19(3H,s).1.42(3H,s),3.29(2H,t,J7.0Hz),3.37(1H,dd,J6.7,10.7Hz),3.80(3H,t,J7.0Hz),5.24(1H,d,J17.4Hz),5.34(1H,d,J11.0Hz),5.70(1H,d,J8.5Hz),6.48(1H,dd,J11.0,17.4Hz)和7.50(1H,s)；MS(ES)m/z 452(M-H)-.
实施例117．14-(2-二乙氨基丙酰基)-氨甲酸姆替林
步骤1．14-(2-二乙氨基丙酰基)-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(200mg)在乙酸乙酯(2ml)中用二乙胺(312mg,0.44ml)室温处理。2小时后t.l.c.分析表明没有原料存在。用饱和碳酸氢钠水溶液、水(两次)和食盐水洗涤该溶液，无水硫酸镁干燥。浓缩得到无色泡沫状的标题化合物(197mg,92％)；υ最大(CH2Cl2)1770,1697,1520和1458cm-1；MS(EI)m/z504(M+)。测定值：504.3548,C29H48N2O5理论值504.3563。
步骤2．14-(2-二乙氨基丙酰基)-氨甲酸姆替林步骤1的产物(320mg)如实施例116步骤2所述转换成标题化合物。得到无色泡沫状的产物(153mg,49％)。υ最大(二氯甲烷)1772,1735,1703和1520cm-1；1HNMR(CDCl3)inter,alia 0.76(3H,d,J6.6Hz),0.87(3H,d,J7.0Hz),1.08(6H,t,J7.2Hz),1.17(3H,s),1.43(3H,s),3.34(1H,dd,J6.5,11.2Hz),5.21(1H,d,J17.4Hz),5.37(1H,d,J11.0Hz),5.71(1H,d,J8.5Hz)和6.59(1H,dd,J11.0,17.4Hz)；MS(EI)m/z490(M+)，测定值：490.3414,C28H46N2O5理论值490.3407.
实施例118．14-(丙烯酰基)-氨甲酸姆替林
步骤1．14-(丙烯酰基)-氨甲酸姆替林
14-(2-氯丙酰基)-氨甲酸姆替林(150mg)在二氯甲烷(1ml)中用三乙胺(67mg,0.092ml)室温处理。2小时后t.l.c.分析表明没有原料。溶液用硅胶色谱纯化得到无色泡沫状的标题化合物(135mg,98％)；υ最大(CH2Cl2)3625,3563,3389,1779,1735,1697,1625和1485cm-1；
1HNMR(CDCl3)特别0.75(3H,d,J6.8Hz),0.89(3H,d,J7.0Hz),1.12
(3H,s),1.45(3H,s),3.37(1Hdd,J6.6,10.7Hz),5.23(1H,d,J17.3Hz),5.37
(1H,d,J11.1Hz),5.72(1H,d,J8.5Hz),5.89(1H,d,J10.4Hz),6.50(2H,dd,J
10.4,17.4Hz),7.06(1H,dd,J11.1,17.3Hz)和7.60(1H,s)；MS(CI)m/z 435
(M+NH4)+.
实施例119．14-(1-苯甲基哌啶-4-酰基)-氨甲酸姆替林
步骤1．1-苯甲基哌啶-4-羧酸
1-苯甲基哌啶-4-羧酸乙酯(13.73g)在甲醇(100ml)中用40％氢氧化钠水溶液(8.3ml)室温处理16小时。真空去除溶剂，残留物再次溶于水(100ml)，用稀盐酸酸化到pH=4并浓缩。用热乙醇(200ml)提取残留物，再次过滤并浓缩，加入二氯甲烷结晶得到无色结晶固体状的标题化合物(3.24g,27％)。从滤液中去除溶剂并用醚研制得到第二批白色非晶形固体(9.24g,27％)；υ最大(CH2Cl2)2496(vbr),1720和1604(br)cm-1。
步骤2．14-(1-苯甲基哌啶-4-酰基)-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
用草酰氯(319mg,0.22ml)和一滴DMF在1小时内将1-苯甲基哌啶-4-羧酸(500mg)转换成酰氯。向这个均匀溶液中加入氰酸银(684mg)并回流反应混合物1小时。混和物冷却到室温，加入(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(334mg)。5分钟后滴加三乙胺(0.32ml)。2小时后硅藻土过滤反应混和物。用水、饱和碳酸氢钠水溶液和食盐水洗涤，无水硫酸镁干燥，真空去除溶剂，硅胶色谱纯化，得到无色泡沫状的标题化合物(355mg,61％)；υ最大(CH2Cl2)3384,1782,1784,1699和1478cm-1；MS(ES)m/z579(M+H)+。
步骤3．14-(1-苯甲基哌啶-4-酰基)-氨甲酸姆替林
14-(1-苯甲基哌啶-4-酰基)-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(304mg)在二噁烷(0.5ml)中用浓盐酸(0.5ml)处理，直至t.l.c.分析表明没有原料存在。真空去除溶剂，残留物在饱和碳酸氢钠水溶液和二氯甲烷之间分配，无水硫酸镁干燥有机相，真空去除溶剂。粗产物硅胶色谱纯化，得到泡沫状标题化合物(172mg,58％)；υ最大(CH2Cl2)3622,3562,3383,1782,1735,1703和1477cm-1；1HNMR(CDCl3)特别0.72(3H,d,J6.6Hz),0.88(3H,d,J7.0Hz),1.18(3H,s),1.42(3H,s),3.36(1H,dd,J
6.6,10.5Hz).3.51(2H,s),5.21(1H,d,J17.3Hz),5.35(1H,d,J10.9Hz),5.69
(1H,d,J8.4Hz),6.48(1H,d,J10.9,17.3Hz)和7.30(4H,m)；MS(CI)m/z 564
(M+)，测定值：564.3538,C34H48N2O5理论值564.3564.
实施例120．14-[1-(4-甲氧基苯甲基)哌啶-4-酰基]-氨甲酸姆替林
步骤1．1-(4-甲氧基苯甲基)哌啶-4-羧酸乙酯
异哌啶甲酸乙酯(5g,4.9ml)和4-甲氧基苯甲酰氯(5g,4.44ml)在DMF(40ml)中与碳酸钾(8.8g)一起于70℃加热2小时，然后室温放3天，再于70℃加热2小时。反应混和物在乙酸乙酯/水之间分配，水(×2)和食盐水洗涤，无水硫酸镁干燥并浓缩。得到黄色油状的标题化合物(8.05g，定量)；υ最大(CH2Cl2)1725,1611,1585,1511和1466cm-1；MS(EI)m/z277(M+)。测定值：277.1682,C16H23NO3理论值277.1678。
步骤2．1-(4-甲氧基苯甲基)哌啶-4-羧酸
步骤1的产物羧酸乙酯(8.05g)按照实施例119步骤1所述方法，用氢氧化钠水解成相应的酸。随后分离粗产物，用醚研制泡沫状过夜得到白色结晶固体状的标题化合物(6.23g,86％)；υ最大(KBr)1731,1613,1516和1457cm-1；MS(EI)m/z249(M+)。测定值：249.1368,C14H19NO7理论值249.1365。
步骤3．14-[1-(4-甲氧基苯甲基)哌啶-4-酰基]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤2的产物(747mg)在二氯甲烷(10ml)中用草酰氯(0.27ml)转换成酰氯，然后与氰酸银(600mg)反应，并在三乙胺(0.42ml)存在下偶合到(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(500mg)，如实施例119步骤2所述。纯化后得到无色泡沫状的标题化合物(515mg,56％)；υ最大(CH2Cl2)3383,1782,1749,1699,1611,1511和1648cm-1；MS(EI)m/z608(M+)，测定值：608.3813,C36H52N2O6理论值608.3825。
步骤4．14-[1-(4-甲氧基苯甲基)哌啶-4-酰基]-氨甲酸姆替林
14-[1-(4-甲氧基苯甲基)哌啶-4-酰基]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(485mg)在二噁烷(2ml)中按照实施例119步骤3的方法转换成标题化合物。产物纯化后得到无色泡沫状(433mg,92％)；υ最大(CH2Cl2)3624,3565,3385,1783,1734,1705,1611,1151和1468cm-1；
1HNMR(CDCl3)特别0.73(3H,d,J6.7Hz),0.89(3H,d,J6.9Hz),1.18
(3H,s),1.43(3H,s),2.61(2H,s),3.81(3H,s),5.22(1H,d,J19.4Hz),5.36(1H,
d,J11.1Hz),5.70(1H,d,J8.0Hz),6.49(1H,dd,J11.1,19.4Hz),6.85(2H,d,J
8.6Hz),7.22(2H,d,J8.6Hz)和7.32(1H,s)；MS(EI)m/z 594(M+)，测定值：
594.3657,C35H50N2O6理论值594.3669.
实施例121．14-[1-(4-甲氧基苯甲基)哌啶-4-酰基]-氨甲酸姆替林盐酸盐
14-[1-(4-甲氧基苯甲基)哌啶-4-酰基]-氨甲酸姆替林(100mg)在乙酸乙酯(1ml)中用4M盐酸的二噁烷溶液滴加处理，直至不再出现沉淀为止。滤出白色固体，用乙酸乙酯洗涤且真空干燥，得到白色非晶形固体状标题化合物(70mg,66％)；
                1HNMR(d6-DMSO)特别0.63(3H,
d,J6.2Hz),0.83(3H,d,J6.7Hz),1.08(3H,s),1.40(3H,s),3.79(3H,s),4.20
(2H,brs),4.56(1H,d,J5.9Hz),5.06(1H,d,J11.0Hz),5.10(1H,d,J17.6Hz),
5.50(1H,d,J7.8Hz),6.22(1H,dd,J11.0,17.6Hz),7.01(2H,d,J8.5Hz),7.50
(2H,d,J8.5Hz),10.30(1H,brs)和10.51(1H,s).
实施例122．14-[1-(4-氟苯甲基)哌啶-4-酰基]-氨甲酸姆替林
步骤1．1-(4-氟苯甲基)哌啶-4-羧酸乙酯
在DMF(40ml)中用4-氟苄基溴(6.02g,3.97ml)在碳酸钾(8.8g)存在下将异哌啶甲酸乙酯(5g,4.9ml)如实施例120步骤1所述进行烷基化。得到黄色油状的标题化合物(7.52g,89％)；υ最大(CH2Cl2)1725,1603,1508和1449cm-1；MS(EI)m/z265(M+)。测定值：265.1478,C15H20FNO2理论值265.1478。
步骤2．1-(4-氟苯甲基)哌啶-4-羧酸
步骤1的产物(7.52g)按照实施例120步骤2所述方法，用40％氢氧化钠(4.3ml)水解。完成后得到无色固体状的标题化合物(4.26g,63％)；υ最大(KBr)1722,1605,1511和1447cm-1；MS(EI)m/z237(M+)。测定值：237.1160,C13H16NO2理论值237.1165。
步骤3．14-[1-(4-氟苯甲基)哌啶-4-酰基]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤2的产物(711mg)用草酰氯(0.27ml)转换成酰氯，然后用氰酸银(600mg)处理，并在三乙胺(0.42ml)存在下偶合到(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(500mg)上，如实施例120步骤3所述。纯化后分离得到无色泡沫状的标题化合物(539mg,60％)；υ最大(CH2Cl2)3678,3381,1781,1748,1699,1603,1508和1478cm-1；MS(ES)m/z597(MH)+.步骤4．14-[1-(4-氟苯甲基)哌啶-4-酰基]-氨甲酸姆替林
14-[1-(4-氟苯甲基)哌啶-4-酰基]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(510mg)按照实施例120步骤4所述转换成标题化合物。纯化后得到无色泡沫状产物(346mg,70％)；υ最大(CH2Cl2)3563,3386,1783,1735,1705,1604,1508和1478cm-1；
                            1HNMR(CDCl3)特别0.72(3H,d,J6.6Hz),0.89(3H,d,J8.0Hz),1.19(3H,s),1.43(3H,s),3.37(1H,dd,J6.6,10.2Hz),3.45(2H,s),5.22(1H,d,J17.5Hz),5.36(1H,d,J9.9Hz),5.70(1H,d,J8.4Hz),6.49(1H,dd,J9.9,17.5Hz),7.00(2H,m),7.26(2H,m)和7.35(1H,s)；MS(EI)m/z 582(M+)，测定值：582.3472,C35H47FN2O5理论值582.3469.
实施例123．14-[1-(吡啶-2-基甲基)哌啶-4-酰基]-氨甲酸姆替林
步骤1．1-(吡啶-2-基甲基)哌啶-4-羧酸乙酯
在DMF(40ml)中用2-氯甲基吡啶盐酸盐(5g)和碳酸钾(12.62g)将异哌啶甲酸乙酯(4.79g,4.7ml)如实施例120步骤1所述进行烷基化。得到黄色油状的标题化合物(6.09g,81％)；υ最大(CH2Cl2)1724,1590,1570,1476,1449和1433cm-1；MS(ES)m/z249(MH)+。
步骤2．1-(吡啶-2-基甲基)哌啶-4-羧酸
步骤1的产物(6.08g)按照实施例120步骤2所述方法，用40％氢氧化钠(3.7ml)的甲醇(50ml)溶液水解。分离后得到浅绿色泡沫状的标题化合物(5.01g,93％)。发现一部分材料可从二氯甲烷结晶得到无色结晶固体；υ最大(KBr)1685(br),1601和1463cm-1；MS(ES)m/z221(MH)+。
步骤3．14-[1-(吡啶-2-基甲基)哌啶-4-酰基]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤2的产物(440mg)用草酰氯(267mg,0.18ml)转换成酰氯，然后用氰酸银(450mg)处理，并在三乙胺(0.28ml)存在下偶合到(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(334mg)上，如实施例120步骤3所述。纯化后分离得到浅黄色泡沫状的标题化合物(267mg,46％)；υ最大(CH2Cl2)3382,1782,1749,1699,1590和1475cm-1；MS(EI)m/z580(MH)+。测定值：580.3741,C34H50N3O5理论值580.3750。
步骤4．14-[1-(吡啶-2-基甲基)哌啶-4-酰基]-氨甲酸姆替林
14-[1-(吡啶-2-基甲基)哌啶-4-酰基]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(248mg)按照实施例120步骤4的方法用浓盐酸转换。完成后粗产物再溶解在稀盐酸中，用二氯甲烷洗涤，用饱和碳酸氢钠水溶液碱化并再提取。干燥后去除溶剂得到浅黄色固体状的标题化合物(135mg,56％)；υ最大(CH2Cl2)3676,3622,3564,3384,1782,1735,1703,1590和1475cm-1；
                           1HNMR(CDCl3)特别
0.73(3H,d,J6.6Hz),0.89(3H,d,J6.9Hz),1.18(3H,s),1.42(3H,s),3.36(1H,
dd,J6.6,10.5Hz),3.67(3H,s),5.22(1H,d,J17.3Hz),5.36(1H,d,J11.1Hz),
5.70(1H,d,J8.4Hz),6.49(1H,dd,J11.1,17.3Hz),7.17(1H,m),7.45(2H,m),
7.66(1H,m)和8.55(1H,d,J4.0Hz)；MS(ES)m/z 565(M+)；测定值
565.3527,C33H47N3O5理论值565.3516.
实施例124．14-{1-[(2-甲基噻唑-4-基)甲基]哌啶-4-酰基}-氨甲酸姆替林
步骤1．1-[(2-甲基噻唑-4-基)甲基]哌啶-4-羧酸乙酯
在DMF(40ml)中用4-氯甲基-2-甲基噻唑盐酸盐(3.68g)与碳酸钾(8.28g)将异哌啶甲酸乙酯(3.14g,3.08ml)如实施例120步骤1所述进行烷基化。硅胶色谱纯化后分离得到黄色油状的标题化合物(3.26g,61％)；υ最大(CH2Cl2)1724cm-1；MS(EI)m/z269(MH)+。测定值：269.1318,C13H21N2O2S理论值269.1324。
步骤2．1-[(2-甲基噻唑-4-基)甲基]哌啶-4-羧酸
步骤1的产物(3.06g)按照实施例120步骤2所述方法，用40％氢氧化钠(1.73ml)水解成酸。纯化后分离得到无色固体状的标题化合物(3.08g,99％)；υ最大(KBr)1719,1665,1591和1392cm-1；MS(EI)m/z240(M+)。测定值：240.0934,C11H16N2O2S理论值240.0932。
步骤3．14-[1-[(2-甲基噻唑-4-基)甲基]哌啶-4-酰基]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤2的产物(720mg)用草酰氯(0.27ml)转换成酰氯，然后用氰酸银(600mg)处理，并在三乙胺(0.42ml)存在下偶合到(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(500mg)上，如实施例120步骤3所述。纯化后得到浅黄色泡沫状的标题化合物(405mg,45％)；υ最大(CH2Cl2)3382,1781,1784,1698和1478cm-1；MS(EI)m/z599(M+)。测定值：599.3406,C33H49N3O5S理论值599.3392。
步骤4．14-{1-[(2-甲基噻唑-4-基)甲基]哌啶-4-酰基]}-氨甲酸姆替林
14-{1-[(2-甲基噻唑-4-基)甲基]哌啶-4-酰基}-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(391mg)按照实施例121步骤4的方法转换成标题化合物。得到的产物是白色固体(241mg,63％)；υ最大(CH2Cl2)3677,3384,1783,1735,1705和1477cm-1；
                 1HNMR(CDCl3)特别0.73(3H,d,J6.6Hz),
0.89(3H,d,J6.9Hz),1.18(3H,s),1.42(3H,s),2.71(3H,s),2.99(2H,d,J
10.3Hz),3.36(1H,dd,J6.6,10.5Hz),3.63(2H,s),5.24(1H,d,J17.0Hz),5.36
(1H,d,J11.1Hz),5.72(1H,d,J8.4Hz),6.48(1H,dd,J11.1,17.0Hz),6.95(1H,
s)和7.38(1H,s).
实施例125．14-(N-3-吡啶乙酰基)-氨甲酸姆替林
步骤1．14-(N-3-吡啶乙酰基)-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
3-吡啶乙酸(520mg,3mmol)在二氯甲烷(5ml)中用草酰氯(0.45ml,5.2mmol)和一滴DMF室温处理2小时。真空去除溶剂和过量的草酰氯，残留物溶于甲苯，再次真空去除溶剂。
粗酰氯在干二氯甲烷(10ml)中用氰酸银(900mg,6mmol)和(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(335mg,1mmol)处理。室温搅拌18小时后，按照实施例31步骤2所述的步骤，分离得到标题化合物(360mg,72％)；υ最大(CH2Cl2)3380,1752和1699cm-1；
                                 1H NMR(CDCl3)0.80
(3H,d,J6.9Hz),1.01(3H,d,J6.4Hz),1.08-1.37(3H,m),1.19(3H,s),1.21(3H,
s),1.56(4H,m),1.73(1H,d,J11.3Hz),1.99(2H,m),2.20(1H,m),2.49(1H,
dd,J15.2,10.1Hz),2.88(1H,q,J6.3Hz),3.21(3H,s),3.44(1H,m),4.18(2H,
m),5.04(1H,d,J17.5Hz),5.34(1H,d,J10.8Hz),5.74(1H,d,J9.9Hz),6.62(1H,
dd,J17.5,10.6Hz),7.28(2H,m),7.65(1H,dt,J7.8,1.9Hz)7.72(1H,s),8.54
(1H,s)；MS(NH3DCI)m/z 497(MH+)，测定值：496.2948,C29H40N2O5
理论值496.2937.
步骤2．14-(N-3-吡啶基乙酰基)-氨甲酸姆替林
步骤1的产物(310mg)在二噁烷(2ml)中用浓盐酸中的饱和氯化锌溶液(2ml)处理，如实施例1步骤2所述，得到标题化合物(173mg,58％)；υ最大(二氯甲烷)3383,1754,1734和1716cm-1；
1H NMR(CDCl3)0.70(3H,d,J6.7Hz),0.91(3H,d,J7.0Hz),1.17(1H,m),
1.19(3H,s),1.40(3H,s),1.36-1.82(8H,m),2.05-2.36(5H,m),3.37(1H,dd,
J10.1,6.7Hz),4.14(2H,AB四重峰,J16.3Hz),5.24(1H,dd,J17.4,1.4Hz),5.39
(1H,dd,J11.1,1.3Hz),5.71(1H,d,J8.4Hz),6.49(1H,dd,J17.4,11.0Hz),7.26
(1H,m),7.56(1H,s),7.63(1H,d,J7.8Hz),8.52(2H,m)；MS(NH4DCI)m/z
483(MH+)，测定值：483.2856,C28H38N2O5理论值483.2859.
实施例126．14-(N-2-吡啶基甲基)-氨甲酸姆替林
步骤1．14-(N-2-吡啶基甲基)-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
2-氨甲基吡啶(0.31ml,3mmol)在二氯甲烷(10ml)中与14-氯甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(400mg,1mmol)反应，如实施例12步骤2所述；得到标题化合物(463mg,98％)；υ最大(CH2Cl2)3446和1709cm-1；
                                         1H NMR(CDCl3)0.85(3H,d,
J6.9Hz),0.98(3H,d,J6.5Hz),1.05-1.61(6H,m),1.19(3H,s),1.22(3H,s),1.68
(1H,d,J15.3Hz),1.71(1H,d,J11.2Hz),1.99(2H,m),2.19(1H,m),2.43(1H,
dd,J15.1,10.1Hz),2.94(1H,q,J6.4Hz),3.22(3H,s),3.46(1H,ddd,J11.3,8.2,
5.3Hz),4.52(2H,t,J5.3Hz),5.00(1H,d,J17.5Hz),5.29(1H,d,J10.7Hz),5.68
(2H,m),6.77(1H,dd,J17.5,10.6Hz),7.20(1H,dd,J7.5,5.3Hz),7.29(1H,m)
7.67(1H,s),8.55(1H,d,J4.5Hz)；MS(EI)m/z 468(M+),(NH3DCI)m/z 469
(MH+)，测定值：468.2991,C28H40N2O4理论值468.2988.
步骤2．14-(N-2-吡啶基甲基)-氨甲酸姆替林
步骤1的产物(398mg)在二噁烷(2ml)中用浓盐酸中的饱和氯化锌溶液(2ml)处理，如实施例1步骤2所述，得到标题化合物(184mg,48％)；υ最大(二氯甲烷)3445,1732和1713cm-1；
                                                     1H
NMR(CDCl3)0.75(3H,d,J6.0Hz),0.86(3H,d,J7.0Hz),1.1(1H,m),1.17(3H,
s),1.42(3H,s),1.43(4H,m),1.71(4H,m),2.04(2H,m),2.21(2H,m),2.37
(1H,五重峰,J6.8Hz),3.35(1H,dd,J10.8,6.7Hz),4.48(2H,m),5.20(1H,dd,
J17.4,1.5Hz),5.34(1H,d,J11.1Hz),5.68(2H,包括1Hd,J8.4Hz),6.59(1H,
dd,J17.4,11.0Hz),7.20(2H,m),7.62(1H,td,J7.6,1.7Hz),8.53(1H,d,
J4.3Hz)；MS(EI)m/z 455(MH+),(NH3DCI)m/z 455(MH+)，测定值：454.2833,
C27H38N2O4理论值454.2832.
实施例127．14-[N-3-(1-甲基-1,2,3-三唑-4-基)丙烯酰基]-氨甲酸(E)-姆替林
步骤1．甲基-(E)-3-(1-甲基-1,2,3-三唑-4-基)丙烯酸酯
1-甲基-1,2,3-三唑-4-醛(carboxaldehyde)(1g,9mmol)加入到甲氧基羰基亚甲基三苯膦(4.5g,13.5mmol)的二氯甲烷(50ml)溶液中，室温搅拌3.5小时。去除溶剂，残留物硅胶色谱纯化得到标题化合物(3.2g)。
步骤2．(E)-3-(1-甲基-1,2,3-三唑-4-基)丙烯酸
向步骤1的产物(3.2g)溶液中加入10％氢氧化钠溶液(3ml)。室温搅拌混和物15小时，再加入10％氢氧化钠溶液(2ml)，加热至回流3小时。冷却后在乙酸乙酯和水之间分配反应混合物。用饱和碳酸氢钠溶液再提取有机相，合并的含水提取物用浓盐酸酸化到pH=1。乙酸乙酯提取后硫酸镁干燥，去除溶剂后得到标题化合物(748mg)；
1H NMR(d6-DMSO)4.07(3H,s),6.53(1H,d,J16.0Hz),7.53(1H,d,
J16.0Hz),8.44(1H,s),12.48(1H,br).
步骤3．14-[N-3-(1-甲基-1,2,3-三唑-4-基)丙烯酰基]-氨甲酸的(E)-(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(E)-3-(1-甲基-1,2,3-三唑-4-基)丙烯酸(306mg,2mmol)在二氯甲烷(10ml)中用草酰氯(0.35ml,4mmol)和一滴DMF室温处理2小时。真空去除溶剂和过量的草酰氯。残留物溶于甲苯，再次真空去除溶剂。
粗酰氯溶于干二氯甲烷(10ml)中，用氰酸银(450mg,3mmol)和(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(335mg,1mmol)处理。室温搅拌1.5小时后按照实施例31步骤2所述，分离得到标题化合物(310mg,60％)；υ最大(CH2Cl2)3388,1775,1748和1691cm-1；
                                                    1H
NMR(CDCl3)0.86(3H,d,J6.8Hz),1.00(3H,d,J6.4Hz),1.07-1.55(6H,m),
1.21(3H,s),1.24(3H,s),1.67(1H,d,J15.5Hz),1.73(1H,d,J11.5Hz),2.02
(2H,m),2.20(1H,m),2.50(1H,dd,J15.3,10.1Hz),2.89(1H,q,J6.3Hz),3.23
(3H,s),3.46(1H,m),4.15(3H,s),5.03(1H,d,J17.5Hz),5.34(1H,d,J10.7Hz),
5.76(1H,d,J9.9Hz),6.69(1H,dd,J17.5,10.7Hz),7.62(1H,s),7.65(1H,d,
J15.5Hz)7.76(1H,s),7.84(1H,d,J15.7Hz)；MS(NH3DCI)m/z513(MH+).
步骤4．14-[N-3-(1-甲基-1,2,3-三唑-4-基)丙烯酰基]-氨甲酸(E)-姆替林
步骤3产物(272mg)在二噁烷(2ml)中用浓盐酸中的饱和氯化锌溶液(1ml)处理,如实施例1步骤2的方法，得到标题化合物(173mg,65％)；υ最大(CH2Cl2)3390,1777和1735cm-1；
                                                         1H
NMR(CDCl3)0.76(3H,d,J6.6Hz),0.89(3H,d,J7.0Hz),1.18(3H,s),1.19
(1H,m),1.45(3H,s),1.46(3H,m),1.57-1.81(2H,m),1.62(3H,s),2.05-2.36
(5H,m),3.37(1H,dd,J10.7,6.6Hz),4.14(3H,s),5.24(1H,dd,J17.4,1.3Hz),
5.40(1H,dd,J11.1,1.3Hz),5.75(1H d,J8.4Hz),6.53(1H,dd,J17.3,11.0Hz),
7.54(1H,s),7.60(1H,d,J15.7Hz),7.74(1H,s),7.81(1H,d,J15.7Hz)；MS(EI)
m/z 498(M+),(NH3DCI)m/z 516(MH4 +),499(MH+)，测定值：498.2844,
C27H38N4O5理论值498.2842.
实施例128．14-N-{[2-(N,N-二甲氨基)-乙硫基]丙烯酰基}-氨甲酸姆替林盐酸盐
14-N-{[2-(N,N-二乙氨基)-乙硫基]乙酰基}-氨甲酸姆替在甲醇(4ml)中用氯代三甲基硅烷(0.1ml)处理，混和物静置10分钟。去除溶剂，加入氯仿再去除(×2)。残留物用乙醚研制，过滤分离所得固体，然后在五氧化二磷上真空干燥得到标题化合物(70mg,59％),υ最大(KBr)2926,2674,1770,1728,1512,1506,1453和1215cm-1；
               1H NMR[(CD3)2SO]0.65(3H,d,J6.3Hz),
0.82(3H,d,J6.7Hz),1.08(4H，叠加在m上的1.07,s),1.15-1.80(约
16H,m包括t,J7.2Hz,1.20和s,1.40),2.0-2.3(ca.3H,m),2.41
(1H,br s),2.95-3.00(2H,m),3.05-3.18(4H,m),3.18-3.30(2H,m),3.46
(1H,br t；d,J5.4在D2O交换后),3.52(2H,s),4.57(1H,d,J6.0Hz,在D2O中
交换),5.04-5.15(2H,m),5.49(1H,d,J8.0Hz),6.21(1H,dd,J10.4,17.7Hz),
9.98(1H,br s,D2O交换),和10.64(1H,s,D2O交换).
实施例129．14-N-(甲酰氧基-乙酰基)-氨甲酸姆替林
14-N-(氯乙酰基)-氨甲酸姆替林(110mg,0.25mmol)和碘化钾(332mg)在N,N-二甲基甲酰胺(4ml)中搅拌10分钟，然后用甲酸钠(68mg)、随后用更多的N,N-二甲基甲酰胺(1ml)处理。混和物搅拌4天，然后加入乙酸乙酯和水，水层用乙酸乙酯再提取。合并的提取物用食盐水洗涤，硫酸镁干燥并蒸发。残留物硅胶色谱纯化，用乙酸乙酯和己烷混和物洗脱，蒸发所需要的馏份后得到标题化合物(120mg，定量)；υ最大(CH2Cl2)3564,3381,2944,1791(w),1755(sh),1739,1724,1472,1393,1214,1160,1116,1016,978和936cm-1；
                                            1HNMR(CDCl3)特别0.74(3H,d,J6.9Hz),0.90(3H,d,J7.0Hz),1.20(s),1.42(s),3.37(1H,dd,J6.6,10.6Hz),5.12和5.21(2H,ABq J17.2Hz),5.24(1H,dd,J1.4,17.5Hz),5.38(1H,dd,J1.3,11.1Hz),5.69(1H,d,J8.5Hz),6.45
(1H,dd,J11.1,17.4Hz),7.67(1H,br s),8.06(1H,s)；MS(CI)m/z 467
(MNH4 +).
实施例130．14-N-(羟乙酰基)-氨甲酸姆替林
14-N-(甲酰氧基乙酰基)-氨甲酸姆替林(140mg,0.31mmol)在甲醇(5ml)中搅拌78小时之后除去甲醇。残留物硅胶色谱纯化，乙酸乙酯/己烷混和物洗脱，得到固体状标题化合物(58mg,44％)；υ最大(CH2Cl2)3564,3386,2932,1786(w),1756,1735,1712,1472和1209cm-1；
                                    1H NMR(CDCl3)特别0.73(3H,d,
J6.8Hz),0.89(3H,d,J7.1Hz),1.19(s),1.42(s),2.99(1H,t,J4.9Hz),3.37
(1H,dd,J6.6,10.6Hz),4.4-4.6(2H,m),5.22(1H,dd,J1.4,17.5Hz),5.37
(1H,dd,J1.3,11.1Hz),5.71(1H,d,J8.5Hz),6.45(1H,dd,J11.0,17.4Hz),
7.81(1H,br s)；MS(ES+)m/z 534(M-H+TFA)+；MS(ES-)m/z 420(M-H)-.
实施例131．14-N-(碘代乙酰基)-氨甲酸姆替林
14-N-(氯乙酰基)-氨甲酸姆替林(400mg,0.91mmol)在丙酮(50ml)中用碘化钾(1.2g,7.2mmol)处理，室温搅拌混和物5天。然后加入乙酸乙酯和水，分层。用食盐水洗涤乙酸乙酯层，硫酸镁干燥并蒸发。粗产物硅胶色谱纯化，用乙酸乙酯/己烷混和物洗脱，得到标题化合物(475mg,86％)；
1H NMR(CDCl3)0.77(3H,d,J6.7Hz),0.90(3H,d,J7.0Hz),1.0-1.3
(4H,m,包括1.20处的s),1.3-1.9(12H,m,包括1.42处的s),2.0-2.4(4H,
m),3.37(1H,dd,J6.6,10.5Hz),4.18和4.32(2H,ABq J9.6Hz),5.24(1H,
dd,J1.4,17.4Hz),5.39(1H,dd.J1,3,10.9Hz),5.74(1H,d,J8.5Hz),6.48
(1H,dd,J11.0,17.4Hz),7.47(1H,s).
实施例132．14-N-(叠氮乙酰基)-氨甲酸姆替林
14-N-(碘乙酰基)-氨甲酸姆替林(133mg,0.25mmol)和叠氮化钠(16mg,0.25mmol)与N,N-二甲基甲酰胺一起搅拌24小时。然后加入乙酸乙酯和水分层，水层用乙酸乙酯再提取。合并的乙酸乙酯层用水和食盐水洗涤，硫酸镁干燥并蒸发。硅胶色谱纯化，用6∶4的乙酸乙酯/己烷洗脱，蒸发所需要的馏份后得到标题化合物(101mg,90％)；υ最大(CH2Cl2)3381,2931,2111,1789(w),1755,1724,1470和1206cm-1；
                 1H NMR(CDCl3)0.73(3H,d,J6.7Hz),0.89(3H,
d,J7.0Hz),1.0-1.3(4H,m，包括1.19处的s),1.3-1.9(12H,m，包括1.43处
的s)，2.0-2.4(4H,m),3.36(1H,dd,J6.6,10.6Hz),4.31 and 4.40(2H,ABq
J18.3Hz),5.23(1H,dd,J1.4,17.4Hz),5.37(1H,dd,J1.3,11.1Hz),5.69(1H,
d,J8.5Hz),6.45(1H,dd,J11.0,17.4Hz),7.72(1H,s)；MS(ES-)m/z445(M-
H-).
实施例133．14-N-[2-(3-羟基吡啶-2-基硫代)-乙酰基]-氨甲酸姆替林
14-N-(氯代乙酰基)-氨甲酸姆替林(110mg,0.25mmol)在N,N-二甲基甲酰胺(4ml)中用碘化钾(166mg,1mmol)处理。10分钟后加入3-羟基-2-巯基吡啶(35mg,0.275mmol)、碳酸钾(35mg,0.25mmol)和N,N-二甲基甲酰胺(1ml)溶液。混和物搅拌24小时，然后加入到乙酸乙酯和水中。分层后，水层用乙酸乙酯再提取。合并的乙酸乙酯层用硫酸镁干燥并蒸发。残留物硅胶色谱纯化，用乙酸乙酯和己烷混和物洗脱，得到标题化合物(110mg,83％)；υ最大(KBr)2956,1782,1725,1711,1523,1491,1449和1299cm-1；
                             1H NMR[(CD3)2SO]0.66(3H,d,J6.1Hz),
0.82(3H,d,J6.7Hz),0.9-1.8(ca15H,m，包括1.14处的s和1.39处的s)，
2.0-2.3(4H,m),2.41(1H,br s),3.44(1H,br t,d,J5.4Hz在D2O交换后)，
4.04(2H,s),4.53(1,d J6.0Hz,D2O交换)5.04-5.15(2H,m),5.50(1H,d,J
7.9Hz),6.22(1H,dd,J11.1,17.7Hz),6.94-7.06(2H,m),7.83(1H,dd J1.4
和4.6Hz),10.43(1H,br s,D2O交换)，10.65(1H,s,D2O交换)；MS(CI)m/z
531(M+H)+.
实施例134．14-N-[2-(4-甲基嘧啶-2-基硫代)-乙酰基]-氨甲酸姆替林
使用实施例133所述同样步骤将2-巯基-4-甲基嘧啶(42mg,0.26mmol)经3天转换成标题化合物(95mg,71％)；υ最大(CH2Cl2)3377,3179,2961,1782(w),1734,1576,1545,1332,1217,1116和1016cm-1；
                                         1H NMR(CDCl3)特别0.61
(3H,d,J6.5Hz),0.87(3H,d,J7.0Hz),1.19(s,1.43(s),2.51(3H,s),3.34(1H,
dd,J6.6,11.1Hz),3.84和3.92(2H,ABq J15.1Hz),5.22(1H,dd,J1.4,17.3
Hz),5.37(1H,dd,J1.4,10.9Hz),5.71(1H,d,J8.5Hz),6.54(1H,dd,J11.0,
17.4Hz),6.96(1H,d J5.1Hz),8 41(1H,dJ5.2Hz),9.57(1H,brs)；MS(EI)
m/z 589(M+)；测定值：529.2607,C28H39N3O5S理论值529.2610.
实施例135．14-N-[2-(1-氧代吡啶-2-基硫代)-乙酰基]-氨甲酸姆替林
使用实施例133所述同样步骤将2-巯基吡啶1-氧化物(32mg,0.25mmol)经3天转换成标题化合物(87mg,65％)；υ最大(CH2Cl2)3386,2962,2932,1783,1734,1484,1204,1116和1016cm-1；
    1H NMR(CDCl3)特别0.72(3H,d,J6.7Hz),0.89(3H,d,J
7.0Hz),1.18(s),1.42(s),,3.36(1H,dd,J6.6,10.5Hz),4.06(2H,s),5.24(1H,
dd,J1.3,17.4Hz),5.41(1H,dd,J1.3,11.0Hz),5.73(1H,d,J8.4Hz),6.50
(1H,dd,J11.0,17.4Hz),7.3(1H,dt J1.7,6.5Hz),7.27(1H,dt,Jca.1.2,8
Hz)7.51(1H,dd J1.7,8.2Hz),8.27(1H,dd,J0.9,6.4),8.36(1H,br s)；
MS(CI)m/z 531(MH)+.
实施例136．14-N-(乙硫基-乙酰基)-氨甲酸姆替林
使用实施例133所述同样步骤，将氯代乙酰基化合物(280mg,0.64mmol)和乙硫醇钠(79mg)，没有碳酸钾情况下在26小时中转换成标题化合物(194mg,65％)；υ最大(CH2Cl2)3386,2962,2932,1782,1756(sh),1734,1716(sh),1484,1204,1116和1016cm-1；
                 1H NMR(CDCl3)特别0.76(3H,d,J6.7Hz),
0.89(3H,d,J7.1Hz),1.18(s),1.26(t,J7.4Hz),1.44(s),2.56(2H,q,J7.4
Hz),3.36(1H,dd,J6.6,11.7Hz),3.51和3.60(2H,ABq,J15.2Hz),5.22(1H,
dd,J1.5,17.4Hz),5.38(1H,dd,J1.4,10.9Hz),5.73(1H,d,J8.5Hz),6.51
(1H,dd,J11.0,17.3Hz),7.95(1H,br s)；MS(CI)m/z 483(MNH4)+.
实施例137．14-N-(乙基亚磺酰基-乙酰基)-氨甲酸姆替林
14-N-(乙硫基乙酰基)-氨甲酸姆替林(74mg,0.16mmol)在二氯甲烷(4ml)中用冰浴冷却并用间氯过苯甲酸(55％纯度，50mg,0.16mmol)处理，混和物搅拌2小时。用二氯甲烷稀释，碳酸氢钠水溶液洗涤，硫酸镁干燥并蒸发。残留物硅胶色谱纯化，用乙酸乙酯/己烷混和物洗脱，得到非对映体亚砜混和物的标题化合物(57mg,73％)；υ最大(CH2Cl2)3380,2940,2932,1781,1735,151 8,1470,1211,1116,1014和910cm-1；MS(ES-)m/z480(M-H)-。
实施例138．14-N-(乙基磺酰基-乙酰基)-氨甲酸姆替林
14-N-(乙硫基乙酰基)-氨甲酸姆替林(74mg,0.16mmol)在二氯甲烷(4ml)中用冰浴冷却并用间氯过苯甲酸(55％纯度，100mg,0.32mmol)处理，混和物搅拌2小时。用二氯甲烷稀释混和物，稀碳酸氢钠水溶液洗涤，硫酸镁干燥并蒸发。残留物硅胶色谱纯化，用乙酸乙酯/己烷混和物洗脱，得到标题化合物(36mg,45％)；υ最大((CH2Cl2)3373,2944,1787,1757,1733,1706,1469,1324,1208,1153,1116,1016,939和910cm-1；
                                                    1HNMR
(CDCl3)特别0.75(3H,d,J6.8Hz),0.89(3H,d,J7.0Hz),1.18(s),3.25
(2H,q,J7.5Hz),3.37(1H,dd,J6.7,9.8Hz),4.50(2H,br ABq),5.24(1H,dd,J
1.3,17.3Hz),5.37(1H,dd,J1.3,10.9Hz),5.71(1H,d,J8.4Hz),6.47(1H,dd,
J11.1,17.4Hz),8.19(1H,br s)；MS(ES-)m/z 496(M-H)-.
实施例139．14-N-[叔丁氧基羰基甲硫基乙酰基]-氨甲酸姆替林
14-N-(氯代乙酰基)-氨甲酸姆替林(55mg,0.125mmol)在N,N-二甲基甲酰胺(2ml)中用碘化钾(84mg,0.5mmol)和碳酸钾(18mg,0.125mmo1)处理。加入2-巯基乙酸叔丁酯(18.5mg,0.125mmol)的N,N-二甲基甲酰胺(0.5ml)溶液。混和物振荡17小时之后用乙酸乙酯(5ml)/水(7.5ml)处理。分离后乙酸乙酯层用1M氢氧化钠洗涤，硫酸镁干燥并蒸发。残留物硅胶色谱纯化，用乙酸乙酯/己烷混和物洗脱，得到标题化合物(44mg,63％)；
   1H NMR(CDCl3)特别0.76(3H,d,J6.7Hz),0.88(3H,d,J7.0Hz),
1.18(s),1.44(s),1.47(s),3.26(2H,s),3.36(1H,dd,J6.6,10.8Hz),3.64(2H,
br s),5.22(1H,dd,J1.4,17.3Hz),5.37(1H,dd,J1.3,11.0Hz),5.71(1H,d,J
8.4Hz),6.51(1H,dd,J11.0,17.3Hz),8.35(1H,br s).
实施例140．14-N-[2-(乙氧基羰基)乙硫基-乙酰基]-氨甲酸姆替林
使用实施例139所述同样步骤，将14-N-(氯乙酰基)-氨甲酸姆替林(55mg,0.125mmol)和3-巯基丙酸乙酯(16.8mg,0.125mmol)转化成标题化合物(51mg,75％)；                           1H NMR(CDCl3)
特别0.75(3H,d,J6.7Hz),0.88(3H,d,J7.0Hz),1.19(s),1.26(t,J7.2
Hz),1.44(s),2.62(2H,t,J6.8Hz),2.84(2H,t,J6.7Hz),3.36(1H,dd,J6.6,
10.6Hz),3.56和3.64(2H,ABq,J15.0Hz),5.22(1H,dd,J1.4,17.3Hz),5.37
(1H,dd,J1.3,11.0Hz),5.71(1H,d,J8.4Hz),6.48(1H,dd,J11.0,17.3Hz),
7.90(1H,br s).
实施例141．14-N-[(5-甲基-1,3,4-噻二唑-2-基硫代)-乙酰基]-氨甲酸姆替林
使用实施例139所述同样方法，将14-N-(氯乙酰基)-氨甲酸姆替林(55mg,0.125mmol)和2-巯基-5-甲基-1,3,4-噻二唑(16.5mg,0.125mmol)转换成标题化合物(38mg,56％)；
                                              1H
NMR(CDCl3)特别0.65(3H,d,J6.7Hz),0.88(3H,d,J7.0Hz),1.18(s),
1.42(s),2.74(s,3H),3.35(1H,dd,J6.6,10.9 Hz),4.14和4.33(2H,ABq,J
15.5Hz),5.22(1H,dd,J1.4,17.3Hz),5.38(1H,dd,J1.4,11.0Hz),5.70(1H,
d,J8.4Hz),6.53(1H,dd,J11.0,17.3Hz),9.05(1H,br s).
实施例142．14-N-[(1-甲基四唑-5-基硫代)-乙酰基]-氨甲酸姆替林
使用实施例139所述同样方法将14-N-(氯乙酰基)-氨甲酸姆替林(55mg,0.125mmol)和5-巯基-1-甲基-四唑(14.5mg,0.125mmol)转换成标题化合物(28mg,43％)；
                                                      1HNMR
(CDCl3)特别0.71(3H,d,J6.7Hz),0.89(3H,d,J6.9Hz),1.19(s),1.41
(s),3.36(1H,dd,J6.6,10.7Hz),3.98(3H,s),4.46和4.54(2H,ABq,J16.8
Hz),5.24(1H,dd,J1.4,17.4Hz),5.39(1H,dd,J1.3,11.1Hz),5.71(1H,d,J
8.4Hz),6.49(1H,dd,J11.0,17.3Hz),8.44(1H,br s).
实施例143．14-N-[(1-苯基-四唑-5-基硫代)-乙酰基]-氨甲酸姆替林
使用实施例139所述同样方法将14-N-(氯乙酰基)-氨甲酸姆替林(55mg,0.125mmol)和5-巯基-1-苯基-四唑(22.3mg,0.125mmol)转换成标题化合物(60mg,82％)；
                                                     1HNMR
(CDCl3)特别0.72(3H,d,J6.7Hz),0.89(3H,d,J7.0Hz),1.20(s),1.44
(s),3.37(1H,dd,J6.6,10.8Hz),4.50和4.60(2H,ABq,J16.6Hz),5.24(1H,
dd,J1.4,17.4Hz),5.38(1H,dd,J1.3,11.0Hz),5.73(1H,d,J8.7Hz),6.50
(1H,dd,J11.0,17.4Hz),7.58(5H,s),8.39(1H,br s).
实施例144．14-N-[(1,3,4-噻二唑-2-基硫代)-乙酰基]-氨甲酸姆替林
使用实施例139所述同样方法将14-N-(氯乙酰基)-氨甲酸姆替林(55mg,0.125mmol)和2-巯基-1,3,4-噻二唑(14.9mg,0.125mmol)转换成标题化合物(37mg,60％)；
                                                     1HNMR
(CDCl3)特别0.67(3H,d,J6.7Hz),0.88(3H,d,J6.9Hz),1.19(s),1.42
(s),3.36(1H,dd,J6.5,10.9Hz),4.29和4.47(2H,ABq,J15.8Hz),5.24(1H,
d,J17.3Hz),5.38(1H,d,J12.0Hz),5.70(1H,d,J8.4Hz),6.51(1H,dd,J
11.0,17.4Hz),8.77(1H,br s),9.13(1H,s).
实施例145．14-N-[(5-氨基羰基-1,3,4-噻二唑-2-基硫代)-乙酰基]-氨甲酸姆替林
使用实施例139所述同样方法将14-N-(氯乙酰基)-氨甲酸姆替林(55mg,0.125mmol)和2-巯基-1,3,4-噻二唑-5-氨甲酸酯(16.1mg,0.125mmol)转换成标题化合物(21mg,29％)；
                                                1H
NMR(CDCl3)特别0.67(3H,d,J6.7Hz),0.88(3H,d,J7.0Hz),1.19(s),
1.42(s),3.36(1H,dd,J6.5,10.8Hz),4.29和4.47(2H,ABq,J15.8Hz),5.24
(1H,d,J17.5Hz),5.39(1H,d,J10.9Hz),5.71(1H,d,J8.4Hz),5.86(1H,s),
6.51(1H,dd,J11.0,17.3Hz),7.10(1H,s),8.48(1H,br s).
实施例146．14-N-[(5-氨基羰基-1,3,4-噁二唑-2-基硫代)-乙酰基]-氨甲酸姆替林
使用实施例139所述同样方法将14-N-(氯乙酰基)-氨甲酸姆替林(55mg,0.125mmol)和2-巯基-1,3,4-噁二唑-5-氨甲酸酯(20.1mg,0.125mmol)转换成标题化合物(8mg,11％)；                   1H
NMR(CDCl3)特别0.73(3H,d,J6.8Hz),0.90(3H,d,J6.8Hz),1.19(s),
1.43(s),3.37(1H,dd),4.54和4.61(2H,ABq,J17.0Hz),5.25(1H,dd,J1.3,
17.4Hz),5.39(1H,dd,J1.2,11.0Hz),5.72(1H,d,J8.4Hz),6.01(1H,br s),
6.48(1H,dd,J11.1,17.4Hz),7.01(1H,br s),8.21(1H,br s).
实施例147．14-N-[1-(2-二甲氨基乙基)-四唑-5-基硫代]-乙酰基}-氨甲酸姆替林
14-N-(碘代乙酰基)-氨甲酸姆替林(133mg,0.25mmol)在N,N-二甲基甲酰胺(2ml)中用碳酸钾(35mg,0.25mmol)和1-(2-二甲氨基乙基)-5-巯基四唑(43mg,0.25mmol)处理。混和物摇荡17小时后用乙酸乙酯(5ml)/水(5ml)处理。分离后水层用乙酸乙酯(5ml)再提取，食盐水洗涤合并的乙酸乙酯层，硫酸镁干燥并蒸发。残留物硅胶色谱纯化，用乙酸乙酯/己烷混和物洗脱，得到标题化合物(96mg,66％)；υ最大(CH2Cl2)3384,2948,1782,1733,1468,1390,1215,112,1116,1016和938cm-1；
    1H NMR(CDCl3)特别0.68(3H,d,J6.7Hz),0.87(3H,d,J7.0Hz),
1.17(s),1.42(s).2.23(s),2.73(2H,t,J6.2Hz),3.34(1H,dd,J6.5,10.5Hz),
4.33(4H,tJ6.1Hz),5.21(1H,dd,J1.3,17.3Hz),5.37(1H,dd,J1.3,11.0Hz),
5.69(1H,d,J8.4Hz),6.49(1H,dd,J11.0,17.4Hz),8.68(1H,br s)；MS(EI)
m/z 576(M+)；测定值：576.3072,C28H44N6O5S理论值576.3094.
实施例148．14-N-[(1,2,3-三唑-5-基硫代)-乙酰基]-氨甲酸姆替林
使用实施例147同样方法将14-N-(碘代乙酰基)-氨甲酸姆替林(133mg,0.25mmol)和5-巯基-1,2,3-三唑的钠盐(31mg,0.25mmol)在没有碳酸钾情况下转换成标题化合物(75mg,55％)；υ最大(CH2Cl2)3408,3220,2930,1781,1733,1471,1410,1387,1209,1116和1016cm-1；
                       1H NMR(CDCl3)特别0.70(3H,d,
J6.7Hz),0.87(3H,d,J7.0Hz),1.17(s),1.42(s),3.35(1H,br s),3.93(2H,
s),5.21(1H,dd,J1.3,17.4Hz),5.35(1H,dd,J1.2,11.1Hz),5.69(1H,d,J8.4
Hz),6.49(1H,dd,J11.0,17.4Hz),7.67(1H,s),8.65(1H,br s)；MS(CI)m/z
522(MNH4)+.
实施例149．14-N-{[1-(甲氧基羰基甲基)-四唑-5-基硫代]-乙酰基}-氨甲酸姆替林
使用实施例147同样方法将14-N-(碘代乙酰基)-氨甲酸姆替林(133mg,0.25mmol)和5-(巯基-四唑-1-基)乙酸甲酯(44mg,0.25mmol)转换成标题化合物(77mg,53％)；υ最大(CH2Cl2)3380,2958,1783,1759,1733,1459,1217,1183,1116,1016和939cm-1；
                                                      1H
NMR(CDCl3)特别0.69(3H,d,J6.8Hz),0.87(3H,d,J7.0Hz),1.17(s),
1.41(s),3.35(1H,dd,J6.5,10.7Hz),4.46和4.56(2H,ABq J16.9Hz),5.13
(2H,s),5.22(1H,dd,J1.3,17.3Hz),5.37(1H,dd,J1.3,11.1Hz),5.69(1H,d,
J8.4Hz),6.47(1H,dd,J11.0,17.4Hz),8.26(1H,br s)；MS(CI)m/z 595
(MNH4)+.
实施例150．14-N-{[3-(甲氧基羰基)-吡啶-2-基硫代]-乙酰基}-氨甲酸姆替林
使用实施例147同样方法将14-N-(碘代乙酰基)-氨甲酸姆替林(133mg,0.25mmol)和2-巯基-吡啶-3-羧酸甲酯(42mg,0.25mmol)转换成标题化合物(48mg,33％)；υ最大(CH2Cl2)3380,2956,1781,1720,1401,1214,1139,1116,1071和1016cm-1；
   1H NMR(CDCl3)特别0.55(3H,d,J6.6Hz),0.84(3H,d,J7.0Hz),
1.14(s),1.36(s),3.31(1H,dd,J6.6,11.0Hz),3.91(2H,s),3.94(3H,s),5.19
(1H,dd,J1.4,17.3Hz),5.35(1H,dd,J1.4,10.9Hz),5.65(1H,d,J8.5Hz),
6.47(1H,dd,J11.0,17.4Hz),7.20(1H,ddJ5.0,7.8Hz),8.30(1H,dd J1.8,
7.8Hz),8.55(1H,dd,J1.7,4.8Hz),9.45(1H,br s)；MS(CI)m/z 573(MH)+.
实施例151．14-N-[(2-呋喃甲基硫代)-乙酰基]-氨甲酸姆替林
使用实施例147同样方法将14-N-(碘代乙酰基)-氨甲酸姆替林(133mg,0.25mmol)和2-(呋喃基)-甲基硫醇(29mg,0.25mmol)转换成标题化合物(43mg,53％)；υ最大(CH2Cl2)3382,2930,1783,1734,1483,1206,1152,1116,1014和938cm-1；
                                                 1H NMR(CDCl3)
特别0.73(3H,d,J6.6Hz),0.87(3H,d,J7.0Hz),1.18(s),1.42(s),3.35
(1H,dd,J6.7,10.7Hz),3.48和3.56(2H,ABq J15.7Hz),3.76(2H,s),5.21
(1H,dd,J1.4,17.3Hz),5.36(1H,dd,J1.3,11.1Hz),5.70(1H,d,J8.4Hz),
6.21(1H,d,J3.4Hz),6.28(1H,J d1.9,5.01Hz),6.48(1H,dd,J11.0,17.4
Hz),7.34(1H,dd J0.8,1.9Hz),7.80(1H,br s)；MS(CI)m/z 535(MNH4)+.
实施例152．14-N-[(2,3-二羟丙基硫代)-乙酰基]-氨甲酸姆替林
使用实施例147同样方法将14-N-(碘代乙酰基)-氨甲酸姆替林(133mg,0.25mmol)和3-巯基-1,2-丙二醇(0.021ml,27mg,0.25mmol)转换成标题化合物(37mg,28％)；υ最大(CH2Cl2)3380,2929,1782,1733,1471,1409,1206,1115和1016cm-1；
                                                      1H NMR
(CDCl3)特别0.74(3H,d,J6.5Hz),0.87(3H,d,J7.0Hz),1.17(s),1.42
(s),2.56-2.81(2H,m),3.12(1H,s,D2O交换),3.35(1H,dd,J6.6,10.5Hz；d,
J6.4在D2O交换后),3.50-3.58(1H,m),3.96-4.11(2H,m),4.13-4.21(1H,
m),5.21(1H,dd,J1.3,17.4Hz),5.36(1H,d,J11.1Hz),5.69(1H,d,J8.4Hz),
6.47(1H,dd,J11.0,17.4Hz),7.99(1H,br s)；MS(ES+)m/z 529(MNH4)+.
实施例153．14-N-[(吡啶-2-基硫代)-乙酰基]-氨甲酸姆替林
使用实施例147同样方法将14-N-(碘代乙酰基)-氨甲酸姆替林(133mg,0.25mmol)和2-巯基-吡啶(28mg,0.25mmol)转换成标题化合物(107mg,83％)；υ最大(CH2Cl2)3557,3379,3151,2932,1779,1733,1584,1527,1456,1417,1220,1152,1116,1034和1016cm-1；
1H NMR(CDCl3)特别0.56(3H,d,J6.4Hz),0.84(3H,d,J
7.0Hz),1.14(s),1.38(s),3.32(1H,d,J6.5,Hz),3.70和3.84(2H,ABq,J
14.5Hz),5.19(1H,dd,J1.5,17.4Hz),5.35(1H,dd,J1.5,10.9Hz),5.65(1H,
d,J8.6Hz),6.57(1H,dd,J10.9,17.3Hz),7.06-7.16(1H,m),7.24-7.30(2H,
m),7.55(1H,m),8.42-8.45(1H,m),10.71(1H,br s)；MS(EI)m/z 514(M+)；
测定值：514.2485,C28H38N2O5S理论值514.2501.
实施例154．14-N-[(氰基硫代)-乙酰基]-氨甲酸姆替林
使用实施例147同样方法将14-N-(碘代乙酰基)-氨甲酸姆替林(133mg,0.25mmol)和硫氰酸铵(19mg,0.25mmol)在没有碳酸钾情况下转换成标题化合物(105mg,90％)；υ最大(CH2Cl2)3376,2931,1752,1735,1721,1472,1216,1188,1116,1016和939cm-1；
1H NMR(CDCl3)特别0.72(3H,d,J6.9Hz),0.88
(3H,d,J7.0Hz),1.18(s),1.41(s),3.36(1H,dd,J6.6,10.4Hz),4.37(2H,s),
5.23(1H,dd,J1.3,17.3Hz),5.38(1H,dd,J1.2,10.9Hz),5.68(1H,d,J8.5
Hz),6.41(1H,dd,J11.0,17.4Hz),7.94(1H,brs)；MS(ES-)m/z 461(M-H)-.
实施例155．14-N-[N-乙酰基甘氨酰基]-氨甲酸姆替林
14-N-(叠氮基乙酰基)-氨甲酸姆替林(113mg,0.25mmol)在干四氢呋喃(1ml)中于氩气氛用三正丁基膦(0.045ml,55mg,0.275mmol)处理，氩气氛下搅拌混和物1小时。然后将溶液冷却到-50℃，加入乙酰氯(0.024ml,21mg,0.275mmol)。混和物搅拌45分钟后加入饱和碳酸氢钠水溶液(0.5ml)，让混和物暖热到室温。加入乙酸乙酯和食盐水，分层，硫酸镁干燥乙酸乙酯层并蒸发。残留物硅胶色谱纯化，用乙酸乙酯/己烷混和物洗脱，得到标题化合物(20mg,17％)；υ最大(CH2Cl2)3427,3385,2961,2935,1783,1756,1732,1674,1509和1474cm-1；
        1H NMR(CDCl3)特别0.71(3H,d,J6.8Hz),0.87(3H,d,
J7.0Hz),1.17(s),1.41(s),2.04(s),2.54(1H,br d J6.0Hz\),4.38和4.47
(2H,dABq,J4.9和19Hz),5.21(1H,dd,J1.1,17.3Hz),5.36(1H,dd,J1.1,
10.9Hz),5.68(1H,d,J8.4Hz),6.26(1H,brt,J约4.6Hz),6.46(1H,dd,J
11.1,17.4Hz),8.06(1H,br s)；(MS)(ES-)461(M-H)-.
实施例156．14-N-(N,N-二乙基甘氨酰基)-氨甲酸姆替林
14-N-(碘代乙酰基)-氨甲酸姆替林(133mg,0.25mmol)在乙醚(1.5ml)中用二乙胺(0.03ml)处理。2小时和再6小时后，加入等分试样的二乙胺(0.03ml)，继续搅拌17小时。加入乙酸乙酯/水，随后加入1M氢氧化钠(2ml)。用乙酸乙酯再提取水层，硫酸镁干燥合并的乙酸乙酯层并蒸发。硅胶色谱纯化，用6∶4的乙酸乙酯/己烷混和物洗脱，蒸发所需要的馏份得到标题化合物(103mg,83％)；MS(CI)m/z477(MH)+。
实施例157．14-{N-[(1-甲基-1,2,3-三唑-4-基)-羰基]-氨甲酸}姆替林
步骤1．14-{N-[(1-甲基-1,2,3-三唑-4-基)-羰基]-氨甲酸}的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
1-甲基-1,2,3-三唑-4-羧酸(2.0g)在二氯甲烷(50ml)中用草酰氯(2.40g)和两滴DMF室温处理3小时。IR分析表明完全转换成酰氯。真空去除溶剂和过量的草酰氯，再从甲苯蒸发残留物得到白色固体状的酰氯。
酰氯(0.436g)、氰酸银(450mg)和(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(334mg)悬浮在干二氯甲烷(5ml)中，室温搅拌4小时。所得悬浮液通过硅藻土过滤，用二氯甲烷充分洗涤。有机溶液用水、饱和氯化钠溶液洗涤，硫酸镁干燥。过滤后蒸发溶剂得到粗产物。硅胶色谱纯化，乙酸乙酯-己烷混和物洗脱得到无色泡沫状的标题化合物(486mg)；
                                                           1H NMR
(CDCl3)0.90(3H,d,J6.9Hz),1.00(3H,d,J6.4Hz),1.05-1.80(m),1.21(3H,s),
1.30(3H,s),1.90-2.10(2H,m),2.14-2.28(1H,m)2.52(1H,dd,J10.1,15.3Hz),
2.90(1H,q,J6.4Hz),3.24(3H,s),3.40-3.55(1H,m),4.20(3H,s),5.00(1H,d,
J17.5Hz),5.30(1H,d,J10.8Hz),5.83(1H,d,J9.9Hz),6.78(1H,dd,
J10.7,17.5Hz),8.20(1H,s)和9.10(1H,s).
步骤2．14-{N-[(1-甲基-1,2,3-三唑-4-基)-羰基]-氨甲酸}姆替林
步骤1的产物(450mg)在1,4-二噁烷(4ml)中于室温用卢卡斯试剂(1.25ml)处理8小时，然后用乙酸乙酯稀释溶液，用饱和碳酸氢钠溶液中和。将有机溶液用饱和氯化钠洗涤，硫酸镁干燥并蒸发得到粗产物。硅胶色谱纯化，分离得到白色固体状的标题化合物(405mg)；
1H NMR(CDCl3)0.79(3H,d,J6.5Hz),0.89(3H,d,
J7.0Hz),1.20(3H,s),1.40-1.90(m),1.52(3H,s),2.08-2.45(5H,m),3.39(1H,
dd,J6.6,11.0Hz),4.19(3H,3),5.22(1H,dd,J1.5,17.4Hz),5.39(1H,dd,
J1.4,10.9Hz),5.83(1H,d,J8.4Hz),6.59(1H,dd,J10.95,17.3Hz)8.19(1H,s)
和9.03(1H,s)；MS(NH4DCI)m/z 490(MNH4 +),473(MH+).
实施例158．14-{N-[(1,2,3-噻二唑-4-基)-羰基]-氨甲酸}姆替林
步骤1．14-{N-[(1,2,3-噻二唑-4-基)-羰基]-氨甲酸}的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
1,2,3-噻二唑-4-羧酸转换成酰氯并与(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(334mg)如实施例157所述进行反应。硅胶色谱纯化后，得到无色泡沫状的标题化合物(490mg)；
1H NMR(CDCl3)0.90(3H,d,J6.9Hz),1.00(3H,d,J6.4Hz),1.05-1.68(m),
1.21(3H,s),1.30(3H,s),1.7-1.82(2H,m),1.92-2.10(2H,m),2.14-2.28(1H,
m)2.58(1H,dd,J10.1,15.3Hz),2.90(1H,q,J6.3Hz),3.25(3H,s),3.40-3.55
(1H,m),5.02(1H,d,J17.5Hz),5.32(1H,d,J10.0Hz),5.89(1H,d,J9.9Hz),
6.77(1H,dd,J10.6,17.5Hz),9.42(1H,s)和9.43(1H,s)
步骤2．14-{N-[(1,2,3-噻二唑-4-基)-羰基]-氨甲酸}姆替林
步骤1的产物(460mg)在1,4-二噁烷(4ml)中于室温用卢卡斯试剂(1.25ml)处理7小时。然后用乙酸乙酯稀释溶液，用饱和碳酸氢钠溶液中和。有机溶液用饱和氯化钠洗涤，硫酸镁干燥并蒸发得到粗产物。硅胶色谱纯化后，分离得到白色固体状的标题化合物(359mg)；
1H NMR(CDCl3)0.81(3H,d,J6.7Hz),0.90(3H,d,
J7.0Hz),1.20(3H,s),1.38-1.88(m),1.55(3H,s),2.10-2.45(5H,m),3.39(1H,
dd,J6.6,10.9Hz),5.22(1H,dd,J1.5,17.2Hz),5.40(1H,dd,J1.4,11.1Hz),5.89
(1H,d,J8.5Hz),6.59(1H,dd,J11.05,17.4Hz)和9.40(2H,s):MS(NH4DCI)
m/z 493(MNH4 +).
实施例159．14-{N-[(1-乙基-5-甲基吡唑-3-基)-羰基]-氨甲酸}姆替林
步骤1．14-{N-[(1-乙基-5-甲基吡唑-3-基)-羰基]-氨甲酸}的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
1-乙基-5-甲基吡唑-3-羧酸转换成酰氯并与(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(334mg)如实施例157所述进行反应。硅胶色谱纯化后，得到无色泡沫状的标题化合物(140mg)；
1H NMR(CDCl3)0.90(3H,d,J6.9Hz),1.00(3H,d,J6.4Hz),1.05-1.64(m),
1.20(3H,s),1.37(3H,s),1.42(3H,t,J7.3Hz),1.71(1H,d,J5.5Hz),1.79(1H,s),
1.95-2.10(2H,m),2.12-2.29(1H,m),2.31(3H,s),2.52(1H,dd,J10.1,15.3Hz),
2.92(1H,q,J6.3Hz),3.22(3H.s),3.40-3.55(1H,m),4.12(2H,q,J7.25Hz),5.02
(1H,d,J17.5Hz),5.28(1H,d,J10.7Hz),5.83(1H,d,J9.9Hz),6.63(1H,s),6.78
(1H,dd,J10.7,17.5Hz)，和8.88(1H,s).
步骤2．14-{N-[(1-乙基-5-甲基吡唑-3-基)-羰基]-氨甲酸)姆替林步骤1的产物(130mg)在1,4-二
Figure A9618017701261
烷(3.5ml)中于室温和卢卡斯试剂(1.0ml)处理5小时。然后用乙酸乙酯稀释溶液，饱和碳酸氢钠溶液中和。将有机相用饱和氯化钠洗涤，硫酸镁干燥并蒸发得到粗产物。硅胶色谱纯化后，分离得到白色固体状的标题化合物(13.3mg)；
           1H NMR(CDCl3)0.80(3H,d,J6.5Hz),O.90(3H,d,
J7.0Hz),1.19(3H,s),1.35-1.88(m),1.46(3H,t,J7.22Hz),1.55(3H,s),2.30
(3H,s),2.05-2.45(5H,m),3.38(1H,dd,J6.5,10.9Hz),4.10(2H,q,J7.25Hz),
5.22(1H,dd,J1.6,17.4Hz),5-39(1H,dd,J1.4,10.9Hz),5.85(1H,d,J8.5Hz),
6.59(1H,dd,J11.0,17.4Hz)6.61(1H,s)和8.80(1H,s)；MS(EI)m/z 499.
实施例160．14-{N-[(1,5-二甲基吡唑-3-基)-羰基]-氨甲酸}姆替林
步骤1．14-{N-[(1,5-二甲基吡唑-3-基)-羰基]-氨甲酸}的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
1,5-二甲基吡唑-3-羧酸转换成酰氯并与(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(334mg)如实施例157所述进行反应。硅胶色谱纯化后，得到无色多泡的标题化合物(450mg)；
1H NMR(CDCl3)0.90(3H,d,J6.9Hz),1.00(3H,d,J6.4Hz),1.05-1.65(m),
1.20(3H,s),1.35(3H,s),1.70(1H,d,J6.5Hz),1.78(1H,d,J2.2Hz),1.95-2.10
(2H,m),2.14-2.28(1H,m),2.30(3H,s),2.51(1H,dd,J10.1,15.3Hz),2.92(1H,
q,J6.3Hz),3.22(3H,s),3.40-3.57(1H,m),3.81(3H,s),5.0(1H,d,J17.2Hz),
5.29(1H,d,J10.7Hz),5.82(1H,d,J9.9Hz),6.63(1H,s),6.78(1H,dd,
J10.7,17.5Hz),和8.84(1H,s).
步骤2．14-{N-[(1,5-二甲基吡唑-3-基)-羰基]-氨甲酸}姆替林
步骤1的产物(420mg)在1,4-二噁烷(4.0ml)中于室温用卢卡斯试剂(1.4ml)处理4小时。然后用乙酸乙酯稀释溶液，饱和碳酸氢钠溶液中和。有机相用饱和氯化钠洗涤，硫酸镁干燥并蒸发得到粗产物。硅胶色谱纯化后，分离得到白色固体状的标题化合物(360mg)；
      1H NMR(CDCl3)0.80(3H,d,J6.5Hz),0.90(3H,d,
J7.0Hz),1.19(3H,s),1.32-1.88(m),1.55(3H,s),2.29(3H,s),2.05-2.45(5H，
m),3.39(1H,dd,J6.5,10.9Hz),3.80(3H,s),5.22(1H,dd,J1.6,17.4Hz),5.39
(1H,dd,J1.4,10.9Hz),5.82(1H,d,J8.5Hz),6.60(1H,dd,J11.0,17.4Hz)6.62
(1H,s)和8.79(1H,s)；MS(EI)m/z 485.
实施例161．14-[N-(N-甲基哌啶甲酰基)-氨甲酸]姆替林
步骤1．14-[N-(N-甲基哌啶甲酰基)-氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
N-甲基哌啶甲酸(()-乙酯(5.0g)溶于5M盐酸(100ml)并于室温搅拌16小时。然后减压蒸发溶液,残留物从甲苯(×2)再蒸发。研制得到(()-N-甲基哌啶甲酸盐酸盐的白色固体(3.91g)。
(±)-N-甲基哌啶甲酸盐酸盐(1.0g)悬浮于二氯甲烷(25ml)并与草酰氯(0.58ml)和一滴DMF室温搅拌2小时。蒸发溶剂得到N-甲基哌啶甲酰氯盐酸盐的浅黄色固体。
上述酰氯(0.596g)悬浮于干二氯甲烷中并与(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(334mg)和氰酸银(450mg)以及三乙胺(0.276ml)室温搅拌4小时。硅藻土过滤悬浮液，用乙酸乙酯稀释，水和饱和氯化钠溶液洗涤。用硫酸镁干燥有机溶液并蒸发得到粗产物。硅胶色谱纯化，用0-5％的9∶1甲醇/35％氨溶液的二氯甲烷溶液梯度洗脱，得到无色油状非对映体混和物的标题化合物(290mg)；
                                               1H NMR(CDCl3)0.85
and 0.88(2xd,所有3H,J6.9Hz),1.00(3H,d,J6.4Hz),1.05-1.85(m),1.20(3H,s),
1.25(3H,s),1.9-2.40(6H,m),2.32(3H,2xs),2.48(1H,m),2.69(1H,宽
res.),2.80-2.98(3H,宽q,),3.22(3H,s),3.40-3.53(1H,m),4.98(1H,d,
J17.6Hz),5.29(1H,d,J10.7Hz),5.62-5.72(1H,2xd,J9.9Hz)和6.78-6.91
(1H,m)；MS(EI)m/z 503.
步骤2．14-[N-(N-甲基哌啶甲酰基)-氨甲酸]-姆替林
步骤1的产物(250mg)在1,4-二噁烷(3.0ml)中于室温与浓盐酸(2.0ml)搅拌4小时。然后用乙酸乙酯稀释溶液，饱和碳酸氢钠溶液中和。饱和氯化钠洗涤有机溶液，硫酸镁干燥并蒸发得到粗产物。硅胶色谱纯化，0-5％的9∶1甲醇/35％氨溶液的二氯甲烷溶液梯度洗脱，分离得到白色泡沫状的非对映体混和物的标题化合物(205mg)；
                                                    1H NMR
(CDCl3)0.78(3H,2xd,J6.7Hz),0.89(3H,d,J7.0Hz),1.19(3H,s),1.35-2.40
(m),1.47(3H,s),2.30(3H,2xs),2.63-2.90(2H,宽res.),3.35(1H,宽
res.),5.22(1H,d,J17.4Hz),5.39(1H,dd,J1.4,11.0Hz),5.60-5.72(1H,2xd,J8.5
Hz),和6.63(1H,dd,J11.0,17.4Hz)；MS(EI)m/z 488.
实施例162．14-[N-(1-甲基-吡咯烷-3-酰基)-氨甲酸]姆替林
步骤1．3-乙氧基羰基-1-甲基吡咯烷-2-酮
1-甲基-2-吡咯烷酮(9.9g)和碳酸二乙酯(50g)溶于甲苯并在带有除水配置(Dean和Stark装置)下回流1小时。冷却后仔细加入氢化钠(50％油中分散体；8.53g)，氩气氛下搅拌加热至回流该悬浮液4小时。冷却后加入醋酸(15ml)并过滤该悬浮液。蒸发滤液，硅胶色谱纯化残留物，得到无色油状所需要的产物(5.9g)；
   1H NMR(CDCl3)1.30(3H,t),2.18-2.50(2H,m),2.88(3H,s),3.3-3.59(3H,m),4.25(2H,t).
步骤2．3-乙氧基羰基-1-甲基吡咯烷
步骤1的产物(2.0g)溶于干二氯甲烷(MDC)并加入四氟硼酸三乙氧鎓(2.8g)的MDC(100ml)溶液。氩气氛下室温搅拌溶液16小时然后蒸发。残留物溶于乙醇，氩气氛下冷却到冰浴温度并加入硼氢化钠(0.889g)。室温搅拌所得溶液16小时。加入水(15ml)，蒸发溶液，并再从甲苯蒸发(×2)。残留物硅胶色谱纯化，用0-20％甲醇/35％氨溶液(9∶1)的DMC溶液梯度洗脱，得到浅黄色油状所需要的产物(450mg)；MS(ES)m/z158(MH)+。
步骤3．14-[N-(1-甲基吡咯烷-3-酰基)-氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤2的乙酯按照实施例5步骤1所述方法转换成酰氯。这种酰氯按照实施例5方法与(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(668mg)进行反应，得到浅黄色泡沫状非对映体混和物的标题化合物(350mg)；MS(ES)m/z489(MH+)。
步骤4．14-[N-(1-甲基吡咯烷-3-酰基)-氨甲酸]姆替林
步骤3产物(320mg)在1,4-二噁烷(4.0ml)中用浓盐酸(2.0ml)室温搅拌处理4小时。然后用乙酸乙酯稀释溶液，用饱和碳酸氢钠溶液中和。用饱和氯化钠溶液洗涤有机溶液，硫酸镁干燥并蒸发得到粗产物。硅胶色谱纯化，0-5％甲醇/35％氨溶液(9∶1)的二氯甲烷溶液梯度洗脱，分离得到浅黄色泡沫状非对映体混和物的标题化合物(245mg)；
1H NMR(CDCl3)特别0.75(3H,d,J6.7Hz),0.89(3H,d,J7.0Hz),1.19
(3H,s),1.48(3H,s),2.42(3H,2xs),2.82-3.05(2H,宽res.),3.37(1H,宽
res.),5.22(1H,d),5.38(1H,d)5.60-5.72(1H,2xd,J8.6Hz),和6.50-6.65(1H,
m)；MS(ES)m/z 475(MH+).
实施例163．14-[N-(1-烯丙基哌啶-4-酰基)-氨甲酸]姆替林
步骤1．14-[N-(1-烯丙基哌啶-4-酰基)-氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
1-烯丙基哌啶-4-羧酸按照实施例161所述工序转换成酰氯盐酸盐。然后将这种酰氯与(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(334mg)按照实施例161所述工序进行反应，硅胶色谱后得到无色泡沫状标题化合物(373mg)；MS(ES)m/z529(MH+)。
步骤2．14-[N-(1-烯丙基哌啶-4-酰基)-氨甲酸]-姆替林
步骤1的产物(340mg)在1,4-二噁烷(3.0ml)中于室温与浓盐酸(2.0ml)搅拌7小时，然后用乙酸乙酯稀释溶液，饱和碳酸氢钠溶液中和。用饱和氯化钠溶液洗涤有机溶液，硫酸镁干燥并蒸发得到粗产物。硅胶色谱纯化，用0-10％的9∶1甲醇/35％氨溶液的二氯甲烷溶液梯度洗脱，分离得到白色固体状的标题化合物(192mg)；
                               1H NMR(CDCl3)0.75(3H,d,J6.5Hz),0.89
(3H,d,J7.0Hz),1.20(3H,s),1.40-2.45(m),1.45(3H,s),2.90-3.10(5H,m),
3.39(1H,dd,J6.6,10.4Hz),5.10-5.30(3H,m),5.37(1H,dd,J1.2,10.9Hz),5.70
(1H,d,J8.4Hz),5.78-5.98(1H,m),6.50(1H,dd,J11.10,17.4Hz)和7.43(1H,
s)；MS(ES)m/z 515(MH+)
实施例164．14-[N-(1-环丙基甲基哌啶-4-酰基)-氨甲酸]姆替林
步骤1．14-[N-(1-环丙基甲基哌啶-4-酰基)-氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
1-环丙基甲基哌啶-4-羧酸按照实施例161所述工序转换成酰氯盐酸盐。然后将这种酰氯与(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(334mg)按照实施例161所述工序进行反应，硅胶柱色谱后得到无色泡沫状标题化合物(450mg)；MS(EI)m/z542(M+)。
步骤2．14-[N-(1-环丙基甲基哌啶-4-酰基)-氨甲酸]-姆替林
步骤1的产物(400mg)在1,4-二噁烷(5.0ml)中于室温与浓盐酸(2.0ml)搅拌7小时，然后用乙酸乙酯稀释溶液，饱和碳酸氢钠溶液中和。饱和氯化钠溶液洗涤有机溶液，硫酸镁干燥并蒸发得到粗产物。硅胶色谱纯化，用0-10％的9∶1甲醇/35％氨溶液的二氯甲烷溶液梯度洗脱，分离得到白色固体状的标题化合物(190mg)；
                        1H NMR(CDCl3)0.12(2H,m),0.53(2H,
m),0.75(3H,d,J6.5Hz),0.90(3H,d,J7.0Hz),1.20(3H,s),1.35-2.40(m),1.42
(3H,s),2.95-3.18(3H,m),3.39(1H,dd,J6.6,10.4Hz),5.25(1H,dd,J1.4,
17.4Hz),5.38(1H,dd,J1.2,10.9Hz),5.70(1H,d,J8.4Hz),6.50(1H,dd,
J11.10,17.4Hz)和7.40(1H,s)；MS(EI)m/z 515.
实施例165．14-[N-(1-哌啶甲酰基)-氨甲酸]姆替林
步骤1．N-叔丁氧羰基哌啶甲酸
(±)-哌啶甲酸溶于水(25ml)并于室温与叔丁氧基羰基酸酐(3.27g)的二噁烷(25ml)溶液快速搅拌16小时。然后蒸发溶液减少体积，加入5M盐酸溶液调节pH到2.0，所得沉淀用二氯甲烷提取。用食盐水洗涤有机溶液，硫酸镁干燥并减压蒸发。残留物用醚/己烷研制，过滤收集所得的白色固体(1.10g)；MS(EI)m/z229。
步骤2．11-二氯乙酰基-14-[N-(N-叔丁氧基羰基哌啶甲酰基)-氨甲酸]-姆替林
步骤1的产物(458mg)按照实施例161所述方法转换成酰氯。然后将其溶于干二氯甲烷(20ml)并与氰酸银(600mg)、11-二氯乙酸姆替林(432mg)和四(三苯膦)钯(0)(2mg)室温剧烈搅拌3天。硅藻土过滤悬浮液，减压蒸发溶剂。残留物硅胶色谱纯化，用乙酸乙酯/己烷混和物洗脱，得到白色泡沫状的标题化合物(213mg)；υ最大(CH2Cl2)3383,1784,1755,1735和1686cm-1。
步骤3．14-[N-(N-叔丁氧羰基-哌啶甲酰基)-氨甲酸]姆替林
步骤2产物溶于四氢呋喃(2ml)并与1M氢氧化钠溶液(0.407ml)室温剧烈搅拌1.5小时。用乙酸乙酯稀释反应溶液，用食盐水洗涤，无水硫酸镁干燥并蒸发。硅胶色谱纯化，得到一种油状非对映体混和物的标题化合物(103mg)；υ最大(CH2Cl2)3540,3419,1783,1732和1697cm-1；MS(ES)m/z573[(M-H)+]。
步骤4．14-[N-(哌啶甲酰基)-氨甲酸]姆替林
步骤3产物(80mg)溶于二氯甲烷(2ml)并用三氟乙酸(0.120ml)处理，室温搅拌溶液16小时。然后蒸发溶剂，残留物在乙酸乙酯和饱和氯化钠溶液之间分配，用食盐水洗涤有机溶液，硫酸镁干燥并减压蒸发。硅胶色谱纯化，用0-10％的甲醇/35％氨溶液(9∶1)的二氯甲烷溶液梯度洗脱，得到白色泡沫状非对映体混和物的标题化合物(35mg)；υ最大(CH2Cl2)1771,1734和1702cm-1；
         1H NMR(CDCl3)特别0.78(3H,2xd,6.9Hz),0.89(3H,
d,7.02),1.20(3H,2xs,),1.48(3H,s),3.32-3.41(1H,宽res.),5.22(1H,d,
J17.3Hz),5.37(1H,d,J11.1Hz)，和6.60(1H,2xdd,J10.9,17.3Hz)；MS(CI)
m/z 475(MH+).
实施例166．14-[N-(4-氨基-3-甲氧基苯甲酰基)]-氨甲酸姆替林
步骤1．3-甲氧基-4-硝基苯甲酰氯
向搅拌的3-甲氧基-4-硝基苯甲酸(1.21g,6.24mmol)的二氯甲烷(6ml)溶液中加入草酰氯(1.1ml)，随后加一滴N,N-二甲基甲酰胺。氩气氛下室温搅拌混和物3小时。真空蒸发溶剂，残留物硅胶色谱纯化，50％乙酸乙酯的己烷混和物洗脱，得到标题化合物(890mg,66％)；υ最大(CH2Cl2)1771cm-1；MS(EI)m/z215(M+)；测定值M+214.9984,C8H6NO4Cl理论值214.9985。
步骤2．14-[N-(3-甲氧基-4-硝基苯甲酰基)-氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
氰酸银(669mg,4.5mmol)在氩气氛下悬浮于干二氯甲烷(10ml)。加入步骤1的酰氯(890mg,4.1mmol)的干二氯甲烷(10ml)溶液，并在避光下回流搅拌非均相混和物。40分钟后让反应冷却，并用(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(668mg,2.0mmol)处理，搅拌反应17小时。硅藻土过滤混和物，提取物用饱和碳酸氢钠溶液(×2)和食盐水洗涤，硫酸镁干燥，真空蒸发溶剂。残留物用硅胶色谱纯化，用己烷中20、30和40％的乙酸乙酯洗脱得到标题化合物(720mg,65％)；υ最大(CH2Cl2)3054,2987,1780,1698和1421cm-1；1H NMR(CDCl3)特别
3.23(3H,s),3.42-3.52(1H,m),4.03(3H,s),5.03(1H,d,J17.4Hz),5.31
(1H,d,J10.7Hz),5.86(1H,d,J9.9Hz),6.66(1H,dd,J10.7,17.5Hz),7.34(1H,
dd,J1.6,8,3Hz),7.62(1H,d,J,1.6Hz),7.89(1H,d,J8.3Hz),8.07(1H,bs)；
MS(CI)m/z 574.3(MNH4 +).
步骤3．14-[N-(4-氨基-3-甲氧基苯甲酰基)-氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
14-[N-(3-甲氧基-4-硝基苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(720mg,1.29mmol)悬浮于乙醇(30ml)。暖热加入乙酸乙酯(6ml)而完全溶解。加入氯化锡(Ⅱ)(1.26g,6.65mmol)并使反应在氩气氛下暖热至回流。4小时后真空蒸发溶剂，残留物被乙酸乙酯和水吸收，形成一种乳液，Kieselguhr过滤去除。有机相用碳酸氢钠溶液(×2)中和，食盐水洗涤，硫酸镁干燥。残留物硅胶色谱纯化，用己烷中20、30和40％的乙酸乙酯洗脱，得到标题化合物(211mg,31％)；υ最大(CH2Cl2)3100,2986,1771,1698,1617和1479cm-1；
                                          1HNMR
(CDCl3)特别3.22(3H,s),3.42-3.50(1H,m),3.91(3H,s),4.32(2H,s),
5.01(1H,d,J17.5Hz),5.29(1H,d,J10.7Hz),6.66(1H,d,J8.2Hz),6.75(1H,
dd,J10.6,17.5Hz),7.20(1H,dd,J1.9,8.2Hz),7.40(1H,d,J1.8Hz),7.99
(1H,bs)；MS(EI)m/z 526(M+).
步骤4．14-[N-(4-氨基-3-甲氧基苯甲酰基)]-氨甲酸姆替林
步骤3产物(191mg,0.36mmol)在二噁烷(2ml)中用浓盐酸中的饱和氯化锌溶液(2ml)处理1小时，室温搅拌反应1小时。然后将溶液倾入乙酸乙酯和饱和碳酸氢钠溶液。水相用乙酸乙酯再提取(×2)，用食盐水洗涤合并的有机相。硫酸镁干燥有机相并真空蒸发溶剂。残留物硅胶色谱纯化，用己烷中60、70、80、90和100％的乙酸乙酯洗脱，得到标题化合物(56mg,30％)；υ最大(CH2Cl2)3100,2986,1772,1733,1617和1479cm-1；
                                             1H NMR
(CDCl2)，特别3.34-3.41(1H,m),3.90(3H,s),4.29(2H,s),5.27(1H,dd,J
1.4,17.4Hz),5.36(1H,dd,J1.4,11.0Hz),5.83(1H,d,J8.4Hz),6.58(2H,dd,J
8.9,15.3Hz),6.65(1H,d,J6.2Hz),7.17(1H,dd,J1.9,8.2Hz),7.37(1H,d,J
1.8Hz),7.85(1H,bs)；MS(NH3DCI)m/z 513(MH+).
实施例167．14-[N-(4-氟苯甲酰基)]-氨甲酸姆替林
步骤1．14-[N-(4-氟苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
将4-氟苯甲酰氯(0-57ml,4.82mmol)在干二氯甲烷(12ml)中与(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(978mg,2.92mmol)和氰酸银(787mg,5.25mmol)如实施例166步骤2进行反应，得到标题化合物(979mg,82％)；υ最大(CH2Cl2)3420,3054,2986,1778,1698,1604和1479cm-1；
                           1H NMR(CDCl3)特别3.23(3H,s),
3.42-3.50(1H,m),5.02(1H,d,J17.5Hz),5.28(1H,d,J9.9Hz),5.85(1H,d,J
10.0Hz),6.70(1H,dd,J10.7,17.5Hz),7.14-7.21(2H,m),7.84-7.89(2H,
m),8.07(1H,bs)；MS(CI)m/z 517(MNH4 +).
步骤2．14-[N-(4-氟苯甲酰基)]-氨甲酸姆替林
步骤1的产物(959mg,1.92mmol)在二噁烷(12ml)中用浓盐酸中的饱和氯化锌溶液(12ml)如实施例166步骤4处理，得到标题化合物(140mg,15％)；υ最大(二氯甲烷)3414,3054,2987,1779,1684,1604和1479cm-1；1H NMR(CDCl3)特别3.33-3.40(1H,
m),5.22(1H,dd,J1.4,17.4Hz),5.33(1H,dd,J1.4,10.9Hz),5.81(1H,d,J
8.5Hz),6.52(1H,dd,J11.0,17.3Hz),7.03-7.17(2H,m),7.80-7.88(2H,m),
8.30(1H,bs)；MS(电喷)m/z503(MNH4 +).
实施例168．14-[N-(4-甲磺酰基苯甲酰基)]-氨甲酸姆替林
步骤1．4-甲磺酰基苯甲酰氯
向搅拌的4-甲磺酰基苯甲酸(1g,4.99mmol)在干二氯甲烷(10ml)中加入草酰氯(0.88ml,9.87mmol)随后加两滴DMF。氩气氛下室温搅拌反应5小时，真空蒸发溶剂。产物立即用于下一步反应；υ最大(CH2Cl2)1784cm-1。
步骤2．14-[N-(4-甲磺酰基苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤1的产物在二氯甲烷(12ml)中用氰酸银(787mg,5.25mmol)和(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(814mg,2.43mmol)处理，搅拌反应2小时。按照实施例166步骤2所述分离标题化合物(1.19g,91％)；υ最大(CH2Cl2)3064,2984,1780,1718和1476cm-1；
                                            1H
NMR(CDCl3)特别3.09(3H,s),3.23(3H,s),3.42-3.49(1H,m),5.03(1H,
d,J17.4Hz),5.31(1H,d,J10.7Hz),5.85(1H,d,J9.9Hz),6.68(1H,dd,J10.7
,17.5Hz),7.96-8.00(2H,m),8.04-8.07(2H,m),8.12(1H,bs)；MS
(电喷)m/z 558(M-H-).
步骤3．14-[N-(4-甲磺酰基苯甲酰基)]-氨甲酸姆替林
步骤2产物(1.17g,2.14mmol)在二噁烷(13ml)中用浓盐酸中的饱和氯化锌溶液(13ml)处理，按照实施例166步骤4所述，得到标题化合物(342mg,30％)；υ最大(CH2Cl2)3057,2936,1782,1733和1478cm-1；
            1H NMR(CDCl3)特别3.08(3H,s),3.38(1H,dd,J
10.7,6.6Hz),5.2H(1H,dd,J17.4,1.4Hz),5.38(1H,dd,J10.9,1.3Hz),5.82
(1H,d,J8.5Hz),6.53(1H,dd,J11.1,17.4Hz),7.94-7.97(2H,m),8.02-8.05
(2H,m),8.07(1H,s)；MS(电喷)m/z 544(M-H-).
实施例169．14-[N-(3-(2-二甲氨基乙氧基)-4-氟苯甲酰基)]-氨甲酸姆替林
步骤1．4-氟-3-羟基苯甲酸
硫酸(浓，11ml)搅拌并加热到90℃，在25分钟期间分批加入2-氟-5-三氟甲基苯酚(2.5g,13.88mmol)。混和物加热到120℃10分钟，然后将混合物冷却到环境温度，倾在冰水混和物上。分离沉淀，用水洗涤并干燥，得到标题化合物(1.01g,47％)；υ最大(CH2Cl2)3420,3054,2987,1636和1422cm-1；MS(EI)m/z156(M+)。测定值M+156.0223,C7H5O3F理论值156.0223。
步骤2．3-乙酰氧基-4-氟苯甲酸
步骤1产物(1.0g,6.41mmol)在二氯甲烷(35ml)中用三乙胺(1.95ml,12.97mmol)和4-二甲氨基吡啶(24.7mg,0.20mmol)处理。反应在冰浴中冷却，用乙酐(0.62ml,6.57mmol)处理，氩气氛下室温搅拌2小时。溶液用5M盐酸和水洗涤，硫酸镁干燥，真空蒸发溶剂得到标题化合物(1.08g,86％)；υ最大(CH2Cl2)3054,2987,1777,1670和1422cm-1；MS(电喷)m/z197(M-H-)。测定值M+198.0326,C9H7O4F理论值198.0328。
步骤3．3-乙酰氧基-4-氟苯甲酰氯
步骤2产物(1.06g,5.35mmol)在二氯甲烷(14ml)中用草酰氯(0.60ml,6.88mmol)处理随后加入一滴DMF，如实施例168步骤1。产物立即用于下一步反应；υ最大(CH2Cl2)1778cm-1。
步骤4．14-[N-(3-乙酰氧基-4-氟苯甲酰基)-氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤3产物在二氯甲烷(20ml)中用氰酸银(840mg,5.60mmol)和(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(640mg,1.92mmol)处理，搅拌反应3小时。如实施例166步骤2分离标题化合物(1.06g,96％)；υ最大(CH2Cl2)3418,3054,2986,1779,1697和1422cm-1；MS(电喷)m/z556(M-H+)。
步骤5．14-[N-(4-氟-3-羟基苯甲酰基)-氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤4产物(1.06g,1.90mmol,70％纯度)在二噁烷(15ml)中用1.0M氢氧化钠溶液(7ml)室温处理3小时。反应物倾入乙酸乙酯和稀盐酸。水相用乙酸乙酯再提取。食盐水洗涤有机相，硫酸镁干燥，真空去除溶剂。残留物硅胶色谱纯化，用己烷中20、30、40和50％的乙酸乙酯洗脱，得到标题化合物(420mg,43％)；υ最大(CH2Cl2)3420,3054,2986,1778,1697和1480cm-1；
                              1H NMR(CDCl3)特别
2.52(1H,dd,J10.1,15.3Hz),2.90(1H,q,J6.3Hz),3.23(1H,s),3.42-3.49
(1H,m),5.01(1H,d,J17.5Hz),5.27(1H,d,J10.7Hz),5.85(1H,d,J9.9Hz),
6.69(1H,dd,J10.7 and 17.5Hz),7.14-7.21(1H,m),7.33-7.39(1H,m),7.52-
7.56(1H,m),8.05(1H,bs)；MS(ES)m/z 516(MH+).测定值515.2686
C29H38NO6F理论值515.2683.
步骤6．14-N-[3-(2-二甲氨基乙氧基)-4-氟苯甲酰基)-氨甲酸]的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
步骤5产物(400mg,0.78mmol)溶于丙酮(6ml)并用二甲氨基乙基氯盐酸盐(113mg,0.78mmol)和碳酸钾(213mg)处理。氩气氛下反应加热至回流12小时。用乙酸乙酯稀释反应，用食盐水和水洗涤，硫酸镁干燥有机相，真空去除溶剂。残留物硅胶色谱纯化，用乙酸乙酯中25和50％乙醇洗脱，得到标题化合物(150mg,33％)；υ最大(CH2Cl2)3054,2986,1777,1698和1480cm-1；1H NMR(CDCl3)2.38(6H,s),2.55(1H,dd,J10.1,15.2Hz),2.81(2H,t,J5.7Hz),2.91(1H,dd,J6.5,
12.9Hz),3.23(3H,s),3.43-3.50(1H,m),4.21(2H,t,J5.7Hz),5.03(1H,d,J
17.4Hz),5.31(1H,d,J10.7Hz),6.72(1H,dd,J10.7和17.5Hz),7.12-7.20
(1H,m),8.02(1H,bs).
步骤7．14-N-[3-(2-二甲氨乙氧基)-4-氟苯甲酰基]-氨甲酸姆替林
步骤6产物(80mg,0.14mmol)在二噁烷(1ml)中用浓盐酸(1ml)处理，室温搅拌反应4小时。按照实施例166步骤4所述，分离得到标题化合物(65mg,76％)；υ最大(CH2Cl2)3054,2988,1777,1732,1609和1422cm-1；
1H NMR(CDCl3)特别2.45(6H,s),2.91(2H,t,J5.5Hz)3.37
(1H,d,J6.4Hz),4.28(2H,t,J5.5Hz),5.23(1H,dd,J1.3,17.4Hz),5.36(1H,
dd,J1.3,11.1Hz),5.83(1H,d,J8.4Hz),6.55(1H,dd,J11.0,17.3Hz),7.10-
7.19(1H,m),7.33-7.39(1H,m),7.55-7.62(1H,m),8.33(1H,bs)；MS(ES)m/z
573(M+H+),571(M-H-).
实施例170．14-{N-[4-(2-二甲氨基乙氧基)-苯甲酰基]}-氨甲酸姆替林盐酸盐
步骤1．14-{N-[4-(2-二甲氨基乙氧基)苯甲酰基]}-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
14-[N-(4-羟基-苯甲酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(1g,2mmol)在丙酮(20ml)中用粉末碳酸钾(560mg)和2-二甲氨基乙基氯盐酸盐(290mg)处理，氩气氛下回流搅拌11小时。将混合物用乙酸乙酯稀释，用水洗涤，干燥并蒸发。硅胶色谱纯化，用2∶1的乙酸乙酯/乙醇洗脱，得到黄色泡沫状的标题化合物(510mg,45％)；υ最大(CHCl3)3436,1775,1697,1606,1579,1512,1488和1168cm-1；
        1H NMRδ(CDCl3)0.87(3H,d,J6.7Hz),0.98(3H,d,J6.3Hz),1.0-
1.6(12H,m),1.6-1.75(2H,m),1.85-2.05(2H,m),2.1-2.2(1H,m),2.32(6H,s),
2.4-2.55(1H,m),2.73(2H,t,J5.5Hz),2.87(1H,q,J6.3Hz),3.18(3H,s),3.35-
3.5(1H,m),4.08(2H,t,J5.5Hz),4.95(1H,d,J17.5Hz),5.22(1H,d,J
10.7Hz),5.81(1H,d,J9.8Hz),6.67(1H,dd,J17.5和10.7Hz),6.94(2H,d,J
8.8Hz),7.81(2H,d,J8.8Hz)；MS(氨CI)m/z 569(MH+,10％),352
(20％),317(70％),303(50％),235(100％),209(70％)；(负离子
电喷)m/z567(M-H-,100％).
步骤2．14-{N-[4-(2-二甲氨基乙氧基)-苯甲酰基]}-氨甲酸姆替林
步骤1产物(500mg)在二噁烷(6ml)中被冰冷却，用浓盐酸中的饱和氯化锌溶液(2ml)处理，室温搅拌反应5小时。用乙酸乙酯稀释混和物，用过量的碳酸氢钠水溶液和水洗涤混和物，干燥并蒸发。硅胶色谱纯化，用3∶1然后1∶1的乙酸乙酯/乙醇洗脱，得到胶体的标题化合物(230mg,47％)；υ最大(CHCl3)3565,3442,1777,1731,1709,1606,1579,1513和1469cm-1；
1H NMR δ(CDCl3)0.79(3H,d,J6.4Hz),0.87(3H,d,J6.9Hz),1.0-1.2(4H,
m),1.3-1.8(11H,m),2.0-2.3(5H,m),2.36(6H,s),2.78(2H,t,J5.5Hz),3.36
(1H,d,J6.3Hz),4.11(2H,t,J5.5Hz),5.20(1H,dd,J17.5和1.3Hz),5.31
(1H,dd,J11和1.1Hz),5.80(1H,d,J8.3Hz),6.52(1H,dd,J17.5和11Hz),
6.95(2H,d,J8.9Hz),7.79(2H,d,J8.9Hz),8.40(1H,s)；MS(EI)m/z 554(M+,
5％),163(100％)；(NH3DCI)m/z 555(MH+,30％),235(100％).
步骤3．14-{N-[4-(2-二甲氨基乙氧基)-苯甲酰基]}-氨甲酸姆替林盐酸盐
步骤2产物(225mg)在乙酸乙酯(5ml)中用4M盐酸的二噁烷(0.25ml)溶液处理。蒸发溶剂后留下白色固体状的产物(193mg)；υ最大(CHCl3)3676,3434,2287(br),1778,1733,1654,1607和1468cm-1；
            1H NMRδ((CD3)2SO)0.70(3H,d,J5.9Hz),0.83(3H,d,J7.7Hz),
1.0-1.2(4H:,m),1.2-1.8(10H,m),2.0-2.3(4H,m),2.42(1H,s),2.83(6H,s),
3.4-3.6(3H,m),4.43(2H,t,J5Hz),4.55(1H,d,J5.9Hz,在D2O交换消失
),5.0-5.2(2H,m),5.60(1H,d,J7.8Hz),6.26(1H,dd,J17.5和
11.1Hz),7.10(2H,d,J8.9Hz),7.88(2H,d,J8.9Hz),10.36(1H,br s,
在D2O交换消失)，10.63(1H,s，在D2O交换消失)。
实施例171．14-{N-[4-(葡糖酰氧基)-苯甲酰基]}-氨甲酸姆替林
步骤1．14-{N-[4-(四-氧桥-乙酰基-葡糖酰氧基)-苯甲酰基]}-氨甲酸姆替林
乙酰溴代-α-D-葡萄糖(411mg,1mmol)在丙酮(2ml)中加入到14-[N-(4-羟基-苯甲酰基)]-氨甲酸姆替林(483mg,1mmol)、1N氢氧化钠(1ml)的水(2ml)溶液和丙酮(5ml)的溶液。室温3小时后，加入另一份1N氢氧化钠(1ml)，随后加入乙酰溴代-α-D-葡萄糖(411mg)的丙酮(2ml)溶液。混和物室温静置过夜，然后以水稀释，用乙酸乙酯提取。用食盐水洗涤提取物，硫酸镁干燥并蒸发，硅胶色谱纯化，用20％丙酮-甲苯洗脱得到泡沫状的标题化合物(140mg)；Rf0.2；υ最大(CHCl3)3439w,1757br和1721(肩峰)cm-1；
                                          1H NMR(d6丙酮)
特别8.6(1H,br s,NH),7.80-7.82(2H,芳族),7.02-7.04(2H,芳族),6.57
(1H,dd,J17.5,11),5.81(1H,d,J8,H-14),5.35(1H,dd,J11,1.5),5.32(1H,
dd,J9,9,葡糖苷H-3),5.28(1H,dd,J9,9,葡糖苷H-2),5.23(1H,dd,J17.5,1.5),
5.21(1H,d,J7.4,葡糖苷H-1),5.16(1H,dd,J9,9,葡糖苷H-4),4.28(1H,dd J12.3,
5.5,葡糖苷H-6),4.17(1H,dd,J12.3,2.5,葡糖苷H-6)，3.94(1H,ddd,J7.9,5.5,2.5,
葡糖苷H-5),3.40(1H,dd,J10.4,6.5)；13C NMR特别169.2,169.4,170.1和d
170.4(4x,乙酸酯的C=O),98.2(CH of葡糖苷)；MS(+ve离子电喷)
m/z 814(MH+),831(MNH4 +),836(MNa+)。
步骤2．14-{N-[4-(葡糖酰氧基)-苯甲酰基]}-氨甲酸姆替林
步骤1产物(117mg,0.14mmol)部分溶于甲醇(4ml)并加入三乙胺(0.02ml)。室温搅拌混和物总计48小时，其期间加入另一部分三乙胺(0.02ml×2)并同时用t.l.c.监视反应。混和物蒸发至干燥，硅胶色谱纯化，用20％的乙醇/氯仿洗脱，得到白色固体状的标题化合物(55mg,61％)；Rf 0.33；
                                            1H
NMR(d6丙酮)特别8.00(1H,br s,NH),ca7.9(2H,芳族),ca7.15(2H,
芳族),6.46(1H,dd,J17.6,11),5.77(1H,d,J8,H-14),5.25(1H,dd,J17.6,2),
5.18(1H,dd,J11,2),4.60(1H,dJ3.5,D2O交换)，4.35(1H,d,J3.5,D2O
交换),4.27(1H,d,J3.5 D2O交换),3.87(1H,dd,J11.8,1.4 with D2O)；MS(-ve
离子电喷)m/z 644(100％,M-H-).
实施例172．14-[N-(2-叠氮-苯基-乙酰基)]-氨甲酸姆替林
步骤1．14-[N-(2-叠氮-苯基-乙酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(667mg,2mmol)的二氯甲烷(25ml)溶液加入到D-(-)-α-叠氮基-苯基乙酰氯(5mmol)与氰酸银(750mg,5mmol)的二氯甲烷(10ml)的搅拌混和物。室温搅拌混和物过夜，过滤并蒸发至干。粗产物硅胶色谱纯化，用5％的丙酮-甲苯洗脱，得到白色固体状的标题化合物(841mg,80％)；Rf 0.32；υ最大(CHCl3)3389,2119,1787,1756,1719和1697cm-1；
              1H NMR(CDCl3)特别8.0(1H,br s,D2O交换
    ),7.42(5H，芳族)，6.49(1H,dd，约18,10.7),5.70(1H,d,J10),5.52(1H,
brs,PhCH-CO),5.26(1H,d,J10.7)；MS(-ve离子电喷)m/z 535(M-H-).
步骤2．14-[N-(4-叠氮基-苯基-乙酰基)]-氨甲酸姆替林
步骤1的产物(536mg,1mmol)溶于二噁烷(15ml)中，用冷水浴冷却加入浓盐酸中的饱和氯化锌溶液(4ml)。室温搅拌清亮黄色溶液3.5小时。用碳酸氢钠冷水溶液稀释混和物，用乙酸乙酯提取。用水和食盐水洗涤提取物，硫酸镁干燥。蒸发得到粗产物，硅胶色谱纯化，用5％丙酮-甲苯洗脱，得到白色泡沫状标题化合物(413mg,79％)；Rf0.05；υ最大(CHCl3)3565,3388,2112,1789,1756(肩峰)和1725cm-1；
                                1H NMR(CDCl3)特别
7.84(1H,br s),7.40(5H,芳族)，6.38(1H,dd,J17,11),5.67(1H,d,J8.5),
5.54(1H,br s,PhCH-CO),5.23(1H,d,J11),5.11(1H,d,J17)；3.33(1H,dd,J
10.5,6.5)；MS(+ve离子电喷)m/z 540(MNH4 +),MS(-ve
离子电喷)m/z 521(100％,M-H-).
实施例173．14-[N-((-氨基-苯基乙酰基)]-氨甲酸的19,20-二氢姆替林盐酸盐
14-[N-(4-叠氮基-苯基-乙酰基)]-氨甲酸姆替林(240mg,0.46mmol)(实施例172)溶于二噁烷(5ml)和水(1ml)，并加入4M盐酸的二噁烷(0.25ml)溶液。氢气氛下加入10％钯/碳(100mg)摇荡溶液45分钟。过滤去除催化剂，并用二噁烷的水溶液洗涤。滤液蒸发成油，并与乙醇和与氯仿共沸。从乙醇-醚将所得粗产物再结晶，得到灰白色固体状的标题化合物(123mg,50％)；m.p.175-180℃；υ最大(CHCl3)大约2600-3200,1757,1733和1703cm-1；
    1H NMR(d4甲醇)特别7.49(5H,芳族),5.72(1H,br,PhCH-
CO),5.55(1H,d,J8),3.41(1H,d,J6)；13C NMR(CDCl3-d4甲醇)特别
7.7,10.9,14.5,16.0,20.4,24.7,26.0,26.7,30.2,34.4(CH和CH2),36.5,
40.5,40.7,41.9,45.5,57.0,58.4,71.5,75.9,128.5,129.2,130.0,131.4,150.5,
169,218.0；MS(NH3DCI)m/z 499(100％,MH+)；MS(甘油FAB)测定值
m/z 499,3170(MH+)C29H43N2O5理论值499,3172
实施例174．14-[N-(环己基-乙酰基)]-氨甲酸姆替林
步骤1．14-[N-(环己基-乙酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
环己基-乙酰基异氰酸酯(2.5mmol)在二氯甲烷(10ml)中的溶液室温加入一份(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(334mg,1mmol)的二氯甲烷(3ml)溶液。室温搅拌溶液过夜并蒸发至干。粗产物硅胶色谱纯化，用1∶2的乙酸乙酯洗脱，得到白色泡沫状的标题化合物(252mg,50％)；Rf 0.42；υ最大(CHCl3)3395,1782w,1749和1697cm-1；
                    1H NMR(CDCl3)特别7,47(1H,br s,D2O交换),6,64(1H,dd,J17,5,10,5),5,74(1H,d,J10),5,33(1H,d,J10.5),5,03(1H,d,J17,5),3,4-3.5(1H,m)；MS(NH3 DCI))m/z 519(8％,MNH4 +).
步骤2．14-[N-(环己基-乙酰基)]-氨甲酸姆替林
步骤1的产物(400mg,0.8mmol)溶于二噁烷(4ml)中并加入浓盐酸中的饱和氯化锌溶液(2ml)。室温搅拌溶液2小时，用冷碳酸氢钠水溶液稀释混和物，用乙酸乙酯提取。用碳酸氢钠水溶液和食盐水洗涤提取物，硫酸镁干燥。蒸发得到粗产物，硅胶色谱纯化，用1∶2的乙酸乙酯洗脱，得到白色固体状标题化合物(152mg,39％)；熔点198-200℃；υ最大(CHCl3)3397,2928,1735和1712cm-1；
1H NMR(CDCl3)特别7.29(1H,br s),6.49(1H,dd,J17.3,11),5.70(1H,
d,J7.5),5.38(1H,dd,J11,1.4),5.23(1H,d,J17.3,1.4)；3.36(1H,dd,J10.5,
6.5),2.62(2H,d,J6.6)；MS(-ve离子电喷)m/z 486(50％,M-H-).
实施例175．14-[N-(肉桂酰基)]-氨甲酸姆替林
步骤1．14-[N-(肉桂酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
异氰酸肉桂酰基酯(2mmol)在二氯甲烷(5ml)中室温加入到一份(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(501mg,1.5mmol)的二氯甲烷(5ml)溶液。室温搅拌1小时，加入另一份异氰酸肉桂酰基酯(1mmol)的二氯甲烷(2.5ml)溶液。室温搅拌混和物2天并蒸发至干。粗产物硅胶色谱纯化，用1∶4的乙酸乙酯洗脱，得到白色固体状的标题化合物(710mg,93％)；Rf 0.38；υ最大(CHCl3)3400,1776w,1747,1690和1621cm-1；
                   1H NMR(CDCl3)特别7.89(1H,d,J16),
7.59-7.65(2H,m),7.58(1H,d,J16),7.50(1H,br s,D2O交换),7.4-7.5(3H,
m),6.68(1H,dd,J17.5,10.5),5.78(1H,d,J10),5.36(1H,d,J10.5),5.05(1H,d,J17.5),3.4-3.5(1H,m),3.23(3H,s)；MS(NH3DCI))m/z 508(MH+),525(MNH4 +).
步骤2．14-[N-(肉桂酰基)]-氨甲酸姆替林
步骤1的产物(507mg,1mmol)溶于二噁烷(4ml)中加入浓盐酸中的饱和氯化锌溶液(2ml)。室温搅拌溶液过夜，用冷碳酸氢钠水溶液稀释混和物，用乙酸乙酯提取；水和食盐水洗涤提取物，硫酸镁干燥。蒸发得到粗产物，硅胶色谱纯化，用1∶2的乙酸乙酯洗脱，得到白色固体状标题化合物(316mg,64％)；熔点148-151℃；υ最大(CHCl3)3400,1735,1682和1622cm-1；MS(NH3DCI)m/z494(10％,MH+),511(12％,MNH4 +)。
实施例176．14-(1-甲基哌啶-4-酰基)-氨甲酸的19,20-二氢姆替林
14-(1-甲基哌啶-4-酰基)-氨甲酸姆替林(100mg)的THF(5ml)溶液于室温用10％钯/碳氢化1小时。硅藻土滤出催化剂并浓缩溶液，得到无色固体状的标题化合物(100mg，定量)；υ最大(CHCl3)3630(w),3390(w),1732,1710,1470和1406cm-1；
                                                      1H NMR
(CDCl3)特别1.40(3H,s),1.43(3H,s),2.89(2H,dJ11.4Hz),3.07(1H,
m),3.41(1H,d,J6.0Hz),5.55(1H,d,J8.03Hz)和7.38(1H,s)；MS(EI)m/z
490(M+)(测定值：M+,490.341；C28H46N2O5理论值490.341).
实施例177．14-(1-甲基哌啶-4-酰基)-氨甲酸的19,20-二氢姆替林盐酸盐
14-(1-甲基哌啶-4-酰基)-氨甲酸19,20-二氢姆替林(348mg)在乙酸乙酯中室温剧烈搅拌并滴加1M盐酸的醚液，直至观察不到沉淀产生。滤出标题化合物并真空干燥12小时，得到白色固体(302mg,81％)；
                                    1H NMR(D2O)特别
0.68(6H,m),0.86(3H,d,J7.2Hz),2.85(3H,s),3.04(2H,d,J11.0),3.55(3H,
m)和5.56(1H,dJ7.8Hz).
实施例178．14-{N-[(3S,4R)-1-氮杂双环[2.2.1]庚-3-基羰基]}-氨甲酸的19,20-二氢姆替林
14-{N-(3S,4R)-1-氮杂双环[2.2.1]庚-3-基羰基]}-氨甲酸姆替林溶液(95mg,0.20mmol)在1∶1的乙醇-四氢呋喃(10ml)中在10％钯/碳(90mg)上氢化12小时。硅藻土过滤溶液，真空蒸发溶剂，得到标题化合物(85mg,87％)；υ最大(KBr)3421,2957,1772,1733,1702和1464cm-1；
        1H NMR(d6-DMSO)特别0.68(3H,d,J7.1Hz),0.82(3H,d,J
6.8Hz),4.46(1H,d,J5.9Hz),5.46(1H,d,J7.6Hz),10.53(1H,bs)；MS(EI)
m/z 488(M+).测定值：M+,488.3256；C28H44N2O5理论值488.3250.
实施例179．14-[N-(奎宁环-4-羰基)]-氨甲酸的19,20-二氢姆替林
14-[N-(奎宁环-4-羰基)]-氨甲酸姆替林(100mg,0.20mmol)在2∶1的四氢呋喃∶乙醇(30ml)中在10％钯/碳(10mg)上氢化1小时。通过硅藻土滤出溶液，真空蒸发溶剂，得到白色固体状的标题化合物(90mg,90％)；υ最大(CH2Cl2)2920,1782,1733,1716和1479cm-1；
                                                    1H NMR
(CDCl3)特别0.69(3H,d,J6.6Hz),3.42(1H,d,J5.9Hz),5.61(1H,d,J
8.2Hz),7.37(1H,bs)；MS(EI)m/z 502(M+).测定值M+,502.3411；
C29H46N2O5理论值502.3407.
实施例180．14-[N-(3-(2-二甲氨基乙氧基)-4-氟苯甲酰基)]-氨甲酸的19,20-二氢姆替林
14-[N-(3-(2-二甲氨基乙氧基)-4-氟苯甲酰基)]-氨甲酸姆替林(200mg)溶于乙醇(30ml)，大气压力的氢气氛下加入10％钯/碳在环境温度摇荡2小时。硅藻土过滤悬浮液，蒸发滤液得到白色泡沫状标题化合物(201mg)；
    1HNMR特别(CDCl3)0.75-0.85(6H,m),0.90-1.05(6H,m),1.51(3H,
    s),2.38(6H,s),2.79(2H,t,J5.61Hz),3.41(1H,d,J5.95Hz),4.20(2H,t,J
5.64Hz),5.70(1H,d,J8.03Hz),7.11(1H,dd,J8.43和10.35Hz),7.28-7.38
(1H,m),7.55(1H,dd,J2.0和7.9Hz),8.0(1h，宽s)；MS(ES)m/z 575
(MH+).
实施例181．14-[N-(奎宁环-3-酰基)]-氨甲酸姆替林
步骤1．14-[N-(奎宁环-3-酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
奎宁环-3-羧酸按照实施例161所述方法转换成酰氯盐酸盐。然后将这种酰氯与(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(1.002g)反应，按照实施例161的步骤经过硅胶色谱纯化，得到无色泡沫状标题化合物(1.116g)；MS(ES)m/z515(MH+)。
步骤2．14-[N-(奎宁环-3-酰基)]-氨甲酸姆替林
步骤1的产物(1.13g)在1,4-二噁烷(12ml)中用浓盐酸(5ml)室温搅拌7小时。乙酸乙酯稀释溶液，用饱和碳酸氢钠溶液中和。用饱和氯化钠溶液洗涤有机溶液，硫酸镁干燥并蒸发得到粗产物。硅胶色谱纯化，0-20％的9∶1甲醇/35％氨溶液的二氯甲烷溶液梯度洗脱，分离得到白色固体状的标题化合物(340mg)。这种固体是两种非对映体混合物，用热乙酸乙酯蒸煮，过滤收集所得白色固体，得到一种纯的非对映体的标题化合物(0.140g)；
            1H NMR特别(CDCl3)0.75(3H,d,J6.5Hz),0.90(3H,d,
J7.0Hz),1.20(3H,s),1.40(3H,s),2.70-3.10(5H,m),3.20-3.42(3H,m),5.15-
5.40(2H,ddd),5.70(1H,d,J8.3Hz),6.50(1H,dd,J10.95,17.4Hz)and 7.40
(1H,s)；MS(ES)m/z 501(MH+).
母液含有另一种主要的非对映体的标题化合物(0.200g)；
                                       1H NMR 特别
(CDCl3)0.75(3H,d,J6.5Hz),0.90(3H,d,J7.0Hz),1.20(3H,s),1.41(3H,s),
2.12-2.4(3H,m),2.70-3.10(5H,m),3.24-3.42(3H,m),5.15-5.45(2H,m),
5.69(1H,d,J8.3Hz),6.50(1H,dd,J11.0,17.35Hz)和7.40(1H,s)；MS(ES)
m/z 501(MH+).
实施例182．14-{N-[(3S,4R)-1-氮杂双环[2.2.1]庚-3-基羰基]}-氨甲酸姆替林盐酸盐
14-{N-[(3S,4R)-1-氮杂双环[2.2.1]庚-3-基羰基]}-氨甲酸姆替林(1.0g,2.06mmol)的丙酮(100ml)溶液用1M盐酸的乙醚(4.2m1,4.20mmol)溶液处理。室温搅拌溶液1小时，之后真空浓缩。残留物用乙醚研制，得到白色固体状的标题化合物(1.02g,95％)；υ最大(KBr)3421,2924,1772,1734,1704和1465cm-1；
                          1H NMR(D2O) 特别0.62(3H,d,J6.0Hz),0.90(3H,d,J6.9Hz),5.22(2H,dd,J16.7,11.1Hz),5.61(1H,d,J8.1Hz),6.35(1H,dd,J17.5,11.1Hz).
实施例183．14-[N-(1-氮杂双环[3.2.1]辛-5-酰基)]-氨甲酸姆替林
步骤1．14-[N-(1-氮杂双环[3.2.1]辛-5-酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
向搅拌的外消旋1-氮杂双环[3.2.1]辛烷-5-碳酰氯盐酸盐(4mmol)、(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(668mg,2mmol)和氰酸银(600mg)在二氯甲烷(25ml)的混合物中加入三乙胺(0.58ml,4.2mmol)。室温搅拌混合物过夜，过滤，滤液蒸发至干。粗产物硅胶色谱纯化，用1∶9∶90的35％氨溶液溶液∶甲醇∶二氯甲烷洗脱，得到白色固体状的标题化合物(480mg)；Rf0.1；
1H NMR(CDCl3)特别7.4(1H,br s),5.79(1H,d,
J10),3.21(3H,s),2.75-3.0(6H,m)；MS(+ve离子电喷)m/z 515(30％,
MNH4 +),m/z 556(100％,M+H+MeCN+).
步骤2．14-[N-(1-氮杂双环[3.2.1]辛-5-酰基)]-氨甲酸姆替林
步骤1的产物(480mg,0.93mmol)溶于二噁烷(2.5ml)，冰浴冷却下缓慢加入浓盐酸(2.5ml)。室温搅拌清亮溶液4小时，用水稀释溶液并加入碳酸钠碱化；将混合物用乙酸乙酯提取，食盐水洗涤。硫酸镁干燥并蒸发得到粗产物；硅胶色谱纯化，用1∶9∶90的35％氨溶液溶液∶甲醇∶二氯甲烷洗脱，得到白色固体状两种非对映体混合物的标题化合物(274mg,58％)；Rf 0.08；υ最大(CHCl3)2962,1772,1736和1628cm-1；
                                                1H NMR
(CDCl3)特别7.58(1H,br s),6.51(1H,dd,J17,11),5.75(1H,d,J8.4),
5.34(1H,dd,J11,1.25),5.19(1H,d,J17,1.25),3.36(1H,br),3.08-3.2(1H,m),
2.7-3.05(5H,m)；MS(+ve离子电喷)m/z 501(100％,MH+),MS(-ve
离子电喷)m/z 499(100％,M-H-)
实施例184．14-[N-(1-氮杂双环[2.2.2]辛-2-酰基)]-氨甲酸姆替林
步骤1．14-[N-(1-氮杂双环[2.2.2]辛-2-酰基)]-氨甲酸的(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林
向搅拌的外消旋1-氮杂双环[2.2.2]辛烷-2-碳酰氯盐酸盐(约3mmol)、(3R)-3-脱氧代-11-脱氧-3-甲氧基-11-氧代-4-表姆替林(501mg,1.5mmol)和氰酸银(225mg)在二氯甲烷(10ml)的混合物内加入三乙胺(0.2ml,1.5mmol)。室温搅拌混合物过夜，过滤，滤液用二氯甲烷稀释，用饱和碳酸氢钠溶液和食盐水洗涤。硫酸镁干燥并蒸发得到粗产物，硅胶色谱纯化，用1∶1的乙酸乙酯∶正己烷洗脱，得到无色胶体的标题化合物(220mg)；Rf 0.12。
步骤2．14-[N-(1-氮杂双环[2.2.2]辛-2-酰基)]-氨甲酸姆替林
步骤1的产物(200mg)溶于二噁烷(2ml)，冰浴冷却下缓慢加入浓盐酸(2ml)。室温搅拌清亮溶液3小时，用水稀释溶液并用碳酸氢钠碱化；用乙酸乙酯提取混合物，食盐水洗涤。硫酸镁干燥并蒸发得到粗产物；硅胶色谱纯化，用5％甲醇的氯仿溶液洗脱，得到白色泡沫状两种非对映体的标题化合物(135mg,69％)；Rf0.08；υ最大(CHCl3)3309,2946,1780,1735和1713cm-1；MS(+ve离子电喷)m/z501(22％,MH+),MS(-ve离子电喷)m/z499(100％,M-H-)。

Claims (9)

1．一种通式(1A)的化合物或其可药用的盐或衍生物，
式中Y是氨基甲酰氧基，并且其中的N-原子是未取代或一取代或二取代的。
2．一种通式(3)的化合物或其可药用的盐或衍生物，
Figure A9618017700022
其中，
R1是乙烯基或乙基；
R2和R3是相同或不同的基团，选自
氢；
直链或支链，饱和或不饱和，任选取代的C1-C6烃基；
饱和或不饱和，任选取代的C3-C8环烃基；
任选取代的杂环基；
任选取代的芳基；
或一起形成有3-8环原子的任选取代的环基，任选地含有一个选自N、O和S的另外的杂原子，和任选地稠合到烃环、杂环或芳上；或者
R2是上述单价基团之一且R3是一种选自SO2R4、COR5、OR5和NR6R7的基团，其中
R4选自直链或支链，饱和或不饱和，任选取代的C1-C6烃基；饱和或不饱和，任选取代的C3-C8环烃基；任选取代的杂环基；任选取代的芳基；任选取代的C1-C6烷基氨基；和任选取代的芳基氨基；
R5选自氢；直链或支链，饱和或不饱和，任选取代的C1-C6烃基；饱和或不饱和，任选取代的C3-C8环烃基；任选取代的杂环基；任选取代的芳基；
R6和R7是相同或不同的基团，选自氢；直链或支链，饱和或不饱和，任选取代的C1-C6烃基；饱和或不饱和，任选取代的C3-C8环烃基；任选取代的杂环基；任选取代的芳基；或一起形成有3-8环原子的任选取代的环基，任选地含有一个选自N、O和S的另外的杂原子，和任选地稠合到烃环、杂环或芳基上。
3．根据前述任一权利要求的化合物，基本如说明书任一实施例所述。
4．一种权利要求1化合物的制备方法，包括将通式(4)或(5)的化合物与合适取代的氨甲酸酯型试剂反应，
通式(4)中的X是氢或羟基的保护基。
5．一种权利要求2化合物的制备方法，包括将通式(4)化合物与以下化合物反应，通式(4)中X是氢或羟基的保护基，
(a)R2NCO化合物，
(b)R2R3NCOCl化合物，或
(c)光气或氯代甲酸酯或碳酸酯随后与R2R3NH化合物反应，
其中R2和R3如上定义，并且被合适地保护，和必要时在11位置将X脱保护产生羟基，脱保护被护的R2和R3，将一个R2或R3基团转换成另一个R2或R3基团，或者氢化12位置的乙烯基形成乙基。
6．一种权利要求2化合物的制备方法，包括将通式(5)化合物与以下化合物反应，
(a)R2NCO化合物，
(b)R2R3NCOCl化合物，或
(c)光气或或氯代甲酸酯或碳酸酯随后与R2R3NH化合物反应。
其中R2和R3如上定义并且被合适地保护，用酸处理产物，脱保护被护的基团R2和R3，将一个R2或R3基团转换成另一个R2或R3基团，或者氢化12位的乙烯基形成乙基。
7．一种药物组合物，包括权利要求1,2或3的化合物与一种可药用的载体或赋形剂。
8．一种治疗动物、特别是人类和家养动物微生物感染的方法，包括将抗微生物有效量的权利要求1、2或3的化合物或者权利要求7的组合物给药待治的病人。
9．权利要求1、2或3化合物在制备用于治疗细菌感染的药物组合物的应用。
CN96180177A 1996-01-03 1996-12-19 姆替林的氨基甲酰氧基衍生物及其抗菌素用途 Pending CN1214039A (zh)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102249982A (zh) * 2010-05-18 2011-11-23 中国科学院上海药物研究所 新型截短侧耳素类化合物、其药物组合物及其制备方法和用途
CN106699690A (zh) * 2016-12-07 2017-05-24 华南农业大学 一种具有酰基哌嗪基侧链的截短侧耳素衍生物及其制备方法和用途
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Families Citing this family (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6753006B1 (en) 1993-02-22 2004-06-22 American Bioscience, Inc. Paclitaxel-containing formulations
PL327737A1 (en) * 1996-01-03 1998-12-21 Smithkline Beecham Plc Carbamoyloxylic derivatives of mutiline and their application as bactericides
HUP0001741A3 (en) * 1996-08-02 2000-11-28 Smithkline Beecham Plc Azabicyclic carbamoyloxy mutilin derivatives for antibacterial use, process for preparing them, pharmaceuticals contg. them and their use
GB9719187D0 (en) 1997-09-09 1997-11-12 Glaxo Group Ltd Compounds
UY25225A1 (es) * 1997-10-29 2000-12-29 Smithkline Beecham Plc Derivados de pleuromutilina utiles como agentes antimicrobianos
GB9817029D0 (en) * 1998-08-05 1998-09-30 Smithkline Beecham Plc Novel compounds
AU3036200A (en) * 1998-12-18 2000-07-12 Smithkline Beecham Plc Mutilin 14-ester derivatives having antibacterial activity
GB9912657D0 (en) * 1999-06-01 1999-07-28 Smithkline Beecham Plc Novel compounds
MXPA02009816A (es) 2000-04-04 2003-03-27 Smithkline Beecham Plc Derivados de carbamato de 2-hidroxi-multilina para uso antibacteriano.
GB0018951D0 (en) 2000-08-03 2000-09-20 Smithkline Beecham Plc Novel compounds
PE20020676A1 (es) * 2000-09-13 2002-08-27 Biochemie Gmbh Compuestos de mutilina como antibacterianos
GB0024811D0 (en) 2000-10-10 2000-11-22 Smithkline Beecham Plc Novel compounds
US20030054042A1 (en) * 2001-09-14 2003-03-20 Elaine Liversidge Stabilization of chemical compounds using nanoparticulate formulations
FR2835186B1 (fr) * 2002-01-28 2006-10-20 Aventis Pharma Sa Nouveaux composes heterocycliques, actifs comme inhibiteurs de beta-lactamases
EP1490030B2 (en) * 2002-03-20 2010-07-14 Elan Pharma International Limited Nanoparticulate compositions of angiogenesis inhibitors
US20080220075A1 (en) * 2002-03-20 2008-09-11 Elan Pharma International Ltd. Nanoparticulate compositions of angiogenesis inhibitors
GB0218578D0 (en) * 2002-08-09 2002-09-18 Glaxo Group Ltd Novel method
GB0308114D0 (en) * 2003-04-08 2003-05-14 Glaxo Group Ltd Novel compounds
CA2591898A1 (en) * 2004-12-27 2006-07-06 Kyorin Pharmaceutical Co., Ltd. Mutilin-derivative substituted at position 12
GB0504314D0 (en) 2005-03-02 2005-04-06 Glaxo Group Ltd Novel polymorph
US7696112B2 (en) 2005-05-17 2010-04-13 Milliken & Company Non-woven material with barrier skin
US7651964B2 (en) 2005-08-17 2010-01-26 Milliken & Company Fiber-containing composite and method for making the same
US7825050B2 (en) 2006-12-22 2010-11-02 Milliken & Company VOC-absorbing nonwoven composites
CA2688008A1 (en) * 2007-05-24 2008-11-27 Kyorin Pharmaceutical Co., Ltd. Mutilin derivative having heterocyclic aromatic ring carboxylic acid structure in substituent at 14-position
TWM384453U (en) * 2010-03-02 2010-07-11 Winharbor Technology Co Ltd Pull-resistant illuminating/heat generating structure capable of being charged in wireless manner
WO2012006276A1 (en) * 2010-07-06 2012-01-12 North Carolina State University Inhibition of bacterial biofilms with aryl carbamates
US9125408B2 (en) 2010-09-01 2015-09-08 North Carolina State University Use of aryl carbamates in agriculture and other plant-related areas
ES2561105T3 (es) 2011-08-18 2016-02-24 Nippon Shinyaku Co., Ltd. Derivado heterocíclico como inhibidor de prostaglandina E sintasa microsómica (mPGES)
CZ307500B6 (cs) * 2012-08-15 2018-10-24 Zentiva, K.S. Způsob přípravy derivátu 2-methyl-2´-fenylpropionové kyseliny využívající nové intermediáty
US10874679B2 (en) * 2016-03-02 2020-12-29 Bill & Melinda Gates Foundation Boron-containing small molecules
EP3423159A4 (en) * 2016-03-02 2019-11-06 Anacor Pharmaceuticals, Inc. BORN SMALL MOLECULES
TWI762573B (zh) 2017-02-10 2022-05-01 奧地利商納畢瓦治療有限責任公司 截短側耳素之純化

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT301752B (de) * 1969-07-21 1972-09-25 Biochemie Gmbh Verfahren zur Herstellung neuer Pleuromutilin-Derivate
US3979423A (en) * 1969-07-25 1976-09-07 Biochemie Gesellschaft M.B.H. 14-Desoxy-14-tosyloxyacetoxy-mutilin
BE789629A (fr) * 1971-10-05 1973-04-03 Sandoz Sa Nouveaux derives de la pleuromutiline, leur preparation et leurapplication en therapeutique
US3919290A (en) * 1972-10-03 1975-11-11 Sandoz Ltd Substituted 14-desoxy-mutilins
CH627940A5 (de) * 1976-12-23 1982-02-15 Sandoz Ag Kokzidiostatisches kombinationspraeparat.
DE2966635D1 (en) * 1979-01-12 1984-03-08 Sandoz Ag New pleuromutilin derivatives, their production and pharmaceutical compositions containing them
PL327737A1 (en) * 1996-01-03 1998-12-21 Smithkline Beecham Plc Carbamoyloxylic derivatives of mutiline and their application as bactericides

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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CN102249982B (zh) * 2010-05-18 2013-10-23 中国科学院上海药物研究所 新型截短侧耳素类化合物、其药物组合物及其制备方法和用途
CN109195608A (zh) * 2016-03-02 2019-01-11 比尔及梅琳达盖茨基金会 含硼小分子
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CN111574395A (zh) * 2020-06-18 2020-08-25 华南农业大学 一种具有酰胺侧链的截短侧耳素衍生物及制备与应用
CN111574395B (zh) * 2020-06-18 2021-07-02 华南农业大学 一种具有酰胺侧链的截短侧耳素衍生物及制备与应用

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