CN111253287A - 液相汇聚式合成索马鲁肽侧链的方法 - Google Patents
液相汇聚式合成索马鲁肽侧链的方法 Download PDFInfo
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- CN111253287A CN111253287A CN202010046905.8A CN202010046905A CN111253287A CN 111253287 A CN111253287 A CN 111253287A CN 202010046905 A CN202010046905 A CN 202010046905A CN 111253287 A CN111253287 A CN 111253287A
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Abstract
一种液相汇聚式合成索马鲁肽侧链1的方法:将原料2‑(2‑氨基乙氧基)乙醇的氨基用R1保护,接着与溴乙酸乙酯发生亲核取代反应,再经酯水解一锅制得化合物4,将化合物4的羧基用R2保护,并脱除R1,得到化合物6,化合物6与芴甲氧羰基‑L‑谷氨酸1‑叔丁酯经缩合反应,得到化合物8,将化合物8的R2脱除,再与化合物6进行偶联反应,得到化合物10,脱除化合物10的Fmoc,再与18‑(叔丁氧基)‑18氧代十八烷酸进行酰胺化缩合偶联反应,得到化合物13,化合物13脱除R2,得到产物1;本发明方法合成过程有效、可控、低成本高产率,可适用于放大生产;
Description
技术领域
本发明属于多肽类药物合成领域,具体涉及一种治疗二型糖尿病的多肽类药物索马鲁肽的侧链的汇聚式液相合成。
背景技术
索马鲁肽属于胰高血糖素样肽-1(GLP-1)受体激动剂,其分子式为C187H291N45O59,分子量为4113.58,CAS号为910463-68-2。GLP-1是一种诱导胰岛素分泌的激素,对包括胰腺、心脏和肝脏等在内的多种重要器官具有有益作用。GLP-1受体激动剂类药物的优点在于可以有效控制血糖,同时明显降低低血糖事件发生率,并且还有明显减轻体重、降心血管事件风险的获益。
索马鲁肽在2017年获美国FDA批准上市(0.5mg或1mg注射液),临床用于治疗II型糖尿病。2019年9月20日美国FDA正式批准索马鲁肽口服胰岛素上市,用于结合饮食和运动改善II型糖尿病患者的血糖控制。诺和诺德每日口服一次的索马鲁肽药片是第一款获得FDA正式批准的口服胰高血糖素样肽-1(GLP-1)。
索马鲁肽侧链的结构如下:
可以看做由2分子8-氨基-3,6-二氧杂辛酸、一分子谷氨酸和一分子十八烷二酸单叔丁酯组成。该侧链的存在使得索马鲁肽可以与蛋白更紧密的结合,降低被肾脏清除的速率及防止被快速代谢降解,使得药物半衰期的延长。目前工业上常用固相合成的方式偶联及切割合成索马鲁肽及其侧链,由于固相合成原子经济性差,开发液相合成在工业上将具有潜在应用价值。
本发明采用液相合成的方法合成上述索马鲁肽侧链1。
发明内容
本发明的目的在于应用汇聚式液相合成的方式低成本、高收率、短周期的合成索马鲁肽侧链,为工业化应用提供一种可能。
本发明最终目标产物结构式如下:
本发明的技术方案如下:
一种液相汇聚式合成索马鲁肽侧链1的方法,包括如下步骤:
(1)将原料2-(2-氨基乙氧基)乙醇的氨基用R1保护,接着与溴乙酸乙酯发生亲核取代反应延长碳链,并通过酯水解一锅制得化合物4;
所述R1为Fmoc、Alloc、Boc、PMB、Cbz、Trt、Tos、Mtt、Mmt、Bom、Sem或MEM,优选为Fmoc、Trt或Boc,更优选Trt或Boc,R1保护所用的反应溶剂选自甲醇、乙醇、乙酸乙酯、二氯甲烷、1,2-二氯乙烷、DMF、DMSO、四氢呋喃、乙腈、N-甲基吡咯烷酮中的一种或几种任意比例的混合溶剂,优选乙醇或甲醇;
与溴乙酸乙酯发生亲核取代反应所用的反应溶剂选自甲醇、乙醇、乙酸乙酯、二氯甲烷、1,2-二氯乙烷、DMF、DMSO、四氢呋喃、乙腈、N-甲基吡咯烷酮中的一种或几种任意比例的混合溶剂,优选四氢呋喃:甲醇=1:1(v:v);
酯水解在无机碱的作用下进行,所述无机碱选自氢氧化钠、氢氧化锂、碳酸钾、碳酸钠、氢氧化钙、氢氧化钡中的一种或几种任意比例的混合物,优选氢氧化钠;所述无机碱与原料2-(2-氨基乙氧基)乙醇的物质的量之比为0.5~4:1,优选0.5~2:1更优选2:1;
(2)将化合物4游离的羧基用R2保护,并且脱除R1保护基,得到化合物6;
所述R2为Bn、Pfp、Me、Allyl、t-Bu、PMB、MEM或TBS,优选Bn或Me,更优选Bn;
脱除R1保护基在酸试剂的作用下进行,所述酸试剂为盐酸、醋酸或三氟乙酸,优选三氟乙酸;脱除R1保护基所用的反应溶剂选自甲醇、乙醇、乙酸乙酯、二氯甲烷、1,2-二氯乙烷、DMF、DMSO、四氢呋喃、乙腈、N-甲基吡咯烷酮中的一种或几种任意比例的混合溶剂,优选二氯甲烷;特别优选的,脱除R1保护基在三氟乙酸:二氯甲烷体积比1:1~2(优选1:1)的体系中进行;
(3)化合物6与芴甲氧羰基-L-谷氨酸1-叔丁酯经缩合反应,得到化合物8;
缩合反应的溶剂选自甲醇、乙醇、乙酸乙酯、二氯甲烷、1,2-二氯乙烷、DMF、DMSO、四氢呋喃、乙腈、N-甲基吡咯烷酮中的一种或几种任意比例的混合溶剂,优选1,2-二氯乙烷或二氯甲烷,更优选二氯甲烷;缩合反应在缩合剂的作用下进行,所述缩合剂选自DIC、DCC、HBTU、PyBOP、BOP、HATU、TBTU、DIC/HOBT、DCC/DMAP、EDCI/DMAP、EDCI/HOBT、HATU/HOBT中的任意单一缩合剂或者复合缩合剂,优选EDCI/DMAP、EDCI/HOBT或HATU,更优选EDCI/HOBT,并且EDCI和HOBT的物质的量之比为1:0.5~2,优选1:1;缩合反应的温度在20~70℃,优选20~40℃,更优选30℃;
(4)将化合物8的R2保护基脱除,再与化合物6进行偶联反应,得到化合物10;
R2保护基脱除使用钯碳加氢的方法,所述钯碳中钯的质量占钯碳总质量的5%,钯的用量占化合物8的物质的量的1%~20%,优选5%~15%,更优选为5%;R2保护基脱除所用的反应溶剂选自甲醇、乙醇、乙酸乙酯、二氯甲烷、1,2-二氯乙烷、DMF、DMSO、四氢呋喃、乙腈、N-甲基吡咯烷酮中的一种或几种任意比例的混合溶剂,优选甲醇或乙腈,更优选甲醇;
偶联反应的溶剂选自甲醇、乙醇、乙酸乙酯、二氯甲烷、1,2-二氯乙烷、DMF、DMSO、四氢呋喃、乙腈、N-甲基吡咯烷酮中的一种或几种任意比例的混合溶剂,优选1,2-二氯乙烷或二氯甲烷,更优选二氯甲烷;偶联反应在缩合剂的作用下进行,所述缩合剂选自DIC、DCC、HBTU、PyBOP、BOP、HATU、TBTU、DIC/HOBT、DCC/DMAP、EDCI/DMAP、EDCI/HOBT、HATU/HOBT中的任意单一缩合剂或者复合缩合剂,优选EDCI/DMAP、EDCI/HOBT或HATU,更优选EDCI/HOBT,并且EDCI和HOBT的物质的量之比为1:0.5~2,优选1:1;偶联反应的温度在20~70℃,优选20~40℃,更优选30℃;
(5)脱除化合物10的Fmoc保护基后,再与18-(叔丁氧基)-18氧代十八烷酸进行酰胺化缩合偶联反应,得到化合物13;
脱除Fmoc保护基在有机碱的作用下进行,所述有机碱选自二乙胺、N,N-二异丙基乙胺、三乙胺、哌啶、咪唑、吡啶或DBU,优选三乙胺、DBU或二乙胺,更优选二乙胺;脱除Fmoc保护基所用的反应溶剂选自甲醇、乙醇、乙酸乙酯、二氯甲烷、1,2-二氯乙烷、DMF、DMSO、四氢呋喃、乙腈、N-甲基吡咯烷酮中的一种或几种任意比例的混合溶剂,优选乙腈或甲醇,更优选乙腈;
酰胺化缩合偶联反应的溶剂选自甲醇、乙醇、乙酸乙酯、二氯甲烷、1,2-二氯乙烷、DMF、DMSO、四氢呋喃、乙腈、N-甲基吡咯烷酮中的一种或几种任意比例的混合溶剂,优选1,2-二氯乙烷或二氯甲烷,更优选二氯甲烷;酰胺化缩合偶联反应在缩合剂的作用下进行,所述缩合剂选自DIC、DCC、HBTU、PyBOP、BOP、HATU、TBTU、DIC/HOBT、DCC/DMAP、EDCI/DMAP、EDCI/HOBT、HATU/HOBT中的任意单一缩合剂或者复合缩合剂,优选EDCI/DMAP、EDCI/HOBT或HATU,更优选EDCI/HOBT,并且EDCI和HOBT的物质的量之比为1:0.5~2,优选1:1;酰胺化缩合偶联反应的温度在20~70℃,优选20~40℃,更优选30℃;
(6)化合物13脱除R2保护基,得到最终目标产物1;
R2保护基的脱除在无机碱的作用下进行,所述无机碱选自氢氧化钾、氢氧化钡、氢氧化钙、氢氧化铝、氢氧化锂、氢氧化镁或氢氧化锌,优选氢氧化钾或氢氧化锂,更优选氢氧化锂,推荐无机碱以水溶液的形式投料,例如0.5~2M(优选1M)氢氧化锂水溶液;脱除R2保护基所用的反应溶剂选自甲醇、乙醇、乙酸乙酯、二氯甲烷、1,2-二氯乙烷、DMF、DMSO、四氢呋喃、乙腈、N-甲基吡咯烷酮中的一种或几种任意比例的混合溶剂,优选乙醇或甲醇,更优选甲醇。
本发明最终合成的产物可直接与索马鲁肽Lys残基上游离的氨基发生缩合反应从而连接至索马鲁肽主链上。
本发明的优点在于:使用汇聚式合成的方法降低反应成本,缩短了反应时间。合成过程有效、可控、低成本高产率,可适用于放大生产。
本发明中的缩写含义如下:
His:组氨酸
Aib:2-甲基丙氨酸
Glu:谷氨酸
Gly:甘氨酸
Thr:苏氨酸
Phe:苯丙氨酸
Thr:苏氨酸
Ser:丝氨酸
Asp:天冬氨酸
Val:缬氨酸
Leu:亮氨酸
Gln:谷氨酰胺
Ala:丙氨酸
Lys:赖氨酸
Fmoc:芴甲氧羰基
Alloc:烯丙氧羰基
Boc:叔丁氧羰基
PMB:对甲氧基苄基
Trt:三苯甲基
Tos:对甲苯磺酰基
Mtt:4-甲基-三苯甲基
Mmt:4-甲氧基三苯甲基
Sem:三甲基硅乙氧基甲基
MEM:2-甲氧基乙氧基甲基
EDCI:1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐
HOBT:1-羟基苯并***
HATU:O-(7-氮杂苯并***-1-基)-N,N,N′,N′-四甲基脲
DIC:N,N'-二异丙基碳二亚胺
DCC:二环己基碳二亚胺
HBTU:苯并***-1-四甲基六氟磷酸酯
DMAP:4-二甲氨基吡啶
PyBOP:1H-苯并***-1-基氧三吡咯烷基六氟磷酸盐
BOP:苯并***-1-三(三甲氨基)-三氟磷酸酯
TBTU:O-(1H-苯并***-1-基)-N,N,N',N'-四甲基异脲四氟化硼
附图说明
图1为本发明具体实施例1的合成路线图。
图2为化合物1的MS图。
图3为化合物1的IR光谱
具体实施方式
下面通过具体实施例对本发明作进一步的说明,但本发明的保护范围并不仅限于此。
以R1=Boc,R2=Bn为具体实施例1,按照图1的索马鲁肽侧链的合成路线进行液相合成
实施例1-1:
将2-(2-氨基乙氧基)乙醇2为起始原料(300mmol,31.5g)溶解500mL的乙醇溶液,在冰浴条件下缓慢滴加二碳酸二叔丁酯(300mmol,69mL),撤除冰浴,室温下反应2h,减压蒸馏除去乙醇溶剂;四氢呋喃重新溶解,0~-10℃加入氢化钠(1.2-1.5eq),保持冰浴搅拌半小时,将溴乙酸乙酯3(1.2-1.5eq)缓慢滴入反应液,滴加完毕撤除冰浴,室温下搅拌过夜。向反应体系加入MeOH,使MeOH:THF=1:1,反应液呈黄色澄清透明。另称取固体NaOH(1-2.2eq)加入反应液,加热回流,反应2h。反应完毕,减压蒸馏除去溶剂,残留物使用水重新溶解,乙酸乙酯萃取两次,收集水层,调成pH 1~3,乙酸乙酯萃取两次,收集有机层,减压蒸馏得黄色油状液体4。收率为82%。
实施例1-2:
(1)冰浴条件下,向化合物4(1-1.2eq)和三乙胺(1-1.2eq)的二氯甲烷(100mL)溶液中缓慢滴加氯甲酸苄酯5(100mmol,12.9mL),搅拌5min后向反应液加入DMAP(0.1-0.3eq),室温下过夜反应,TLC监测反应(CH2Cl2:EA=10:1)。反应完毕,减压蒸馏除去溶剂,残留物用乙酸乙酯重新溶解,依次使用10%的柠檬酸(75mL×2),饱和碳酸氢钠溶液(75mL×2)萃取,饱和食盐水(100mL)洗,收集有机层,使用无水硫酸钠干燥。减压蒸馏除去溶剂得无色油状液体。收率63%。
(2)将上述无色油状液体溶解在二氯甲烷溶液中,使用三氟乙酸:二氯甲烷(v:v)=1:1脱Boc保护,减压蒸馏除去三氟乙酸得到黄色油状液体6待用。
实施例1-3:
称芴甲氧羰基-L-谷氨酸1-叔丁酯(1g,2.35mmol)溶解于25mL的二氯甲烷中,依次加入DIPEA(3eq,1.2mL),缩合剂EDCI(1.2eq,541mg)和HOBT(1.2eq,380mg),搅拌30min后加入化合物6(1.2eq),30℃下搅拌,TLC监测反应。反应完毕,减压蒸馏除去溶剂,残留物用乙酸乙酯重新溶解,使用10%的柠檬酸水溶液,饱和碳酸氢钠溶液萃取,饱和食盐水(75mL)洗,收集有机层,使用无水硫酸钠干燥。减压蒸馏除去溶剂,通过柱层析纯化得黄色油状体8。收率92%。
实施例1-4:
(1)脱苄基;将2.64g(4mmol)化合物8溶于15mL甲醇溶液,至于三口烧瓶内,氮气置换空气,加入催化量5%的钯碳(钯质量分数为5%)424mg(0.2mmol),气球充氢气,置换瓶内的氮气,室温反应2h,抽滤掉钯碳,旋干得到化合物9待用,收率90%。
(2)将2.05g化合物9溶解于25mL的二氯甲烷中,依次加入DIPEA(3eq,1.8mL),缩合剂EDCI(1.2eq,830mg)和HOBT(1.2eq,583mg),搅拌30min后加入化合物6(1.2eq),30℃下搅拌,TLC监测反应。反应完毕,减压蒸馏除去溶剂,残留物用乙酸乙酯重新溶解,依次使用10%的柠檬酸(50mL×2),饱和碳酸氢钠溶液(50mL×2)萃取,饱和食盐水(75mL)洗,收集有机层,使用无水硫酸钠干燥。减压蒸馏除去溶剂,通过柱层析纯化(CH2Cl2:MeOH=20:1)得黄色色油状体10。收率85%。
实施例1-5:
将上述原料10(1.7mmol,1.36g)溶解在30-40mL的无水乙腈中,逐滴加入二乙胺(3-4mL),室温下搅拌3h,TLC监测反应。通过柱层析纯化(CH2Cl2:MeOH=10:1)得黄色油状物11。收率66%。
实施例1-6:
取25mL圆底烧瓶,将18-(叔丁氧基)-18氧代十八烷酸(0.83mmol,308mg)溶解于5mL的二氯甲烷中,随后依次加入DIPEA(3eq,0.41mL),缩合剂EDCI/HOBT(1.2eq),搅拌30min后加入上述中间体11(0.1mmol,583mg),TLC监测反应。反应完毕,减压蒸馏除去溶剂,残留物用乙酸乙酯重新溶解,依次使用10%的柠檬酸(10mL×2),饱和碳酸氢钠溶液(10mL×2)萃取,饱和食盐水(20mL)洗,收集有机层,使用无水硫酸钠干燥。减压蒸馏除去溶剂得油状液体13,收率82%。
实施例1-7:
取25mL圆底烧瓶,将上述中间体13溶解于2mL MeOH,向反应液中逐滴加入1mol/L的LiOH水溶液,室温下搅拌2h,减压蒸馏除去溶剂,通过柱层析纯化(CH2Cl2:MeOH=5:1),得最终产物1。收率90%。
以R1=Trt,R2=Bn为具体实施例2
实施例2-1:
将2-(2-氨基乙氧基)乙醇2为起始原料(100mmol,10.5g)溶解150mL的二氯甲烷溶液,在冰浴条件下缓慢滴加三乙胺(100mmol,14mL),保持这个温度搅拌半小时,将Trt-Cl(1.2eq)缓慢滴入反应液,滴加完毕撤除冰浴,室温下搅拌1h。反应完毕,减压蒸馏除去溶剂。THF重新溶解,0~-10℃加入碳酸钾(2eq),保持这个温度搅拌半小时,将溴乙酸苄酯(1.2-1.5eq)缓慢滴入反应液,滴加完毕撤除冰浴,50℃下搅拌过夜。反应完毕,减压蒸馏除去溶剂,乙酸乙酯萃取两次,饱和食盐水洗涤,收集有机层,无水硫酸钠干燥。减压蒸馏得目标产物。收率为90%。
实施例2-2:
将上述产物溶解在二氯甲烷溶液中,使用三氟乙酸:二氯甲烷(v:v)=1:1脱Boc保护,减压蒸馏除去三氟乙酸得到黄色油状液体6待用。
后续制备得到最终产物1的步骤与实施例1中相同。
本具体实施例用来补充和说明本发明的可行性,在不背离本发明的精神和范围的情况下可以作出许多其它的更改和修改。因此,所附权利要求范围还应包含在本发明的基础上的变化和修改。
本发明提供了一种汇聚式的液相合成方式完成索马鲁肽侧链1的高效合成,降低了反应成本,为工业化生产提供了可能。
Claims (7)
1.一种液相汇聚式合成索马鲁肽侧链1的方法,其特征在于,包括如下步骤:
(1)将原料2-(2-氨基乙氧基)乙醇的氨基用R1保护,接着与溴乙酸乙酯发生亲核取代反应延长碳链,并通过酯水解一锅制得化合物4;
(2)将化合物4游离的羧基用R2保护,并且脱除R1保护基,得到化合物6;
(3)化合物6与芴甲氧羰基-L-谷氨酸1-叔丁酯经缩合反应,得到化合物8;
(4)将化合物8的R2保护基脱除,再与化合物6进行偶联反应,得到化合物10;
(5)脱除化合物10的Fmoc保护基后,再与18-(叔丁氧基)-18氧代十八烷酸进行酰胺化缩合偶联反应,得到化合物13;
(6)化合物13脱除R2保护基,得到最终目标产物1;
2.如权利要求1所述液相汇聚式合成索马鲁肽侧链1的方法,其特征在于,步骤(1)中,所述R1为Fmoc、Alloc、Boc、PMB、Cbz、Trt、Tos、Mtt、Mmt、Bom、Sem或MEM,R1保护所用的反应溶剂选自甲醇、乙醇、乙酸乙酯、二氯甲烷、1,2-二氯乙烷、DMF、DMSO、四氢呋喃、乙腈、N-甲基吡咯烷酮中的一种或几种任意比例的混合溶剂;
与溴乙酸乙酯发生亲核取代反应所用的反应溶剂选自甲醇、乙醇、乙酸乙酯、二氯甲烷、1,2-二氯乙烷、DMF、DMSO、四氢呋喃、乙腈、N-甲基吡咯烷酮中的一种或几种任意比例的混合溶剂;
酯水解在无机碱的作用下进行,所述无机碱选自氢氧化钠、氢氧化锂、碳酸钾、碳酸钠、氢氧化钙、氢氧化钡中的一种或几种任意比例的混合物;所述无机碱与原料2-(2-氨基乙氧基)乙醇的物质的量之比为0.5~4:1。
3.如权利要求1所述液相汇聚式合成索马鲁肽侧链1的方法,其特征在于,步骤(2)中,所述R2为Bn、Pfp、Me、Allyl、t-Bu、PMB、MEM或TBS;
脱除R1保护基在酸试剂的作用下进行,所述酸试剂为盐酸、醋酸或三氟乙酸;脱除R1保护基所用的反应溶剂选自甲醇、乙醇、乙酸乙酯、二氯甲烷、1,2-二氯乙烷、DMF、DMSO、四氢呋喃、乙腈、N-甲基吡咯烷酮中的一种或几种任意比例的混合溶剂。
4.如权利要求1所述液相汇聚式合成索马鲁肽侧链1的方法,其特征在于,步骤(3)中,缩合反应的溶剂选自甲醇、乙醇、乙酸乙酯、二氯甲烷、1,2-二氯乙烷、DMF、DMSO、四氢呋喃、乙腈、N-甲基吡咯烷酮中的一种或几种任意比例的混合溶剂;缩合反应在缩合剂的作用下进行,所述缩合剂选自DIC、DCC、HBTU、PyBOP、BOP、HATU、TBTU、DIC/HOBT、DCC/DMAP、EDCI/DMAP、EDCI/HOBT、HATU/HOBT中的任意单一缩合剂或者复合缩合剂;缩合反应的温度在20~70℃。
5.如权利要求1所述液相汇聚式合成索马鲁肽侧链1的方法,其特征在于,步骤(4)中,R2保护基脱除使用钯碳加氢的方法,所述钯碳中钯的质量占钯碳总质量的5%,钯的用量占化合物8的物质的量的1%~20%;R2保护基脱除所用的反应溶剂选自甲醇、乙醇、乙酸乙酯、二氯甲烷、1,2-二氯乙烷、DMF、DMSO、四氢呋喃、乙腈、N-甲基吡咯烷酮中的一种或几种任意比例的混合溶剂;
偶联反应的溶剂选自甲醇、乙醇、乙酸乙酯、二氯甲烷、1,2-二氯乙烷、DMF、DMSO、四氢呋喃、乙腈、N-甲基吡咯烷酮中的一种或几种任意比例的混合溶剂;偶联反应在缩合剂的作用下进行,所述缩合剂选自DIC、DCC、HBTU、PyBOP、BOP、HATU、TBTU、DIC/HOBT、DCC/DMAP、EDCI/DMAP、EDCI/HOBT、HATU/HOBT中的任意单一缩合剂或者复合缩合剂;偶联反应的温度在20~70℃。
6.如权利要求1所述液相汇聚式合成索马鲁肽侧链1的方法,其特征在于,步骤(5)中,脱除Fmoc保护基在有机碱的作用下进行,所述有机碱选自二乙胺、N,N-二异丙基乙胺、三乙胺、哌啶、咪唑、吡啶或DBU;脱除Fmoc保护基所用的反应溶剂选自甲醇、乙醇、乙酸乙酯、二氯甲烷、1,2-二氯乙烷、DMF、DMSO、四氢呋喃、乙腈、N-甲基吡咯烷酮中的一种或几种任意比例的混合溶剂;
酰胺化缩合偶联反应的溶剂选自甲醇、乙醇、乙酸乙酯、二氯甲烷、1,2-二氯乙烷、DMF、DMSO、四氢呋喃、乙腈、N-甲基吡咯烷酮中的一种或几种任意比例的混合溶剂;酰胺化缩合偶联反应在缩合剂的作用下进行,所述缩合剂选自DIC、DCC、HBTU、PyBOP、BOP、HATU、TBTU、DIC/HOBT、DCC/DMAP、EDCI/DMAP、EDCI/HOBT、HATU/HOBT中的任意单一缩合剂或者复合缩合剂;酰胺化缩合偶联反应的温度在20~70℃。
7.如权利要求1所述液相汇聚式合成索马鲁肽侧链1的方法,其特征在于,步骤(6)中,R2保护基的脱除在无机碱的作用下进行,所述无机碱选自氢氧化钾、氢氧化钡、氢氧化钙、氢氧化铝、氢氧化锂、氢氧化镁或氢氧化锌;脱除R2保护基所用的反应溶剂选自甲醇、乙醇、乙酸乙酯、二氯甲烷、1,2-二氯乙烷、DMF、DMSO、四氢呋喃、乙腈、N-甲基吡咯烷酮中的一种或几种任意比例的混合溶剂。
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