CN115433102B - 一种反式-(1r,2r)-2-氨基环己烷羧酸乙酯盐酸盐的制备方法 - Google Patents
一种反式-(1r,2r)-2-氨基环己烷羧酸乙酯盐酸盐的制备方法 Download PDFInfo
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- YYFIGOPUHPDIBO-UHFFFAOYSA-N propanoic acid;hydrochloride Chemical compound Cl.CCC(O)=O YYFIGOPUHPDIBO-UHFFFAOYSA-N 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 22
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 14
- RVGOKHBYNZPVGI-NKWVEPMBSA-N (1r,2r)-2-aminocyclohexane-1-carbonitrile Chemical compound N[C@@H]1CCCC[C@H]1C#N RVGOKHBYNZPVGI-NKWVEPMBSA-N 0.000 claims abstract description 12
- USQHEVWOPJDAAX-PHDIDXHHSA-N (1r,2r)-2-aminocyclohexane-1-carboxylic acid Chemical compound N[C@@H]1CCCC[C@H]1C(O)=O USQHEVWOPJDAAX-PHDIDXHHSA-N 0.000 claims abstract description 10
- DINLIZUFVHTMDX-UHFFFAOYSA-N 7-azabicyclo[4.1.0]heptane Chemical compound C1CCCC2NC21 DINLIZUFVHTMDX-UHFFFAOYSA-N 0.000 claims abstract description 9
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- 238000005886 esterification reaction Methods 0.000 claims description 2
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
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- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
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- XMQSOBPCWYVZSW-SCLLHFNJSA-N ethyl (1r,2r)-2-aminocyclohexane-1-carboxylate;hydrochloride Chemical compound Cl.CCOC(=O)[C@@H]1CCCC[C@H]1N XMQSOBPCWYVZSW-SCLLHFNJSA-N 0.000 description 1
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- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
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- C07C253/00—Preparation of carboxylic acid nitriles
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- C07B57/00—Separation of optically-active compounds
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- C07C227/26—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing carboxyl groups by reaction with HCN, or a salt thereof, and amines, or from aminonitriles
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Abstract
本发明公开了一种反式‑(1R,2R)‑2‑氨基环己烷羧酸乙酯盐酸盐的制备方法,属于医药中间体技术领域。1)7‑氮杂双环[4.1.0]庚烷与氰化试剂在B(C6F5)3存在下,升温加压反应,得到反式‑2‑氨基环己烷‑1‑甲腈;2)与L‑DBTA在有机溶剂进行对映异构体拆分得到反式‑(1R,2R)‑2‑氨基环己烷‑1‑甲腈;3)接着在酸条件下水解得到反式‑2‑氨基环己烷羧酸;4)最后与乙醇在氯化亚砜作用下酯化得到反式‑(1R,2R)‑2‑氨基环己烷羧酸乙酯盐酸盐。该方法反应操作简便,得到产品大于99.5%ee,拆分剂L‑DBTA回收率为85%,成本低廉,具备潜在的工业化放大前景。
Description
技术领域
本发明涉及一种反式-(1R,2R)-2-氨基环己烷羧酸乙酯盐酸盐的制备方法,属于医药中间体技术领域。
背景技术
反式-(1R,2R)-2-氨基环己烷羧酸乙酯盐酸盐,CAS 28250-14-8,英文名称Ethyltrans-(1R,2R)-2-aminocyclohexanecarboxylate,为一种β-环状氨基酸。传统肽类药物在体内环境下易水解,具有不稳定性,以β-氨基酸为基本单位β-肽相比传统α-肽,引入特殊的结构进行构象限制,从而使药代动力学参数更加良好,体内环境保留时间更长,可克服传统肽类药物对酶不稳定的缺点,为药物设计提供了系列新活性候选药物分子,蕴藏着非常大药物开发价值。β-氨基酸类化合物具有广泛的生物活性,如调节蛋白相互作用、抗病毒、抗菌、细胞穿透性能、受体激动剂和激素调节剂等。
文献[European Journal of Organic Chemistry,2003,4,721-726]路线用六步得到反式-2-氨基环己烷羧酸,其中需要将顺式转化为反式,其构象还是混合(即不纯)。文献[Journal of Organic Chemistry,2000,vol.65,#15,p.4766-4769]同样是需要将顺式转化为反式。
因此,仍需对反式-2-氨基环己烷羧酸乙酯盐酸盐反应路线进行深入研究,避免顺式转化反式的反应,从而规避转化率及相关纯化问题,同时降低成本,得到大于99.5%eeβ-环状氨基酸,并提供一种原料易得、稳定的反应路线,以满足日益增长的市场需求。
发明内容
为了克服上述技术缺陷,本发明公开了一种反式-(1R,2R)-2-氨基环己烷羧酸乙酯盐酸盐的制备方法。1)7-氮杂双环[4.1.0]庚烷与氰化试剂在B(C6F5)3存在下,升温加压反应,得到反式-2-氨基环己烷-1-甲腈;2)与L-DBTA在有机溶剂进行对映异构体拆分得到反式-(1R,2R)-2-氨基环己烷-1-甲腈;3)接着在酸条件下水解得到反式-2-氨基环己烷羧酸;4)最后与乙醇在氯化亚砜作用下酯化得到反式-(1R,2R)-2-氨基环己烷羧酸乙酯盐酸盐。该方法反应操作简便,得到产品大于99.5%ee,拆分剂L-DBTA回收率为85%,成本低廉,具备潜在的工业化放大前景。
本发明所述一种反式-(1R,2R)-2-氨基环己烷羧酸乙酯盐酸盐的制备方法,包括如下步骤:
1)开环反应:7-氮杂双环[4.1.0]庚烷与氰化试剂,在酸性催化剂存在下,有机溶剂中高温反应得到反式-2-氨基环己烷-1-甲腈;
2)成盐拆分:将L-DBTA与反式-2-氨基环己烷-1-甲腈,在乙醇溶剂中反应,过滤得到反式-(1R,2R)-2-氨基环己烷-1-甲腈与L-DBTA络合物,随后加酸调至酸性,溶剂萃取,水相保留;
3)水解反应:将第2)步中水相加酸,升温水解,得到反式-(1R,2R)-2-氨基环己烷羧酸;
4)酯化反应:将反式-2-氨基环己烷羧酸与乙醇,在氯化亚砜存在下,升温回流反应,得到反式-(1R,2R)-2-氨基环己烷羧酸乙酯盐酸盐。
上述四步反应,采用反应方程式表示如下:
进一步地,在上述技术方案中,步骤1)所述氰化试剂选自氰化钠、氰化钾或三甲基氰硅烷(TMSCN)。
进一步地,在上述技术方案中,步骤1)所述酸性催化剂选自B(C6F5)3,有机溶剂选自选自二氧六环、乙腈、DMSO中的任意一种与水混合物。开环时体系添加四正丁基氟化铵时,可进一步缩短反应时间。
进一步地,在上述技术方案中,步骤1)所述7-氮杂双环[4.1.0]庚烷与氰化试剂摩尔比为1:1.4-1.7。
进一步地,在上述技术方案中,步骤2)所述反式-2-氨基环己烷-1-甲腈与L-DBTA摩尔比为1:0.45-0.50。
进一步地,在上述技术方案中,步骤3)所述酸选自60-65%浓硫酸或30%盐酸,反应温度选自60-85℃。
进一步地,在上述技术方案中,步骤4)所述反式-2-氨基环己烷羧酸、乙醇与氯化亚砜摩尔比例为1:10-15:1.15-1.20;后处理纯化采用甲基叔丁基醚或异丙醚打浆。
发明有益效果
A、通过氰基对7-氮杂双环[4.1.0]庚烷开环,完全得到反式化合物;高温高压反应时通过选择特殊催化剂,氰化试剂用量更少,反应更为彻底。
B、采用L-DBTA这种对映体拆分剂,通过结晶拆分法一次就可得到单一手性的对映体。且L-DBTA可回收套用。
C、采用浓硫酸水解氰基更彻底,相比用强碱水解,酰胺及杂质更少,收率更高。
具体实施例
下面通过具体实例对本发明进行进一步说明。这些实施例应理解为仅用于说明本发明而不用于限制本发明的保护范围。在阅读了本发明记载的内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等效变化和修改同样落入本发明权利要求所限定的范围。
实施例1:
将7-氮杂双环[4.1.0]庚烷97.2g(1.0mol,1eq)、NaCN 83.3g(1.7mol,1.7eq)、B(C6F5)310.2g(0.02mol,0.02eq)和30%乙腈水溶液600mL投入到高压反应釜,密闭下升温至120-130℃反应过夜。检测反应完毕降温至0℃,加入30%NaOH调节pH碱性,减压浓缩后,二氯甲烷萃取,饱和碳酸钠洗涤,有机相浓缩得到反式-2-氨基环己烷-1-甲腈104.6g,收率84.2%,GC 95.4%。GC-MS[M+H]+=125.1;1HNMR(400MHz,CDCl3):3.44-3.47(m,1H),2.42-2.46(m,1H),1.10-2.20(m,10H).
实施例2
将7-氮杂双环[4.1.0]庚烷97.2g(1.0mol,1eq)、KCN 91.2g(1.4mol,1.4eq)、B(C6F5)310.2g(0.02mol,0.02eq)和30%乙腈水溶液600mL投入到高压反应釜,密闭下升温至120-130℃反应过夜。检测反应完毕,降温至0℃,加入30%NaOH调节pH碱性,减压浓缩后,二氯甲烷萃取,饱和碳酸钠洗涤,有机相浓缩得到反式-2-氨基环己烷-1-甲腈108.7g。收率87.5%,GC 96.2%。
实施例3:
将7-氮杂双环[4.1.0]庚烷97.2g(1.0mol,1eq)、TMSCN148.8g(1.5mol,1.5eq)、B(C6F5)310.2g(0.02mol,0.02eq)、四丁基氟化铵52.3g(0.2mol,0.2eq)和80%二氧六环水溶液500mL投入到高压反应釜内,密闭下升温至120-130℃反应过夜。检测反应完毕,降温至0℃,加入30%NaOH调节pH碱性,减压浓缩后,二氯甲烷萃取,饱和碳酸钠洗涤,有机相浓缩得到反式-2-氨基环己烷-1-甲腈102.7g。收率82.7%,GC 94.5%。
实施例4
向反应瓶内投入反式-2-氨基环己烷-1-甲腈99.4g(0.8mol,1eq)和无水乙醇350mL,搅拌溶清后,室温下2小时内滴加入L-DBTA 150.4g(0.40mol,0.50eq)和无水乙醇400mL混合溶液。滴加完毕,继续搅拌2小时。过滤,滤饼少量冷乙醇淋洗,得到反式-(1R,2R)-2-氨基环己烷-1-甲腈与L-DBTA络合物。将滤饼重新投入反应瓶内,加入甲基叔丁基醚和10%盐酸调节pH=1.0-1.5,分层,有机相为拆分剂及少量杂质(可回收),保留水相加入30%NaOH调节pH=12-13,二氯甲烷萃取,有机相浓缩,得到反式-(1R,2R)-2-氨基环己烷-1-甲腈39.2g,收率39.5%,GC99.5%,99.6%ee。
实施例5
向反应瓶内加入反式-(1R,2R)-2-氨基环己烷-1-甲腈49.7g(0.4mol,1eq)和甲苯200mL,升温至60℃,滴加65%浓硫酸162.8g(1mol,2.5eq),继续升温至75-80℃反应6小时,降温至50℃,分去有机相,保留水相,水相加入10%KOH调节等电点pH=6.72-6.86,随后降温至10℃,产品析出,过滤得到反式-2-氨基环己烷羧酸52.5g;收率91.7%,99.5%ee(衍生法测定)。1HNMR(400MHz,CD3OD):3.45-3.49(m,1H),2.63-2.66(m,1H),1.10-2.20(m,8H)
实施例5
向反应瓶内加入反式-(1R,2R)-2-氨基环己烷-1-甲腈49.7g(0.4mol,1eq)、30%盐酸300mL和甲醇50mL混合。升温至回流反应17小时,降温后减压浓缩除掉甲醇,加入MTBE萃取杂质,水相加入10%KOH调节等电点pH=6.72-6.86,随后降温至10℃,产品析出,过滤,滤饼得到反式-2-氨基环己烷羧酸50.5g;收率88.2%,99.4%ee(衍生法)。
实施例6
向反应瓶内加入反式-2-氨基环己烷羧酸50.1g(0.35mol,1eq)与乙醇300mL混合,20-30℃缓慢滴加氯化亚砜50g(0.42mol,1.2eq),随后升温回流8小时,减压浓缩至不流液,加入MTBE打浆得到反式-(1R,2R)-2-氨基环己烷羧酸乙酯盐酸盐67.1g。收率92.3%,99.5%ee(衍生法,绝对构型通过与标准品对照)。1HNMR(400MHz,CDCl3):8.50(s,3H),4.23-4.26(m,2H),3.38-3.41(m,1H),2.72-2.76(m,1H),2.38-1.23(m,11H).
以上所述,仅为本发明较佳的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明披露的技术范围内,根据本发明的技术方案及其发明构思加以等同替换或改变,都应涵盖在本发明的保护范围之内。
Claims (6)
1.一种反式-(1R,2R)-2-氨基环己烷羧酸乙酯盐酸盐的制备方法,其特征在于,包括如下步骤:
1) 开环反应:7-氮杂双环[4.1.0]庚烷与氰化试剂,在酸性催化剂存在下,有机溶剂中高温反应得到反式-2-氨基环己烷-1-甲腈;所述氰化试剂选自氰化钠、氰化钾或三甲基氰硅烷;所述酸性催化剂选自B(C6F5)3,有机溶剂选自乙腈与水混合物;
2) 成盐拆分:将L-DBTA与反式-2-氨基环己烷-1-甲腈,在乙醇溶剂中反应,过滤得到反式-(1R,2R)-2-氨基环己烷-1-甲腈与L-DBTA络合物,随后加酸调至酸性,溶剂萃取,水相保留;
3) 水解反应:将第2)步中水相加酸,升温水解,得到反式-(1R,2R)-2-氨基环己烷羧酸;
4) 酯化反应:将反式-2-氨基环己烷羧酸与乙醇,在氯化亚砜存在下,升温回流反应,得到反式-(1R,2R)-2-氨基环己烷羧酸乙酯盐酸盐。
2.根据权利要求1所述反式-(1R,2R)-2-氨基环己烷羧酸乙酯盐酸盐的制备方法,其特征在于:步骤1) 所述7-氮杂双环[4.1.0]庚烷与氰化试剂摩尔比为1:1.4-1.7。
3.根据权利要求1所述反式-(1R,2R)-2-氨基环己烷羧酸乙酯盐酸盐的制备方法,其特征在于:步骤2) 所述反式-2-氨基环己烷-1-甲腈与L-DBTA摩尔比为1:0.45-0.50。
4.根据权利要求1所述反式-(1R,2R)-2-氨基环己烷羧酸乙酯盐酸盐的制备方法,其特征在于:步骤3) 所述酸选自60-65%浓硫酸或30%盐酸,反应温度选自60-85℃。
5.根据权利要求1所述反式-(1R,2R)-2-氨基环己烷羧酸乙酯盐酸盐的制备方法,其特征在于:步骤4) 所述反式-2-氨基环己烷羧酸、乙醇与氯化亚砜摩尔比例为1:10-15:1.15-1.20。
6.根据权利要求1所述反式-(1R,2R)-2-氨基环己烷羧酸乙酯盐酸盐的制备方法,其特征在于:步骤4) 后处理纯化时,采用甲基叔丁基醚或异丙醚打浆。
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Denomination of invention: A method for preparing trans - (1R, 2R) -2-aminocyclohexanecarboxylic acid ethyl ester hydrochloride Granted publication date: 20240227 Pledgee: Dalian Branch of Bank of Communications Co.,Ltd. Pledgor: Dalian Shuangbo Pharmaceutical Chemical Co.,Ltd. Registration number: Y2024980026072 |