CN102143937A - 制备光学活性(s)-(-)-2-(n-丙基氨基)-5-甲氧基四氢化萘和(s)-(-)-2-(n-丙基氨基)-5-羟基四氢化萘化合物的方法 - Google Patents
制备光学活性(s)-(-)-2-(n-丙基氨基)-5-甲氧基四氢化萘和(s)-(-)-2-(n-丙基氨基)-5-羟基四氢化萘化合物的方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 238000000034 method Methods 0.000 title claims abstract description 22
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- OQDYWUDOCVRCBH-LYKKTTPLSA-N (6s)-6-(2-thiophen-2-ylpentylamino)-5,6,7,8-tetrahydronaphthalen-1-ol Chemical compound N([C@@H]1CC2=CC=CC(O)=C2CC1)CC(CCC)C1=CC=CS1 OQDYWUDOCVRCBH-LYKKTTPLSA-N 0.000 abstract 1
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
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- JRZGPXSSNPTNMA-UHFFFAOYSA-N 1,2,3,4-tetrahydronaphthalen-1-amine Chemical compound C1=CC=C2C(N)CCCC2=C1 JRZGPXSSNPTNMA-UHFFFAOYSA-N 0.000 description 1
- BRCPWISABURVIH-UHFFFAOYSA-N 5-methoxy-3,4-dihydro-2h-naphthalen-1-one Chemical compound O=C1CCCC2=C1C=CC=C2OC BRCPWISABURVIH-UHFFFAOYSA-N 0.000 description 1
- ONMOULMPIIOVTQ-UHFFFAOYSA-N 98-47-5 Chemical compound OS(=O)(=O)C1=CC=CC([N+]([O-])=O)=C1 ONMOULMPIIOVTQ-UHFFFAOYSA-N 0.000 description 1
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- 0 CCCNC1Cc2cccc(O*)c2CC1 Chemical compound CCCNC1Cc2cccc(O*)c2CC1 0.000 description 1
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- 238000005481 NMR spectroscopy Methods 0.000 description 1
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- 125000000217 alkyl group Chemical group 0.000 description 1
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- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
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- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
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- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 1
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- 238000007614 solvation Methods 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明描述制备光学活性(S)-(-)-2-(N-丙基氨基)-5-甲氧基四氢化萘和(S)-(-)-2-(N-丙基氨基)-5-羟基四氢化萘化合物的新方法,其分别基于旋光拆分2-(N-丙基氨基)-5-甲氧基四氢化萘和2-(N-丙基氨基)-5-羟基四氢化萘的对映异构体混合物。该方法包括(a)将所述化合物的对映异构体混合物与光学活性有机酸反应以形成非对映体盐,并通过结晶分开上述盐。所述化合物用于制备(6S)-(-)-5,6,7,8-四氢-6-[丙基-(2-噻吩基)乙基]氨基-1-萘酚(罗替伐汀)。罗替伐汀是多巴胺激动剂并且适于治疗帕金森氏疾病。
Description
发明领域:
本发明涉及分别自2-(N-丙基氨基)-5-甲氧基四氢化萘(II)和2-(N-丙基氨基)-5-羟基四氢化萘(III)对映异构体的混合物经由与光学活性酸形成非对映异构盐并进行旋光拆分制备高旋光纯度的光学活性(S)-(-)-2-(N-丙基氨基)-5-甲氧基四氢化萘化合物(此后称为S-(II))和(S)-(-)-2-(N-丙基氨基)-5-羟基四氢化萘(此后称为S-(III))的方法。
中间体化合物S-(II)和S-(III)可用于制备(6S)-(-)-5,6,7,8-四氢-6-[丙基-(2-噻吩基)乙基]氨基-1-萘酚(罗替伐汀)。
发明背景:
US专利4564628描述展示多巴胺能活性的氨基四氢化萘的烷基衍生物。在这些化合物中尤其发现(I),
后续研究的结果描述于US专利4657925,其显示对映异构体(6S)-(-)-5,6,7,8-四氢-6-[丙基-(2-噻吩基)乙基]氨基-1-萘酚(此后称为S-(I))的多巴胺能作用比对映异构体(6R)-(+)-5,6,7,8-四氢-6-[丙基-(2-噻吩基)乙基]氨基-1-萘酚高多至140倍。
US专利4885308描述S-(I)(称为罗替伐汀的活性成分)治疗帕金森病的用途。
因此,需要制备不含R-(I)对映异构体的光学纯S-(I)对映异构体的方法。
目前已报道的制备S-(I)的方法基于制备中间体化合物(S)-2-(N-丙基氨基)-5-甲氧基四氢化萘,即S-(II)。
US专利4657925公开通过拆分相应外消旋混合物制备(S)-2-(N-丙基氨基)-5-甲氧基四氢化萘,即S-(II)。然而,其并未详细描述所用的拆分方法。
Hoeve等人,J.Org.Chem.,1985,第50卷,第4508-4515页,描述通过用手性(R)-(+)-4-(2-氯苯基)-5,5-二甲基-2-羟基-1,3,2-二氧杂磷杂环己烷-2-氧化物磷酸作为外消旋拆分试剂进行外消旋混合物的旋光拆分制备S-(II)。该方法是昂贵且冗繁的,原因是其需要制备其本身又牵涉旋光拆分步骤的上述试剂。
Seiler等人,J.Med.Chem.,1986,第29卷,第912-917卷,描述通过(S)-(-)-2-(N-苄基氨基)-5-甲氧基四氢化萘的丙基化和随后的脱苄基化制备S-(II),上述化合物的制备描述于McDermed等人J.Med.Chem.,1976,第19卷,4,547-549:用苄胺还原胺化5-甲氧基四氢萘酮,结晶(S)-对映异构体富集的(-)-扁桃酸的非对映体盐,通过在乙醚中六次连续的重结晶旋光纯化该盐,并且最终作为碱释放胺。该方法耗时并且其工业应用成本不菲。
US专利4968837描述通过用L-(-)-二苯甲酰酒石酸在对映异构体中拆分中间体化合物(II),但是根据本发明作者的经验-通过应用该方法即使在连续纯化非对映体盐之后也不能实现高旋光纯度。
如上所述,现有的制备S-(II)乃至S-(I)的方法都无法令人满意地用于工业应用。因此,需要提供制备罗替伐汀(S-(I))的备择工业应用方法。
发明概要:
本发明针对的问题是提供易于在工业水平用于制备具有使其可用于药物用途的高旋光纯度的化合物(6S)-(-)-5,6,7,8-四氢-6-[丙基-(2-噻吩基)乙基]氨基-1-萘酚(S-(I))的备择方法。
本发明提供的解决方案基于发明人观察到某些光学活性有机酸在反应介质中与(II)(R-(II)和S-(II)对映异构体)和(III)(R-(III)和S-(III)对映异构体)能够形成不同溶解度的非对映异构盐,这使得可以通过结晶将它们分离。在反应介质中或在适宜溶剂中结晶这些非对映体盐的混合物时,由于其不同的溶解度,所形成的晶体将富集S-(II)和S-(III)对映异构体的非对映体盐,它们是可用于制备S-(I)的中间体化合物。非对映体盐的分离和纯化及其随后的释放产生高旋光纯度的上述中间体。
本发明方法通过相应非对映体盐的连续重结晶或再悬浮可以获得中间体化合物S-(II)和S-(III),其具有类似或高于99%,优选高于99.9%的旋光纯度。
发明详述:
外消旋形式的化合物(II)和(III)能够通过描述于文献中任意方法制备:例如描述于Hacksell等人,J.Med.Chem.,1979,第22(12)卷,第1469-1475页的方法,自用1-丙胺还原胺化5-甲氧基-2-四氢萘酮提供(II),随后用48%HBr脱保护苯酚基团提供(III)。
制备中间体化合物S-(II)和S-(III)的合成途径-本发明目的-示于方案1:
方案1
本发明提供的制备S-(II)对映异构体的方法这样进行:通过在适宜溶剂中用(+)-N-(3,5-二硝基苯甲酰基)-α-苯基甘氨酸处理(II)对映异构体混合物进行旋光拆分。可以按需要的次数重结晶或再悬浮所获得的盐直至获得所希望的旋光纯度。随后,可以将胺自所形成的盐释放并作为游离碱获得S-(II)。
本发明提供的制备S-(III)对映异构体的方法这样进行:在适宜溶剂中用(-)-N-(3,5-二硝基苯甲酰基)-α-苯基甘氨酸处理(III)对映异构体混合物进行旋光拆分。可以按需要的次数重结晶或再悬浮所获得的盐直至获得所希望的旋光纯度。随后,可以将胺自所形成的盐释放并可以作为游离碱获得S-(III)。
这些非对映体盐的沉淀和随后的重结晶或再悬浮可以在适宜的溶剂比如水、醇、腈或其混合物中进行。在具体实施方式中,该溶剂是乙腈和水的混合物。
与初始胺相比,待加入的光学活性有机酸的比例可以是约0.5至约1.2,优选约0.6至1当量。
本发明的目的还是提供所述中间体化合物S-(II)和S-(III)与光学活性(-)-N-(3,5-二硝基苯甲酰基)-α-苯基甘氨酸和(+)-N-(3,5-二硝基苯甲酰基)-α-苯基甘氨酸的盐,分别为下述结构(V)和(VI)。
类似地,本发明目的是提供如此获得的化合物S-(II)和S-(III)在根据方案2制备罗替伐汀(S-(I))中作为中间体的用途:
方案2
其中X是适宜的离去基团,选自卤素,比如氯或溴,磺酸酯,比如甲磺酸酯、间硝基苯磺酸酯或甲苯磺酸酯,等。
类似地,本发明目的是提供(V)和(VI)盐在制备罗替伐汀(S-(I))中作为中间体化合物的用途。
本发明的实施方式
额外提供下述实施例以说明本发明,但是并不期望限制本发明范围。
实施例1
通过用(+)-N-(3,5-二硝基苯甲酰基)-α-苯基甘氨酸旋光拆分自外消旋混合物制备(S)-(-)-2-(N-丙基氨基)-5-甲氧基四氢化萘(S-(II))
将10g的(II)溶于120mL乙腈-水混合物(60∶40)。然后,加入9.4g(0.6当量)(+)-N-(3,5-二硝基苯甲酰基)-α-苯基甘氨酸。加热混合物直至溶解。在混合物缓慢地冷却之后,首先出现混浊,然后出现固体沉淀。让混合物在0-5℃放置2小时。滤出悬浮液,在炉中干燥所得固体。
获得9.8g的盐(38%收率)。对所得产品进行HPLC分析,显示S-(II)/R-(II)对映异构体比率为83∶17。
在10体积乙腈-水混合物(80∶20)中依次重结晶固体,加热至回流,然后冷却至0-5℃。在三次重结晶之后,获得3.8g(15%总收率)盐(V),通过手性HPLC分析显示(S)-对映异构体比率高于99.5%。
熔点(DSC峰):220.27℃
IR(cm-1,KBr):3423,2955,2838,1664,1621,1585,1542,1345,731,705
1H-NMR(dmso-d6)δ:0.88(t,3H),1.54-1.63(m,3H),2.14(m,1H),2.42(m,1H),2.75(m,2H),2.83(t,2H),3.03(dd,1H),3.18(m,1H),3.35(s宽峰,2H,NH2 +),3.73(s,3H,OCH3),5.25(d,1H,CH-COOH),6.62(d,1H,Ar-H),6.74(d,1H,Ar-H),7.07(t,1H,Ar-H),7.16(m,1H,Ar-H),7.23(t,2H,Ar-H),7.45(d,2H,Ar-H),8.91(s,1H,Ar-H)9.03(s,2H,Ar-H),9.42(d,1H,NH酰胺)
在搅拌下,将经纯化的无水盐悬浮于甲苯(20mL)和5%K2CO3(60mL)的混合物中,加热至60℃直至完全溶解。分层,用5%K2CO3(15mL)随后水(8mL)洗涤有机层。浓缩有机层直至完全除去溶剂。获得1.44g的S-(II),是油状物(98%收率)。
IR(cm-1,NaCl):2955,2930,2834,1586,1469,1438,1260,1095,766
1H-NMR(CDCl3)δ:0.92(t,3H,CH2-CH3),1.48-1.60(m,3H,CH2-CH2-CH3和N-CH-CH2-CH2-C),1.80(s宽峰,1H,NH),2.07(m,1H,N-CH-CH2-CH2-C),2.50-2.61(m,2H,C-CH2-CHN和N-CH-CH2-CH2-C),2.66(t,2H,CH2-CH2-CH3),2.84-2.93(m,2H,C-CH2-CHN和N-CH-CH2-CH2-C),2.95-3.10(dd,1H,C-CH2-CHN)3.78(s,3H,0CH3),6.63(d,1H,Ar-H),6.68(d,1H,Ar-H),7.07(t,1H,Ar-H)
所得产品的旋光度是[α]20 D:-73.49(c=1,甲醇中)。在US 4968837在描述为-65而在Seiler,M.P.等人,J.Med.Chem.1986,29(6),912-917中描述为-72.7(c=1,甲醇中)。
实施例2
通过用(-)-N-(3,5-二硝基苯甲酰基)-α-苯基甘氨酸旋光拆分自外消旋混合物制备(S)-(-)-2-(N-丙基氨基)-5-羟基四氢化萘(S-(III))
将10g的(III)和11.7g(0.7当量)(-)-N-(3,5-二硝基苯甲酰基)-α-苯基甘氨酸的160mL乙腈-水混合物(70∶30)悬浮液加热直至溶解。缓慢地冷却形成的溶液,首先出现混浊,然后出现固体沉淀。将混合物在0-5℃下放置2小时。滤出悬浮液,在炉中干燥所得固体。
获得11.2g的盐(42%收率)。对所得产品进行HPLC分析,显示S-(III)/R-(III)对映异构体比率为91∶9。
在10体积乙腈-水混合物(80∶20)中依次重结晶固体,加热至回流然后冷却至0-5℃。在两次重结晶之后,获得6.0g(24%总收率)盐(VI),通过手性HPLC分析显示(S)-对映异构体比率高于99.9%。
IR(cm-1,KBr):3450,3032,2972,2854,1652,1621,1539,1467,1376,1275,729
1H-NMR(dmso-d6)δ:0.87(t,3H),1.53-1.62(m,3H),2.13(m,1H),2.39(m,1H),2.72(m,2H),2.83(t,2H),3.00(dd,1H),3.18(m,1H),3.35(s宽峰,2H,NH2 +),5.23(d,1H,CH-COOH),6.46(d,1H,Ar-H),6.58(d,1H,Ar-H),6.87(t,1H,Ar-H),7.17(m,1H,Ar-H),7.24(t,2H,Ar-H),7.44(d,2H,Ar-H),8.91(s,1H,Ar-H)9.03(d,2H,Ar-H),9.41(d,1H,NH酰胺),9.55(s,1H,OH)
在搅拌下,将经纯化的无水盐悬浮于甲苯(20mL)和5%K2CO3(60mL)的混合物中,加热至60℃直至完全溶解。分层,有机层用5%K2CO3(15mL)随后水(8mL)洗涤。浓缩有机层直至完全除去溶剂。获得1.8g的S-(III),是固体(98%收率)。
熔点(DSC峰):88.3℃
IR(cm-1,KBr):3532,3269,2923,2854,1585,1464,1281,773
1H-NMR(dmso-d6)δ:0.86(t,3H),1.40(m,3H),1.94(m,1H),2.38(m,2H),2.53(t,2H),2.69(m,2H),2.84(dd,1H),3.36(s宽峰,1H,NH),6.46(d,1H,Ar-H),6.54(d,1H,Ar-H),6.84(t,1H,Ar-H),9.08(s,1H,OH)
旋光度[α]20 D:-74.89(c=1,甲醇中)。在Seiler,M.P.等人,J.Med.Chem.1986,29(6),912-917中描述为-75。
实施例3
自(S)-(-)-2-(N-丙基氨基)-5-甲氧基四氢化萘(S-(II))制备(S)-(-)-2-(N-丙基氨基)-5-羟基四氢化萘(S-(III))
将根据实施例1获得的10g的(S)-(-)-2-(N-丙基氨基)-5-甲氧基四氢化萘(S-(II))与40mL的48%HBr和20mL乙酸混合。回流所得混合物3小时。在该时间间隔期间,固体开始沉淀。将悬浮液逐渐冷却至0-5℃,加入30mL水。滤出反应混合物,获得11.7g(90%收率)的S-(-)-2-(N-丙基氨基)-5-羟基四氢化萘氢溴酸化物。
将该固体悬浮于110mL水,加热悬浮液至40℃。加入10M NaOH直至pH为12.5,混合物变为溶液。随后,用6M HCl将混合物酸化至pH 9-9.5,发生固体沉淀。将混合物逐渐冷却至0-5℃,滤出。获得7.5g的S-(-)-2-(N-丙基氨基)-5-羟基四氢化萘(S-(III))(90%收率)。
熔点(DSC峰):88.25℃
旋光度[α]20 D:-74.95(c=1,甲醇中)。
实施例4
自S-(-)-2-(N-丙基氨基)-5-羟基四氢化萘(S-(III))制备(6S)-(-)-5,6,7,8-四氢-6-[丙基-(2-噻吩基)乙基]氨基-1-萘酚(S-(I))
将根据实施例2获得的10g的(S)-(-)-2-(N-丙基氨基)-5-羟基四氢化萘(S-(III))与80mL乙腈中的9g的NaHCO3(2.2当量)和16g的2-硝基苯磺酸2-(2-噻吩基)乙醇酯(1.05当量)混合。回流混合物9小时,然后冷却并过滤除去悬浮盐。加入60mL水至滤液,蒸馏浓缩除去乙腈。加入40mL甲苯,分层。用10%NaHCO3洗涤有机层两次。然后,加入50mL水和H3PO4直至pH=1-2。在分层之后,用30%K2CO3将含水酸层中和至pH=7-7.5,用20mL乙酸乙酯萃取。有机层用10mL水洗涤,蒸馏浓缩除去溶剂,提供10g的(6S)-(-)-5,6,7,8-四氢-6-[丙基-(2-噻吩基)乙基]氨基-1-萘酚(S-(I)),是白色固体(70%收率)。
熔点(DSC峰):78.94℃
IR(cm-1,KBr):3500,3098,3065,2969,2932,1585,1465,1281,775,701
1H NMR(CDCl3)δ:0.89(t,3H,N-CH2-CH2-CH3);1.51(六重峰,2H,N-CH2-CH2-CH3);1.58(ddd,1H,N-CH-CH2-CH2-C);2.10(ddd,1H,N-CH-CH2-CH2-C);2.55(t,2H,N-CH2-CH2-CH3);2.47-2.60(m,1H,C-CH2-CHN);2.67-2.87(m,4H,N-CH-CH2-CH2-C和N-CH2-CH2-噻吩);2.90(m,1H,C-CH2-CHN);2.92-3.01(m,3H,C-CH2-CHN和N-CH2-CH2-噻吩);4.83(s,1H,OH);6.57(d,1H,Ar-H);6.67(d,1H,Ar-H);6.80(d,1H,Ar-H);6.90(dd,1H,Ar-H);6.97(t,1H,Ar-H);7.10(d,1H,Ar-H)
实施例5
自(S)-(-)-2-(N-丙基氨基)-5-甲氧基四氢化萘(S-(II))制备(S)-2-(N-正-丙基-N-2-噻吩基乙基氨基)-5-甲氧基四氢化萘氢溴酸化物(S-(IV).HBr)
将根据实施例1获得的10g的(S)-(-)-2-(N-丙基氨基)-5-甲氧基四氢化萘(S-(II))与60mL乙腈中的13.8g的K2CO3(2.2当量)和15g的2-硝基苯磺酸2-(2-噻吩基)乙醇酯(1.05当量)混合。回流混合物9小时,然后冷却至室温。加入80mL水,蒸馏浓缩除去乙腈。加入40mL甲苯,分层。通过于60℃加热两相混合物用40mL的5%NaHCO3洗涤有机层两次,最终用水洗涤。然后,向有机层加入40mL水和H3PO4直至pH=1-2)。在分层之后,用NaOH 10M碱化含水酸层直至pH=11,用30mL甲苯萃取。用20mL水洗涤有机层,蒸馏浓缩直至获得油状产品。通过在乙酸乙酯中再溶剂化并加入HBr/AcOH,将产品转化为其氢溴酸化物。过滤回收所形成的固体,干燥。获得15.3g的(S)-2-(N-正-丙基-N-2-噻吩基乙基氨基)-5-甲氧基四氢化萘氢溴酸化物,S-(IV).HBr,是白色固体(82%收率)。
熔点(DSC峰):142.59℃
IR(cm-1,KBr):2933,2623,2546,1587,1469,1438,1258,1093,772
1H NMR(CDCl3.)δ:1.01(t,3H),1.90(m,1H),2.08(m,1H),2.59(m,2H),3.00-3.70(m,11H),3.78(s,1H,OCH3),6.67(d,1H,Ar-H),6.70(d,1H,Ar-H),6.92(m,2H,Ar-H),7.11(t,1H,Ar-H),7.17(d,1H,Ar-H),11.43(s,1H,NH)
实施例6
自(S)-2-(N-正-丙基-N-2-噻吩基乙基氨基)-5-甲氧基四氢化萘氢溴酸化物(S-(IV).HBr)制备(6S)-(-)-5,6,7,8-四氢-6-[丙基-(2-噻吩基)乙基]氨基-1-萘酚(S-(I))
在室温下将10g的(S)-2-(N-正-丙基-N-2-噻吩基乙基氨基)-5-甲氧基四氢化萘氢溴酸化物(S-(IV).HBr)溶于50mL二氯甲烷。在低于0-5℃的温度冷却混合物。逐滴加入55mL BBr3的二氯甲烷(5当量)溶液,将混合物于0-5℃保持搅拌6小时。加入60mL水至反应混合物。沉淀出白色固体,通过过滤回收。在室温下将湿润固体悬浮于20mL水和40mL乙酸乙酯。用30%K2CO3将混合物碱化至pH=7-7.5。分层,用20mL乙酸乙酯萃取水层,将其与先前的有机层合并。有机层用10mL水洗涤,蒸馏浓缩。获得6.9g的(6S)-(-)-5,6,7,8-四氢-6-[丙基-(2-噻吩基)乙基]氨基-1-萘酚(S-(I)),是白色固体(90%收率)。
熔点(DSC峰):78.37℃。
Claims (9)
2.根据权利要求1的方法,其中光学活性S-(II)化合物的制备包括用(+)-N-(3,5-二硝基苯甲酰基)-α-苯基甘氨酸旋光拆分相应化合物(II)。
3.根据权利要求1的方法,其中光学活性S-(III)化合物的制备包括用(-)-N-(3,5-二硝基苯甲酰基)-α-苯基甘氨酸旋光拆分相应化合物(III)。
6.通过权利要求2的方法获得的光学活性S-(II)化合物在制备(6S)-(-)-5,6,7,8-四氢-6-[丙基-(2-噻吩基)乙基]氨基-1-萘酚(罗替伐汀)中作为中间体的用途。
7.通过权利要求3的方法获得的光学活性S-(III)化合物在制备(6S)-(-)-5,6,7,8-四氢-6-[丙基-(2-噻吩基)乙基]氨基-1-萘酚(罗替伐汀)中作为中间体的用途。
8.根据权利要求4的式(V)盐在制备(6S)-(-)-5,6,7,8-四氢-6-[丙基-(2-噻吩基)乙基]氨基-1-萘酚(罗替伐汀)中作为中间体的用途。
9.根据权利要求5的式(VI)盐在制备(6S)-(-)-5,6,7,8-四氢-6-[丙基-(2-噻吩基)乙基]氨基-1-萘酚(罗替伐汀)中作为中间体的用途。
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Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
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SE8004002L (sv) * | 1980-05-29 | 1981-11-30 | Arvidsson Folke Lars Erik | Terapeutiskt anvendbara tetralinderivat |
US4564628A (en) | 1983-01-03 | 1986-01-14 | Nelson Research & Development Co. | Substituted 2-aminotetralins |
US4657925A (en) | 1984-08-13 | 1987-04-14 | Nelson Research & Development Co. | Method and compositions for reducing the intraocular pressure of mammals |
US4584828A (en) * | 1984-05-07 | 1986-04-29 | Bentley Robert J | Brush rake |
US4885308A (en) | 1984-08-13 | 1989-12-05 | Nelson Research & Development Co. | Method and compositions for treatment of parkinsonism syndrome in mammals |
US5234945A (en) | 1989-05-09 | 1993-08-10 | Whitby Research, Inc. | Method of producing body weight and food intake using a dopamine D2 receptor agonist |
AU5439890A (en) * | 1989-05-09 | 1990-11-29 | Whitby Research, Inc. | A method of reducing body weight and food intake using a dopamine d2 receptor agonist |
RU2086535C1 (ru) * | 1989-05-31 | 1997-08-10 | Дзе Апджон Компани | Производные 1,2,3,4-тетрагидро-2-нафтиламина |
US4968837A (en) | 1989-07-28 | 1990-11-06 | Ethyl Corporation | Resolution of racemic mixtures |
GB8921304D0 (en) * | 1989-09-20 | 1989-11-08 | Wyeth John & Brother Ltd | New method of treatment and heterocyclic compounds used therein |
US5442117A (en) * | 1993-12-13 | 1995-08-15 | Albemarle Corporation | Enantiomeric resolution |
WO2002053551A1 (fr) | 2000-12-28 | 2002-07-11 | Takeda Chemical Industries, Ltd. | Procede de preparation de composes a base de 2,3-dihydrobenzofurane a activite optique |
JP2002265460A (ja) * | 2000-12-28 | 2002-09-18 | Takeda Chem Ind Ltd | 光学活性2,3−ジヒドロベンゾフラン化合物の製造法 |
ES2200699B1 (es) * | 2002-07-12 | 2005-10-01 | Ragactives, S.L | Procedimiento para la separacion de r(-) y s(+)-5-(2-((2-(etoxifenoxi)etil)amino)propil-2-metoxibenceno-sulfonamida. |
DE10359528A1 (de) | 2003-12-18 | 2005-07-28 | Schwarz Pharma Ag | (S)-2-N-Propylamino-5-hydroxytetralin als D3-agonistisches Therapeutikum |
DE10361258A1 (de) | 2003-12-24 | 2005-07-28 | Schwarz Pharma Ag | Verwendung von substituierten 2-Aminotetralinen zur vorbeugenden Behandlung von Morbus Parkinson |
US8604242B2 (en) | 2008-10-13 | 2013-12-10 | Interquim, S.A. | Process for the preparation of optically active (S)-(−)-2-(N-propylamino)-5-methoxytetraline and (S)-(−)-2-(N-propylamino)-5-hydroxytetraline compounds |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113234057A (zh) * | 2021-06-03 | 2021-08-10 | 成都工业学院 | 一种罗替戈汀的制备方法 |
CN114805095A (zh) * | 2022-05-11 | 2022-07-29 | 上海柏狮生物科技有限公司 | 一种(s)-5-甲氧基-1,2,3,4-四氢-n-丙基-2-萘胺的制备方法 |
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BRPI0920645A2 (pt) | 2016-01-12 |
IL211791A0 (en) | 2011-06-30 |
US20110152543A1 (en) | 2011-06-23 |
CL2011000830A1 (es) | 2012-03-30 |
RU2011119224A (ru) | 2012-11-20 |
US8604242B2 (en) | 2013-12-10 |
AU2009305477A1 (en) | 2010-04-22 |
MX2011003930A (es) | 2011-05-03 |
PE20110366A1 (es) | 2011-06-20 |
WO2010043571A1 (en) | 2010-04-22 |
CA2735101A1 (en) | 2010-04-22 |
RU2473538C2 (ru) | 2013-01-27 |
AU2009305477B2 (en) | 2014-04-17 |
EP2346811A1 (en) | 2011-07-27 |
ES2396066T3 (es) | 2013-02-19 |
CA2735101C (en) | 2015-09-29 |
CN102143937B (zh) | 2014-07-02 |
KR101624760B1 (ko) | 2016-05-26 |
JP2012505183A (ja) | 2012-03-01 |
EP2346811B1 (en) | 2012-08-15 |
IL211791A (en) | 2014-06-30 |
HK1160106A1 (zh) | 2012-08-10 |
JP5595404B2 (ja) | 2014-09-24 |
KR20110069036A (ko) | 2011-06-22 |
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