CN113527108B - 一种制备光学纯的5,7-二氟-1,2,3,4-四氢化萘-2-胺及其盐的方法 - Google Patents
一种制备光学纯的5,7-二氟-1,2,3,4-四氢化萘-2-胺及其盐的方法 Download PDFInfo
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- CN113527108B CN113527108B CN202111083696.5A CN202111083696A CN113527108B CN 113527108 B CN113527108 B CN 113527108B CN 202111083696 A CN202111083696 A CN 202111083696A CN 113527108 B CN113527108 B CN 113527108B
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- 150000003839 salts Chemical class 0.000 title claims abstract description 18
- AAXQLCRQEWZHDB-UHFFFAOYSA-N 5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-amine Chemical compound C1=C(F)C=C2CC(N)CCC2=C1F AAXQLCRQEWZHDB-UHFFFAOYSA-N 0.000 title claims abstract description 8
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- HOUVATQQKYAEBB-UHFFFAOYSA-N 5,7-difluoro-3,4-dihydro-1h-naphthalen-2-one Chemical compound C1CC(=O)CC2=CC(F)=CC(F)=C21 HOUVATQQKYAEBB-UHFFFAOYSA-N 0.000 description 3
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
- C07C209/50—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of carboxylic acid amides
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/62—Quaternary ammonium compounds
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- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
- C07C209/74—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by halogenation, hydrohalogenation, dehalogenation, or dehydrohalogenation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C231/16—Preparation of optical isomers
- C07C231/18—Preparation of optical isomers by stereospecific synthesis
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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Abstract
本发明公开了一种制备如式a和b所示的光学纯的5,7‑二氟‑1,2,3,4‑四氢化萘‑2‑胺及其盐的方法,包括:(1)将3,5‑二氟苯乙酸在溶剂存在下与SOCl2反应生成酰氯,然后在三氯化铝的作用下和乙烯进行傅克反应;(2)在有机溶剂中酸催化条件下,5,7‑二氟‑3,4‑二氢化萘‑2(1H)‑酮和酰胺反应脱水生成烯胺;(3)烯胺在手性催化剂的存在下,催化氢化制备光学纯的中间体酰胺;(4)酰胺在酸性或碱性条件下水解得到光学纯的5,7‑二氟‑1,2,3,4‑四氢化萘‑2‑胺(a或者b)及其盐的形式。本发明提供了一种简洁、方便、易工业化生产制备光学纯的5,7‑二氟‑1,2,3,4‑四氢化萘‑2‑胺及其盐的方法。
Description
技术领域
本发明涉及一种制备四氢萘手性胺的合成方法,更具体地讲,本发明涉及一种制备光学纯的(R)- 5,7-二氟-1,2,3,4-四氢化萘-2-胺和(S)-5,7-二氟-1,2,3,4-四氢化萘-2-胺及其盐形式的方法。
背景技术
手性胺化合物具有广泛的生物学活性,是新药研发中一类重要中间体;这类化合物的合成方法和活性分子的研究一直非常活跃,并且在手性胺在药物合成领域是非常重要的组成部分。
欧洲专利EP 2202318 B1公开一种制备旋光手性胺的方法,该方法包括:a)提供氨基受体和作为氨基给体的丙氨酸;b)使氨基受体和氨基给体与(R)-或(S)-选择性转氨酶反应;c)获得期望的旋光手性胺和作为α-酮副产物的丙酮酸;和d)用脱羧酶从反应混合物中除去丙酮酸。
中国专利CN202010118880.8公开了一种含氟手性胺类化合物的合成方法。该合成方法包括:氨基供体与含氟二羟基缩酮类化合物在转氨酶的催化下,反应生成含氟手性胺类化合物;其中,转氨酶来源于多个菌种。转氨酶对含氟二羟基缩酮类化合物具有底物特异性,能够有效催化此类底物转化为含氟手性胺类化合物,而且,该转氨酶对多种含氟二羟基缩酮类化合物都具有催化活性,反应选择性和活性均较高。
转氨酶是一种生物酶,在工业上的大规模应用存在一定难度。
目前,(R)-5,7-二氟-1,2,3,4-四氢化萘-2-胺和(S)-5,7-二氟-1,2,3,4-四氢化萘-2-胺是在研新药的重要中间体,其常用的合成路线如下:
这两条路线中,我们对第一条进行了验证,发现叔丁基亚磺酰胺反应收率较低,只有60%左右,下一步还原尝试了NaBH4、BH3、L-selectride和DIBAL等,ee值都较低,通过核磁检测发现和叔丁基亚磺酰胺反应并没有生产亚胺中间体(3’,见上面反应式所示),而是生成了一种烯胺中间体(3a,见上面反应式所示),导致直接还原手性纯度差,并且该路线中使用了价格昂贵的叔丁基亚磺酰胺,导致总成本很高。
路线二,根据WO 2009/021055 A1报道,第二步中间体2到3b还原使用LAH,反应风险大,并且ee值只能达到92.4%;后面步骤使用叠氮钠,在生产过程中存在安全风险。
总之,现有技术主要有以下缺点:第一,反应多步用到了氢化铝锂、甲基磺酰氯、叠氮钠等危险试剂,反应的安全风险以及环境友好性不足,不利于放大生产的需要;第二,关键手性还原步骤手性选择性不高,手性纯度只有92%,无法满足后续药物生产的需求;第三,反应路线较长,且收率不高,使得路线总成本较高。
因此,有必要提供一种生产过程相对简单、基本不用或少用危险试剂、总收率高和手性纯度高的合成方法。
发明内容
本发明的发明目的是提供一种制备光学纯的5,7-二氟-1,2,3,4-四氢化萘-2-胺的方法,该方法相对简单、收率高,手性纯度可达到99.5%以上。
为了实现上述的发明目的,本发明提供了一种制备如式(a)或式(b)所示的光学纯5,7-二氟-1,2,3,4-四氢化萘-2-胺及其盐的方法,
该方法包括如下步骤:
(1)在溶剂存在下,式(1)所示的3,5-二氟苯乙酸与SOCl2反应生成酰氯,然后,在三氯化铝的作用下与通入的乙烯发生傅克反应,形成式(2)所示的5,7-二氟-3,4-二氢化萘-2(1H)-酮;
(2)将步骤(1)制备的5,7-二氟-3,4-二氢化萘-2(1H)-酮与酰胺RCONH2在酸催化条件下,利用溶剂回流,脱水形成式(3)所示的烯胺;
(3)将步骤(2)所制备的烯胺在手性催化剂的催化下,进行氢化反应,还原双键得到式(4S)或式(4R)所示的手性酰胺中间体;
(4)将步骤(3)制备的手性酰胺中间体在酸性条件下进行脱保护,制得式(a)或式(b)所示的手性胺或其盐。
上述本发明方法的反应路线如下:
在本发明的上述方法中,步骤(2)中所采用的酰胺RCONH2中的R可以为选自于如下一组中的基团:C1~C8烷基或环烷基、具有一个或者多个卤素取代的C1~C8烷基、苯基及其衍生物。
更优选地,上述的酰胺可以为选自于如下一组酰胺中的一种或一种以上:
在本发明的上述方法中,步骤(2)中反应所使用的酸催化剂可以为选自于如下一组中的一种或一种以上:苯基磺酸、苯环上单取代或多取代的苯基磺酸、磺酸、硫酸、磷酸、三氟乙酸、烷基磺酸、一个或多个卤素取代的烷基磺酸、氟硼酸、硼酸、以及弱碱和强酸形成的盐。例如,弱碱和强酸形成的盐可以是吡啶-对甲苯磺酸盐。
在本发明的上述方法中,步骤(3)中反应所使用的手性催化剂可以是由手性膦配体与钌络合物或铑络合物形成的催化体系。其中,所采用的钌络合物可以为选自于如下一组中的一种或一种以上:RuLCl2、[Ru(benzene)(L)Cl]Cl、[Ru(cymene)(L)Cl]Cl、RuLCl2(DMF)m、[NH2Me2]+[(RuClL)2(μ-Cl3)] 、Ru(cod)(methallyl)2、RuCl2(CH3CN)2、和Ru(cod)(O2CCF3)2;所采用的铑络合物可以为选自于如下一组中的一种或一种以上:RhCl2、Rh(COD)BF4和Rh(COD)Cl2。
在本发明的上述方法中,所采用的手性膦配体可以为选自于如下一组中的一种或一种以上:Me-DuPhos、Et-DuPhos、Me-BPE、Et-BPE、i-Pr-BPE、Ph-BPE、SunPhos、DifluroPhos、SynPhos、BINAP、Me-Biphemp、MeOBiphep、NorPhos、QuinoxP、 BenzP、DioxyBenzP、SegPhos、Tol-SegPhos、t-Bu-SegPhos、DM-segphos、DMM-SegPhos、DTBM-SegPhos和DifluroPhos。
例如,所采用的手性膦配体可以为选自于如下一组中的一种或一种以上:
需要注意的是,上述的手性膦配体可以与钌络合物或铑络合物形成制备(S)-5,7-二氟-1,2,3,4-四氢化萘-2-胺的催化体系;而如果要 制备(R)-5,7-二氟-1,2,3,4-四氢化萘-2-胺所用催化剂,则可以选用上述手性膦配体中的一种或一种以上的对应异构体。
在本发明的上述方法中,步骤(1)中傅克反应的温度可以控制在-30~80℃;步骤(2)中反应温度可以控制在80~130℃;步骤(3)中反应温度可以控制在20~100℃;步骤(4)中反应温度可以控制在30~150℃。
在本发明方法的各步骤中,具体的工艺条件在不同场合下可以有不同选择。
在本发明方法的步骤(1)中,由3,5-二氟苯乙酸在溶剂存在下与SOCl2所形成的酰氯,在三氯化铝的作用下与乙烯进行傅克反应,形成5,7-二氟-1,2,3,4-四氢化萘-2-酮。
步骤(1)中反应溶剂可以使用二氯甲烷、1,2-二氯乙烷等,但并不限于这些溶剂;反应温度通常控制在-30~80℃,优选控制在-20~30℃,更优选控制在-20~20℃。例如,傅克反应的温度控制在-10~30℃。
另外,在步骤(1)中,反应时间通常是0.1~6小时,优选0.2~2小时;反应中使用的氯化亚砜当量通常是0.5~2,三氯化铝的当量为0.8~2,乙烯的当量为1.1~3。优选地,氯化亚砜的当量是1.0~1.5,三氯化铝的当量为1.0~1.5,乙烯的当量为1.2~2。
在本发明方法的步骤(2)中,5,7-二氟-1,2,3,4-四氢化萘-2-酮与酰胺在酸催化条件下,使用溶剂回流进行脱水生产烯胺。
步骤(2)中反应溶剂的实例包括基于烃的溶剂(己烷、乙酸乙酯、苯、甲苯、二甲苯、氯苯等);步骤(2)中反应温度通常是为80~130℃,优选100~120℃,更优选为90~115℃;步骤(2)中酰胺的当量通常为0.5~3;酸当量通常为0.001~1;优选地,酰胺当量为1~3,更优选地,酰胺当量通常为0.8~2;酸当量优选为0.01~0.5,更优选为0.1~0.5。
在本发明方法的步骤(3)中,烯胺在有机醇溶剂中,在手性膦配体和钌或铑络合物的存在下,催化氢化制备光学纯的中间体酰胺。
步骤(3)中,催化剂的当量通常为0.0005~0.5,优选为0.001~0.2;步骤(3)中,氢化使用氢气的压力通常为为0.1~10 MPa,优选为 0.5~6MPa;步骤(3)中,所使用的有机醇溶剂可以为C1-C8烷基醇、一个或者多个氟取代的C1-C8烷基醇等。
在本发明方法的步骤(4)中,中间体4R或者4S在酸性或者碱性条件下进行脱保护,得到手性胺或者是胺盐。
步骤(4)中,使用酸或者碱进行水解时,所使用的酸或碱可以为盐酸、氢溴酸、硫酸、氢氧化钠、氢氧化钾中的一种;步骤(4)中酸或碱的当量通常为1~20,优选为5~20,更优选为3~15;步骤(4)中反应温度通常是30~150℃,优选50~120℃;步骤(4)中所使用的溶剂可以为C1-C8烷基醇、一个或者多个卤素取代的C1-C8烷基醇等。
相对于现有技术,本发明的制备方法不需要使用氢化铝锂、甲基磺酰氯、叠氮钠等危险试剂,反应的安全风险相对较低,对环境更为友好,而且反应路线较短,收率较高,使得路线总成本较低,同时ee值>98%(ee是指对映体过量百分数,即在手性合成中,生成目标产物为非外消旋体,具有光活性,也即是一个对映体超过另一个对映体的百分数),甚至可以达到99.5%以上。
下面,结合附图和具体实施方式对本发明作进一步的说明,但这些具体实施方式只是针对本发明某些特定的具体实施方式的说明而已,并非是对本发明的限定。
附图说明
图1是按照本发明方法制备的(S)-5,7-二氟-1,2,3,4-四氢化萘-2-胺盐酸盐的HNMR图谱;
图2是按照本发明方法制备的(S)-5,7-二氟-1,2,3,4-四氢化萘-2-胺的HNMR图谱。
具体实施方式
实施例1 (S)-5,7-二氟-1,2,3,4-四氢化萘-2-胺及其盐酸盐的制备
(1)将100克3,5-二氟苯乙酸1溶于500 mL二氯甲烷中,搅拌下加入50克氯化亚砜,然后升温至40~50℃,保持此温度反应4h后通过HPLC和TLC检测反应完毕,降温,浓缩,加入二氯甲烷稀释暂存,作为制备好的酰氯;向另一反应瓶中加入500 mL二氯甲烷,再加入150g三氯化铝,再将前述制备好的酰氯滴加入反应体系,加入完毕后,向体系中通入乙烯气体,反应至原料反应完全,将体系中加入500 mL纯化水淬灭反应,淬灭完毕后将体系分液,有机相浓缩,柱层析得中间体2,产率80%;
(2)将80克中间体2溶于400 mL甲苯中,再加入150克乙酰胺和5克对甲苯磺酸,升温至80~120℃反应,保持此温度反应16h后通过HPLC和TLC检测反应完毕,体系降温,盐洗,盐洗后的有机相浓缩干得中间体3,产率83%;
(3)先制备催化剂:氮气保护下,将200 mg (1,5-环辛二烯)二氯化钌加入10 mL二氯甲烷中,再加入200 mg (R,R)-Me-BPE,将体系加热至40℃,反应8 h反应完毕,体系浓缩干,用正己烷打浆,过滤,滤饼真空烘干得不对称还原步骤的催化剂;
将50克中间体3溶于500 mL乙二醇中,加入上述制备好的R构型100 mg催化剂,将体系置换为氢气,保持氢气压力1MPa,将体系升温至40~50℃反应,20h后检测反应完毕,体系降温浓缩得中间体4S,产率95%,ee值>98%;
(4)将50克中间体4S溶于500 mL乙醇中,加入100 mL浓盐酸,将体系升温至60~70℃反应,24h后检测反应完毕,体系降温加入乙酸乙酯搅拌,过滤后,得到S构型产品盐酸盐,产品为白色固体,1H NMR (400 MHz, DMSO-d6) d 8.43 (m,3H), 7.03 (d,J=8.8 Hz,1H),6.94 (d, J=8.8 Hz, 1H), 3.40 (m,1H),3.13 (m,1H),2.87 (m,2H),2.65 (m,1H),2.19(m,1H),1.79 (m,1H)。
将上述S构型产品盐酸盐再用氢氧化钠水溶液条件pH至9,用乙酸乙酯萃取,有机相浓缩得到得S构型产品a,产率80%, ee值>99.5%;产品为淡黄色油状物;1H NMR (400MHz, DMSO-d6) d 6.90 (d,J=6.4 Hz,1H), 6.94 (d, J=6.4 Hz, 1H), 2.98 (m,1H),2.86 (m,1H),2.75 (m,1H),2.50 (m,1H),2.42 (m,1H),1.88 (m,1H),1.43 (m,1H)。
实施例2 (R)-5,7-二氟-1,2,3,4-四氢化萘-2-胺及其盐酸盐的制备
(1)将100克3,5-二氟苯乙酸1溶于500 mL二氯甲烷中,搅拌下加入50克氯化亚砜,然后升温至40~50℃,保持此温度反应4.5h后通过HPLC和TLC检测反应完毕,降温,浓缩,加入二氯甲烷稀释暂存,作为制备好的酰氯;向另一反应瓶中加入500 mL二氯甲烷,再加入150 g三氯化铝,再将前述制备好的酰氯滴加入反应体系,加入完毕后,向体系中通入乙烯气体,反应至原料反应完全,将体系中加入500 mL纯化水淬灭反应,淬灭完毕后将体系分液,有机相浓缩,柱层析得中间体2,产率80%;
(2)将80克中间体2溶于400 mL甲苯中,再加入150克乙酰胺和5克对甲苯磺酸,升温至80~120℃反应,保持此温度反应16h后通过HPLC和TLC检测反应完毕,体系降温,盐洗,盐洗后的有机相浓缩干得中间体3,产率83%;
(3)制备催化剂:氮气保护下,将200 mg (1,5-环辛二烯)二氯化钌加入10 mL二氯甲烷中,再加入200 mg (S,S)-Me-BPE,将体系加热至40℃,反应8 h反应完毕,体系浓缩干,用正己烷打浆,过滤,滤饼真空烘干得不对称还原步骤的催化剂;
将50克中间体3溶于500 mL乙二醇中,加入上述制备好的S构型100 mg催化剂,将体系置换为氢气,保持氢气压力1MPa,将体系升温至40~50℃反应,20h后检测反应完毕,体系降温浓缩得中间体构型4R,产率95%,ee值>98%;
(4)将50克中间体4R溶于500 mL乙醇中,加入100 mL浓盐酸,将体系升温至60~70℃反应,24h后检测反应完毕,体系降温加入乙酸乙酯搅拌,过滤后,得到R构型产品盐酸盐,产品为白色固体。再用氢氧化钠水溶液条件pH至9,用乙酸乙酯萃取,有机相浓缩得到得R构型产品b,产率80%, ee值>99.5%。产品为淡黄色油状物。
实施例3 (S)-5,7-二氟-1,2,3,4-四氢化萘-2-胺及其盐酸盐的制备
(1)将100克3,5-二氟苯乙酸1溶于500 mL二氯甲烷中,搅拌下加入50克氯化亚砜,然后升温至40~50℃,保持此温度反应4h后通过HPLC和TLC检测反应完毕,降温,浓缩,加入二氯甲烷稀释暂存,作为制备好的酰氯;向另一反应瓶中加入500 mL二氯甲烷,再加入150g三氯化铝,再将前述制备好的酰氯滴加入反应体系,加入完毕后,向体系中通入乙烯气体,反应至原料反应完全,将体系中加入500 mL纯化水淬灭反应,淬灭完毕后将体系分液,有机相浓缩,柱层析得中间体2,产率80%;
(2)将80克中间体2溶于400 mL甲苯中,再加入150克乙酰胺和5克对甲苯磺酸,升温至80~120℃反应,保持此温度反应16h后通过HPLC和TLC检测反应完毕,体系降温,盐洗,盐洗后的有机相浓缩干得中间体3,产率83%;
(3)先制备催化剂:氮气保护下,将200 mg 二(1,5-环辛二烯)四氟硼酸铑(I)加入10 mL二氯甲烷中,再加入320mg R-(-)-1,1'-联萘-2,2'-双二苯膦,将体系加热至40℃,反应8 h反应完毕,体系浓缩干,用正己烷打浆,过滤,滤饼真空烘干得不对称还原步骤的催化剂;
将50克中间体3溶于500 mL乙二醇中,加入上述制备好的R构型100 mg催化剂,将体系置换为氢气,保持氢气压力1MPa,将体系升温至40~50℃反应,20h后检测反应完毕,体系降温浓缩得中间体4S,产率95%,ee值>98%;
(4)将50克中间体4S溶于500 mL乙醇中,加入100 mL浓盐酸,将体系升温至60~70℃反应,24h后检测反应完毕,体系降温加入乙酸乙酯搅拌,过滤后,得到S构型产品盐酸盐,产品为白色固体,1H NMR (400 MHz, DMSO-d6) d 8.43 (m,3H), 7.03 (d,J=8.8 Hz,1H),6.94 (d, J=8.8 Hz, 1H), 3.40 (m,1H),3.13 (m,1H),2.87 (m,2H),2.65 (m,1H),2.19(m,1H),1.79 (m,1H)。
将上述S构型产品盐酸盐再用氢氧化钠水溶液条件pH至9,用乙酸乙酯萃取,有机相浓缩得到得S构型产品a,产率80%, ee值>99.5%;产品为淡黄色油状物;1H NMR (400MHz, DMSO-d6) d 6.90 (d,J=6.4 Hz,1H), 6.94 (d, J=6.4 Hz, 1H), 2.98 (m,1H),2.86 (m,1H),2.75 (m,1H),2.50 (m,1H),2.42 (m,1H),1.88 (m,1H),1.43 (m,1H)。
Claims (4)
1.一种制备如式(a)或式(b)所示的光学纯的5,7-二氟-1,2,3,4-四氢化萘-2-胺及其盐的方法,
该方法包括如下步骤:
步骤一、在溶剂存在下,式(1)所示的3,5-二氟苯乙酸与SOCl2反应生成酰氯,然后,在三氯化铝的作用下与通入的乙烯发生傅克反应,形成式(2)所示的5,7-二氟-3,4-二氢化萘-2(1H)-酮;
步骤二、将步骤一制备的5,7-二氟-3,4-二氢化萘-2(1H)-酮与酰胺RCONH2在使用酸催化剂的条件下,利用溶剂回流,脱水形成式(3)所示的烯胺;
步骤三、将步骤二所制备的烯胺在手性催化剂的催化下,进行氢化反应,还原双键得到式(4S)或式(4R)所示的手性酰胺中间体;
其中,步骤三中反应所使用的所述手性催化剂是由手性膦配体与钌络合物或铑络合物形成的催化体系,所述的钌络合物为选自于如下一组中的一种以上:RuLCl2、[Ru(benzene)(L)Cl]Cl、[Ru(cymene)(L)Cl]Cl、RuLCl2(DMF)m、[NH2Me2]+[(RuClL)2(μ-Cl3)]、Ru(cod)(methallyl)2、RuCl2(CH3CN)2、和Ru(cod)(O2CCF3)2,所述的铑络合物为选自于如下一组中的一种以上:RhCl2、Rh(COD)BF4和Rh(COD)Cl2,所述的手性膦配体选自Me-BPE或BINAP;
步骤四、将步骤三制备的手性酰胺中间体在酸性条件下进行脱保护,制得式(a)或式(b)所示的手性胺或其盐。
2.如权利要求1所述的方法,其中,步骤二中反应所使用的酸催化剂为选自于如下一组中的一种以上:苯基磺酸、苯环上单取代或多取代的苯基磺酸、磺酸、硫酸、磷酸、三氟乙酸、烷基磺酸、一个或多个卤素取代的烷基磺酸、氟硼酸、硼酸。
4.如权利要求1所述的方法,其中,步骤一中傅克反应的温度控制为-30~80℃;步骤二中反应温度控制为80~130℃;步骤三中反应温度控制为20~100℃;步骤四中反应温度为30~150℃。
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