CN1939911A - Chiral oxazoline and its production - Google Patents
Chiral oxazoline and its production Download PDFInfo
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- CN1939911A CN1939911A CN 200610096004 CN200610096004A CN1939911A CN 1939911 A CN1939911 A CN 1939911A CN 200610096004 CN200610096004 CN 200610096004 CN 200610096004 A CN200610096004 A CN 200610096004A CN 1939911 A CN1939911 A CN 1939911A
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- oxazoline
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- chiral oxazoline
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- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 150000001414 amino alcohols Chemical class 0.000 claims abstract description 8
- JSOLVAGDJFHTHQ-UHFFFAOYSA-N piperidine;propanenitrile Chemical compound CCC#N.C1CCNCC1 JSOLVAGDJFHTHQ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 239000000126 substance Substances 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 229910052761 rare earth metal Inorganic materials 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- -1 rare earth compound Chemical class 0.000 claims description 5
- 229910021381 transition metal chloride Inorganic materials 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 2
- 239000000463 material Substances 0.000 claims 2
- 238000009472 formulation Methods 0.000 claims 1
- 150000003053 piperidines Chemical class 0.000 claims 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 abstract description 12
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 238000000034 method Methods 0.000 abstract description 5
- 239000003446 ligand Substances 0.000 abstract description 4
- 230000003197 catalytic effect Effects 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 150000002910 rare earth metals Chemical class 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 2
- 150000002918 oxazolines Chemical class 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- ODLMAHJVESYWTB-UHFFFAOYSA-N propylbenzene Chemical compound CCCC1=CC=CC=C1 ODLMAHJVESYWTB-UHFFFAOYSA-N 0.000 description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- QCXJGKAAECBGGP-GFCCVEGCSA-N (4S)-2-(2-piperidin-1-ylethyl)-4-propan-2-yl-4,5-dihydro-1,3-oxazole Chemical compound CC(C)[C@H]1COC(CCN2CCCCC2)=N1 QCXJGKAAECBGGP-GFCCVEGCSA-N 0.000 description 1
- CVOCQPLULGKWAN-INIZCTEOSA-N (4S)-4-benzyl-2-(2-piperidin-1-ylethyl)-4,5-dihydro-1,3-oxazole Chemical compound C([C@@H]1N=C(OC1)CCN1CCCCC1)C1=CC=CC=C1 CVOCQPLULGKWAN-INIZCTEOSA-N 0.000 description 1
- UHGCNKBRHFTNHM-OAHLLOKOSA-N (4S)-4-phenyl-2-(2-piperidin-1-ylethyl)-4,5-dihydro-1,3-oxazole Chemical compound C1([C@@H]2N=C(OC2)CCN2CCCCC2)=CC=CC=C1 UHGCNKBRHFTNHM-OAHLLOKOSA-N 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- DSURYTHAURAOID-ZDUSSCGKSA-N C(CCC)[C@@H]1N=C(OC1)CCN1CCCCC1 Chemical compound C(CCC)[C@@H]1N=C(OC1)CCN1CCCCC1 DSURYTHAURAOID-ZDUSSCGKSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 238000006117 Diels-Alder cycloaddition reaction Methods 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHGABBBZRPRJV-UHFFFAOYSA-N Hydroxysanguinarine Chemical compound C12=CC=C3OCOC3=C2C(=O)N(C)C(C2=C3)=C1C=CC2=CC1=C3OCO1 UFHGABBBZRPRJV-UHFFFAOYSA-N 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000005575 aldol reaction Methods 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 238000005888 cyclopropanation reaction Methods 0.000 description 1
- PKKGKUDPKRTKLJ-UHFFFAOYSA-L dichloro(dimethyl)stannane Chemical compound C[Sn](C)(Cl)Cl PKKGKUDPKRTKLJ-UHFFFAOYSA-L 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002463 imidates Chemical class 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
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- Plural Heterocyclic Compounds (AREA)
Abstract
一种新型手性噁唑啉，其特征在于：由以下化学式表示的化合物，其化学名称为1－[2－(4S)－4－R基－4，5－二氢化－2－噁唑啉－乙基]哌啶：式中R为：L、D－CH2CH (CH3) 2或L、D－CH2 (CH3) 2或L、D－Ph或L、D－CH2Ph。本手性噁唑啉是以六氢吡啶丙腈与手性氨基醇为原料在有机溶剂和催化剂存在条件下合成的，其配合物具有良好的不对称催化活性和高对映选择性，可作为催化剂用于不对称领域的有机合成。本方法一步合成手性噁唑啉配体，收率65％～85％，是一种简单、高效的有机合成方法。
A novel chiral oxazoline, characterized in that: the compound represented by the following chemical formula, its chemical name is 1-[2-(4S)-4-R base-4,5-dihydro-2-oxazoline -Ethyl]piperidine: where R is: L, D-CH 2 CH (CH 3 ) 2 or L, D-CH 2 (CH 3 ) 2 or L, D-Ph or L, D-CH 2 Ph . This chiral oxazoline is synthesized from hexahydropyridine propionitrile and chiral amino alcohol in the presence of organic solvent and catalyst. The complex has good asymmetric catalytic activity and high enantioselectivity, and can be used as Catalysts are used in organic synthesis in the asymmetric field. The method synthesizes the chiral oxazoline ligand in one step with a yield of 65%-85%, and is a simple and efficient organic synthesis method.
Description
一、技术领域1. Technical field
本发明涉及一种新化合物及其制备方法，确切地说是一种新型手性噁唑啉及其制备方法。The present invention relates to a new compound and its preparation method, specifically a novel chiral oxazoline and its preparation method.
二、背景技术2. Background technology
手性噁唑啉与稀土金属配位形成手性催化剂在Diels-Alder环加成反应，Michael加成反应，Friedel-Crafts反应，Aldol反应，环丙烷化等许多反应中表现出良好的不对称催化活性和高对映选择性，因而受到广泛的关注。Chiral oxazolines coordinate with rare earth metals to form chiral catalysts, which show good asymmetric catalysis in many reactions such as Diels-Alder cycloaddition reaction, Michael addition reaction, Friedel-Crafts reaction, Aldol reaction, cyclopropanation, etc. activity and high enantioselectivity, and thus received extensive attention.
手性噁唑啉配体的制备始于1884年，已有100多年的历史，它的合成方法主要有三种：The preparation of chiral oxazoline ligands began in 1884 and has a history of more than 100 years. There are three main synthetic methods:
(1)酰氯和氨基醇直接缩合形成双羟酰氨，然后由羟酰氨关环生成双噁唑啉。(1) Acid chlorides and amino alcohols are directly condensed to form bishydroxyamides, which are then ring-closed to generate bisoxazolines.
(2)直接由羧酸酯与氨基醇缩合形成双羟酰氨，然后进行关环而成双噁唑啉。(2) Directly condense carboxylate and amino alcohol to form bishydroxyamide, and then perform ring closure to form bisoxazoline.
(3)第三种方法是由二氰出发，在乙醇中与无水氯化氢反应生成亚氨酯，然后与氨基醇缩合一步形成双噁唑啉。(3) The third method is to start from dicyanide, react with anhydrous hydrogen chloride in ethanol to generate imidoester, and then condense with amino alcohol in one step to form bisoxazoline.
三、发明内容3. Contents of the invention
本发明旨在为不对称催化领域提供一类新型的手性催化剂及其相应的合成方法。所要解决的技术问题是使原料在一定条件下闭环生成手性噁唑啉。The invention aims to provide a novel chiral catalyst and its corresponding synthesis method in the field of asymmetric catalysis. The technical problem to be solved is to make the ring closure of raw materials under certain conditions to generate chiral oxazoline.
本发明所称的手性噁唑啉是以下所示的化合物：The said chiral oxazoline in the present invention is the compound shown below:
式中R为左旋或右旋的异丁基(L、D-CH2CH(CH3)2或异丙基(L、D-CH(CH3)2或苯基(L、D-Ph)或苄基(L、D-CH2Ph)。In the formula, R is left-handed or right-handed isobutyl (L, D-CH 2 CH (CH 3 ) 2 or isopropyl (L, D-CH (CH 3 ) 2 or phenyl (L, D-Ph) Or benzyl (L, D-CH 2 Ph).
由以上基团构成的四种手性噁唑啉依次简称1a、1b、1c和1d。其化学名称：1-[2-(4S)-4-R基-4，5-二氢化-2-噁唑啉-乙基]哌啶。The four chiral oxazolines composed of the above groups are referred to as 1a, 1b, 1c and 1d in turn. Its chemical name: 1-[2-(4S)-4-Ryl-4,5-dihydro-2-oxazoline-ethyl]piperidine.
本手性噁唑啉是以六氢吡啶丙腈与手性氨基醇为原料合成的，This chiral oxazoline is synthesized from hexahydropyridine propionitrile and chiral amino alcohol.
式中R为左旋或右旋的异丁基(L、D-CH2CH(CH3)2或异丙基(L、D-CH(CH3)2或苯基(L、D-Ph)或苄基(L、D-CH2Ph)。In the formula, R is left-handed or right-handed isobutyl (L, D-CH 2 CH (CH 3 ) 2 or isopropyl (L, D-CH (CH 3 ) 2 or phenyl (L, D-Ph) Or benzyl (L, D-CH 2 Ph).
本手性噁唑啉的制备方法包括合成、分离和纯化，所述的合成就是六氢吡啶丙腈与手性氨基醇在有机溶剂和催化剂存在条件下于115℃～150℃反应40～50小时，催化剂用量为原料量的1～3wt％(重量百分比，下同)。The preparation method of the chiral oxazoline includes synthesis, separation and purification. The synthesis is the reaction of hexahydropyridine propionitrile and chiral amino alcohol at 115°C to 150°C for 40 to 50 hours in the presence of an organic solvent and a catalyst. , the amount of catalyst used is 1 to 3 wt% (percentage by weight, the same below) of the amount of raw materials.
优选125℃～145℃反应45～48小时，催化剂用量为原料量的2wt％。Preferably, the reaction is carried out at 125° C. to 145° C. for 45 to 48 hours, and the amount of catalyst used is 2 wt % of the raw material amount.
所述的有机溶剂应选择惰性的、其沸点与反应温度相适应的有机溶剂，比如甲基吡碇或氯苯或二氯苯或乙苯或二甲苯或丙苯或烷烃或卤代烷烃等。Described organic solvent should select the organic solvent of inert, its boiling point and reaction temperature adapt, such as methylpyridine or chlorobenzene or dichlorobenzene or ethylbenzene or xylene or propylbenzene or alkane or halogenated alkane etc.
所述的催化剂选自AlCl3或稀土金属氯化物(三氯稀土)或过渡金属氯化物(ZnCl2、CuCl2、NiCl2、CoCl2、FeCl3、MnCl2等)或烷氧基金属化合物(四异丙氧基钛、二甲基二氯锡烷等)。优选三氯稀土或过渡金属氯化物。The catalyst is selected from AlCl 3 or rare earth metal chlorides (trichloro rare earths) or transition metal chlorides (ZnCl 2 , CuCl 2 , NiCl 2 , CoCl 2 , FeCl 3 , MnCl 2 , etc.) or metal alkoxide compounds ( tetraisopropoxytitanium, dimethyldichlorostannane, etc.). Preference is given to rare earth trichlorides or transition metal chlorides.
本方法一步合成手性噁唑啉配体，收率65％～85％，是一种简单、高效的有机合成方法。本配体可作为催化剂用于不对称领域的有机合成。The method synthesizes the chiral oxazoline ligand in one step with a yield of 65%-85%, and is a simple and efficient organic synthesis method. The ligand can be used as a catalyst for organic synthesis in the asymmetric field.
四、附图说明4. Description of drawings
图1～图4依次是表征手性噁唑啉1a结构的碳谱图、氢谱图、红外图和质谱图。Figures 1 to 4 are the carbon spectrum, hydrogen spectrum, infrared spectrum and mass spectrum that characterize the structure of chiral oxazoline 1a in sequence.
图5～图8依次是表征手性噁唑啉1b结构的碳谱图、氢谱图、红外图和质谱图。Figures 5 to 8 are the carbon spectrum, hydrogen spectrum, infrared spectrum and mass spectrum that characterize the structure of chiral oxazoline 1b in sequence.
图9～图12依次是表征手性噁唑啉1c结构的碳谱图、氢谱图、红外图和质谱图。Figures 9 to 12 are the carbon spectrum, hydrogen spectrum, infrared spectrum and mass spectrum that characterize the structure of chiral oxazoline 1c in sequence.
图13～图16依次是表征手性噁唑啉1d结构的碳谱图、氢谱图、红外图和质谱图。Figures 13 to 16 are the carbon spectrum, hydrogen spectrum, infrared spectrum and mass spectrum that characterize the chiral oxazoline 1d structure in sequence.
五、具体实施方式5. Specific implementation
现以L-氨基醇(浙江宁波求是化工科技有限公司出品)为例，非限定实施例叙述如下。另一原料六氢吡啶丙腈为进口，Taking L-amino alcohol (produced by Zhejiang Ningbo Qiushi Chemical Technology Co., Ltd.) as an example, the non-limiting examples are described as follows. Another raw material, hexahydropyridine propionitrile, is imported.
1a：1-[2-(4S)-4-异丁基-4，5-二氢化-2-噁唑啉-乙基]哌啶的制备1a: Preparation of 1-[2-(4S)-4-isobutyl-4,5-dihydro-2-oxazoline-ethyl]piperidine
1-[2-(4S)-4-i-butyl-4，5-dihydro-oxazol-2-yl-ethyl]-piperidine的制备Preparation of 1-[2-(4S)-4-i-butyl-4,5-dihydro-oxazol-2-yl-ethyl]-piperidine
在100mL两口瓶中，加入无水ZnCl2 60mg(0.37mmol)，20mL氯苯或乙苯或二甲苯，(沸点依次为132℃、136℃、139℃)，六氢吡啶丙腈1.0g(7.2mmol)，L-异丁基亮氨醇2g，将混合物在高温下回流46h，停止反应，减压以除去溶剂，，将剩余物用水溶解，并用CHCl3(20mL×2)萃取，有机相用无水硫酸钠干燥，旋转除去溶剂，将粗产品用石油醚/二氯甲烷/乙醚(1∶4∶2)柱层析，得红褐色粘稠油状液体1.24g产率72％。In a 100mL two-necked flask, add 60mg (0.37mmol) of anhydrous ZnCl 2 , 20mL of chlorobenzene or ethylbenzene or xylene (boiling points are 132°C, 136°C, 139°C in turn), 1.0g (7.2 mmol), L-isobutylleucinol 2g, the mixture was refluxed at high temperature for 46h, the reaction was stopped, the solvent was removed under reduced pressure, the residue was dissolved in water, and extracted with CHCl 3 (20mL×2), the organic phase was washed with anhydrous Dry over sodium sulfate, and spin to remove the solvent. The crude product is subjected to column chromatography of petroleum ether/dichloromethane/diethyl ether (1:4:2) to obtain 1.24 g of a reddish-brown viscous oily liquid with a yield of 72%.
[a]5D＝-50.2°(c＝0.828，CH2Cl2)；1HNMR(300MHz，CDCl3，27℃)，δ(ppm)＝4.18-4.24(t，7.95Hz，1H)，3.99～4.04(m，1H)，3.67～3.70(t，0.12Hz，1H)，2.56～2.61(m，2H)，2.33～2.42(m，6H)，1.63～1.70(m，1H)，1.47～1.55(m，4H)，1.35～1.39(m，2H)，1.14～1.24(m，1H)，0.84～0.88(m，6H).13CNMR，22.58(×2)，22.62，24.17，25.21，25.81(×2)，45.50，54.07(×2)，55.20，64.38，72.59，165.89.IR：3290，3076，2936，2867，2854，2810，1644，1553，1469，1444，1367，1275，1255，1155，1116，1041，1071；HRMS(EI)：m/z(％)：calcd for Cl4H26N2O：238.2045；found：238.2036。[a]5D=-50.2°(c=0.828, CH 2 Cl 2 ); 1HNMR (300MHz, CDCl 3 , 27°C), δ(ppm)=4.18-4.24(t, 7.95Hz, 1H), 3.99～4.04 (m, 1H), 3.67～3.70(t, 0.12Hz, 1H), 2.56～2.61(m, 2H), 2.33～2.42(m, 6H), 1.63～1.70(m, 1H), 1.47～1.55(m , 4H), 1.35～1.39(m, 2H), 1.14～1.24(m, 1H), 0.84～0.88(m, 6H).13CNMR, 22.58(×2), 22.62, 24.17, 25.21, 25.81(×2) , 45.50, 54.07(×2), 55.20, 64.38, 72.59, 165.89.IR: 3290, 3076, 2936, 2867, 2854, 2810, 1644, 1553, 1469, 1444, 1367, 1275, 1255, 1155, 1116, 1041 , 1071; HRMS (EI): m/z (%): calcd for Cl 4 H 2 6N 2 O: 238.2045; found: 238.2036.
1b：1-[2-(4S)-4-异丙基-4，5-二氢化-2-噁唑啉-乙基]哌啶的制备1b: Preparation of 1-[2-(4S)-4-isopropyl-4,5-dihydro-2-oxazoline-ethyl]piperidine
1-[2-(4S)-4-isopropyl-4，5-dihydro-oxazol-2-yl-ethyl]-piperidine的制备Preparation of 1-[2-(4S)-4-isopropyl-4,5-dihydro-oxazol-2-yl-ethyl]-piperidine
在100ml两口烧瓶中加入无水三氯稀土70mg，25mL甲基吡啶(沸点128℃～144℃)，六氢吡啶丙腈1.0g(7.2mmol)，L-异丙基亮氨醇2g，将混合物在高温下回流46h，停止反应，减压以除去溶剂，，将剩余物用水溶解，并用CHCl3(20mL×2)萃取，有机相用无水硫酸钠干燥，旋转除去溶剂，将粗产品用石油醚/二氯甲烷/乙醚(1∶4∶2)柱层析，得红褐色粘稠油状液体1.06g产率65％。Add 70 mg of anhydrous trichloro rare earth, 25 mL of picoline (boiling point 128°C to 144°C), 1.0 g (7.2 mmol) of hexahydropyridine propionitrile, and 2 g of L-isopropylleucinol into a 100 ml two-necked flask, and the mixture Reflux at high temperature for 46h, stop the reaction, remove the solvent under reduced pressure, dissolve the residue in water, and extract with CHCl 3 (20mL×2), dry the organic phase with anhydrous sodium sulfate, spin to remove the solvent, and dilute the crude product with petroleum Ether/dichloromethane/diethyl ether (1:4:2) column chromatography gave 1.06 g of a reddish-brown viscous oily liquid with a yield of 65%.
[a]5D＝-46.9°(c＝0.677，CH2Cl2)，δ(ppm)＝4.08-4.13(m，1H)，3.79～3.87(m，1H)，2.55～2.61(m，2H)，2.33～2.42(m，6H)，1.63～1.70(m，2H)，1.47～1.55(m，4H)，1.35～1.39(m，2H)，1.14～1.24(m，1H)，0.86～0.88(d，3H)，0.78～0.81(d，3H，CH3).13CNMR，17.84，18.58，24.21，25.77(×2)，25.85，32.36，53.77，54.10，55.32，69.53，71.92，166.01.IR：3306，2935，2854，2809，2775，2248，1668，1548，1469，1444，1379，1352，1302，1229，1156，1116，1042，991，913，862，748，401；HRMS(EI)：m/z(％)：calcd for Cl4H26N2O：224.1889；found：224.1896。[a] 5D = -46.9° (c = 0.677, CH 2 Cl 2 ), δ (ppm) = 4.08-4.13 (m, 1H), 3.79-3.87 (m, 1H), 2.55-2.61 (m, 2H) , 2.33～2.42(m, 6H), 1.63～1.70(m, 2H), 1.47～1.55(m, 4H), 1.35～1.39(m, 2H), 1.14～1.24(m, 1H), 0.86～0.88( d, 3H), 0.78～0.81 (d, 3H, CH 3 ). 13CNMR, 17.84, 18.58, 24.21, 25.77 (×2), 25.85, 32.36, 53.77, 54.10, 55.32, 69.53, 71.92, 166.01. IR: 3306 , 2935, 2854, 2809, 2775, 2248, 1668, 1548, 1469, 1444, 1379, 1352, 1302, 1229, 1156, 1116, 1042, 991, 913, 862, 748, 401; HRMS (EI): m/ z(%): calcd for Cl 4 H 2 6N 2 O: 224.1889; found: 224.1896.
1c：1-[2-(4S)-4-苯基-4，5-二氢化-2-噁唑啉-乙基]哌啶的制备1c: Preparation of 1-[2-(4S)-4-phenyl-4,5-dihydro-2-oxazoline-ethyl]piperidine
1-[2-(4S)-4-phenyl-4，5-dihydro-oxazol-2-yl-ethyl]-piperidine的制备Preparation of 1-[2-(4S)-4-phenyl-4,5-dihydro-oxazol-2-yl-ethyl]-piperidine
在100ml两口烧瓶中加入NiCl2 65mg、30mL辛烷或壬烷或1、2-二溴乙烷或1、1、2、2-四氯乙烷，六氢吡啶丙腈1.0g(7.2mmol)，L-苯基亮氨醇2g，将混合物在高温下回流47h，停止反应，减压以除去溶剂，，将剩余物用水溶解，并用CHCl3(20mL×2)萃取，有机相用无水硫酸钠干燥，旋转除去溶剂，将粗产品用石油醚/二氯甲烷/乙醚(1∶4∶2)柱层析，得红褐色粘稠油状液体1.87g产率75％。Add NiCl 2 65mg, 30mL octane or nonane or 1,2-dibromoethane or 1,1,2,2-tetrachloroethane, and hexahydropyridine propionitrile 1.0g (7.2mmol) in a 100ml two-necked flask , L-phenylleucinol 2g, the mixture was refluxed at high temperature for 47h, the reaction was stopped, the solvent was removed under reduced pressure, the residue was dissolved in water, and extracted with CHCl 3 (20mL×2), the organic phase was anhydrous sulfuric acid Sodium was dried, and the solvent was removed by rotation. The crude product was subjected to column chromatography of petroleum ether/dichloromethane/diethyl ether (1:4:2) to obtain 1.87 g of a reddish-brown viscous oily liquid with a yield of 75%.
[a]5D＝-44.0°(c＝0.170，CH2Cl2)，δ(ppm)＝7.26～7.37(m，5H)，5.12～5.18(t，0.309Hz，1H)，4.55～4.61(m，1H)，4.04～4.10(t，0.93Hz，1H)，2.74～2.79(m，2H)，2.58～2.69(m，2H)，2.47(m，6H)，1.47～1.63(m，4H)，1.45～1.47(m，2H)，0.92～0.96(m，2H)；13CNMR，24.29，25.90，25.94，54.27(×2)，55.30，69.61，74.54，126.64(×2)，127.46，128.62(×2)，142.52，167.65.IR：2934，2852，2802，2773，1667，1493，1469，1454，1443，1379，1353，1302，1270，1226，1171，1156，1122，1116，991，961，913，759，700；HRMS(EI)：m/z(％)：calcd for Cl4H26N2O：258.1732；found：258.1727。[a] 5D=-44.0°(c=0.170, CH 2 Cl 2 ), δ(ppm)=7.26~7.37(m, 5H), 5.12~5.18(t, 0.309Hz, 1H), 4.55~4.61(m , 1H), 4.04～4.10(t, 0.93Hz, 1H), 2.74～2.79(m, 2H), 2.58～2.69(m, 2H), 2.47(m, 6H), 1.47～1.63(m, 4H), 1.45～1.47(m, 2H), 0.92～0.96(m, 2H); 13CNMR, 24.29, 25.90, 25.94, 54.27(×2), 55.30, 69.61, 74.54, 126.64(×2), 127.46, 128.62(×2 ), 142.52, 167.65. IR: 2934, 2852, 2802, 2773, 1667, 1493, 1469, 1454, 1443, 1379, 1353, 1302, 1270, 1226, 1171, 1156, 1122, 1116, 991, 961, 913, 759,700; HRMS (EI): m/z (%): calcd for Cl 4 H 2 6N 2 O: 258.1732; found: 258.1727.
1d：1-[2-(4S)-4-苄基-4，5-二氢化-2-噁唑啉-乙基]哌啶的制备1d: Preparation of 1-[2-(4S)-4-benzyl-4,5-dihydro-2-oxazoline-ethyl]piperidine
1-[2-(4S)-4-benzyl-4，5-dihydro-oxazol-2-yl-ethyl]-piperidine的制备Preparation of 1-[2-(4S)-4-benzyl-4,5-dihydro-oxazol-2-yl-ethyl]-piperidine
在100mL两口瓶中，加入无水ZnCl260mg(0.37mmol)，20mL氯苯或乙苯或二甲苯，(沸点依次为132℃、136℃、139℃)，六氢吡啶丙腈1.0g(7.2mmol)，L-苄基亮氨醇2g，将混合物在高温下回流48h，停止反应，减压以除去溶剂，，将剩余物用水溶解，并用CHCl3(20mL×2)萃取，有机相用无水硫酸钠干燥，旋转除去溶剂，将粗产品用石油醚/二氯甲烷/乙醚(1∶4∶2)柱层析，得红褐色粘稠油状液体1.68g产率85％。In a 100mL two-necked flask, add 60mg (0.37mmol) of anhydrous ZnCl 2 , 20mL of chlorobenzene or ethylbenzene or xylene (boiling points are 132°C, 136°C, 139°C in turn), 1.0g (7.2 mmol), L-benzylleucinol 2g, the mixture was refluxed at high temperature for 48h, the reaction was stopped, and the solvent was removed under reduced pressure, the residue was dissolved in water, and extracted with CHCl 3 (20mL×2), and the organic phase was extracted with Dry over sodium sulfate and spin to remove the solvent. The crude product is subjected to column chromatography of petroleum ether/dichloromethane/ether (1:4:2) to obtain 1.68 g of a reddish-brown viscous oily liquid with a yield of 85%.
[a]5D＝-50.7°(c＝0.148，CH2Cl2)，δ(ppm)＝7.18～7.32(m，5H)，4.35(m，1H)，4.11～4.16(t，3.66Hz，1H)，3.91～3.96(m，1H)，3.05～3.11(d，d，5.07，2.07，2H)，2.62～2.67(m，3H)，2.38～2.49(m，5H)，1.43～1.62(m，6H).13CNMR，24.42，25.99，26.07，41.84(×2)，54.37(×2)，55.41，67.31，71.58，126.60，128.61(×2)，129.38(×2)，138.04，167.05.IR：3306，3085，3061，3026，2933，2852，2802，2782，1740，1668，1632，1603，1583，1496，1454，1442，1380，1360，1306，1261，1225，1174，1156，1116，1040，988，942，924，862，802，750，700.HRMS(EI)：m/z(％)：calcd for Cl4H26N2O：272.1889；found：272.1885.[a] 5D=-50.7°(c=0.148, CH 2 Cl 2 ), δ(ppm)=7.18~7.32(m, 5H), 4.35(m, 1H), 4.11~4.16(t, 3.66Hz, 1H ), 3.91～3.96(m, 1H), 3.05～3.11(d, d, 5.07, 2.07, 2H), 2.62～2.67(m, 3H), 2.38～2.49(m, 5H), 1.43～1.62(m, 6H).13CNMR, 24.42, 25.99, 26.07, 41.84(×2), 54.37(×2), 55.41, 67.31, 71.58, 126.60, 128.61(×2), 129.38(×2), 138.04, 167.05.IR: 3306 . , 942, 924, 862, 802, 750, 700. HRMS (EI): m/z (%): calcd for Cl 4 H 2 6N 2 O: 272.1889; found: 272.1885.
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| CN101824031A (en) * | 2010-05-17 | 2010-09-08 | 合肥工业大学 | Chiral oxazoline and use thereof |
| CN101973952A (en) * | 2009-09-30 | 2011-02-16 | 合肥工业大学 | Chiral oxazoline and synthetic method thereof |
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