CN103214493B - The selective reduction of chirality B catalyst is utilized to prepare (-) α-Noscapine - Google Patents
The selective reduction of chirality B catalyst is utilized to prepare (-) α-Noscapine Download PDFInfo
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- AKNNEGZIBPJZJG-UHFFFAOYSA-N alpha-noscapine Natural products CN1CCC2=CC=3OCOC=3C(OC)=C2C1C1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 230000009467 reduction Effects 0.000 title claims abstract description 12
- 239000003054 catalyst Substances 0.000 title claims abstract description 11
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 49
- 238000006243 chemical reaction Methods 0.000 claims description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 20
- 229910000085 borane Inorganic materials 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- BDOLXPFAFMNDOK-UHFFFAOYSA-N oxazaborolidine Chemical group B1CCON1 BDOLXPFAFMNDOK-UHFFFAOYSA-N 0.000 claims description 2
- 230000002829 reductive effect Effects 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 5
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 claims 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 229960004708 noscapine Drugs 0.000 abstract description 19
- AKNNEGZIBPJZJG-MSOLQXFVSA-N (-)-noscapine Chemical compound CN1CCC2=CC=3OCOC=3C(OC)=C2[C@@H]1[C@@H]1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-MSOLQXFVSA-N 0.000 abstract description 16
- PLPRGLOFPNJOTN-UHFFFAOYSA-N narcotine Natural products COc1ccc2C(OC(=O)c2c1OC)C3Cc4c(CN3C)cc5OCOc5c4OC PLPRGLOFPNJOTN-UHFFFAOYSA-N 0.000 abstract description 15
- 150000002466 imines Chemical class 0.000 abstract description 10
- 238000000034 method Methods 0.000 abstract description 7
- 230000008901 benefit Effects 0.000 abstract description 3
- 238000000926 separation method Methods 0.000 abstract description 3
- 230000000536 complexating effect Effects 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- 230000006340 racemization Effects 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229930040373 Paraformaldehyde Natural products 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229920002866 paraformaldehyde Polymers 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 3
- GRWFGVWFFZKLTI-IUCAKERBSA-N 1S,5S-(-)-alpha-Pinene Natural products CC1=CC[C@@H]2C(C)(C)[C@H]1C2 GRWFGVWFFZKLTI-IUCAKERBSA-N 0.000 description 2
- WNZQDUSMALZDQF-UHFFFAOYSA-N 2-benzofuran-1(3H)-one Chemical compound C1=CC=C2C(=O)OCC2=C1 WNZQDUSMALZDQF-UHFFFAOYSA-N 0.000 description 2
- SFDGJDBLYNJMFI-UHFFFAOYSA-N 3,1-benzoxazin-4-one Chemical compound C1=CC=C2C(=O)OC=NC2=C1 SFDGJDBLYNJMFI-UHFFFAOYSA-N 0.000 description 2
- 0 CCCc(c(C(*)C[C@](c(c1c2OC)ccc2OC)OC1=O)c1OC)cc2c1OCO2 Chemical compound CCCc(c(C(*)C[C@](c(c1c2OC)ccc2OC)OC1=O)c1OC)cc2c1OCO2 0.000 description 2
- CZSPXFXJXAAGPK-UHFFFAOYSA-N COC1=C2C(OC(C2=CC=C1OC)C(=O)O)=C=O Chemical compound COC1=C2C(OC(C2=CC=C1OC)C(=O)O)=C=O CZSPXFXJXAAGPK-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 240000001090 Papaver somniferum Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIRKNQLZZXALBI-MSVGPLKSSA-N Squalamine Chemical compound C([C@@H]1C[C@H]2O)[C@@H](NCCCNCCCCN)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CC[C@H](C(C)C)OS(O)(=O)=O)[C@@]2(C)CC1 UIRKNQLZZXALBI-MSVGPLKSSA-N 0.000 description 2
- UIRKNQLZZXALBI-UHFFFAOYSA-N Squalamine Natural products OC1CC2CC(NCCCNCCCCN)CCC2(C)C2C1C1CCC(C(C)CCC(C(C)C)OS(O)(=O)=O)C1(C)CC2 UIRKNQLZZXALBI-UHFFFAOYSA-N 0.000 description 2
- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 description 2
- 229960001372 aprepitant Drugs 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- UOALEFQKAOQICC-UHFFFAOYSA-N chloroborane Chemical compound ClB UOALEFQKAOQICC-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- -1 colchicine analog structure compound Chemical class 0.000 description 2
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- XOKSLPVRUOBDEW-UHFFFAOYSA-N pinane Chemical compound CC1CCC2C(C)(C)C1C2 XOKSLPVRUOBDEW-UHFFFAOYSA-N 0.000 description 2
- 229950001248 squalamine Drugs 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- WTARULDDTDQWMU-RKDXNWHRSA-N (+)-β-pinene Chemical compound C1[C@H]2C(C)(C)[C@@H]1CCC2=C WTARULDDTDQWMU-RKDXNWHRSA-N 0.000 description 1
- WTARULDDTDQWMU-IUCAKERBSA-N (-)-Nopinene Natural products C1[C@@H]2C(C)(C)[C@H]1CCC2=C WTARULDDTDQWMU-IUCAKERBSA-N 0.000 description 1
- NSAZIMJIRLGSEG-UHFFFAOYSA-N B(N1C2CCC1)OC2(c1ccccc1)c1ccccc1 Chemical compound B(N1C2CCC1)OC2(c1ccccc1)c1ccccc1 NSAZIMJIRLGSEG-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- VMKAFJQFKBASMU-UHFFFAOYSA-N CB(N1C2CCC1)OC2(c1ccccc1)c1ccccc1 Chemical compound CB(N1C2CCC1)OC2(c1ccccc1)c1ccccc1 VMKAFJQFKBASMU-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical group O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 1
- 229930189413 Esperamicin Natural products 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 102000029749 Microtubule Human genes 0.000 description 1
- 108091022875 Microtubule Proteins 0.000 description 1
- 239000008896 Opium Substances 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 235000008753 Papaver somniferum Nutrition 0.000 description 1
- WTARULDDTDQWMU-UHFFFAOYSA-N Pseudopinene Natural products C1C2C(C)(C)C1CCC2=C WTARULDDTDQWMU-UHFFFAOYSA-N 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- XCPQUQHBVVXMRQ-UHFFFAOYSA-N alpha-Fenchene Natural products C1CC2C(=C)CC1C2(C)C XCPQUQHBVVXMRQ-UHFFFAOYSA-N 0.000 description 1
- MVNCAPSFBDBCGF-UHFFFAOYSA-N alpha-pinene Natural products CC1=CCC23C1CC2C3(C)C MVNCAPSFBDBCGF-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
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- 229930006722 beta-pinene Natural products 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
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- 150000003883 epothilone derivatives Chemical class 0.000 description 1
- LJQQFQHBKUKHIS-WJHRIEJJSA-N esperamicin Chemical compound O1CC(NC(C)C)C(OC)CC1OC1C(O)C(NOC2OC(C)C(SC)C(O)C2)C(C)OC1OC1C(\C2=C/CSSSC)=C(NC(=O)OC)C(=O)C(OC3OC(C)C(O)C(OC(=O)C=4C(=CC(OC)=C(OC)C=4)NC(=O)C(=C)OC)C3)C2(O)C#C\C=C/C#C1 LJQQFQHBKUKHIS-WJHRIEJJSA-N 0.000 description 1
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- 229930013397 isoquinoline alkaloid Natural products 0.000 description 1
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- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 210000004688 microtubule Anatomy 0.000 description 1
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Abstract
The invention discloses a kind of method using the selective reduction of chirality B catalyst to generate Noscapine, the method imine intermediate taken full advantage of in Noscapine building-up process easily resonates the characteristic of racemization, use for reference chiral separation principle, from four steric isomers, optionally restore (-)-α-Noscapine by specific chiral reduction agent and imines complexing.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to utilize chiral reduction agent optionally to reduce and prepare Noscapine.
Technical background
(-)-α-Noscapine [noscapineor (-)-α-narcotine] is the isoquinoline alkaloid in poppy opium, nearly 100 years history is had as cough medicine. in the random antitumor action screening of colchicine analog structure compound, find the anti-tumor activity of Noscapine in the recent period, Noscapine and derivative Anticancer Effect and Mechanism thereof are by affecting microtubule dynamics character, thus play antitumor action. the research of Noscapine and tetrahydroisoquinoliderivs derivs thereof becomes hot fields in recent years.
The acquisition one of Noscapine is straight through plant extract for a long time, and opium poppy is as unique plant origin of Noscapine, is subject to strict control always.Naturally occurring Noscapine is the representative medicine of phthalide-type tetrahydroisoquinolicompounds, and its 1 and 9 has two chiral carbon. its absolute configuration is (1R, 9S),
1911, directly there is condensation with cotrnine and Me-conine in Robinson etc. (J.Chem.Soc., 1914,105,2085), the reported first synthesis of (±) Noscapine.The method can produce 4 steric isomers
And the separation and purification of these four isomer is and difficulty, often will by obtaining with chirality padding HPLC preparation, this method is suitable only for laboratory, can not be applied to large-scale production.Selectivity synthesis (-)-α-Noscapine is so far without any report.
Chiral organicatalyst has the features such as high yield and selectivity, reaction conditions be gentle and environmentally friendly, day by day receives publicity in pharmaceutical synthesis field.By the participation of borane reagent, realize the synthesis of particular configuration chipal compounds, a kind of important channel obtaining high optical purity compound. the Stereoselective reduction reaction that borane reagent participates in has been widely used in the synthesis of chiral drug and intermediate thereof, as current global annual sales amount reaches the statins antilipemic drugs of multi-million dollar, by blocking the hypolipidemic Zetia (Ezetimibe) of cholesterol intestinal absorption, chemotherapy antiemetic Aprepitant (Aprepitant), there is the steroid compound squalamine (Squalamine) of antibacterial and antitumor action and act on the new type antineoplastic medicine esperamicin (Epothilone) etc. of cellular microtubules. conventional chirality borane reagent comprises borane of chiral oxazole and pinene vinyl borine.
Oxazaborolidine compounds is chiral catalyst important in enantioselective catalytic reduction, 1981, and HIRAOA etc. find its catalytic activity with ITSUNOS etc., and 1987, COREYEJ etc. determined its catalytic mechanism, and this compounds is referred to as CBS catalyzer.The advantage of this important method of asymmetric synthesis is that reaction conditions is gentle, speed of reaction is fast, selectivity is high, and reclaims conveniently, and the rate of recovery is also higher.Conventional catalyzer is:
The chirality organic boron that firpene derives also original reagent is the compounds by α-or beta-pinene and various borine reaction generation, and this kind of reductive agent utilizes the stereoselectivity of the sterically hindered controlling factors reaction of pinane base in molecule.Conventional catalyzer is:
Summary of the invention
The present invention's imine intermediate taken full advantage of in Noscapine building-up process easily resonates the characteristic of racemization, uses for reference chiral separation principle, proposes dynamic chiral reduction imagination.From four steric isomers, (-)-α-Noscapine is optionally restored by specific chiral reduction agent and imines complexing.Shown in its principle following (scheme1):
The synthesis of key intermediate imines is as shown in scheme2, with 2-(7-methoxyl group benzo [d] [1, 3] bis-oxazole-5-bases) ethamine is starting raw material (synthetic method is see CN102690253), with 4, 5-dimethoxy-3-carbonyl-1, 3-dihydroisobenzofuran-1-carboxylic acid reaction obtains 4, 5-dimethoxy-N-(2-(7-methoxyl group benzo [d] [1, 3] bis-oxazole-5-bases) ethyl)-3-carbonyl-1, 3-dihydroisobenzofuran-1-methane amide, in phosphorus oxychloride, close ring again obtain imines (6, 7-dimethoxy-3-(4-methoxyl group-7, 8-dihydro-[1, 3] bis-oxazoles also [4, 5-g] isoquinoline 99.9-5-base) isobenzofuran-1 (3H)-one)
Imines reacts with borine in methylene dichloride under chirality borane reagent participates in, and control temperature of reaction and reaction times obtain corresponding amine.The reduction effect of each catalyzer is listed in table 1.(in table, all experiments are all solvent with methylene dichloride, and 1M borine tetrahydrofuran solution reduces in-20 DEG C of reactions and obtains for 10 hours)
Table 1: various chiral catalyst is to the reduction selectivity of Noscapine
| Catalyst type | Transformation efficiency | (-) α/(-) β/(+) α/(+) β ratio (%) |
| Catalyzer 1 | 78.2％ | 55.6/16.3/21.6/6.5 |
| Catalyzer 2 | 85.1％ | 63.3/12.5/20.1/4.1 |
| Catalyzer 3 | 81.0％ | 21.0/6.9/54.0/18.1 |
| Catalyzer 4 | 89.7％ | 20.3/4.0/64.1/11.6 |
| Catalyzer 5 | 42.3％ | 46.0/18.8/25.0/10.2 |
| Catalyzer 6 | 65.0％ | 63.5/10.7/22.0/3.8 |
| Catalyzer 7 | 53.8％ | 47.6/10.7/44.0/7.7 |
| Catalyzer 8 | 50.9％ | 48.1/21.9/20.6/9.4 |
| Catalyzer 9 | 60.7％ | 26.0/4.6/59.4/10.0 |
| Catalyzer 10 | 58.3％ | 9.4/40.6/40.6/9.4 |
Each catalyzer has selectivity in various degree as can be seen from the above table, and wherein α configuration (erythro form) is better than beta comfiguration (Soviet Union's formula).Wherein the ratio of required configuration and enantiomorph can be brought up to about 5: 1 by catalyst S-Me-CBS (catalyzer 2) and diisopinocampheylchloroborane base chloroborane (catalyzer 6).
Embodiment
Below by specific embodiment, this invention is further described.
The synthesis of embodiment 1 (6,7-dimethoxy-3-(4-methoxyl group-7,8-dihydro-[1,3] bis-oxazoles are [4,5-g] isoquinoline 99.9-5-base also) isobenzofuran-1 (3H)-one)
In 100ml single port bottle, add 4,5-dimethoxy-3-carbonyl-1,3-dihydroisobenzofuran-1-carboxylic acid 4.3g, dissolve with thionyl chloride 20ml, be heated to 80 degree of back flow reaction two hours, cooling, add 20ml methylene dichloride after revolving desolventizing and dissolve for subsequent use.Separately get 250ml single port bottle, add 2-(7-methoxyl group benzo [d] [1,3] two oxazole-5-base) ethamine 5.0g, pyridine 6ml, add methylene dichloride 50ml and dissolve, the acyl chlorides made is added dropwise in reaction, stirred overnight at room temperature.Reaction terminates rear methyl alcohol 5ml cancellation reaction, and organic phase 50ml washing twice, revolve desolventizing after anhydrous sodium sulfate drying, gained crude product 10% ethyl acetate/dichloromethane crosses post, obtains 3.2g faint yellow solid.
The solid 2.0g 20ml phosphorus oxychloride upper step obtained is dissolved, reflux 4 hours, cooling, revolves organic solvent, with twice, toluene band, steam the cooling of residual frozen water, add 8ml methyl alcohol cancellation residue phosphorus oxychloride, instilled in methyl tertiary butyl ether by methanol solution and separate out solid, solid methyl tertiary butyl ether stirs to wash and obtains crude product 2.2g for twice, cross post by 5% ethanol/methylene after crude product 0.1mol/L sodium hydroxide is free, obtain 1.6g product.
The synthesis of embodiment 2 Noscapine
Get 50ml single port bottle and add 5ml methylene dichloride,-20 DEG C are cooled under nitrogen protection, add S-Me-CBS34.8mg, add borine tetrahydrofuran (THF) (1M) 1.3ml, add stirring after 20 minutes, intermediate imine 500mg is dissolved in 5ml methylene dichloride, in instillation reaction, reaction solution reacts 10 hours at-20 DEG C, add 5ml methyl alcohol cancellation reaction, PH8-9 is regulated with 0.1mol/L sodium hydroxide, dichloromethane extraction, methylene dichloride is spin-dried for after anhydrous sodium sulfate drying, steam residual 10ml anhydrous alcohol solution, add paraformaldehyde 150mg, add sodium cyanoborohydride 300mg under stirring in batches, add reaction and after 2-3 hour, add 0.5ml acetic acid cancellation reaction, the 50ml that adds water dilutes, dichloromethane extraction obtains crude product, sterling 109mg is obtained after post.
The synthesis of embodiment 3 Noscapine
Get 50ml single port bottle and add 5ml methylene dichloride,-20 DEG C are cooled under nitrogen protection, add R-Me-CBS33.1mg, add borine tetrahydrofuran (THF) (1M) 1.3ml, add stirring after 20 minutes, intermediate imine 1.2mg is dissolved in 5ml methylene dichloride, in instillation reaction solution, reaction solution reacts 10 hours at-20 DEG C, add 5ml methyl alcohol cancellation reaction, PH8-9 is regulated with 0.1mol/L sodium hydroxide, dichloromethane extraction, methylene dichloride is spin-dried for after anhydrous sodium sulfate drying, steam residual 10ml anhydrous alcohol solution, add paraformaldehyde 150mg, add sodium cyanoborohydride 300mg under stirring in batches, add reaction and after 2-3 hour, add 0.5ml acetic acid cancellation reaction, the 50ml that adds water dilutes, dichloromethane extraction obtains crude product, sterling 53mg is obtained after post.
The synthesis of embodiment 4 Noscapine
Get 50ml single port bottle and add 5ml methylene dichloride,-20 DEG C are cooled under nitrogen protection, add diisopinocampheylchloroborane base chloroborane 40.3mg, add borine tetrahydrofuran (THF) (1M) 1.3ml, add stirring after 20 minutes, intermediate imine 500mg is dissolved in 5ml methylene dichloride, in instillation reaction solution, reaction solution reacts 10 hours at-20 DEG C, add 5ml methyl alcohol cancellation reaction, PH8-9 is regulated with 0.1mol/L sodium hydroxide, dichloromethane extraction, methylene dichloride is spin-dried for after anhydrous sodium sulfate drying, steam residual 10ml anhydrous alcohol solution, add paraformaldehyde 150mg, add sodium cyanoborohydride 300mg under stirring in batches, add reaction and after 2-3 hour, add 0.5ml acetic acid cancellation reaction, the 50ml that adds water dilutes, dichloromethane extraction obtains crude product, sterling 139mg is obtained after post.
Claims (2)
1. utilize the selective reduction of chirality B catalyst to prepare (-) α-Noscapine, be in particular and use the selective reduction of chirality B catalyst to generate (-) α-Noscapine
Chirality B catalyst is oxazaborolidine compounds or pinene vinyl borine, is in particular the compound of following structure
Wherein R is methyl or ethyl or sec.-propyl or the tertiary butyl.
2. according to claim 1ly utilize the selective reduction of chirality B catalyst to prepare (-) α-Noscapine, it is characterized in that: reductive agent used is borine tetrahydrofuran solution or borine diethyl ether solution or borane dimethylsulfide ethereal solution; Reaction solvent is methylene dichloride, ether, tetrahydrofuran (THF), or toluene; Temperature of reaction is-78 DEG C of-50 degree.
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