CN1126755C - 制备n-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-n-甲基甲烷磺酰胺的方法 - Google Patents
制备n-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-n-甲基甲烷磺酰胺的方法 Download PDFInfo
- Publication number
- CN1126755C CN1126755C CN00103783A CN00103783A CN1126755C CN 1126755 C CN1126755 C CN 1126755C CN 00103783 A CN00103783 A CN 00103783A CN 00103783 A CN00103783 A CN 00103783A CN 1126755 C CN1126755 C CN 1126755C
- Authority
- CN
- China
- Prior art keywords
- fluorophenyl
- methyl
- sec
- pyrimidine
- propyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 238000000034 method Methods 0.000 title claims description 16
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 title 1
- QMVSXLAUHQNNIX-UHFFFAOYSA-N methane;sulfamide Chemical compound C.NS(N)(=O)=O QMVSXLAUHQNNIX-UHFFFAOYSA-N 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 54
- 239000002585 base Substances 0.000 claims description 51
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 46
- LAXBNTIAOJWAOP-UHFFFAOYSA-N 2-chlorobiphenyl Chemical group ClC1=CC=CC=C1C1=CC=CC=C1 LAXBNTIAOJWAOP-UHFFFAOYSA-N 0.000 claims description 23
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 23
- 230000005595 deprotonation Effects 0.000 claims description 7
- 238000010537 deprotonation reaction Methods 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 4
- 229910001511 metal iodide Inorganic materials 0.000 claims description 3
- UHNHTTIUNATJKL-UHFFFAOYSA-N n-methylmethanesulfonamide Chemical compound CNS(C)(=O)=O UHNHTTIUNATJKL-UHFFFAOYSA-N 0.000 claims description 3
- 239000003444 phase transfer catalyst Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229910001508 alkali metal halide Inorganic materials 0.000 claims description 2
- 150000008045 alkali metal halides Chemical class 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 150000001350 alkyl halides Chemical class 0.000 claims description 2
- 229910052728 basic metal Chemical class 0.000 claims description 2
- 150000003818 basic metals Chemical class 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- XGRJZXREYAXTGV-UHFFFAOYSA-N chlorodiphenylphosphine Chemical compound C=1C=CC=CC=1P(Cl)C1=CC=CC=C1 XGRJZXREYAXTGV-UHFFFAOYSA-N 0.000 abstract 1
- 239000003112 inhibitor Substances 0.000 abstract 1
- TYRDEZUMAVRTEO-UHFFFAOYSA-N pyrimidin-5-ylmethanol Chemical compound OCC1=CN=CN=C1 TYRDEZUMAVRTEO-UHFFFAOYSA-N 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 72
- 239000000203 mixture Substances 0.000 description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 239000007787 solid Substances 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
- 238000001035 drying Methods 0.000 description 7
- 238000003810 ethyl acetate extraction Methods 0.000 description 7
- 238000001556 precipitation Methods 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000000376 reactant Substances 0.000 description 6
- 235000009518 sodium iodide Nutrition 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000002480 mineral oil Substances 0.000 description 4
- 235000010446 mineral oil Nutrition 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 4
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- YFPJFKYCVYXDJK-UHFFFAOYSA-N Diphenylphosphine oxide Chemical compound C=1C=CC=CC=1[P+](=O)C1=CC=CC=C1 YFPJFKYCVYXDJK-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229940123934 Reductase inhibitor Drugs 0.000 description 1
- AVZLIFPUWWYBAY-UHFFFAOYSA-N [Br+].C(CCC)[N+](CCCC)(CCCC)CCCC Chemical compound [Br+].C(CCC)[N+](CCCC)(CCCC)CCCC AVZLIFPUWWYBAY-UHFFFAOYSA-N 0.000 description 1
- DRGLCHFCDQCXDZ-UHFFFAOYSA-N [Cl+].C(CCC)[N+](CCCC)(CCCC)CCCC Chemical compound [Cl+].C(CCC)[N+](CCCC)(CCCC)CCCC DRGLCHFCDQCXDZ-UHFFFAOYSA-N 0.000 description 1
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 235000007715 potassium iodide Nutrition 0.000 description 1
- 229960004839 potassium iodide Drugs 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/84—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
通过[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基氨基)嘧啶-5-基]甲醇与氯二苯基膦反应制得了通式I表示的N-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-N-甲基甲烷磺酰胺。化合物I是合成药理活性化合物,例如还原酶抑制剂HMG-CoA,的中间体。
Description
本发明制备的N-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-N-甲基甲烷磺酰胺(I)是制备药理活性化合物,例如还原酶抑制剂HMG-CoA,的中间体。(Bioorg.Med.Chem.1997,5,437)。
本发明目的在于提供获得上述化合物的更好的方法。本发明通过权利要求1所述的新方法实现了上述目的。
根据本发明,通式(I)表示的N-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-N-甲基甲烷磺酰胺是通过通式(II)表示的[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基氨基)嘧啶-5-基]甲醇与氯二苯基膦反应制备而得的。本发明合成法的一个重要优点是它的工业适用性。例如用氢化二异丁基铝(EP-A0521471)还原相应的酯,可以方便地获得通式(II)表示的[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基氨基)嘧啶-5-基]甲醇。
通式(II)表示的[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基氨基)嘧啶-5-基]甲醇与氯二苯基膦的反应可以直接进行也可以先去质子化再进行。
较好的是与氯二苯基膦直接反应,然后用碱处理。如果进行“去质子化”,通式(II)表示的[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基氨基)嘧啶-5-基]甲醇可与本领域熟知的去质子化试剂反应,较好的是与氢化碱金属或碱金属六烷基二硅氮烷反应。以用氢化钠为佳。去质子化一般在室温下进行。然后与氯二苯基膦反应。与氯二苯基膦的反应以在80℃至200℃之间的温度进行为宜。
氯二苯基膦可以直接作为溶剂。但是,可以使用其它高沸点惰性溶剂,例如甲苯,二甲苯或十氢化萘,以及各自异构体的混合物。
反应可加催化剂进行。
合适的催化剂是碘,碱金属碘化物,例如碘化钠或碘化钾,碱金属卤化物,例如甲基碘或乙基碘,或二卤烷,例如二溴甲烷。其中以碱金属碘化物为佳。
催化剂的量一般为1mol%至20mol%,以通式II表示的醇为基准。
直接反应在-20℃至130℃之间的温度进行,以20℃至120℃之间为佳。对应于上述“去质子化”,氯二苯基膦可以在直接反应中直接作为溶剂。但是,也可以使用其它高沸点惰性溶剂,例如甲苯,二甲苯或十氢化萘,以及各自异构体的混合物。
与氯二苯基膦反应后,反应混合物与碱反应。合适的碱是碱金属氢氧化物,例如氢氧化钠或氢氧化钾水溶液,或碱金属碳酸盐,例如碳酸钠或碳酸钾。合适的话,可以使用常用的相转移催化剂来加速与碱的反应,例如使用卤化四烷基铵。用冠醚也可以获得良好的效果。
反应结束后,可用本领域的已知技术将通式I表示的N-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-N-甲基甲烷磺酰胺从混合物中分离,所述的分离技术例如用合适的溶剂从混合物中萃取,以及通过结晶。
实施例
实施例1N-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-N-甲基甲烷磺酰胺
先将1.00g(2.83mol)[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基氨基)嘧啶-5-基]甲醇加入5ml顺/反十氢化萘,与204mg(4.68mmol)氢化钠(55%,分散在矿物油中)混合。室温反应30分钟后,加入680mg(2.93mmol)氯二苯基膦,同时剧烈搅拌,历时6分钟。混合物与52.2mg(0.35mmol)碘化钠混合,在184-186℃加热2小时又15分钟。冷却至室温后,加入50ml 38-40%亚硫酸氢钠溶液和50ml乙酸乙酯。分离出有机相,用50ml乙酸乙酯萃取水相。合并有机相,用硫酸镁干燥,减压浓缩。得到1.74g粗制产物,用硅胶柱层析(移动相:正己烷/乙酸乙酯1∶2)纯化。得到382.4mg(25.1%)N-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-N-甲基甲烷磺酰胺无色固体。(熔点:184-185℃)。1HNMR(DMSO-d6,400MHz):δ=1.11(d,J=6.6Hz,6H);
3.28(scpt,J=6.6Hz,1H);
3.40(s,3H);
3.51(s,3H);
4.05(d,J=12.6Hz,2H);
7.07(t,J=8.9Hz,2H);
7.35(m,2H);
7.42(m,4H);
7.5-7.9(m,6H).13CNMR(DMSO-d6,100MHz) δ= 21.52(q);
29.12(td);
31.94(d);
33.07(q);
41.53(q);
114.50(sd);
115.03(dd);
128.54(dd);
130.21(dd);
130.84(dd);
131.64(dd);
133.41(sd);
134.51(sd);
156.54(sd);
162.10(sd);
165.86(sd);
176.49(sd).
实施例2N-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-N-甲基甲烷磺酰胺
先将282.8mg(0.80mmol)[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基氨基)嘧啶-5-基]甲醇加入4.5ml二甲苯(异构体混合物),与55mg(1.30mmol)氢化钠(55%,分散在矿物油中)混合。35分钟后,室温下加入185mg(0.84mmol)氯二苯基膦的1.5ml二甲苯溶液,同时剧烈搅拌,历时5分钟。混合物然后在135℃加热20小时。冷却至室温后,混合物与15ml水混合,用10ml乙酸乙酯萃取。分离出有机相,水相用10ml乙酸乙酯萃取2次。合并有机相,用硫酸镁干燥,减压浓缩。得到510mg粗制产物,用硅胶柱层析(移动相:正己烷/乙酸乙酯1∶2,然后是乙酸乙酯)纯化。分离得到230mg(53.5%)N-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-N-甲基甲烷磺酰胺无色固体。
实施例3N-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-N-甲基甲烷磺酰胺
先将512mg(1.45mmol)[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基氨基)嘧啶-5-基]甲醇加入8ml甲苯,与96mg(2.20mmol)氢化钠(55%,分散在矿物油中)混合。1小时后,室温下加入333.5mg(1.44mmol)氯二苯基膦的2.5ml甲苯溶液,同时剧烈搅拌,历时5分钟。混合物然后与28.7mg(0.19mmol)碘化钠混合,并在108℃加热22小时。6小时后,再加入28.7mg(0.19mmol)碘化钠。冷却至室温后,混合物与30ml38-40%亚硫酸氢钠水溶液混合,用50ml乙酸乙酯萃取。分出有机相,水相用50ml乙酸乙酯萃取。减压浓缩合并的有机相。得到740mg粗制产物,用硅胶柱层析(移动相∶乙酸乙酯)纯化。分离得到212.7mg(27.3%)N-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-N-甲基甲烷磺酰胺无色固体。
实施例4N-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-N-甲基甲烷磺酰胺
先将502.6mg(1.42mmol)[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基氨基)嘧啶-5-基]甲醇加入8ml二甲苯(异构体混合物),与96.6mg(2.21mmol)氢化钠(55%,分散在矿物油中)混合。1小时后,室温下加入340.8mg(1.47mmol)氯二苯基膦的2.5ml二甲苯溶液,同时剧烈搅拌,历时5分钟。混合物然后与34.6mg(0.23mmol)碘化钠混合,并在136℃加热19小时。3小时后,再加入25.1mg碘化钠。冷却至室温后,混合物与30ml亚硫酸氢钠稀水溶液混合,用50ml乙酸乙酯萃取。分离有机相,用50ml乙酸乙酯萃取水相。减压浓缩合并的有机相。得到906mg粗制产物,用硅胶柱层析(移动相∶乙酸乙酯)纯化。分离得到315.96mg(41.3%)N-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-N-甲基甲烷磺酰胺无色固体。
实施例5(直接反应)N-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-N-甲基甲烷磺酰胺
先将1.05g(2.95mmol)[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基氨基)嘧啶-5-基]甲醇加入7g甲苯,与820mg(3.69mmol)氯二苯基膦搅拌混合,同时冰浴冷却。混合物在108℃加热3小时。冷却至室温后,加入553mg(4.43mmol)氢氧化钾水溶液(45%)和97.5mg(0.29mmol)溴四丁铵,混合物在60℃剧烈搅拌1小时。移去热源,反应物趁热与20ml水混合。混合物缓慢冷却至4℃,过滤出固体沉淀。产物用冷水和甲苯洗涤,并在40℃减压干燥。分离得到1.04g(64.1%,纯度:97.6%)N-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-N-甲基甲烷磺酰胺无色固体。
实施例6(直接反应)N-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-N-甲基甲烷磺酰胺
先将2.03g(5.69mmol)[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基氨基)嘧啶-5-基]甲醇加入13g’甲苯,与1.67g(7.51mmol)氯二苯基膦的2g甲苯溶液混合,同时冰浴冷却。混合物在111℃加热2.5小时。冷却至室温后,加入1.08g(8.66mmol)氢氧化钾水溶液(45%)和175mg(0.574mmol)氯四丁铵,混合物在60℃剧烈搅拌2小时。反应物趁热与30ml水混合。混合物在60℃略微搅拌,缓慢冷却至4℃,过滤出固体沉淀。产物用冷水(10ml)和冷甲苯(10ml)洗涤,并在40℃减压干燥。分离得到2.66g(84.1%,纯度:96.6%)N-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-N-甲基甲烷磺酰胺无色固体。
实施例7(直接反应)N-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-N-甲基甲烷磺酰胺
先将2.02g(5.69mmol)[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基氨基)嘧啶-5-基]甲醇加入13.g甲苯,与1.67g(7.51mmol)氯二苯基膦的1.9g甲苯溶液混合,同时冰浴冷却。混合物在109℃加热3小时。冷却至室温后,加入590mg(8.94mmol)氢氧化钾固体和159mg(0.582mmol)18-冠-6醚,混合物在60℃剧烈搅拌3.5小时。反应物趁热与30ml水混合。混合物在60℃略微搅拌,缓慢冷却至4℃,过滤出固体沉淀。产物用冷水(10ml)和冷甲苯(10ml)洗涤,并在40℃减压干燥。分离得到1.82g(59.5%,纯度:95.5%)N-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-N-甲基甲烷磺酰胺无色固体。
实施例8(直接反应)N-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-N-甲基甲烷磺酰胺
先将2.02g(5.69mmol)[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基氨基)嘧啶-5-基]甲醇加入13.1g甲苯,与1.71g(7.69mmol)氯二苯基膦的1.9g甲苯溶液混合,同时冰浴冷却。混合物在111℃加热2.5小时。冷却至室温后,加入1.17g(8.78mmol)30%的氢氧化钠溶液和182mg(0.597mmol)氯化四丁铵,混合物在60℃剧烈搅拌3.5小时。反应物趁热与30ml水混合。混合物在60℃略微搅拌,缓慢冷却至4℃,过滤出固体沉淀。产物用冷水(10ml)和冷甲苯(10ml)洗涤,并在40℃减压干燥。分离得到2.18g(71.3%,纯度:97.3%)N-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-N-甲基甲烷磺酰胺无色固体。(熔点:184-185℃)。
实施例9(直接反应)N-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-N-甲基甲烷磺酰胺
先将9.29g(26.3mmol)[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基氨基)嘧啶-5-基]甲醇加入26g甲苯,与7.64g(34.4mmol)氯二苯基膦混合,同时冰浴冷却。用少量甲苯洗涤,混合物在111℃加热2小时。冷却至室温后,加入4.94g 45%的氢氧化钾溶液和873mg(2.71mmol)溴化四丁铵,混合物在60℃剧烈搅拌1小时。反应物趁热与100ml水混合。混合物在60℃略微搅拌,缓慢冷却至4℃,过滤出固体沉淀。产物用冷水(30ml)和冷甲苯(30ml)洗涤,并在40℃减压干燥。分离得到11.74g(78.4%,纯度:94.4%)N-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-N-甲基甲烷磺酰胺无色固体。
实施例10(不加相转移催化剂的直接反应)N-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-N-甲基甲烷磺酰胺
先将2.03g(5.69mmol)[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基氨基)嘧啶-5-基]甲醇加入13g甲苯,与1.69g(7.60mmol)氯二苯基膦的1.9g甲苯溶液混合,同时冰浴冷却。混合物在109℃加热2.5小时。冷却至室温后,加入1.09g(8.74mmol)45%的氢氧化钾溶液,混合物在60℃剧烈搅拌2小时45分钟。反应物趁热与30ml水混合。混合物在60℃略微搅拌,缓慢冷却至4℃,过滤出固体沉淀。产物用冷水(10ml)和冷甲苯(10ml)洗涤,并在40℃减压干燥。分离得到2.44g(76.8%,纯度:99.1%)N-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-N-甲基甲烷磺酰胺无色固体。
实施例11(直接反应)N-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-N-甲基甲烷磺酰胺
先将60.08g(0.170mol)[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基氨基)嘧啶-5-基]甲醇加入485ml甲苯,在60℃与42.55g(0.192mol;纯度:99.7%)氯二苯基膦混合。混合物搅拌2.5小时,然后在60℃加到70.66g 20%氢氧化钾溶液和5.04g(0.017mol)氯化四丁铵组成的混合物中。所得的混合物再在60℃搅拌2小时。然后加入215ml水和108ml甲苯。在80℃分离出水相。有机相用215ml热水萃取2次。共沸蒸馏去除有机相中残留的水。混合物缓慢(2小时)冷却至0℃,过滤出固体沉淀。产物用160ml甲苯洗涤2次,在40℃减压干燥。分离得到81.94g(89.7%)N-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-N-甲基甲烷磺酰胺无色固体。[纯度(HPLC):100%]。
Claims (10)
2.根据权利要求1所述的方法,通式II表示的[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基氨基)嘧啶-5-基]甲醇直接与氯二苯基膦反应,然后用碱处理。
3.根据权利要求1所述的方法,通式II表示的[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基氨基)嘧啶-5-基]甲醇先被去质子化。
4.根据权利要求3所述的方法,去质子化是用氢化碱金属或碱金属六烷基二硅氮烷进行的。
5.根据权利要求1所述的方法,反应借助催化剂进行。
6.根据权利要求5所述的方法,所用的催化剂是碘,碱金属碘化物,碱金属卤化物或二卤烷。
7.根据权利要求1所述的方法,与氯二苯基膦的反应在80℃至200℃之间的温度进行。
8.根据权利要求2所述的方法,与氯二苯基膦的直接反应在-20℃至130℃之间的温度进行。
9.根据权利要求2或8所述的方法,所用的碱是碱金属氢氧化物。
10.根据权利要求2所述的方法,反应借助相转移催化剂进行。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP99104785 | 1999-03-10 | ||
EP99104786 | 1999-03-10 | ||
EP99104786.1 | 1999-03-10 | ||
EP99104785.3 | 1999-03-10 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1272499A CN1272499A (zh) | 2000-11-08 |
CN1126755C true CN1126755C (zh) | 2003-11-05 |
Family
ID=26152921
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN00103783A Expired - Lifetime CN1126755C (zh) | 1999-03-10 | 2000-03-10 | 制备n-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-n-甲基甲烷磺酰胺的方法 |
Country Status (16)
Country | Link |
---|---|
EP (1) | EP1035127B1 (zh) |
JP (1) | JP4438167B2 (zh) |
KR (1) | KR100586664B1 (zh) |
CN (1) | CN1126755C (zh) |
AT (1) | ATE251633T1 (zh) |
CA (1) | CA2300243C (zh) |
CZ (1) | CZ298235B6 (zh) |
DE (1) | DE50003959D1 (zh) |
DK (1) | DK1035127T3 (zh) |
ES (1) | ES2208167T3 (zh) |
HK (1) | HK1029996A1 (zh) |
HU (1) | HU224967B1 (zh) |
NO (1) | NO324982B1 (zh) |
PL (1) | PL195166B1 (zh) |
PT (1) | PT1035127E (zh) |
SK (1) | SK284027B6 (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003097614A2 (en) * | 2002-05-21 | 2003-11-27 | Ranbaxy Laboratories Limited | Process for the preparation of rosuvastatin |
US7341743B2 (en) | 2004-10-28 | 2008-03-11 | Revlon Consumer Products Corporation | Color cosmetic compositions |
CA2725052C (en) | 2008-05-27 | 2014-09-16 | Changzhou Pharmaceutical Factory Co., Ltd. | Preparation method of rosuvastatin calcium and its intermediates |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2648897B2 (ja) * | 1991-07-01 | 1997-09-03 | 塩野義製薬株式会社 | ピリミジン誘導体 |
-
2000
- 2000-03-07 SK SK332-2000A patent/SK284027B6/sk not_active IP Right Cessation
- 2000-03-07 CZ CZ20000837A patent/CZ298235B6/cs not_active IP Right Cessation
- 2000-03-09 DE DE50003959T patent/DE50003959D1/de not_active Expired - Lifetime
- 2000-03-09 AT AT00105011T patent/ATE251633T1/de active
- 2000-03-09 CA CA002300243A patent/CA2300243C/en not_active Expired - Lifetime
- 2000-03-09 ES ES00105011T patent/ES2208167T3/es not_active Expired - Lifetime
- 2000-03-09 PT PT00105011T patent/PT1035127E/pt unknown
- 2000-03-09 DK DK00105011T patent/DK1035127T3/da active
- 2000-03-09 NO NO20001228A patent/NO324982B1/no not_active IP Right Cessation
- 2000-03-09 EP EP00105011A patent/EP1035127B1/de not_active Expired - Lifetime
- 2000-03-10 PL PL338944A patent/PL195166B1/pl unknown
- 2000-03-10 KR KR1020000012002A patent/KR100586664B1/ko not_active IP Right Cessation
- 2000-03-10 HU HU0001127A patent/HU224967B1/hu unknown
- 2000-03-10 CN CN00103783A patent/CN1126755C/zh not_active Expired - Lifetime
- 2000-03-10 JP JP2000066084A patent/JP4438167B2/ja not_active Expired - Lifetime
-
2001
- 2001-02-08 HK HK01100875A patent/HK1029996A1/xx unknown
Also Published As
Publication number | Publication date |
---|---|
DE50003959D1 (de) | 2003-11-13 |
CZ298235B6 (cs) | 2007-08-01 |
EP1035127B1 (de) | 2003-10-08 |
HK1029996A1 (en) | 2001-04-20 |
SK284027B6 (sk) | 2004-08-03 |
SK3322000A3 (en) | 2000-10-09 |
EP1035127A1 (de) | 2000-09-13 |
HU224967B1 (en) | 2006-04-28 |
ES2208167T3 (es) | 2004-06-16 |
DK1035127T3 (da) | 2003-11-03 |
KR100586664B1 (ko) | 2006-06-07 |
PL338944A1 (en) | 2000-09-11 |
KR20010006773A (ko) | 2001-01-26 |
PT1035127E (pt) | 2004-02-27 |
ATE251633T1 (de) | 2003-10-15 |
NO324982B1 (no) | 2008-01-14 |
CA2300243A1 (en) | 2000-09-10 |
HUP0001127A3 (en) | 2003-07-28 |
NO20001228D0 (no) | 2000-03-09 |
JP2000309595A (ja) | 2000-11-07 |
PL195166B1 (pl) | 2007-08-31 |
HU0001127D0 (en) | 2000-05-28 |
JP4438167B2 (ja) | 2010-03-24 |
HUP0001127A2 (hu) | 2001-06-28 |
CZ2000837A3 (cs) | 2000-10-11 |
NO20001228L (no) | 2000-09-11 |
CN1272499A (zh) | 2000-11-08 |
CA2300243C (en) | 2009-12-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2133356B1 (en) | Process for production of phosphorus-containing -keto acid | |
EP2062903A1 (en) | Statin intermediates and process for the preparation of statins | |
CN1091088C (zh) | α-卤代酮、α-卤代醇和环氧化物的制备方法 | |
KR20210032950A (ko) | 페닐피페리디닐 인돌 유도체를 제조하기 위한 화학적 방법 | |
CN1046288C (zh) | 嘌呤的不饱和膦酸酯衍生物 | |
CN100482632C (zh) | (r)-2-烷基-3-苯基丙酸的制备 | |
CN1126755C (zh) | 制备n-[5-(二苯基氧膦基甲基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基]-n-甲基甲烷磺酰胺的方法 | |
CN1108298C (zh) | 制备取代的苯并二氢吡喃醇衍生物的方法 | |
CN102365272A (zh) | 用于合成罗苏伐他汀或其药学上可接受的盐的关键中间体 | |
JPH05262781A (ja) | L−ホスフィノトリシンおよびその誘導体の製造方法 | |
CN1176641A (zh) | 3-吡咯烷亚基-2-酮-头孢菌素衍生物 | |
EP0742223A1 (en) | A method of preparing a derivative of optically active azetidin-2-one | |
EP2138502B1 (en) | Process for producing phosphorus-containing dehydroamino acid | |
JP5004119B2 (ja) | 2−フタルイミド−3−ホスホノプロピオン酸エステル化合物及びその製造方法 | |
FR2777780A1 (fr) | Derives d'(alpha-aminophosphino) peptides, leur procede de preparation et les compositions qui les contiennent | |
CN101754971A (zh) | 氧化膦维生素d前体的制备方法 | |
Hall et al. | Preparation of new phosphine oxide synthons: synthesis of an analogue of muscarinic antagonists | |
CN103288871A (zh) | 一种制备二羟基酸HMG-CoA还原酶抑制剂用的中间体及其制备方法和应用 | |
CN87103770A (zh) | 4,5二取代γ-丁内酰胺的纯对映体,它们的制备方法和应用 | |
TW530044B (en) | Tetraene derivative and process for producing the same | |
JP3723610B2 (ja) | 光学活性α−アミノホスホン酸誘導体の製造方法および不斉合成用触媒の製造方法並びに新規なホスホネート系化合物 | |
WO1997011954A1 (fr) | Procede de preparation de derives d'acide 1-aminophosphonique optiquement actif et de nouveaux composes de phosphonate | |
US20230416280A1 (en) | Method for producing 4-borono-l-phenylalanine and intermediate thereof | |
JPH0778027B2 (ja) | 共役オレフィンの製法 | |
CN102464594A (zh) | 普瑞巴林的中间体化合物的制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CX01 | Expiry of patent term |
Granted publication date: 20031105 |
|
CX01 | Expiry of patent term |