JP2005518427A - 新規ボロネートエステル - Google Patents
新規ボロネートエステル Download PDFInfo
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- JP2005518427A JP2005518427A JP2003569640A JP2003569640A JP2005518427A JP 2005518427 A JP2005518427 A JP 2005518427A JP 2003569640 A JP2003569640 A JP 2003569640A JP 2003569640 A JP2003569640 A JP 2003569640A JP 2005518427 A JP2005518427 A JP 2005518427A
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- -1 boronate ester Chemical class 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 23
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 18
- 125000003118 aryl group Chemical group 0.000 claims abstract description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 14
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 14
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 13
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 13
- FJLGEFLZQAZZCD-MCBHFWOFSA-N (3R,5S)-fluvastatin Chemical compound C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 FJLGEFLZQAZZCD-MCBHFWOFSA-N 0.000 claims abstract description 5
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims abstract description 5
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229960005370 atorvastatin Drugs 0.000 claims abstract description 5
- 229960005110 cerivastatin Drugs 0.000 claims abstract description 5
- SEERZIQQUAZTOL-ANMDKAQQSA-N cerivastatin Chemical compound COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 SEERZIQQUAZTOL-ANMDKAQQSA-N 0.000 claims abstract description 5
- 229960003765 fluvastatin Drugs 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 229960002797 pitavastatin Drugs 0.000 claims abstract description 5
- VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 claims abstract description 5
- 229960000672 rosuvastatin Drugs 0.000 claims abstract description 5
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 claims abstract description 5
- 150000002367 halogens Chemical class 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 40
- 238000000034 method Methods 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 12
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 6
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 4
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 3
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000003377 acid catalyst Substances 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 7
- 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 abstract description 3
- IPCSIKXLXDFUAC-UHFFFAOYSA-N 2,2-dihydroxyhexanoic acid Chemical class CCCCC(O)(O)C(O)=O IPCSIKXLXDFUAC-UHFFFAOYSA-N 0.000 abstract description 3
- 239000002532 enzyme inhibitor Substances 0.000 abstract description 3
- 150000002148 esters Chemical class 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- 239000000047 product Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- 0 *OC(CC(CC(CC#N)O1)OB1[Al])=O Chemical compound *OC(CC(CC(CC#N)O1)OB1[Al])=O 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 3
- DZAIOXUZHHTJKN-UHFFFAOYSA-N 3,4-dihydroxybutyric acid Chemical compound OCC(O)CC(O)=O DZAIOXUZHHTJKN-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- PSCXFXNEYIHJST-QPJJXVBHSA-N (e)-4-phenylbut-3-enoic acid Chemical compound OC(=O)C\C=C\C1=CC=CC=C1 PSCXFXNEYIHJST-QPJJXVBHSA-N 0.000 description 1
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical class CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 1
- ANTBRXMMNBUYMS-UHFFFAOYSA-N 5-hydroxy-3-oxopentanoic acid Chemical class OCCC(=O)CC(O)=O ANTBRXMMNBUYMS-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical group N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 1
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- GYHQXJTYSBEDPP-UHFFFAOYSA-N [1-(2-diphenylphosphanylnaphthalen-1-yl)naphthalen-2-yl]-diphenylphosphane;ruthenium Chemical compound [Ru].C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 GYHQXJTYSBEDPP-UHFFFAOYSA-N 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 239000003529 anticholesteremic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 150000004648 butanoic acid derivatives Chemical class 0.000 description 1
- 125000000837 carbohydrate group Chemical group 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940116298 l- malic acid Drugs 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- KCKWOJWPEXHLOQ-UHFFFAOYSA-N methyl 3,4-dihydroxybutanoate Chemical compound COC(=O)CC(O)CO KCKWOJWPEXHLOQ-UHFFFAOYSA-N 0.000 description 1
- NQIXPBJBTPYBQH-UHFFFAOYSA-N methyl 3-hydroxy-4-trityloxybutanoate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCC(O)CC(=O)OC)C1=CC=CC=C1 NQIXPBJBTPYBQH-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- KRKPYFLIYNGWTE-UHFFFAOYSA-N n,o-dimethylhydroxylamine Chemical compound CNOC KRKPYFLIYNGWTE-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 238000005949 ozonolysis reaction Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000010963 scalable process Methods 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000011916 stereoselective reduction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- XKGDOWNTFKKNKG-UHFFFAOYSA-N tert-butyl 3,5-dihydroxy-6-trityloxyhexanoate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCC(O)CC(O)CC(=O)OC(C)(C)C)C1=CC=CC=C1 XKGDOWNTFKKNKG-UHFFFAOYSA-N 0.000 description 1
- GAJZMSCUUOBKDJ-UHFFFAOYSA-N tert-butyl 5-hydroxy-3-oxo-6-trityloxyhexanoate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCC(O)CC(=O)CC(=O)OC(C)(C)C)C1=CC=CC=C1 GAJZMSCUUOBKDJ-UHFFFAOYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical class [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- PSCXFXNEYIHJST-UHFFFAOYSA-N trans-styrilacetic acid Natural products OC(=O)CC=CC1=CC=CC=C1 PSCXFXNEYIHJST-UHFFFAOYSA-N 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
-
- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pyrrole Compounds (AREA)
Abstract
【化1】
Description
本発明は、式IIaの光学活性なジヒドロキシヘキサノエート誘導体、より具体的には、アトルバスタチン、セリバスタチン、ロスバスタチン、ピタバスタチン、フルバスタチンのようなHMG−CoA酵素阻害剤の合成のための有用な中間体である式IIの化合物に関する。
Ar=非置換または置換アリールまたはヘテロアリール
R3=1〜8個の炭素を有するアルキル、アリールまたはアラルキル
R4=O、OH、CNまたはハロゲン、および
a=単結合または二重結合)。
Ar=非置換または置換アリールまたはヘテロアリール
R3=1〜8個の炭素を有するアルキル、アリールまたはアラルキル)
の化合物の製造方法であって、
(a)式IIIの化合物を酢酸第三ブチルのアニオンと反応させて式IVの化合物(各式において、Gは、テトラヒドロピラニル、tert−ブチルジメチルシリルまたはトリチル、R3は、1〜8個の炭素を有するアルキル、アリールまたはアラルキル)を得、
ことを包含する方法を提供する。
式IIの化合物は、スタチン類の合成に有用な重要な物質のための良好な中間体として作用する。式IIの化合物は、塩化トシル、塩化メタンスルホニルにより処理することにより易離脱性基(facile leaving group)に変換することができ、得られる中間体をシアン化物で置換して式VIIの化合物を得ることができる。
3,4−ジヒドロキシブタン酸メチル25gにDCM250mlを加え、攪拌して溶解させ、ピリジン19.8gを入れ、0℃に冷却した。塩化トリチル41.4gをDMC50mlに溶解し、0〜5℃で15分間で添加した。温度をRTまで高め、RTで17時間攪拌した。水を加えて、層分離させた。有機層を塩水で洗浄し、乾燥し、濃縮した。残分をシクロヘキサン25mlを用いてすりつぶし、生成物を精製して純粋生成物19gを得た。
THF125mlにジイソプロピルアミン24gを加え、−15℃に冷却した。−15〜−5℃で1.2Nのn−BuLi168mlを加え、30分間攪拌した。予め−45℃に冷却したTHF45ml中の酢酸tert−ブチル21.56gを加え、温度を60分間−45〜−25℃に維持した。この反応混合物を−45℃に冷却し、20分間かけてTHF中の例1を30g加え、攪拌を−25℃で90分間続けた。水を加えて、層分離させた。水層をEtOAcを用いて抽出し、合わせた有機層を塩水、水で洗浄し、乾燥し、濃縮して表題化合物を得、これをそのまま次の工程に用いた。
例2で得た粗製物質にTHF150mlを、ついでMeOH15mlを加え、−60℃に冷却した。MDEB(THF中50%溶液)26mlを20分間かけて加え、攪拌をさらに30分間続けた。この反応混合物を−80℃に冷却し、ナトリウムボロ水素化物5gを少しずつ加え、添加終了後、反応混合物を−78℃で5時間攪拌した。酢酸を加えてpHを7に調節し、水を加えた。水層をEtOAcを用いて抽出し、塩水で洗浄し、乾燥し、濃縮して表題化合物を得、これをそのまま次の工程に用いた。
例3の粗製生成物をトルエン100mlに溶解し、フェニルボロン酸5.6gを加えた。3時間にわたる共沸蒸留により水を除去した。この反応混合物をRTに冷却し、トルエンを減圧下で除去した。メタノール30mlを加え、析出した固体をろ過して表題生成物10gを得た。
例4の生成物5gにDCM20mlを加え、0℃に冷却した。TFA5mlを加え、20℃で6時間攪拌した。水を分離し、有機層を重炭酸塩、塩水で洗浄し、乾燥し、濃縮して表題生成物を得、これをカラムクロマトグラフィーにより精製した。
例5で得た生成物5gをジクロロメタン(50mL)に取り、ピリジン(10mL)を加えた。内容物を−10℃に冷却し、塩化メタンスルホニル(1当量)を滴下した。0℃での5〜6時間の攪拌後、内容物を重炭酸塩、水および塩水で洗浄した。減圧下で溶媒を除去してO−メタンスルホニル誘導体を得、これをそのまま次の工程に用いた。
Claims (9)
- 式II
Ar=非置換または置換アリールまたはヘテロアリール
R3=1〜8個の炭素を有するアルキル、アリールまたはアラルキル)
の化合物の製造方法であって、
(a)式IIIの化合物を酢酸第三ブチルのアニオンと反応させて式IVの化合物(各式において、Gは、テトラヒドロピラニル、tert−ブチルジメチルシリルまたはトリチル、R3は、1〜8個の炭素を有するアルキル、アリールまたはアラルキル)を得、
ことを包含する方法。 - ArB(OH)2が、ボロン酸である請求項3に記載の方法。
- 式IIの化合物をHBr水溶液と反応させることによって、またはトリフェニルホスフィンおよびCBr4との反応によって、式IIの化合物を式IXの化合物に変換する請求項6に記載の方法。
- アトルバスタチン、セリバスタチン、ピタバスタチン、フルバスタチンまたはロスバスタチンの合成において使用される請求項1に記載の生成物。
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EP1323717A1 (en) * | 2001-12-27 | 2003-07-02 | Dsm N.V. | Process for the preparation of 2-(6-Substituted-1,3-Dioxane-4-yL) acetic acid derivatives |
ES2332881T3 (es) | 2002-02-25 | 2010-02-15 | Biocon Limited | Nuevos esteres de boranato. |
US20110076730A1 (en) * | 2006-07-19 | 2011-03-31 | Board Of Trustees Of Michigan State University | Microbial synthesis of d-1,2,4-butanetriol |
WO2008042876A2 (en) | 2006-10-02 | 2008-04-10 | Codexis, Inc. | Compositions and methods for producing stereoisomerically pure statins and synthetic intermediates therefor |
KR100933172B1 (ko) | 2007-11-30 | 2009-12-21 | 씨제이제일제당 (주) | 아토르바스타틴 칼슘염의 개선된 제조방법 |
KR101339648B1 (ko) * | 2012-05-10 | 2013-12-09 | (주) 에프엔지리서치 | 신규한 아토바스타틴 중간체 및 이를 이용한 아토바스타틴의 제조 방법 |
KR101528359B1 (ko) * | 2013-04-24 | 2015-06-15 | (주) 성운파마코피아 | 스타틴 화합물 제조를 위한 신규한 보로네이트 에테르 화합물, 그 제조방법 및 상기 보로네이트 에테르 화합물을 이용한 스타틴 화합물 제조방법 |
CN108033899B (zh) * | 2017-12-06 | 2020-04-10 | 浙江科技学院 | 一种(r)-6-氰基-5-羟基-3-羰基己酸叔丁酯的制备方法 |
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WO2002057229A1 (en) | 2001-01-19 | 2002-07-25 | Biocon India Limited | FORM V CRYSTALLINE [R-(R*,R*)]-2-(4-FLUOROPHENYL)-ß,$G(D)-DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMINO)CARBONYL]-1H-PYRROLE-1- HEPTANOIC ACID HEMI CALCIUM SALT. (ATORVASTATIN) |
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KR20040084915A (ko) | 2004-10-06 |
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US7301046B2 (en) | 2007-11-27 |
IL163333A (en) | 2009-05-04 |
PT1478650E (pt) | 2010-01-04 |
EP1478650A1 (en) | 2004-11-24 |
RO122095B1 (ro) | 2008-12-30 |
HRP20040888A2 (en) | 2005-04-30 |
HRP20040888B1 (en) | 2012-12-31 |
DK1478650T3 (da) | 2010-01-25 |
CA2475586A1 (en) | 2003-08-28 |
ES2332881T3 (es) | 2010-02-15 |
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