JPH03246290A - Production of pyrane derivative - Google Patents
Production of pyrane derivativeInfo
- Publication number
- JPH03246290A JPH03246290A JP2041327A JP4132790A JPH03246290A JP H03246290 A JPH03246290 A JP H03246290A JP 2041327 A JP2041327 A JP 2041327A JP 4132790 A JP4132790 A JP 4132790A JP H03246290 A JPH03246290 A JP H03246290A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- formula
- solvent
- subjected
- mmol
- 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.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical class C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 57
- 238000007248 oxidative elimination reaction Methods 0.000 claims abstract description 5
- 238000006237 Beckmann rearrangement reaction Methods 0.000 claims abstract description 4
- 230000001590 oxidative effect Effects 0.000 claims abstract description 3
- 239000000126 substance Substances 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 150000002923 oximes Chemical class 0.000 claims description 3
- 125000004309 pyranyl group Chemical class O1C(C=CC=C1)* 0.000 claims 2
- 239000002904 solvent Substances 0.000 abstract description 20
- 230000015572 biosynthetic process Effects 0.000 abstract description 11
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 238000007069 methylation reaction Methods 0.000 abstract description 4
- 239000012442 inert solvent Substances 0.000 abstract description 3
- 238000006146 oximation reaction Methods 0.000 abstract description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 abstract description 2
- 239000003810 Jones reagent Substances 0.000 abstract description 2
- 150000001412 amines Chemical class 0.000 abstract description 2
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 2
- 238000007254 oxidation reaction Methods 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 abstract 3
- 230000011987 methylation Effects 0.000 abstract 2
- 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 abstract 2
- 125000001511 cyclopentyl group Chemical class [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 abstract 1
- 230000003647 oxidation Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 12
- 238000001228 spectrum Methods 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical compound O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 7
- 239000002038 ethyl acetate fraction Substances 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- -1 te rt-butanol Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 239000005973 Carvone Substances 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 150000004880 oxines Chemical class 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Substances [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WWCPCQUOGPJFAK-UHFFFAOYSA-N acetic acid;ethyl acetate;methanol Chemical compound OC.CC(O)=O.CCOC(C)=O WWCPCQUOGPJFAK-UHFFFAOYSA-N 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- ULDHMXUKGWMISQ-UHFFFAOYSA-N carvone Chemical compound CC(=C)C1CC=C(C)C(=O)C1 ULDHMXUKGWMISQ-UHFFFAOYSA-N 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 150000001940 cyclopentanes Chemical class 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 229910001927 ruthenium tetroxide Inorganic materials 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate 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
- 239000007858 starting material Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 241001147855 Streptomyces cattleya Species 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- VXDSLUMUNWTSDB-UHFFFAOYSA-N acetic acid;chloroform;methanol Chemical compound OC.CC(O)=O.ClC(Cl)Cl VXDSLUMUNWTSDB-UHFFFAOYSA-N 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclo-pentanone Natural products O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- SOCTUWSJJQCPFX-UHFFFAOYSA-N dichromate(2-) Chemical compound [O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O SOCTUWSJJQCPFX-UHFFFAOYSA-N 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- VUZPPFZMUPKLLV-UHFFFAOYSA-N methane;hydrate Chemical compound C.O VUZPPFZMUPKLLV-UHFFFAOYSA-N 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 239000002032 methanolic fraction Substances 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 239000012022 methylating agents Substances 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- UYYCVBASZNFFRX-UHFFFAOYSA-N n-propan-2-ylcyclohexanamine Chemical compound CC(C)NC1CCCCC1 UYYCVBASZNFFRX-UHFFFAOYSA-N 0.000 description 1
- 229910052762 osmium Inorganic materials 0.000 description 1
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 1
- 239000012285 osmium tetroxide Substances 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyrane Compounds (AREA)
Abstract
Description
【発明の詳細な説明】 成における有用な中間体である式(I)醍イゆ で表されるピラン誘導体の製法に係る。[Detailed description of the invention] Formula (I), which is a useful intermediate in the synthesis of The present invention relates to a method for producing a pyran derivative represented by
1β−メチルチェナマイシンは、式(A)で表され、ス
トレプトマイセス・カトレア(Stre−ptomyc
es cattlea)により産生されるチェナマイシ
ンの1位をメチル基で修飾した非天然型カルバベネム系
抗生物質である。該抗生物質は、チェナマイシンと同様
の強力かつ広域な抗菌活性を示すと共に、チェナマイシ
ンに比べて腎デヒドロペブチダーゼによる不活性化に対
して優れた抵抗性を示すとの利点を有する。1β-Methylchenamycin is represented by the formula (A) and is derived from Streptomyces cattleya (Stre-ptomyc
It is a non-natural carbabenem antibiotic produced by modifying the 1-position of chenamycin produced by S. es cattlea with a methyl group. The antibiotic has the advantage of exhibiting potent and broad-spectrum antibacterial activity similar to chenamycin, and superior resistance to inactivation by renal dehydropeptidase compared to chenamycin.
このような利点のため、1β−メチルチェナマイシン誘
導体は注目を集めており、各種の合成法が開発されてい
る。これらの方法として、たとえば下記の方法がある。Because of these advantages, 1β-methylchenamycin derivatives have attracted attention, and various synthetic methods have been developed. Examples of these methods include the following methods.
(a)「ヘテロサイクルズ(Heterocycles
)J 1984, 219
(b)[テトラヘドロン・
レターズ(Tetrahedron
Lett.)J
987
28。(a) “Heterocycles”
) J 1984, 219 (b) [Tetrahedron Lett. J 987 28.
07
α「1(賢;βl’にシー65:35
しかしながら、従来の方法は、いずれも導入すべきメチ
ル基の立体選択性の点で満足できるものはなかった。07 α'1 (wise; βl' to see 65:35 However, none of the conventional methods was satisfactory in terms of stereoselectivity of the methyl group to be introduced.
本発明者らは、Q一カルボンがら容易に得られるシクロ
ベンタン誘導体(B)を使用して、チェナマイシンの合
成中間体である化合物(C)を合成し、この中間体を経
由してチェナマイシン(D)を合成する方法を既に確立
している([ジャーナル・オブ・ケミカル・ソサエティ
ー ケミカル・コミュニケーション(J. Chem.
Sac.、 Chew. Commun.)J19g
9, 646)。この方法では、非常に良好な立体選択
率でチェナマイシンが得られる。The present inventors synthesized compound (C), which is a synthetic intermediate for chenamycin, using a cyclobentane derivative (B) that is easily obtained from Q-carvone, and synthesized compound (C), which is a synthetic intermediate for chenamycin. A method for synthesizing (D) has already been established ([Journal of Chemical Society Chemical Communication (J. Chem.
Sac. , Chew. Commun. )J19g
9, 646). This method gives chenamycin with very good stereoselectivity.
(D)
そこで、1β−メチルチェナマイシン誘導体の合成に当
たり、上述のものと同様の立体選択反応を利用するため
、上記化合物(C)に対応する合成中間体として前記式
(I)
で表される化合物を考え、ρ一カルボンより簡単に得ら
れる前記式(II)
り\
で表される化合物を用いて立体選択的に合成中間体化合
物を合成できることを見出し、本発明を完成した。(D) Therefore, in the synthesis of the 1β-methylchenamycin derivative, in order to utilize the same stereoselective reaction as described above, the synthetic intermediate corresponding to the above compound (C) is expressed by the above formula (I). The present invention was completed by considering a compound and discovering that a synthetic intermediate compound can be stereoselectively synthesized using the compound represented by the above formula (II) which can be easily obtained from ρ-carboxylic acid.
1β−メチルチェナマイシン誘導体(A)本発明による
ピラン誘導体の合成過程は下記の如く表される。1β-Methylchenamycin derivative (A) The synthesis process of the pyran derivative according to the present invention is expressed as follows.
(■) (Ill) (■) (イ) (Vl VIl (■) +11 次に、上記合成過程における各工程について詳述する。(■) (Ill) (■) (stomach) (Vl VIl (■) +11 Next, each step in the above synthesis process will be explained in detail.
二しユI
この工程(a)は、式(n)で表される化合物をメチル
化する工程である。該メチル化反応は、テトラヒドロフ
ラン、エーテル、ヘキサメチルホスホリックトリアミド
、ジオキサンなどの不活性溶媒中、リチウムジイソプロ
ピルアミド、リチウムへキサメチルジシラジド、リチウ
ムイソプロピルシクロへキンルアミド等の塩基の存在下
、ヨウ化メチルなどのメチル化剤を用いて行われる。Nishiyu I This step (a) is a step of methylating the compound represented by formula (n). The methylation reaction is carried out in the presence of a base such as lithium diisopropylamide, lithium hexamethyldisilazide, lithium isopropylcyclohequinylamide in an inert solvent such as tetrahydrofuran, ether, hexamethylphosphoric triamide, or dioxane. This is done using a methylating agent such as methyl chloride.
二韮ユU
この工程は、前記メチル化反応によって得られた式(I
II)で表される化合物を酸化開裂する工程である。該
酸化開裂に当たっては、酸化剤としてオゾン、四酸化オ
スミウム−過ヨウ素酸ナトリウム、過マンガン酸カリウ
ム、四酸化ルテニウムなどを用いることかでき、溶媒と
しては、酢酸エチル、アセトン、ジクロロメタン、te
rt−ブタノール、テトラヒドロフラン、ジオキサン、
水又はこれらの混合物を使用できる。This step is based on the formula (I) obtained by the methylation reaction.
This is a step of oxidatively cleaving the compound represented by II). In the oxidative cleavage, ozone, osmium tetroxide-sodium periodate, potassium permanganate, ruthenium tetroxide, etc. can be used as an oxidizing agent, and as a solvent, ethyl acetate, acetone, dichloromethane, te
rt-butanol, tetrahydrofuran, dioxane,
Water or mixtures thereof can be used.
二且工0
この工程は、前記酸化開裂によって得られた式(rV)
で表される化合物をオキシム化する工程である。該オキ
シム化は、ヒドロキシルアミン又はその塩酸塩を使用し
、ピリジン、酢酸ナトリウムなどの塩基の存在下又は非
存在下、ジクロロメタン、クロロホルム、テトラヒドロ
フラン、メタノール、エタノール、酢酸エチルなどの溶
媒中で行われる。This step is based on the formula (rV) obtained by the oxidative cleavage.
This is a step of converting the compound represented by the following into an oxime. The oximation is carried out using hydroxylamine or its hydrochloride in the presence or absence of a base such as pyridine or sodium acetate in a solvent such as dichloromethane, chloroform, tetrahydrofuran, methanol, ethanol, or ethyl acetate.
この反応では、E体及び2体の2種の幾何異性体か得ら
れるが、これらは容易に分離可能であり、副生成物であ
る2体は酸処理によりE体へと異性化される。In this reaction, two geometric isomers, E-form and 2-isomer, are obtained, but these can be easily separated, and the 2-isomer, which is a by-product, is isomerized to E-form by acid treatment.
工l(む
この工程は、前記オキシム化によって得られた式(V)
で表される化合物をベックマン転位反応に付す工程であ
る。Step 1 (This step is to convert the formula (V) obtained by the oxime formation into
This is a step in which a compound represented by is subjected to a Beckmann rearrangement reaction.
反応剤として、オキシ塩化リン、塩化チオニル、五塩化
リン、五酸化リン、硫酸などを用い、ジクロロメタン、
クロロホルム、ベンゼンなどの不活性溶媒中、又はピリ
ジン、トリエチルアミン等の有機アミン中で該ベックマ
ン転位反応を行うことができる。As a reactant, phosphorus oxychloride, thionyl chloride, phosphorus pentachloride, phosphorus pentoxide, sulfuric acid, etc. are used, and dichloromethane,
The Beckmann rearrangement reaction can be carried out in an inert solvent such as chloroform or benzene, or in an organic amine such as pyridine or triethylamine.
二1勤と」
この工程は、前記ベックマン転位によって得られた式(
VI)で表される化合物のヒドロキシル保護基を脱保護
する工程である。該脱保護に当たっては、当分野で通常
利用される各種の脱保護反応か用いられるが、たとえば
脱ベンジル化には、パラジウムなどを触媒とする接触水
素化の利用が好適である。This step is based on the formula (
This is a step of deprotecting the hydroxyl protecting group of the compound represented by VI). For the deprotection, various deprotection reactions commonly used in the art may be used; for example, for debenzylation, catalytic hydrogenation using palladium or the like as a catalyst is preferably used.
二程山山二貝
この工程は、前記脱保護によって得られた式(■)で表
される化合物のヒドロキシル基を酸化する工程である。This step is a step of oxidizing the hydroxyl group of the compound represented by formula (■) obtained by the deprotection.
該酸化反応に当たっては、酸化剤としてジョーンズ試薬
、ピリジニウムジクロメート、ピリジニウムクロロクロ
メート、四酸化ルテニウム及び酸素を使用することがで
き、溶媒としては、ジメチルホルムアミド、アセトン、
ジクロロメタン、四塩化炭素、水又はこれらの混合物を
用いることができる。In the oxidation reaction, Jones reagent, pyridinium dichromate, pyridinium chlorochromate, ruthenium tetroxide, and oxygen can be used as the oxidizing agent, and as the solvent, dimethylformamide, acetone,
Dichloromethane, carbon tetrachloride, water or mixtures thereof can be used.
本発明によれば、上述の一連の反応を経て、1β−メチ
ルチェナマイシンの有用な合成中間体である式(I)で
表されるピラン誘導体を立体選択的に合成することがで
きる。According to the present invention, the pyran derivative represented by formula (I), which is a useful synthetic intermediate for 1β-methylchenamycin, can be stereoselectively synthesized through the series of reactions described above.
なお、本発明の製法において使用する出発原料の式(n
)で表される化合物は新規な物質であるが、下記に示す
反応スキームに従い、
公知のシクロペ
ンタン誘導体から容易に合成される。In addition, the formula (n
Although the compound represented by ) is a new substance, it can be easily synthesized from known cyclopentane derivatives according to the reaction scheme shown below.
反迩と乙]tニム 次に、 本発明をさらに詳細に説明するため、 好 適な1具体例である実施例を示すが、 本発明はこ れに限定されない。t-nim next, To explain the invention in more detail, good An example, which is a suitable specific example, is shown below. The present invention is but not limited to.
実施例
キソ
2H−ピラン
3−カルボン
■
のA
成
下記の合成スキームに従い、(4R95R,6R)−5
−ベンジルオキシメチル−3,4,5,6−テトラヒド
ロ−6−メチル−4−(1−メチルエチニル)−2H−
ピラン−2−オン(1)を原料として、所望のピラン化
合物(I)を合成した。Example A synthesis of xo-2H-pyran-3-carvone (4R95R,6R)-5 according to the synthesis scheme below.
-benzyloxymethyl-3,4,5,6-tetrahydro-6-methyl-4-(1-methylethynyl)-2H-
A desired pyran compound (I) was synthesized using pyran-2-one (1) as a raw material.
(1)
(2)
(3)
(4b)
(5)
(6)
(+)
1 3R4S 5R5R−5−ベンジルオキシメチリ
チウム イソプロピルシクロへキシルアミド(115ミ
リモル)のテトラヒドロフラン溶液180 mQに、=
78℃にて、(4R,5R,6R)−5−ベンジルオキ
シメチル−3,4,5,6−テトラヒドロ−6−メチル
−4−(1−メチルエチニル)−2H−ピラン−2−オ
ン(1)6.35g(23ミリモル)のテトラヒドロフ
ラン溶液40−を滴加し、−20℃にて1時間攪拌した
。再び一78℃に冷却し、ヨウ化メチル16.3 g(
115ミリモル)を加え、1時間攪拌した後、酢酸8.
3 gを滴加した。反応液に飽和食塩水を加え、酢酸エ
チルにて抽出し、抽出液を飽和食塩水で洗浄後、硫酸ナ
トリウムにて乾燥し、溶媒を留去した。残留物をシリカ
ゲルカラムクロマトグラフィーに付し、ヘキサン−酢酸
エチル流分より化合物(2)2.1 g (31,5%
)を得た。その後、同じ展開溶媒でさらに溶出すること
により、原料化合物(1)4.07g(64,1%)を
回収した。(1) (2) (3) (4b) (5) (6) (+) 1 3R4S 5R5R-5-Benzyloxymethylithium A solution of isopropylcyclohexylamide (115 mmol) in tetrahydrofuran (180 mQ) =
At 78°C, (4R,5R,6R)-5-benzyloxymethyl-3,4,5,6-tetrahydro-6-methyl-4-(1-methylethynyl)-2H-pyran-2-one ( 1) 6.35 g (23 mmol) of tetrahydrofuran solution 40- was added dropwise and stirred at -20°C for 1 hour. Cool again to -78°C and add 16.3 g of methyl iodide (
After stirring for 1 hour, 8.5 mmol of acetic acid was added.
3 g was added dropwise. Saturated brine was added to the reaction solution, extracted with ethyl acetate, the extract was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and 2.1 g (31.5%) of compound (2) was obtained from the hexane-ethyl acetate fraction.
) was obtained. Thereafter, 4.07 g (64.1%) of starting compound (1) was recovered by further elution with the same developing solvent.
得られた化合物(2)の各物理データは次のとおりであ
る。The physical data of the obtained compound (2) are as follows.
MSスペクトル(C+Jt40a):
理論値(m/z) 288.1725実測値(m/z
) 288.1725NMRスペクトル(CDCQ
a 、 270MHz) 61.22(3H,d、J=
6.7Hz)、1.40(3H,d、J=6.1Hz)
1.63(3H,s)1.67(IHdddd J=
2.4Hz 3.7Hz9.8Hz、9.8Hz)、
2.41(LH,dq、J=11.0Hz、6.7Hz
)2.49(LH,dd、J=11.0Hz、9.8H
z)、3.38(IH,ddJ=3.7Hz、9.8H
z)、3.48(IH,dd、J=2.4Hz、9.8
Hz)4.37(IH,d、J=11.6Hz)、4.
45(IH,d、J=11.6Hz)4.56(IH,
dq、J−9,8Hz、6.1Hz)、4.87(IH
,S)。MS spectrum (C+Jt40a): Theoretical value (m/z) 288.1725 Actual value (m/z
) 288.1725 NMR spectrum (CDCQ
a, 270MHz) 61.22 (3H, d, J=
6.7Hz), 1.40 (3H, d, J=6.1Hz)
1.63 (3H, s) 1.67 (IHdddd J=
2.4Hz 3.7Hz9.8Hz, 9.8Hz),
2.41 (LH, dq, J=11.0Hz, 6.7Hz
) 2.49 (LH, dd, J=11.0Hz, 9.8H
z), 3.38 (IH, ddJ=3.7Hz, 9.8H
z), 3.48 (IH, dd, J=2.4Hz, 9.8
Hz) 4.37 (IH, d, J=11.6Hz), 4.
45 (IH, d, J=11.6Hz) 4.56 (IH,
dq, J-9, 8Hz, 6.1Hz), 4.87 (IH
,S).
4.94(LHlS)、7.26−7.38(5H,m
)36−シメチルー2H−ピラン−2−オン島し狂四1
製
上記工程1)で得られた化合物(2)4.73 g(8
16,4ミリモル)をテトラヒドロフラン100艷に溶
解し、触媒量の四酸化オスミウム及び過ヨウ素ナトリウ
ム7.73gの水溶液100−を加え、室温にて4時間
攪拌した。反応液に水100−を加えた後、酢酸エチル
にて抽出した。抽出液を亜硫酸ナトリウム水溶液及び飽
和食塩水で洗浄後、硫酸ナトリウムにて乾燥し、溶媒を
留去した。残留物をシリカゲルカラムクロマトグラフィ
ーに付し、ヘキサン−酢酸エチル流分より化合物(3)
3.09 g(64,9%)を得た。4.94 (LHlS), 7.26-7.38 (5H, m
) 36-cymethyl-2H-pyran-2-one Shima Shikyoshi 1
4.73 g (8
16.4 mmol) was dissolved in 100 g of tetrahydrofuran, 100 g of an aqueous solution containing catalytic amounts of osmium tetroxide and 7.73 g of sodium periodate were added, and the mixture was stirred at room temperature for 4 hours. After adding 100% of water to the reaction solution, the mixture was extracted with ethyl acetate. The extract was washed with an aqueous sodium sulfite solution and saturated brine, dried over sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and compound (3) was obtained from the hexane-ethyl acetate stream.
3.09 g (64.9%) was obtained.
MSスペクトル(C+vH2204) :理論値(m/
z) 290.1518実測値(m/z) 29
0.1523NMRスペクトル(CDCQ、、 270
MHz)δ:1.22(3H,d、J=6.7Hz)、
1.35(3H,d、J=62.01(LH,dddd
、J=3.7Hz、4.3Hz、9.8Hz7Hz)
10.4Hz)
OHz 6.7Hz)
3.39(LHldd
J=4.3Hz 10.4
48(IH,d、J=11゜
7Hz)、7.27
2.19(3H,s)、2.73(LH,dq、J=1
12.98(IH,dd、J=11.0Hz、lO,4
Hz)J=3.7Hz、10.4Hz)、3.44(L
H,ddHz)、4.41(IHld、J−11,6H
2)、46Hz)、4.49(IH,dq、J=9.8
Hz、67.40(58m)
上記工程2)で得られた化合物(3)56.8mg(0
,2ミリモル)、ピリジン217■(027ミリモル)
及び塩酸ヒドロキシルアミン16.3■(0,24ミリ
モル)をメタノール2mlに溶解し、室温にて2時間攪
拌した。反応液に水10−を加えた後、酢酸エチルにて
抽出した。抽出液を飽和食塩水で洗浄後、硫酸ナトリウ
ムにて乾燥し、溶媒を留去した。残留物をシリカゲルク
ロマトグラフィーに付し、ヘキサン酢酸エチル流分より
化合物(4a)36.5■(592%)を得、その後、
同じ展開溶媒でさらに溶出することにより、化合物(4
bH6,4■(266%)を得た。MS spectrum (C+vH2204): Theoretical value (m/
z) 290.1518 Actual measurement value (m/z) 29
0.1523 NMR spectrum (CDCQ, 270
MHz) δ: 1.22 (3H, d, J = 6.7Hz),
1.35 (3H, d, J = 62.01 (LH, dddd
, J=3.7Hz, 4.3Hz, 9.8Hz7Hz) 10.4Hz) OHz 6.7Hz) 3.39 (LHldd J=4.3Hz 10.4 48 (IH, d, J=11°7Hz), 7.27 2.19 (3H, s), 2.73 (LH, dq, J=1
12.98 (IH, dd, J=11.0Hz, lO, 4
Hz) J=3.7Hz, 10.4Hz), 3.44(L
H, ddHz), 4.41 (IHld, J-11, 6H
2), 46Hz), 4.49 (IH, dq, J=9.8
Hz, 67.40 (58 m) Compound (3) obtained in the above step 2) 56.8 mg (0
, 2 mmol), pyridine 217■ (027 mmol)
and 16.3 μm (0.24 mmol) of hydroxylamine hydrochloride were dissolved in 2 ml of methanol and stirred at room temperature for 2 hours. After adding 10-liters of water to the reaction solution, the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel chromatography to obtain 36.5 μm (592%) of compound (4a) from the hexane-ethyl acetate fraction;
By further elution with the same developing solvent, compound (4
bH6,4■ (266%) was obtained.
MSスペクトル(CI7H2JO4):理論値(m/z
) 305.1626実測値(m/Z) 3051
63O
NMRスペクトル(CDCQ s 、 270MHz)
δ:1.25(3H,d、J=6.7Hz)、1.38
(3H,d、J=6.7Hz)。MS spectrum (CI7H2JO4): Theoretical value (m/z
) 305.1626 Actual value (m/Z) 3051
63O NMR spectrum (CDCQs, 270MHz)
δ: 1.25 (3H, d, J=6.7Hz), 1.38
(3H, d, J=6.7Hz).
1.84(3H,s) 、2.58(IH,dq、J=
11.6Hz、6.7Hz)2.69(IH,dd、J
=11.6Hz、10.4Hz)、3.33(LH,d
d。1.84 (3H, s), 2.58 (IH, dq, J=
11.6Hz, 6.7Hz) 2.69 (IH, dd, J
=11.6Hz, 10.4Hz), 3.33(LH, d
d.
J=3.1Hz、9.8Hz)、3.45(IH,dd
、J=3.1Hz 9.8Hz)4.34(IH,d
、J=11.6Hz)、4.44(IH,d、J=11
.6Hz)4.53(IH,dq、J=9.8Hz、6
.1Hz)、7.26−7.37(5H。J=3.1Hz, 9.8Hz), 3.45(IH, dd
, J=3.1Hz 9.8Hz)4.34(IH,d
, J=11.6Hz), 4.44(IH,d, J=11
.. 6Hz) 4.53 (IH, dq, J=9.8Hz, 6
.. 1Hz), 7.26-7.37 (5H.
m)、8.81(LH,br s)
一一一一
MSスペクトル(C+JtsNOt) :理論値(m/
z) 305.1626実測値(m/ z) 30
5.1621NMRスヘク) ル(CDCQ s 、
270MHz)δ:1.28(3H,dj=7.3Hz
)、1.39(3H,d、J=6.1Hz)。m), 8.81 (LH, br s) 1111 MS spectrum (C+JtsNOt): Theoretical value (m/
z) 305.1626 Actual measurement value (m/z) 30
5.1621 NMR spectrum (CDCQ s,
270MHz) δ: 1.28 (3H, dj=7.3Hz
), 1.39 (3H, d, J=6.1Hz).
1.83(3H,s)、2.12−2.20(IH,m
)、2.81−2.87(IHm)3.36(IH,d
d、J=3.7Hz、10.4Hz) 、3.41(I
H,m)3.49(IH,dd、J=3.1Hz、10
.4Hz)、4J8(IH,d、J=11.6Hz)、
4.47(IH,d、J=11.6Hz)、4.53(
IH,dqJ=9.8Hz 6.1Hz)、7.25
−7.37(5H,m)、9.16(IHbr s)
次に、得られた化合物(4b)を化合物(4a)に異性
化した。すなわち、化合物(4bH33■(0,44ミ
リモル)をエーテル2mlに溶解し、p−トルエンスル
ホン酸100■(053ミリモル)を加え、室温にて2
時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液
を加え、10分間攪拌した後、酢酸エチルにて抽出した
。抽出液を飽和食塩水で洗浄後、硫酸ナトリウムにて乾
燥し、溶媒を留去した。残留物をシリカゲルクロマトグ
ラフィーに付し、ヘキサン−酢酸エチル流分より化合物
(4a)97■(732%)を得、その後、同じ展開溶
媒でさらに溶出することにより、原料化合物(4b)2
7■(205%)を回収した。1.83 (3H, s), 2.12-2.20 (IH, m
), 2.81-2.87 (IHm) 3.36 (IH, d
d, J=3.7Hz, 10.4Hz), 3.41(I
H, m) 3.49 (IH, dd, J=3.1Hz, 10
.. 4Hz), 4J8 (IH, d, J=11.6Hz),
4.47 (IH, d, J = 11.6Hz), 4.53 (
IH, dqJ=9.8Hz 6.1Hz), 7.25
-7.37 (5H, m), 9.16 (IHbr s) Next, the obtained compound (4b) was isomerized to compound (4a). That is, the compound (4bH33) (0.44 mmol) was dissolved in 2 ml of ether, 100 μ (0.53 mmol) of p-toluenesulfonic acid was added, and 2
Stir for hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, stirred for 10 minutes, and then extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel chromatography to obtain 97 mm (732%) of compound (4a) from the hexane-ethyl acetate fraction, and then further elution with the same developing solvent yielded starting compound (4b) 2.
7■ (205%) was recovered.
上記工程3)で得られた化合物(4a)100■(03
3ミリモル)をピリジン1mlに溶解し、冷却下にオキ
シ塩化リン100■(0,66ミリモル)を滴加し、0
℃にて1時間攪拌した。反応液に水10mQを加え、1
時間攪拌した後、酢酸エチルにて抽出した。抽出液を飽
和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄後、
硫酸ナトリウムにて乾燥し、溶媒を留去した。残留物を
シリカゲルクロマトグラフィーに付し、ヘキサン−酢酸
エチル流分より化合物(5)82■(820%)を得た
。Compound (4a) obtained in the above step 3) 100■ (03
3 mmol) was dissolved in 1 ml of pyridine, and 100 mmol of phosphorus oxychloride (0.66 mmol) was added dropwise under cooling.
The mixture was stirred at ℃ for 1 hour. Add 10 mQ of water to the reaction solution,
After stirring for an hour, the mixture was extracted with ethyl acetate. After washing the extract with saturated aqueous sodium hydrogen carbonate solution and saturated saline,
It was dried over sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel chromatography, and 82 cm (820%) of compound (5) was obtained from the hexane-ethyl acetate fraction.
mp: 122℃
5
[α コ : −28° (c= 2.897.
CHCf:i 、ン上記工程4)で得られた化合物(
5)195■(0,64ミリモル)をエタノール2−に
溶解し、2N−塩酸4滴及び10%パラジウム−炭素5
0■を加え、水素雰囲気下室温にて1時間攪拌した。反
応液を濾過し、濾液の溶媒を留去した。残留物をシリカ
ゲルクロマトグラフィーに付し、酢酸エチル−メタノー
ル流分より化合物(6)137■(100%)を得た。mp: 122°C 5 [α co: -28° (c=2.897.
CHCf:i, the compound obtained in step 4) above (
5) Dissolve 195μ (0.64 mmol) in ethanol 2-4 drops of 2N-hydrochloric acid and 10% palladium-carbon 5
The mixture was stirred for 1 hour at room temperature under a hydrogen atmosphere. The reaction solution was filtered, and the solvent of the filtrate was distilled off. The residue was subjected to silica gel chromatography, and 137 μm (100%) of compound (6) was obtained from the ethyl acetate-methanol fraction.
mp: 179−180℃
5
[α] : +57.3°(c= 0.968. C
HCQ s)上記工程5)で得られた化合物(6)50
0mg(2,33ミリモル)をジメチルホルムアミド6
mlに溶解し、ピリジミウムジクロメート3 g(7,
97ミリモル)を加え、室温にて12時間攪拌した。反
応液をシリカゲルクロマトグラフィーに付し、酢酸エチ
ル−メタノール−酢酸流分より粗化合物(1)を得、再
びシリカゲルクロマトグラフィーに付し、クロロホルム
−メタノール−酢酸流分より所望の化合物(I)391
■(73,5%)を得た。mp: 179-180℃ 5 [α]: +57.3° (c=0.968.C
HCQ s) Compound (6) obtained in the above step 5) 50
0 mg (2.33 mmol) in dimethylformamide 6
3 g of pyridimium dichromate (7,
97 mmol) and stirred at room temperature for 12 hours. The reaction solution was subjected to silica gel chromatography, and the crude compound (1) was obtained from the ethyl acetate-methanol-acetic acid stream, and the crude compound (1) was obtained from the ethyl acetate-methanol-acetic acid stream, and the desired compound (I) 391 was again subjected to silica gel chromatography, and the desired compound (I) 391 was obtained from the chloroform-methanol-acetic acid stream.
■ (73.5%) was obtained.
mp: 193℃
5
[α] : +27.9° (c=1994.E
tOH)MSスペクトル(C+。HI6NO11)理論
値(m/ z) 229.0949実測値(m/ z
) 229.0948NMRスペクトル(CDCQs
、 270MHz)δ1.34(3H,d、J=6.7
Hz)、1.42(3H,d、J=6.1Hz)1.9
6(3H,s)、2.52(IHldq、J=11.1
Hz、6.7Hz)2.60(IHdd、J=11.0
Hz、10.4Hz)、4.28(LH,dd各々J=
11.0Hz) 、4.58(IH,dq、J=10.
4Hz、6.1Hz)さらに、本発明による化合物(I
)が1β−メチルチェナマイシン類の合成に有用である
ことを証明するため、上述の実施例で得られた化合物(
I)を使用し、文献(「テトラヘドロン・レターズ」1
987 28、83)に記載の方法に従って操作を行い
、化合物(7)へと導いた。mp: 193℃ 5 [α]: +27.9° (c=1994.E
tOH) MS spectrum (C+.HI6NO11) Theoretical value (m/z) 229.0949 Actual value (m/z
) 229.0948NMR spectrum (CDCQs
, 270MHz) δ1.34 (3H, d, J=6.7
Hz), 1.42 (3H, d, J=6.1Hz) 1.9
6 (3H, s), 2.52 (IHldq, J=11.1
Hz, 6.7Hz) 2.60 (IHdd, J=11.0
Hz, 10.4Hz), 4.28 (LH, dd each J=
11.0Hz), 4.58 (IH, dq, J=10.
4Hz, 6.1Hz) Furthermore, the compound according to the invention (I
) is useful for the synthesis of 1β-methylchenamycins, the compound (
I), and the literature ("Tetrahedron Letters" 1
987 28, 83), and compound (7) was obtained.
(1)
(7)
得られた化合物(7)の各種スペクトルデータは文献(
[ヘテロサイクルズJ 1984.21.29)記載の
値と一致し、比施光度及び融点も一致した。(1) (7) Various spectral data of the obtained compound (7) can be found in the literature (
The values were consistent with those described in [Heterocycles J 1984.21.29), and the specific light absorption and melting point were also consistent.
mp: 118−121℃(文献値120−121°C
)参考例
本発明による製法で使用する化合物(1)については、
下記の合成スキームに従って合成した。mp: 118-121°C (Literature value 120-121°C
) Reference Example Regarding compound (1) used in the production method according to the present invention,
It was synthesized according to the following synthesis scheme.
念或困土二L
(8)
(9)
(1θ)
(11)
(1)
文献(「ヘテロサイクルズJ 1987.26.149
1)記載の(2R/S、 3S、 4R)−3−ヒドロ
キシメチル−2メチル−4−(1−メチルエチニル)シ
クロペンタノンエチレンアセタール(8)18.8g(
88ミリモル)をジメチルホルムアミド360m1に溶
解し、冷却下で60%水素化ナトリウム8.9 g (
220ミリモル)を徐々に加え、30分間攪拌後、ベン
ジルプロミド30g(175ミリモル)を滴加した。さ
らに3時間室温にて攪拌後、氷水を加え、ベンゼンにて
抽出した。(8) (9) (1θ) (11) (1) Literature (Heterocycles J 1987.26.149
18.8 g of (2R/S, 3S, 4R)-3-hydroxymethyl-2methyl-4-(1-methylethynyl)cyclopentanone ethylene acetal (8) described in 1) (
88 mmol) in 360 ml of dimethylformamide and, under cooling, 8.9 g of 60% sodium hydride (
After stirring for 30 minutes, 30 g (175 mmol) of benzyl bromide was added dropwise. After further stirring at room temperature for 3 hours, ice water was added, and the mixture was extracted with benzene.
抽出液を飽和食塩水で洗浄後、硫酸ナトリウムにて乾燥
し、溶媒を留去した。残留物をシリカゲルクロマトグラ
フィーに付し、ヘキサン−酢酸エチル流分より化合物(
9)240g(89,6%)を得た。The extract was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel chromatography, and the compound (
9) Obtained 240g (89.6%).
MSスペクトル(C+JsgOs)
理論値 302.1883
実測値 302.1883
NMRスペクトル(CDCQ s 、 270MHz)
δ0.99(3Hd、J=7.3Hz)、1.67(3
Hs)、1.73(IH,m)1.76(IH,dd、
J=10.4Hz、13.4Hz)、1.95(LH,
dd。MS spectrum (C+JsgOs) Theoretical value 302.1883 Actual value 302.1883 NMR spectrum (CDCQ s, 270MHz)
δ0.99 (3Hd, J=7.3Hz), 1.67 (3
Hs), 1.73 (IH, m) 1.76 (IH, dd,
J=10.4Hz, 13.4Hz), 1.95(LH,
dd.
J=9.2Hz、13.4Hz)、2.05(IH,d
q、J=9.8Hz、6.7Hz)、2.53(LH,
ddd、J=9.2Hz、9.8Hz、10.4Hz)
3.40(IH,dd、J=5
5Hz、9.8Hz)
3.47(IH,dd
J=
3.7Hz 5.5Hz)、3
78−3.94(4H1m)、4.48(2H5)
4.73(2H,s)、7.21−7.36(5H,m
)上記工程1)で得られた化合物(9)24 g(79
ミリモル)をアセトンIQに溶解し、p−トルエンスル
ホン酸750■(39ミリモル)を加え、室温にて12
時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液
を加えた後、アセトンを留去し、酢酸エチルにて抽出し
た。抽出液を硫酸ナトリウムにて乾燥後、溶媒を留去し
、残留物をシリカゲルカラムクロマトグラフィーに付し
、ヘキサン−酢酸エチル流分より化合物(10)19.
5 g(95,1%)を得た。J=9.2Hz, 13.4Hz), 2.05(IH, d
q, J=9.8Hz, 6.7Hz), 2.53(LH,
ddd, J=9.2Hz, 9.8Hz, 10.4Hz)
3.40 (IH, dd, J = 5 5Hz, 9.8Hz) 3.47 (IH, dd J = 3.7Hz 5.5Hz), 3 78-3.94 (4H1m), 4.48 (2H5) 4.73 (2H, s), 7.21-7.36 (5H, m
) Compound (9) obtained in step 1) 24 g (79
mmol) was dissolved in acetone IQ, 750 μm (39 mmol) of p-toluenesulfonic acid was added, and the solution was dissolved at room temperature for 12 mmol.
Stir for hours. After adding a saturated aqueous sodium hydrogen carbonate solution to the reaction solution, acetone was distilled off, and the mixture was extracted with ethyl acetate. After drying the extract over sodium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography to obtain compound (10) 19. from the hexane-ethyl acetate fraction.
5 g (95.1%) were obtained.
MSスペクトル(C+7H2202) :理論値(m/
z) 258.1620実測値(m/z) 258
.1620NMRスペクトル(CDCclg 、 27
0MHz) 61.10(3H,d、J=6.7Hz)
、1.68(3H,s)、1.81(IH,m)2.1
1(LH,dd、J=11.6Hz、18.3Hz)、
2.28(LH,dqJ=11.6Hz、6.7Hz)
、2.44(IH,dd、J=18.3Hz、7.9H
z)、2.80(LH,ddd、J=11.6Hz、1
1.6Hz、7.9Hz)3.47−3.58(2H,
m)、4.49(2H,s)、4.82(2H,s)。MS spectrum (C+7H2202): Theoretical value (m/
z) 258.1620 Actual measurement value (m/z) 258
.. 1620 NMR spectrum (CDCclg, 27
0MHz) 61.10 (3H, d, J=6.7Hz)
, 1.68 (3H, s), 1.81 (IH, m) 2.1
1 (LH, dd, J=11.6Hz, 18.3Hz),
2.28 (LH, dqJ=11.6Hz, 6.7Hz)
, 2.44 (IH, dd, J=18.3Hz, 7.9H
z), 2.80 (LH, ddd, J=11.6Hz, 1
1.6Hz, 7.9Hz) 3.47-3.58 (2H,
m), 4.49 (2H, s), 4.82 (2H, s).
7.22−7.35(5H,m)
上記工程2)で得られた化合物(10)225■(08
7ミリモル)をジクロロメタン16−に溶解し、炭酸水
素カリウム870■(87ミリモル)及びm−クロロ過
安息香酸750■(4,35ミリモル)を加え、室温に
て3時間攪拌後、氷水下でジメチルスルフィド540m
g(8,7ミリモル)を加えた。さらに6時間攪拌後、
固形物を濾去し、濾液の溶媒を留去した。残留物をシリ
カゲルカラムクロマトグラフィーに付し、ヘキサン−酢
酸エチル流分より化合物(11)247■(97,5%
)を得た。7.22-7.35 (5H, m) Compound (10) obtained in the above step 2) 225■ (08
7 mmol) in dichloromethane, 870 μm (87 mmol) of potassium hydrogen carbonate and 750 μm (4.35 mmol) of m-chloroperbenzoic acid were added, and after stirring at room temperature for 3 hours, dimethyl chloride was dissolved under ice water. sulfide 540m
g (8.7 mmol) was added. After stirring for another 6 hours,
The solid matter was filtered off, and the solvent of the filtrate was distilled off. The residue was subjected to silica gel column chromatography, and from the hexane-ethyl acetate fraction, compound (11) 247μ (97.5%) was obtained.
) was obtained.
MSスペクトル(C0JtxOh)
理論値(m/Z) 290.1519実測値(m/z
) 290.1519NMRスペクトル(CDCQ
s 、 270MHz)δ125及び127(計3H,
各々s)、1.36及び1.38(計3H1各々d 、
J=6 、1HzとJ=6.7Hz)、1.53及び
180(計IH,各々m)、2.07及び217(計I
H,各々m)244及び2.57(計IH,各々dd、
J=3.7Hz、16.5HzとJ=16.5Hz 4
.3Hz) 2.53−2.57(2H,m)、2.6
8及び274(計LH,各々dd、各々J=6 、5H
z 、 16 、5Hz)347及び360(計IH,
各々dd、J=3.1Hz、9.8HzとJ=3.7H
z、9.8Hz)、3.53及び3.65(計IH,各
々dd、各々J=3.1Hz、9.8Hz) 、4.3
6−4.55(3H,m)7.27−7.39(5H,
m)
4”1 の−1
酢酸ナトリウム1.87g(22,8ミリモル)、ヨウ
化ナトリウム1.8g(12ミリモル)及び亜鉛末1.
8g(27,5ミリモル)を酢酸8 mQに懸濁させ、
上記工程3)で得られた化合物(11)0.8g(2,
フロミリモル)の酢酸溶液3 mQを滴加し、10分間
攪拌後、反応液にヘンゼンを加え、濾過した。濾液を飽
和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄後、
硫酸ナトリウムにて乾燥し、溶媒を留去した。残留物を
シリカゲルカラムクロマトグラフィーに付し、ヘキサン
−酢酸エチル流分より、所望の化合物(1)455■(
60,2%)を得た。MS spectrum (C0JtxOh) Theoretical value (m/Z) 290.1519 Actual value (m/z
) 290.1519NMR spectrum (CDCQ
s, 270MHz) δ125 and 127 (total 3H,
s), 1.36 and 1.38 (total 3H1 d each,
J = 6, 1 Hz and J = 6.7 Hz), 1.53 and 180 (total IH, each m), 2.07 and 217 (total I
H, each m) 244 and 2.57 (total IH, each dd,
J=3.7Hz, 16.5Hz and J=16.5Hz 4
.. 3Hz) 2.53-2.57 (2H, m), 2.6
8 and 274 (total LH, each dd, each J = 6, 5H
z, 16, 5Hz) 347 and 360 (total IH,
dd, J=3.1Hz, 9.8Hz and J=3.7H respectively
z, 9.8Hz), 3.53 and 3.65 (total IH, each dd, respectively J = 3.1Hz, 9.8Hz), 4.3
6-4.55 (3H, m) 7.27-7.39 (5H,
m) 4"1 of -1 1.87 g (22.8 mmol) of sodium acetate, 1.8 g (12 mmol) of sodium iodide and 1.
8 g (27.5 mmol) were suspended in 8 mQ acetic acid,
Compound (11) obtained in step 3) 0.8g (2,
3 mQ of an acetic acid solution of (fromimole) was added dropwise, and after stirring for 10 minutes, Hensen's solution was added to the reaction solution and filtered. After washing the filtrate with saturated aqueous sodium hydrogen carbonate solution and saturated saline,
It was dried over sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and from the hexane-ethyl acetate fraction, the desired compound (1) was obtained at 455 μl (
60.2%) was obtained.
MSスペクトル(C+、H220m)
理論値(m/ z) 274.1570実測値(m/
z) 274.1573NMRスペクトル(CDC1
2m、 27(1MHz)δ1.39(3H,d、J=
6.1Hz)、1.60(IH,ddd J=3.1
Hz3.1Hz、9.8Hz、9.8Hz)、1.66
(3H,s)、2.44(IHdd、J=6.7Hz、
16.5Hz)、2.70(IH,dd、J=7.9H
z17.1Hz)、2.87(IH,ddd、J=6.
7Hz、7.9Hz、9.8Hz)3.43(IH,d
d、J=3.1Hz、9.2Hz)、3.51(IH,
dd、J3.1Hz、9.2Hz)、4.45(2H,
s)、4.47(IH,dq、J9.8Hz 6.1
Hz)4.76(LH,s)、4.80(IH,s)、
7.26−7.39(51(、m)
以上述べたように、本発明による方法では、安価なO−
カルボンより容易に調製でき、しかも1β−メチルチェ
ナマイシン類に必要な立体配置を有するシクロペンタン
誘導体を用いて、1β−メチルチェナマイシン類の合成
に重要な中間体であるビラン誘導体を立体選択的かつ効
率的に合成できる。MS spectrum (C+, H220m) Theoretical value (m/z) 274.1570 Actual value (m/z)
z) 274.1573 NMR spectrum (CDC1
2m, 27 (1MHz) δ1.39 (3H, d, J=
6.1Hz), 1.60 (IH, ddd J=3.1
Hz3.1Hz, 9.8Hz, 9.8Hz), 1.66
(3H,s), 2.44(IHdd, J=6.7Hz,
16.5Hz), 2.70 (IH, dd, J=7.9H
z17.1Hz), 2.87 (IH, ddd, J=6.
7Hz, 7.9Hz, 9.8Hz) 3.43 (IH, d
d, J=3.1Hz, 9.2Hz), 3.51(IH,
dd, J3.1Hz, 9.2Hz), 4.45 (2H,
s), 4.47 (IH, dq, J9.8Hz 6.1
Hz) 4.76 (LH, s), 4.80 (IH, s),
7.26-7.39 (51(, m) As stated above, the method according to the present invention uses inexpensive O-
Bilane derivatives, which are important intermediates for the synthesis of 1β-methylchenamycins, can be synthesized stereoselectively and using a cyclopentane derivative that can be easily prepared from carvone and has the stereochemistry required for 1β-methylchenamycins. Can be synthesized efficiently.
Claims (1)
I) ▲数式、化学式、表等があります▼ で表される化合物をメチル化し、(b)得られた式(I
II) ▲数式、化学式、表等があります▼ で表される化合物を酸化開裂し、(c)得られた式(I
V) ▲数式、化学式、表等があります▼ で表される化合物をオキシム化し、(d)得られた式(
V) ▲数式、化学式、表等があります▼ で表される化合物をベックマン転位反応に付し、(e)
得られた式(VI) ▲数式、化学式、表等があります▼ で表される化合物のヒドロキシル保護基を脱保護した後
、ヒドロキシル基を酸化することを特徴とする、ピラン
誘導体の製法。[Claims] In the method for producing a pyran derivative represented by formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼, (a) formula (I
I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Methylate the compound represented by (b) The resulting formula (I
II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Oxidative cleavage of the compound represented by (c) The obtained formula (I
V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ The compound represented by is converted into an oxime, and (d) the resulting formula (
V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Subjecting the compound represented by Beckmann rearrangement reaction, (e)
A method for producing a pyran derivative, which is characterized by deprotecting the hydroxyl protecting group of a compound represented by the obtained formula (VI) ▲Mathical formula, chemical formula, table, etc.▼ and then oxidizing the hydroxyl group.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2041327A JPH03246290A (en) | 1990-02-23 | 1990-02-23 | Production of pyrane derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2041327A JPH03246290A (en) | 1990-02-23 | 1990-02-23 | Production of pyrane derivative |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH03246290A true JPH03246290A (en) | 1991-11-01 |
Family
ID=12605426
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2041327A Pending JPH03246290A (en) | 1990-02-23 | 1990-02-23 | Production of pyrane derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH03246290A (en) |
-
1990
- 1990-02-23 JP JP2041327A patent/JPH03246290A/en active Pending
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