EP2129679A2 - Procédé de préparation d'halogénures d'adamantylarylmagnésium substitués - Google Patents
Procédé de préparation d'halogénures d'adamantylarylmagnésium substituésInfo
- Publication number
- EP2129679A2 EP2129679A2 EP07858234A EP07858234A EP2129679A2 EP 2129679 A2 EP2129679 A2 EP 2129679A2 EP 07858234 A EP07858234 A EP 07858234A EP 07858234 A EP07858234 A EP 07858234A EP 2129679 A2 EP2129679 A2 EP 2129679A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- substituted
- reaction
- adamantylarylhalide
- adamantyl
- adamantylarylmagnesium
- 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.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 27
- 150000004820 halides Chemical class 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 40
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims abstract description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 20
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 62
- 239000011777 magnesium Substances 0.000 claims description 12
- 229910052749 magnesium Inorganic materials 0.000 claims description 10
- -1 tetrafluoroborate Chemical compound 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- 229910003002 lithium salt Inorganic materials 0.000 claims 5
- 159000000002 lithium salts Chemical class 0.000 claims 5
- 125000000217 alkyl group Chemical group 0.000 claims 3
- 239000012442 inert solvent Substances 0.000 claims 3
- 125000003342 alkenyl group Chemical group 0.000 claims 2
- 125000000304 alkynyl group Chemical group 0.000 claims 2
- 125000001072 heteroaryl group Chemical group 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- 238000003747 Grignard reaction Methods 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
- 125000003670 adamantan-2-yl group Chemical group [H]C1([H])C(C2([H])[H])([H])C([H])([H])C3([H])C([*])([H])C1([H])C([H])([H])C2([H])C3([H])[H] 0.000 claims 1
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims 1
- 125000005530 alkylenedioxy group Chemical group 0.000 claims 1
- 125000003710 aryl alkyl group Chemical group 0.000 claims 1
- 150000001602 bicycloalkyls Chemical group 0.000 claims 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims 1
- 125000000392 cycloalkenyl group Chemical group 0.000 claims 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims 1
- 125000005842 heteroatom Chemical group 0.000 claims 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims 1
- 229920006395 saturated elastomer Polymers 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 28
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 abstract description 14
- 238000003786 synthesis reaction Methods 0.000 abstract description 14
- 230000015572 biosynthetic process Effects 0.000 abstract description 11
- 239000000047 product Substances 0.000 abstract description 10
- 239000012039 electrophile Substances 0.000 abstract description 9
- 229910052786 argon Inorganic materials 0.000 abstract description 7
- 239000007795 chemical reaction product Substances 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 abstract description 3
- 238000004817 gas chromatography Methods 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- QQAMHHZQONQBFZ-UHFFFAOYSA-N 1-(5-bromo-2-methoxyphenyl)adamantane Chemical compound COC1=CC=C(Br)C=C1C1(C2)CC(C3)CC2CC3C1 QQAMHHZQONQBFZ-UHFFFAOYSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- 239000000758 substrate Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 10
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 229960004132 diethyl ether Drugs 0.000 description 6
- 239000000376 reactant Substances 0.000 description 6
- HYSZKSPAPGPYFQ-UHFFFAOYSA-N 1-(2-methoxyphenyl)adamantane Chemical compound COC1=CC=CC=C1C1(C2)CC(C3)CC2CC3C1 HYSZKSPAPGPYFQ-UHFFFAOYSA-N 0.000 description 5
- STGNTTPGWSZTMO-UHFFFAOYSA-N 1-(5-bromo-2,3-dimethoxyphenyl)adamantane Chemical compound COC1=CC(Br)=CC(C23CC4CC(CC(C4)C2)C3)=C1OC STGNTTPGWSZTMO-UHFFFAOYSA-N 0.000 description 5
- 150000001502 aryl halides Chemical class 0.000 description 5
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- FRPWQGROGLXUPZ-UHFFFAOYSA-N 1-(4-bromo-2-methoxyphenyl)adamantane Chemical compound COC1=CC(Br)=CC=C1C1(C2)CC(C3)CC2CC3C1 FRPWQGROGLXUPZ-UHFFFAOYSA-N 0.000 description 4
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- LZCDAPDGXCYOEH-UHFFFAOYSA-N adapalene Chemical compound C1=C(C(O)=O)C=CC2=CC(C3=CC=C(C(=C3)C34CC5CC(CC(C5)C3)C4)OC)=CC=C21 LZCDAPDGXCYOEH-UHFFFAOYSA-N 0.000 description 4
- 229960002916 adapalene Drugs 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 150000002901 organomagnesium compounds Chemical class 0.000 description 4
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 4
- 230000009257 reactivity Effects 0.000 description 4
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 3
- 208000002874 Acne Vulgaris Diseases 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-ZSJDYOACSA-N Sulfuric acid-d2 Chemical compound [2H]OS(=O)(=O)O[2H] QAOWNCQODCNURD-ZSJDYOACSA-N 0.000 description 3
- 206010000496 acne Diseases 0.000 description 3
- 239000011261 inert gas Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000002734 organomagnesium group Chemical group 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- SETWKWMHYWYXJD-UHFFFAOYSA-N 1-(5-bromo-2-methoxyphenyl)-3,5-dimethyladamantane Chemical compound COC1=CC=C(Br)C=C1C1(C2)CC(C)(C3)CC2(C)CC3C1 SETWKWMHYWYXJD-UHFFFAOYSA-N 0.000 description 2
- LDGIHZJOIQSHPB-UHFFFAOYSA-N CD437 Chemical compound C1C(C2)CC(C3)CC2CC13C1=CC(C2=CC3=CC=C(C=C3C=C2)C(=O)O)=CC=C1O LDGIHZJOIQSHPB-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- HOXDQGKKENOCRK-UHFFFAOYSA-M [Br-].C1C(C2)CC(C3)CC2CC13C1=CC([Mg+])=CC=C1OCC1=CC=CC=C1 Chemical compound [Br-].C1C(C2)CC(C3)CC2CC13C1=CC([Mg+])=CC=C1OCC1=CC=CC=C1 HOXDQGKKENOCRK-UHFFFAOYSA-M 0.000 description 2
- 150000004792 aryl magnesium halides Chemical class 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000007306 functionalization reaction Methods 0.000 description 2
- 125000002524 organometallic group Chemical group 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 2
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 description 1
- VVUPACZQIRRDLY-UHFFFAOYSA-N 1-(2,3-dimethoxyphenyl)adamantane Chemical compound COC1=CC=CC(C23CC4CC(CC(C4)C2)C3)=C1OC VVUPACZQIRRDLY-UHFFFAOYSA-N 0.000 description 1
- INULLDUIYAKZOH-UHFFFAOYSA-N 1-(4-bromo-2-phenylmethoxyphenyl)adamantane Chemical compound C=1C(Br)=CC=C(C23CC4CC(CC(C4)C2)C3)C=1OCC1=CC=CC=C1 INULLDUIYAKZOH-UHFFFAOYSA-N 0.000 description 1
- GVLSPHCBVZUIKP-UHFFFAOYSA-N 1-(5-bromo-2-phenylmethoxyphenyl)adamantane Chemical compound C1C(C2)CC(C3)CC2CC13C1=CC(Br)=CC=C1OCC1=CC=CC=C1 GVLSPHCBVZUIKP-UHFFFAOYSA-N 0.000 description 1
- GJLGGECBUUNDNQ-UHFFFAOYSA-N 2-(4-phenylphenyl)prop-2-enoic acid Chemical class C1=CC(C(=C)C(=O)O)=CC=C1C1=CC=CC=C1 GJLGGECBUUNDNQ-UHFFFAOYSA-N 0.000 description 1
- OYGKAJLOXWVEGP-UHFFFAOYSA-N 4-(1-adamantyl)-6-bromo-1,3-benzodioxole Chemical compound C1C(C2)CC(C3)CC2CC13C1=CC(Br)=CC2=C1OCO2 OYGKAJLOXWVEGP-UHFFFAOYSA-N 0.000 description 1
- UGTJLJZQQFGTJD-UHFFFAOYSA-N Carbonylcyanide-3-chlorophenylhydrazone Chemical compound ClC1=CC=CC(NN=C(C#N)C#N)=C1 UGTJLJZQQFGTJD-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- HHDOELPGMRBQJZ-UHFFFAOYSA-N [2-(1-adamantyl)-5-bromophenoxy]-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OC1=CC(Br)=CC=C1C1(C2)CC(C3)CC2CC3C1 HHDOELPGMRBQJZ-UHFFFAOYSA-N 0.000 description 1
- FPZOBRFHRPQGAA-UHFFFAOYSA-N [3-(1-adamantyl)-4-methoxyphenyl]boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1C1(C2)CC(C3)CC2CC3C1 FPZOBRFHRPQGAA-UHFFFAOYSA-N 0.000 description 1
- YBJABQLZUJNFKS-UHFFFAOYSA-N [3-(1-adamantyl)-4-methoxyphenyl]methanol Chemical compound COC1=CC=C(CO)C=C1C1(C2)CC(C3)CC2CC3C1 YBJABQLZUJNFKS-UHFFFAOYSA-N 0.000 description 1
- UVRUWTVOTRHEDA-UHFFFAOYSA-N [4-(1-adamantyl)-3-methoxyphenyl]boronic acid Chemical compound COC1=CC(B(O)O)=CC=C1C1(C2)CC(C3)CC2CC3C1 UVRUWTVOTRHEDA-UHFFFAOYSA-N 0.000 description 1
- AIYARUNZTVUMQC-UHFFFAOYSA-M [Br-].CC(C)(C)[Si](C)(C)OC1=CC=C([Mg+])C=C1C1(C2)CC(C3)CC2CC3C1 Chemical group [Br-].CC(C)(C)[Si](C)(C)OC1=CC=C([Mg+])C=C1C1(C2)CC(C3)CC2CC3C1 AIYARUNZTVUMQC-UHFFFAOYSA-M 0.000 description 1
- CMFAVTSZPVDNME-UHFFFAOYSA-M [Br-].COC1=CC=C([Mg+])C=C1C1(C2)CC(C3)CC2CC3C1 Chemical compound [Br-].COC1=CC=C([Mg+])C=C1C1(C2)CC(C3)CC2CC3C1 CMFAVTSZPVDNME-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 150000001499 aryl bromides Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000006882 induction of apoptosis Effects 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 150000002602 lanthanoids Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical class OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000000861 pro-apoptotic effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 102000003702 retinoic acid receptors Human genes 0.000 description 1
- 108090000064 retinoic acid receptors Proteins 0.000 description 1
- 150000004492 retinoid derivatives Chemical class 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 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
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/02—Magnesium compounds
Definitions
- the present invention concerns fine organic synthesis, particularly the method for preparing of substituted adamantylarylmagnesium halides.
- Organomagnesium compounds are especially important in contemporary preparative organic chemistry. Since Grignard's discovery in 1900 the methods for preparing and further transformation of these synthetic intermediates are in continuous development and expansion.
- the standard preparative method for preparing organomagnesium compounds (Grignard's reagents) is direct interaction of organic halides with metallic magnesium in an aprotic polar solvent, like tetrahydrofuran (THF) or diethyl ether [C. T. Ho ⁇ e, A. H. HecMeaHOB Me ⁇ o ⁇ bi aneivieHTO - opraHMHecKOM XMMMM. MamnM, ⁇ epunnuM, ⁇ aj ⁇ ibL_,MM, CTPOHUMM, ⁇ apuM. H3fl. AH CCCP M. 1963, 14-27].
- the aim of the present invention is a development of method for preparing substituted adamantylarylmagnesium halides, satisfying the following requirements:
- the compounds produced are active intermediates that can interact with various electrophiles to yield substrates useful for the synthesis of a wide range of biologically active compounds [Charpentier, B.; Bernardon, J.-M.; Eustache, J. et al. Synthesis, structure-affinity relationships, and biological activities of ligands binding to retinoic acid receptor subtypes. J. Med. Chem. 1995, 38 (26), 4993-5006. Cincinelli, R.; Dallavalle, S.; Nannei, R. Synthesis and structure-activity relationships of a new series of retinoid-related biphenyl-4-ylacrylic acids endowed with antiproliferative and proapoptotic activity. J. Med. Chem.
- Adapalene is a pharmaceutical widely used in dermatology as efficient agent for treating acne vulgaris [Waugh, J.; Noble, S.; Scott, L. Spotlight on adapalene in acne vulgaris. J. Am. J. Clin. Dermatol. 2004, 5 (5), 369- 371 ; Jain, S. Topical tretinoin or adapalene in acne vulgaris:
- 3-(1 -Adamantyl)-4-(fe/t-butyldimethylsilyloxy)phenylmagnesium bromide or 3-(1 -adamantyl)-4-benzyloxy- phenylmagnesium bromide can also be used for synthesis of 4-[3-(1 -adamantyl)-4-hydroxyphenyl]-3- chlorocynnamic acid (3-CI-AHPC),
- the reduction of adamantylaryl halide as the main reaction of starting material under the conditions of Grignard's reaction may be the result of the instability of the adamantylarylmagnesium halide or the consequence of low reactivity of the Grignard's reactant with the employed electrophile.
- Grignard's reagent formed from 2-(1- adamantyl)-4-bromoanisole, is an unstable substance and undergoes a formal reduction before interaction with any electrophile.
- the closest prior art to the present invention is the exchange method for preparing organomagnesium reagent [Krasovskiy, A.; Knochel, P. A LiCI-mediated Br/Mg exchange reaction for the preparation of functionalized aryl - and heteroarylmagnesium compounds from organic bromides.
- This method is based on preparing of AIkMgCI-LiCI or AIk 2 Mg-LiCI complexes and their interaction with substituted aryl or heteroaryl halides.
- the present method for preparing substituted adamantyl- arylmagnesium halides is based on assumption that under the standard conditions of organomagnesium synthesis, i.e., acting by aryl halides on magnesium metal, the addition of lithium chloride stabilizes the substituted adamantylarylmagnesium halide by complex formation and prevents further unwanted reactions but does not fatally depress the reactivity of the substituted adamantylarylmagnesium halide.
- Example 1 The method according to the present invention is illustrated by the following examples.
- Example 1 The method according to the present invention is illustrated by the following examples.
- the reaction mixture is decomposed with a solution of 50 ml_ of hydrochloric acid in 50 ml_ water with vigorous stirring without external cooling.
- the mixture is transferred to separating funnel and the water and organic layers separated.
- To the water layer 200 ml_ of water is added and then extracted twice with 10O mL of diethylether.
- the pooled organic solutions are dried on anhydrous sodium sulfate, the solvents removed in vacuo at about 50 0 C in the water bath.
- the residue is treated with 200 ml_ of hexane and left in the freezer overnight.
- the precipitate is filtered off, washed with cold ethyl acetate and dried at 100 0 C. 3-(1 -adamantyl)-4-methoxyphenylboronic acid with m.p.
- the compound was isolated and identified as 2-(1 - adamantyl)anisole.
- the preparative yield is 67%, m.p. 100-102 0 C.
- Example 2 Reaction is performed as described in Example 1.
- adamantylarylhalide 5O g (0.16 M) of 2-(1 -adamantyl)-5-bromoanisole is used.
- 4-(1-adamantyl)-3-methoxyphenylboronic acid, 3 g (6.8%) is obtained.
- the gas chromatography data give the yield 2-(1 - adamantyl)anisole as 81 %.
- the formal reduction product of 2-(1 -adamantyl)-5-bromoanisole was isolated and its identity with 2-(1-adamantyl)anisole obtained in Example 1 confirmed, thus confirming the structure ascribed.
- Example 3 Reaction is performed as described in Example 1.
- adamantylarylhalide 56 g (0.16 M) of 3-(1-adamantyl)-5-bromoveratrol is used.
- 3-(1 -adamantyl)-4,5-methoxyphenylboronic acid 3.7 g (7.3%) is obtained.
- the gas chromatography data give the yield 3-(1 - adamantyl)veratrol as 74%.
- Example 5 Reaction is performed as described in Example 1. Simultaneous addition of arylhalide and 1 ,2-dibromoethane did not change the result.
- reaction mixture according to gas chromatography data contains 70-75% of adamantylbenzene derivative and 3-11 % of the expected arylphenylmethanol
- Grignard's reagent was prepared from 51 g (0.16 M) of 2-(1 - adamantyl)-4-bromoanisole as in Example 1.
- 17 g (16.5 ml_, 0.16 M) of benzaldehyde and 10O mL of dry tetrahydrofuran was introduced, the solution cooled to 0 0 C and under stirring the solution of the Grignard's reagent added within 10 min.
- the mixture was left for 16 h in a refrigerator at about 0 0 C.
- the reaction mixture is decomposed with a solution of 25 ml_ of hydrochloric acid in 25 ml_ of water with vigorous stirring without external cooling.
- the mixture is transferred to separating funnel and the water and organic layers separated, the water layer extracted with 2 portions of 100 ml_ of diethyl ether.
- the pooled organic layers were dried over sodium sulfate.
- Grignard's reagent was prepared from 10 g (0.032 M) of 2-(1 - adamantyl)-4-bromoanisole as in Example 1.
- As the electrphile for functionalization and identification a mixture of D 2 SO 4 - D 2 O was used.
- reaction mixture is decomposed with a solution of 2 ml_ of
- Example 8 (according to prior art) Into a 200 ml_ flask with a magnetic stirrer and dropping funnel 5.14 g (0.016 M) of 2-(1 -adamantyl)-4-bromoanisole and 60 ml_ of dry tetrahydrofuran is introduced. The air in the flask is displaced by argon and all further operations conducted under a slight stream of the inert gas. The mixture is cooled to -5 0 C and 3 Eq of 0.5 M iso-PrMgCI LiCL solution in tetrahydrofuran added, keeping the reaction temperature within -5 - O 0 C range.
- iso-PrMgCI LiCL solution in tetrahydrofuran was prepared beforehand, its concentration determined by titration according to [Krasovskiy, A.; Knochel, P. Convenient titration method for organometallic zinc, magnesium, and lanthanide reagents. Synthesis 2006, 5, 890-891].
- Example 12 Reaction is performed as described in Example 11.
- the Ghgnard's reagent is produced with 0.07g (0.0016 M, 1 eq.) of pulverized anhydrous LiCI.
- the molar rate of substrate ⁇ iCI is 1 :0.1. Yield, according to gas chromatography data is 16%.
- Reaction is performed as described in Example 11.
- the Ghgnard's reagent is produced with 0.34 g (0.008 M) of pulverized anhydrous LiCI.
- the molar rate of substrate ⁇ iCI is 1 :0.5. Yield, according to gas chromatography data is 30%.
- Example 15 Reaction is performed as described in Example 11.
- the Ghgnard's reagent is produced with 0.68 g (0.016 M) of pulverized anhydrous LiCI.
- the molar rate of substrate ⁇ iCI is 1 :1. Yield, according to gas chromatography data is 75%.
- Example 15
- Example 20 Reaction is performed as described in Example 18.
- the Grignard's reagent is produced with 0.68 g (0.016 M) of pulverized anhydrous LiCI.
- the molar rate of substrate ⁇ iCI is 1 :1. Yield, according to gas chromatography data is 74%.
- Example 31 Reaction is performed as described in Example 11.
- adamantylarylhalide 6.35 g (0.016 M) of 3-benzyloxy-4-(1 - adamantyl)brombenzene is used.
- Example 37 Reaction is performed as described in Example 11.
- adamantylarylhalide 7.18 g (0.016 M) of 3-(tert-butyldimethylsilyloxy)-4-[1 - (3,5-dimethyladamantyl)brombenzene is used.
- Example 42 Reaction is performed as described in Example 11.
- adamantylarylhalide 5.84 g (0.016 M) of 3-[2-(2-methyladamantyl)-5- bromoveratrol is used.
- the present method for preparation of substituted adamantylarylmagnesium halides is characterized by stable high yields, technological feasibility and possibility to scale up the reaction volume.
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Abstract
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LV060151A LV13735B (en) | 2006-12-28 | 2006-12-28 | Method for manufacturing substituted adamantylarylmagnesium chalogenides |
PCT/EP2007/064648 WO2008080993A2 (fr) | 2006-12-28 | 2007-12-28 | Procédé de préparation d'halogénures d'adamantylarylmagnésium substitués |
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EP (1) | EP2129679A2 (fr) |
EA (1) | EA015949B1 (fr) |
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LV13735B (en) | 2008-09-20 |
EA015949B1 (ru) | 2011-12-30 |
WO2008080993A3 (fr) | 2009-03-12 |
WO2008080993A2 (fr) | 2008-07-10 |
EA200900899A1 (ru) | 2010-02-26 |
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