JPS6232188B2 - - Google Patents
Info
- Publication number
- JPS6232188B2 JPS6232188B2 JP54137105A JP13710579A JPS6232188B2 JP S6232188 B2 JPS6232188 B2 JP S6232188B2 JP 54137105 A JP54137105 A JP 54137105A JP 13710579 A JP13710579 A JP 13710579A JP S6232188 B2 JPS6232188 B2 JP S6232188B2
- Authority
- JP
- Japan
- Prior art keywords
- general formula
- group
- hydrogen atom
- azabicyclo
- hexane
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000001875 compounds Chemical class 0.000 claims description 45
- 238000000034 method Methods 0.000 claims description 31
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 21
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical group N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 239000013638 trimer Substances 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 239000000376 reactant Substances 0.000 claims description 8
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 125000003435 aroyl group Chemical group 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims 2
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 49
- 239000000243 solution Substances 0.000 description 26
- 239000000203 mixture Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 15
- -1 cyano compound Chemical class 0.000 description 14
- 239000002253 acid Substances 0.000 description 13
- 239000007788 liquid Substances 0.000 description 13
- 238000004519 manufacturing process Methods 0.000 description 13
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- HGWUUOXXAIISDB-UHFFFAOYSA-N 3-azabicyclo[3.1.0]hexane Chemical compound C1NCC2CC21 HGWUUOXXAIISDB-UHFFFAOYSA-N 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- 230000007062 hydrolysis Effects 0.000 description 9
- 238000006460 hydrolysis reaction Methods 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- JFUYLMCSIHJLOX-UHFFFAOYSA-N 3-azabicyclo[3.1.0]hexane-2-carbonitrile Chemical compound N#CC1NCC2CC12 JFUYLMCSIHJLOX-UHFFFAOYSA-N 0.000 description 8
- JBDOTWVUXVXVDR-UHFFFAOYSA-N 3-azoniabicyclo[3.1.0]hexane-2-carboxylate Chemical compound OC(=O)C1NCC2CC12 JBDOTWVUXVXVDR-UHFFFAOYSA-N 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- QRDSDKAGXMWBID-UHFFFAOYSA-N 5-azabicyclo[3.1.0]hexane Chemical compound C1CCN2CC21 QRDSDKAGXMWBID-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- PRSVJIWYTOZNIT-UHFFFAOYSA-N 3-azabicyclo[3.1.0]hex-2-ene Chemical compound C1N=CC2CC21 PRSVJIWYTOZNIT-UHFFFAOYSA-N 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 238000006704 dehydrohalogenation reaction Methods 0.000 description 5
- 238000011065 in-situ storage Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 150000002466 imines Chemical class 0.000 description 4
- 238000005342 ion exchange Methods 0.000 description 4
- 239000000178 monomer Substances 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- FICQFRCPSFCFBY-UHFFFAOYSA-N 2-[bis(methylsulfanyl)methylidene]propanedinitrile Chemical compound CSC(SC)=C(C#N)C#N FICQFRCPSFCFBY-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 238000006136 alcoholysis reaction Methods 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- GJQBHOAJJGIPRH-UHFFFAOYSA-N benzoyl cyanide Chemical group N#CC(=O)C1=CC=CC=C1 GJQBHOAJJGIPRH-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 2
- NBNZQOQGSKQYHV-UHFFFAOYSA-N 3-benzoyl-3-azabicyclo[3.1.0]hexane-2-carbonitrile Chemical compound C1C2CC2C(C#N)N1C(=O)C1=CC=CC=C1 NBNZQOQGSKQYHV-UHFFFAOYSA-N 0.000 description 2
- NNTKUTCIQVNVNH-UHFFFAOYSA-N 3-trimethylsilyl-3-azabicyclo[3.1.0]hexane-2-carbonitrile Chemical compound N#CC1N([Si](C)(C)C)CC2CC21 NNTKUTCIQVNVNH-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000005708 Sodium hypochlorite Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000011260 aqueous acid Substances 0.000 description 2
- 239000012431 aqueous reaction media Substances 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000007883 cyanide addition reaction Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 229960002317 succinimide Drugs 0.000 description 2
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 2
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- QYCLXTCXSIUGSB-UHFFFAOYSA-N 3-chloro-3-azabicyclo[3.1.0]hexane Chemical compound C1N(Cl)CC2CC21 QYCLXTCXSIUGSB-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 150000001264 acyl cyanides Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- WVIIMZNLDWSIRH-UHFFFAOYSA-N cyclohexylcyclohexane Chemical group C1CCCCC1C1CCCCC1 WVIIMZNLDWSIRH-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- QJFZMDWMBRUEMA-UHFFFAOYSA-N ethyl 3-azabicyclo[3.1.0]hexane-2-carboxylate Chemical compound CCOC(=O)C1NCC2CC12 QJFZMDWMBRUEMA-UHFFFAOYSA-N 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910001410 inorganic ion Inorganic materials 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000008635 plant growth Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000010902 straw Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Description
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æ¹æ³ã«é¢ãããDETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for preparing 2-cyano-3-azabicyclo[3.1.0]hexane and certain derivatives thereof.
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æã«ã¯åæãåŸãªãã€ãã 2-carboxy-3-azabicyclo [3.1.0]
Hexane and certain of its salts and esters have useful biological properties and are capable of sterilizing the stamens of plants. Therefore, the methods for producing these compounds are of considerable importance. However, the available manufacturing methods have proven to be relatively complex. One possible synthetic route involves hydrolysis of the corresponding 2-cyano compound, but hitherto this cyano compound could not be easily synthesized.
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æ³ã§ããã European Patent Application No. 79200096 has 2-cyano-3
-Azabicyclo[3.1.0]hexane and certain substituted derivatives thereof may be prepared by reacting the corresponding 2-cyano-4-oxo compound with trialkyl oxonium fluoroborate and then with a reducing agent. This is disclosed. However, this reaction is a two-step process that requires the use of expensive reagents.
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ãã European Patent Application No. 79200034 has 2-cyano-3
-Disclosed that azabicyclo[3.1.0]hexane can be prepared by reacting 3-azabicyclo[3,1.0]hex-2-ene with an alkali metal bisulfite and then with an alkali metal cyanide. ing. This method is also a two-step method.
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¥ãåŸãæ¹æ³ãèŠåºãããã A method has now been found which allows the introduction of a cyano group into a bicyclohexane ring system in one step.
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ãæäŸããã The present invention has the general formula: (In the formula, R 1 is a hydrogen atom, or unsubstituted or 1
represents an alkyl group substituted with one or more alkoxy groups, and R 2 , R 3 , R 4 , R 5 , R 6 and R 7 may be the same or each represents a hydrogen atom or an alkyl, aryl, aralkyl or alkaryl group which is unsubstituted or substituted with one or more alkoxy groups, and (representing a trialkylsilyl group), the general formula: (wherein R 1 to R 7 have the above-mentioned meanings) and/or its trimer are reacted with a cyanide of the general formula: XCN (wherein X has the above-mentioned meanings) provide a method to do so.
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ã®ã§ããã Compounds of the general formula in which X represents an organic acyl group or a trialkylsilyl group are novel, and the present invention therefore also provides these compounds themselves.
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ãã Preferably, R 1 represents a hydrogen atom or an unsubstituted alkyl group having up to 6 carbon atoms, and
R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently a hydrogen atom or an unsubstituted alkyl group having up to 6 carbon atoms, or an unsubstituted aryl, alkaryl or alkyl group having up to 10 carbon atoms. Represents an alkyl group.
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ã«ãã«åºäŸãã°ã¡ãã«åºãè¡šããã More preferably, R 1 represents a hydrogen atom or an alkyl group having up to 4 carbon atoms, such as a methyl group, and R 2 , R 3 , R 4 , R 5 , R 6 and R 7 each independently represent a hydrogen atom or a carbon atom. It represents an alkyl group having up to 4 atoms, for example a methyl group.
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ãã³R7ã¯ããããæ°ŽçŽ ååãè¡šããã Most preferably R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 each represent a hydrogen atom.
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ã«åºã¯ããªã¡ãã«ã·ãªã«åºã§ããã X is, for example, an alkanoyl group, such as an acetyl group,
or an aroyl group such as a benzoyl group. In the trialkylsilyl group X, two or three of the alkyl groups may be the same or different and each alkyl group preferably has up to 4, especially 1 or 2 carbon atoms. . A particularly preferred trialkylsilyl group is trimethylsilyl.
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ããããã宀枩ã§è¡ãã®ãæã奜éœåã§ããã The process of the invention is suitably carried out in the presence of an inert solvent such as an alcohol, an ether such as diethyl ether, or a hydrocarbon or chlorinated hydrocarbon such as dichloromethane. Mixed solvents may also be used. The reaction temperature can range, for example, from 0 to 60°C, preferably from 10 to 30°C. For example, the reaction can be carried out at the reflux temperature of the solvent used. However, it is most convenient to carry out at room temperature.
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ãã In some cases it may be preferable, and indeed necessary, to carry out the reaction under moisture-free conditions. This is the case when acyl cyanides or especially trialkylsilyl cyanides are used as reagents.
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ããããã§ããã The molar ratios of the reactants can vary over a wide range. Cyanide reactant in excess, e.g.
It is possible to use an excess of up to 2 times, preferably up to 3 times, in particular up to 1.5 times. However, it is desirable to use approximately stoichiometric amounts, especially when the cyanide reactant is benzoyl cyanide. This is because separation problems during post-processing are thereby avoided.
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ã¹ããªãŒïŒJ.Org.Chem.ïŒ39ãNo.ïŒïŒ1974幎ïŒã
916é ã«èšèŒã®æ¹æ³ã§åå¿ãããããšã«ãã補é
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ãã The cyanide reactant is optionally added in situ.
(in situ) can be manufactured and used. Trialkylsilyl cyanide is prepared by combining trialkylsilyl chloride and potassium cyanide, optionally in the presence of zinc iodide, in Journal of Organic Chemistry (J.Org.Chem.) 39 , No. 7 (1974). ),
It can be produced by the reaction method described on page 916. Whether the resulting trialkylsilyl cyanide is isolated or used in situ, it is appropriate to keep it protected from moisture.
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ãã Hydrogen cyanide can be generated in situ, for example by the action of an alkali metal cyanide with a strong mineral acid or by using cyanohydrin under alkaline conditions, but preferably it is a gas as such. , in solution in the reaction solvent or preferably in liquid form, to the compound of the general formula and/or its trimer.
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ããšãã§ããã Compounds of the general formula and/or trimers thereof are, for example, of the general formula: (wherein R 1 to R 7 have the meanings given in the general formula) can be produced by direct oxidation of a compound. Manganese dioxide is a suitable reagent and the oxidation can be carried out simply by stirring the compound of general formula and manganese dioxide in the presence of a suitable solvent such as benzene or a hydrocarbon such as gas oil, conveniently at room temperature. can.
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ãšãã§ããã In addition, the compound of the general formula and/or its trimer is of the general formula: (wherein R 1 to R 7 each have the meaning given in the general formula, and Hal represents a chlorine or bromine atom) can also be produced by dehydrohalogenation of a compound.
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ã§ããã Dehydrohalogenation can be carried out using any suitable dehydrohalogenating agent, such as a strong organic base such as triethylamine or pyridine in a non-aqueous solution, or a strong inorganic base such as sodium hydroxide in an aqueous or non-aqueous solution. can also be done. Suitable polar solvents are, for example, ethers, alcohols or water. The reaction is preferably carried out at a temperature of up to 150°C,
It is preferably carried out at a temperature in the range of 20 to 80°C. The process can conveniently be carried out at the reflux temperature of the solvent used.
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åé¢ããªããã°ãªããªãããšãããã The advantage of carrying out the dehydrohalogenation in a non-aqueous reaction medium is that the resulting solution can optionally be used directly in situ in the cyanide addition step of the invention, even when using moisture-sensitive cyanide reagents. This is something that can be done. On the other hand, if an aqueous reaction medium is used, the reaction times required are generally shorter; however, in this case the desired compound must be isolated so that the subsequent cyanide addition can proceed in the absence of moisture. Sometimes.
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ã®çžå¯Ÿçæ¯çã«ç¡é¢ä¿ã«è¡ãããšãã§ããã It is believed that this dehydrohalogenation step results in a solution consisting mostly of monomers of the general formula. Removal of the solvent produces a solid with a complex NMR spectrum, and this is a trimer: (wherein substituents R 2 to R 7 are omitted) is believed to be. Redissolving the solid trimer produces a solution in which the trimer is in equilibrium with the monomer;
The concentration of each species depends on the dilution of the solution.
The process of the invention can be carried out regardless of the relative proportions of monomer and trimer in the reaction solution.
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ã¯äŸãã°å®€æž©ã§è¡ãããšãã§ããã Compounds of the general formula may be prepared, for example, by N-chlorination or N-bromination of compounds of the general formula. Any suitable chlorinating or brominating agent may be used, such as N-halo compounds such as N-bromo- or especially N-chloro-succinimide, or inorganic hypolites such as sodium hypochlorite. Sodium hypochlorite may be conveniently used in the form of sodium hydroxide plus chlorine. The process is suitably carried out by mixing a slight excess of halogenating agent with a compound of the general formula. Any suitable solvent may be used, such as ether. The reaction can be carried out, for example, at room temperature.
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åç©ã®è£œé æ¹æ³ããæäŸããã The invention thus provides for converting a compound of the general formula into a compound of the general formula and/or a trimer thereof, and converting at least a portion of said compound into a compound of the formula XCN
Also provided is a method for preparing a compound of the general formula, which comprises reacting the compound with a compound of the general formula.
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¥ããããšã«ãã補é ãåŸãã Compounds of the general formula in which R 1 , R 6 and R 7 each represent a hydrogen atom have the general formula: (wherein R 2 , R 3 , R 4 and R 5 each have the meanings given above) or its mono- or di-acyl halide or mono- or di-ester or anhydride with ammonia and optionally is reacted with water and the resulting product is cyclized by heating to give the general formula: (wherein R 2 , R 3 , R 4 and R 5 each have the meanings given above) and 2 of the compound of the general formula
and the carbonyl group at position 4, for example, by reduction using lithium aluminum hydride. Compounds of the general formula in which R 1 , R 6 and/or R 7 represent groups other than hydrogen atoms may be prepared by introducing these groups in a manner similar to that known in the art.
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ã®HClå¡©ãçæããã Compounds of the general formula are formed by hydrolysis into the general formula: (wherein R 1 to R 7 have the above-mentioned meanings). Such compounds have interesting pollen-suppressing and plant growth regulating effects. Hydrolysis may be carried out, for example, by refluxing a compound of the general formula in the presence of an aqueous acid. This hydrolysis can produce acid addition salts of compounds of general formula. Refluxing a compound of general formula in the presence of an alcohol and dry hydrogen chloride produces an ester of the compound of general formula or its HCl salt.
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æäŸããã Thus, the present invention also provides a method for producing a compound of the general formula or a salt and/or ester thereof, which comprises hydrolyzing or alcoholysing the compound of the general formula produced by the method of the present invention.
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ã3.1.0ããããµã³ãçããã In the compound of the general formula, the 2-cyano group is
It can be cis or trans to the CR 4 R 5 group, and in addition, for each of these geometric isomers there is a pair of optical isomers based on the chirality of the 2-carbon atom. Furthermore, R 4 , R 5 , R 6 and R 7
Other geometric and/or optical isomers may exist depending on the meaning of . In some applications of the process of the invention, certain isomers are exclusively produced; e.g.
When R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 each represent a hydrogen atom and the cyanide reagent is hydrogen cyanide, the process of the invention will generally be exclusively trans-2-cyano -Produces 3-azabicyclo[3.1.0]hexane.
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ãããã§ããã As mentioned above, compounds of the general formula can be converted to the corresponding 2-carboxylic acids, for example by treatment with strong acids. For example, trans(D,L)2-cyano-3-azabicyclo[3.1.0]hexane is hydrolyzed into trans(D,L)2-carboxy-
It can be 3-azabicyclo[3.1.0]hexane. The production of this single geometric isomer is extremely useful. This is because, in general, the two geometric isomers have different physical properties, and mixtures of geometric isomers pose manufacturing and formulation problems.
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ãã The method of the present invention is directed to the trans 2-carboxy-3
- Of particular importance in the production of azabicyclo[3.1.0]hexane or its salts and/or esters.
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ãããªãã Thus, the preferred routes for the production of trans-2-carboxy-3-azabicyclo[3.1.0]hexane are (i) 3-azabicyclo[3.1.0]hexane, for example by direct oxidation, or by N-chlorination or N- (ii) conversion to 3-azabicyclo[3.1.0]hex-2-ene and/or its trimer by bromination followed by dehydrohalogenation; (ii) trans by reaction of the product from (i) with hydrogen cyanide; Preparation of 2-cyano-3-azabicyclo[3.1.0]hexane and (iii) 2-carboxy-3-azabicyclo[3.1.0]hexane or salts thereof by hydrolysis or alcoholysis of the product from (ii) and/or the production of esters.
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ãªãé«ã³ã¹ãã«ãªãã However, in some cases, direct hydrolysis of a compound of the general formula containing inorganic impurities to the free acid of the general formula or an acid addition salt thereof can be quite costly to carry out on a large scale. The free acid is an amino acid that cannot be distilled and is soluble in both acidic and basic solutions. Therefore, in order to obtain a product free of inorganic impurities, it is preferred to purify the product by passing it through an ion exchange column using a series of aqueous eluents. Although this method is perfectly suitable in the laboratory, it is rather expensive to perform on a large scale given the large amounts of deionized water required to elute the product.
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ãªãã The need for elution is met by alcoholysis of the compound of the general formula obtained by the process of the invention using a lower alkanol in the presence of a non-aqueous acid catalyst, suitably dry hydrogen chloride, to obtain the acid of the general formula. This can be avoided by converting to the corresponding lower alkyl ester. Alkanols having 1 to 3 carbon atoms are suitable. The resulting esters, unlike the free acids, can be distilled and therefore purified by distillation.
The ester may then be hydrolyzed to produce the free acid using water which may optionally contain small amounts of mineral acid or aqueous ammonia. Alkaline hydrolysis is undesirable because it introduces inorganic ions into the reaction mixture that must be removed with an ion exchange column.
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ãŸãã®ã奜ãŸããã If it is necessary to produce a relatively pure trans compound, it is preferred to isolate or further react the trans 2-cyano compound as soon as possible after production.
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åãªæ¹æ³ãæäŸããããã§ããã Thus, the present invention provides alcoholysis of the compound of the general formula produced by the method of the present invention using an alkanol having 1 to 3 carbon atoms, purification of the resulting ester by distillation, and purification of the purified ester. There is also provided a process for producing acids of the general formula, which comprises hydrolyzing to the desired acid using water or aqueous ammonia which may contain a catalytic amount of a mineral acid. This method is particularly advantageous when the compound of general formula is trans-2-cyano-3-azabicyclo[3.1.0]hexane.
Because it is trans 2-carboxy-3-
This is because it provides a convenient method for producing azabicyclo[3.1.0]hexane.
次ã®å®æœäŸã«ããæ¬çºæãæŽã«èª¬æããã The invention is further illustrated by the following examples.
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åãããªãŠã 氎溶液50mlã§ïŒåæŽæ»ãããExample 1 Preparation of trans-2-cyano-3-azabicyclo[3.1.0]hexane A slurry of 23.6 g (0.175 mol) of N-chlorosuccinimide in 500 ml of diethyl ether was stirred at room temperature under a blanket of nitrogen to form 3-azabicyclo. [3.1.0] 8.4 g (0.1 mol) of hexane was added.
The mixture was stirred at room temperature for 21/2 hours under a blanket of nitrogen and then filtered to remove the succinimide. The liquid was washed twice with 100 ml of water each time and once with 50 ml of saturated aqueous sodium chloride solution.
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ïœãåŸãã The combined liquids were dried over Na 2 SO 4 and concentrated on a rotary evaporator at 20-25° C. and a pressure of about 60 mm Hg to a volume of about 60 ml. Pour the remaining solution into absolute ethanol.
Added to 6.6 g of 85% potassium hydroxide in 50 ml at 5-10°C. An exothermic reaction occurred and the temperature rose to 30°C. The mixture was stirred at room temperature overnight under nitrogen atmosphere and then filtered. Add 5.4 g (0.2 mol) of liquid hydrogen cyanide to the solution and raise the temperature to 22â for 5 minutes.
The temperature rose from 29â to 29â. The mixture was stirred at room temperature for 11/2 hours and then stripped on a rotary evaporator at 50°C to give an oily product containing some crystals.
I got g.
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ã Distilled from an oil bath to trans-2-cyano-3-azabicyclo[3.1.0]hexane (boiling point 56â/0.1mm
Hg) was obtained. Yield: 65%.
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ãããExample 2 Preparation of trans-2-carboxy-3-azabicyclo[3.1.0]hexane A slurry of 159 g (1.2 moles) of N-chlorosuccinimide in 500 ml of diethyl ether was stirred at 20°C to produce 3-azabicyclo[3.1.0]. ]Hexane 83
g (1.0 mol) was added over 30 minutes. The mixture was stirred for an additional 1.5 hours and then filtered to remove the succinimide. The filter pad was washed twice with 50 ml each time of diethyl ether, and the liquids were combined.
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ïœïŒãæ·»å ãããããŠæ··åç©ãïŒæéæ¹æããã 48g of sodium hydroxide in 300ml of methanol
(1.2 mol) was added to the above diethyl ether solution of N-chloro-3-azabicyclo[3.1.0]hexane and the mixture was stirred and refluxed overnight (16 hours) once the initial exothermic reaction had subsided. After cooling to 20â, this 3-azabicyclo[3.1.0]hexyl
An excess of liquid hydrogen cyanide (40
g) was added and the mixture was stirred for 1 hour.
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ã Add 800ml of 6N hydrochloric acid to the obtained trans-2-cyano-3-azabicyclo[3.1.0]hexane solution,
The reaction mixture was then heated at 100° C. for 3 hours, during which time diethyl ether and methanol were distilled off to leave an acidic aqueous solution, which was then treated on an ion exchange resin in the H + form using aqueous ammonia as the eluent. . Recrystallization from aqueous isopropyl alcohol gave 77.7 g of white crystalline material (mp 248-250°C, decomposed). The analysis result shows that this product is 98.3
% chemical purity of isomerically pure trans(D,L)2-carboxy-3-azabicyclo[3.1.0]hexane. Overall yield from 3-azabicyclo[3.1.0]hexane: 61.2
%.
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éæ¹æãããPHã¯çŽïŒã§ãã€ããExample 3 Trans 2-carboxy-3- under acidic conditions
Preparation of Azabicyclo[3.1.0]hexane As in Example 1, 3-azabicyclo[3.1.0]hexane (0.15 mol) was treated with N-chlorosuccinimide and then with potassium hydroxide.
The resulting solution was treated with 20 ml of 10N HCl in ethanol. The temperature was kept below 10°C by cooling on an ice bath. The resulting mixture was then treated with 7.7 ml (0.2 mol) of liquid hydrogen cyanide at 10-13°C. The reaction mixture was then allowed to reach room temperature and stirred for 2 hours. The pH was approximately 2.
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ãšã瀺ããã The mixture was then stripped of solvent on a rotary evaporator to obtain a very viscous orange oil, which was purified by distillation. The resulting product was hydrolyzed using 6N hydrochloric acid as in Example 2 to yield 2-carboxy-3-azabicyclo[3.1.0]hexane. 13 C NMR showed no cis isomer present.
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ãšä»¥å€ã¯ãå®æœäŸïŒã®æäœãç¹°è¿ãããã·ã¢ã³å
æ°ŽçŽ æ·»å åŸã®åå¿æ··åç©ã®PHã¯ïŒã10ã§ãã€ããExample 4 Trans 2-cyano-3 under alkaline conditions
-Preparation of azabicyclo[3.1.0]hexane The procedure of Example 3 was repeated, except that HCl was replaced with 1.5 ml of triethylamine. The pH of the reaction mixture after addition of hydrogen cyanide was 9-10.
13C NMRã¯çæç©ããã©ã³ã¹ïŒâã·ã¢ãâïŒ
âã¢ã¶ãã·ã¯ãã3.1.0ããããµã³ã§ãã·ã¹ç°æ§
äœãååšããªãããšã瀺ããã 13 C NMR shows that the product is trans-2-cyano-3
-Azabicyclo[3.1.0]hexane, showing the absence of cis isomer.
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éšåå æ°Žå解
(a) ïŒâã¢ã¶ãã·ã¯ãã3.1.0ãããã»âïŒâãš
ã³ããã³ãã®äžéäœ
ãžãšãã«ãšãŒãã«50mläžã®ïŒâã¢ã¶ãã·ã¯ã
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ãšãã«ãšãŒãã«150mläžã®ïŒ®âã¯ããã³ãã¯ã¯é
ž
ã€ãã23.6ïœã®æžæ¿æ¶²ã«å®€æž©ã§æ·»å ããããã®æž
æ¿æ¶²ã宀枩ã§21/4æéæ¹æãã次ã«éãããã
ãŠæ°ŽæŽããããšãŒãã«æº¶æ¶²ãNa2SO4ã§ä¹Ÿç¥ãã
éãããããŠãã°ããŒïŒvigreauxïŒã«ã©ã äžã§
70âã§çŽ25mlã«æ¿çž®ãããæ®æž£ãã¡ã¿ããŒã«50ml
äžã®KOH6.6ïœïŒ85ïŒ
ïŒã®æº¶æ¶²ã«ïŒã10âã§æ¹æ
äžã«æ»Žå ãããæžæ¿æ¶²ãïŒãïŒâã§ïŒæéæ¹æ
ãã次ã«å®€æž©ã§äžå€æŸçœ®ãããæ··åç©ã35âã18
cmHgã®å§åã§ïŒæéæ¿çž®ãã次ã«æ°Ž50mlãå ã
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ããExample 5 Production of 2-cyano-3-trimethylsilyl-3-azabicyclo[3.1.0]hexane and its partial hydrolysis (a) 3-azabicyclo[3.1.0]hex-2-ene and its trimer Diethyl ether A solution of 8.3 g (0.1 mol) of 3-azabicyclo[3.1.0]hexane in 50 ml was added at room temperature to a suspension of 23.6 g of N-chlorosuccinimide in 150 ml of diethyl ether. The suspension was stirred at room temperature for 21/4 hours, then filtered and washed with water. The ether solution was dried with Na 2 SO 4 and
and under the vigreaux column.
It was concentrated to about 25 ml at 70°C. Add 50ml of methanol to the residue.
was added dropwise to a solution of 6.6 g (85%) of KOH in the solution at 5-10° C. with stirring. The suspension was stirred at 0-5°C for 2 hours and then left at room temperature overnight. Heat the mixture at 35°C for 18
Concentrate for 6 hours at a pressure of cmHg, then add 50 ml of water. The mixture was extracted successively with diethyl ether.
ãžãšãã«ãšãŒãã«ã倧æ°å§ã§çå»ãã次ã«æ®æž£
ã倧æ°å§ã§èžçãããåŸãããæåã®çåïŒæ²žç¹
77ã96âïŒã¯ç¡è²ã®æ¶²äœïŒïœã§ãèµ€å€ããã³
NMRã¹ãã¯ãã«ã«ããåéäœïŒâã¢ã¶ãã·ã¯ã
ã3.1.0ãããã»âïŒâãšã³ã®æ°Žæº¶æ¶²ã§ããããšã
瀺ãããã The diethyl ether was distilled off at atmospheric pressure and the residue was then distilled at atmospheric pressure. The first fraction obtained (boiling point
77-96â) is 3g of colorless liquid, infrared and
The NMR spectrum showed that it was an aqueous solution of the monomer 3-azabicyclo[3.1.0]hex-2-ene.
96ã110âã§æ²žãšããã第äºã®çåã¯åçž®ããŠ
ç°çœè²åºäœïŒèç¹60ã63âïŒ3.8ïœãšãªãããã
ã¯èµ€å€ããã³NMRã¹ãã¯ãã«ã«ããããã®ã€ã
ã³ã®äžéäœã§ããããšã瀺ããããçœè²åºäœã®å
æå€ïŒ
  
C15N3H21ãšããŠ
èšç®å€ 73.2 9.1 17.2
枬å®å€ 74.0 8.7 17.3
(b) ïŒâã·ã¢ãâïŒâããªã¡ãã«ã·ãªã«âïŒâã¢
ã¶ãã·ã¯ãã3.1.0ããããµã³ããã³ãã®éšå
å æ°Žå解
也ç¥CH2Cl2700mläžã®äžèš(a)ã§è£œé ãããã€ã
ã³äžéäœïŒïœïŒ28.8ããªã¢ã«ïŒã®æº¶æ¶²ã«å®€æž©ã§çª
çŽ é°å²æ°äžæ¹¿æ°ãé®æããŠæ¹æãã€ã€ã·ã¢ã³åã
ãªã¡ãã«ã·ãªã«16mlïŒ0.128ã¢ã«ïŒãæ·»å ããã
ãã®æº¶æ¶²ã宀枩ã§24æéæ¹æããŠïŒâã·ã¢ãâïŒ
âããªã¡ãã«ã·ãªã«âïŒâã¢ã¶ãã·ã¯ã
ã3.1.0ããããµã³ã®æº¶æ¶²ãåŸãããã®æº¶æ¶²ãæ°ŽïŒ
ãªããã«äžã«æ³šå ãã宀枩ã§30åæ¹æãããããŠ
CH2Cl2ã§æœåºãããæœåºæ¶²ãNa2SO4ã§ä¹Ÿç¥ãã
ãããŠèžçºãç
®ã€ããŠé»è²æ¶²äœ9.4ïœãåŸãã The second fraction, boiling at 96-110°C, condenses to 3.8 g of an off-white solid (melting point 60-63°C), which infrared and NMR spectra show to be the trimer of this imine. It was done. Analysis of white solid: C H N C 15 N 3 H 21 Calculated value 73.2 9.1 17.2 Measured value 74.0 8.7 17.3 (b) 2-cyano-3-trimethylsilyl-3-azabicyclo[3.1.0]hexane and its partially hydrated Decomposition To a solution of 7 g (28.8 mmol) of the imine trimer prepared above in (a) in 700 ml of dry CH 2 Cl 2 was added 16 ml (0.128 mol) of trimethylsilyl cyanide under a nitrogen atmosphere at room temperature with exclusion from moisture. was added.
This solution was stirred at room temperature for 24 hours to obtain 2-cyano-3.
A solution of -trimethylsilyl-3-azabicyclo[3.1.0]hexane was obtained. Add this solution to 1 part water.
pour over the bottle, stir at room temperature for 30 minutes, and
Extracted with CH2Cl2 . The extract was dried with Na 2 SO 4 and
Then, it was evaporated and boiled down to obtain 9.4 g of a yellow liquid.
ãã®æ¶²äœãèžçã«ãã粟補ãããããŠ0.7mmHg
ã®å§åã§72ã74âã§æ²žãšãããçå5.45ïœã¯
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ã3.1.0ããããµã³ã§ãããšåå®ãããã This liquid was purified by distillation and 0.7mmHg
5.45 g of a distillate boiling at 72-74â at a pressure of
It was identified as 2-cyano-3-azabicyclo[3.1.0]hexane by NMR.
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解
(a) ã€ãã³äžéäœãžã®ã·ã¢ã³åãã³ãŸã€ã«ã®ä»å
也ç¥CH2Cl2700mläžã®äžèšå®æœäŸïŒ(a)ã§è£œé ã
ãã€ãã³äžéäœïŒïœïŒ28.8ããªã¢ã«ïŒã®æº¶æ¶²ã«ã·
ã¢ã³åãã³ãŸã€ã«11.3ïœïŒ86.4ããªã¢ã«ïŒãæ·»å
ããããã®æº¶æ¶²ã宀枩ã§äžå€æ¹æãããããŠæ¬¡ã«
ç
®ã€ãããåŸãããæ²¹ã160âã®æž©åºŠã0.1mmHg
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ãã«ã§åŠçãããããŠéãããExample 6 Preparation of 2-cyano-3-benzoyl-3-azabicyclo[3.1.0]hexane and its hydrolysis (a) Addition of benzoyl cyanide to imine trimer The above implementation in 700 ml of dry CH 2 Cl 2 11.3 g (86.4 mmol) of benzoyl cyanide were added to a solution of 7 g (28.8 mmol) of the imine trimer prepared in Example 5(a). The solution was stirred at room temperature overnight and then boiled down. The resulting oil was heated to a temperature of 160â and 0.1mmHg.
and the distillate was treated with gasoline/ether and filtered.
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ïœã¯èµ€å€ããã³NMRã¹ãã¯ãã«ã«ããïŒâã·ã¢
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IRïŒ1650cm-1ïŒïŒ£ïŒïŒ¯äŒžçž®
2240cm-1ïŒïŒ£ïŒïŒ®äŒžçž®
NMRïŒ0.2ppm1HïŒå€éç·ïŒ
0.7ppm1HïŒå€éç·ïŒ
1.7ppm2HïŒå€éç·ïŒ
3.6ppm2HïŒå€éç·ïŒ
5.1ppm1HïŒå€éç·ïŒ
7.3ppm5HïŒäžéç·ïŒ
(b) ïŒâã«ã«ããã·âïŒâã¢ã¶ãã·ã¯ã
ã3.1.0ããããµã³ã®è£œé
CH2Cl250mläžã®äžèš(a)ã§è£œé ããååç©ïŒïœ
ã®æº¶æ¶²ãäžå€éæµäžã«å ç±æ¹æããããã®æžæ¿æ¶²
ãå·åŽãããžãšãã«ãšãŒãã«ã§æŽæ»ãããããŠæ°Ž
å±€ãèžçºä¹Ÿåºããããæ®æž£ãæ°Žã«æº¶è§£ãããããŠ
é
žæ§ã€ãªã³äº€æã«ã©ã âããŠãšãã¯ã¹
ïŒDOWEXïŒ50âïŒåæšïŒã«éãããã€ãªã³äº€æåº
ãæ°Žã§æŽãããããŠçæç©ã2N NH4OHã§æº¶é¢
ãããã The resulting compound, a solid with a melting point of 74-77°C, 4.8
g was identified as 2-cyano-3-benzoyl-3-azabicyclo[3.1.0]hexane by infrared and NMR spectra. The spectral data are as follows: IR: 1650cm -1 : C=O stretching 2240cm -1 : C=N stretching NMR: 0.2ppm1H (multiplet) 0.7ppm1H (multiplet) 1.7ppm2H (multiplet) 3.6ppm2H ( 5.1ppm1H (multiplet) 7.3ppm5H (singlet) (b) Production of 2-carboxy-3-azabicyclo[3.1.0]hexane 1 g of the compound produced in (a) above in 50 ml of CH 2 Cl 2
The solution was heated and stirred under reflux overnight. The suspension was cooled, washed with diethyl ether and the aqueous layer was evaporated to dryness. The residue was dissolved in water and passed through an acidic ion exchange column "DOWEX 50" (trademark). The ion exchange bed was washed with water and the product was eluted with 2N NH 4 OH.
çæç©0.4ïœãåŸããããNMRã¯ãã®çæç©ã
ã·ã¹ããã³ãã©ã³ã¹ç°æ§äœãïŒïŒïŒã®æ¯ã§å«æã
ãïŒâã«ã«ããã·âïŒâã¢ã¶ãã·ã¯ãã3.1.0ã
ãããµã³ã§ããããšã瀺ããã 0.4 g of product was obtained. NMR shows that the product is 2-carboxy-3-azabicyclo[3.1.0] containing cis and trans isomers in a 1:1 ratio.
It was shown to be hexane.
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žã€ãã4.01KgïŒ30ã¢ã«ïŒã
ãžãšãã«ãšãŒãã«12.5äžã«æžæ¿ããããããŠïŒ
âã¢ã¶ãã·ã¯ãã3.1.0ããããµã³2.08KgïŒ25ã¢
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žåãã
ãªãŠã 1.2KgïŒ30ã¢ã«ïŒã®æº¶æ¶²ã«çªçŽ ã·ãŒã«äž10
âã®æž©åºŠã§ïŒæéã§æ·»å ããã枩床ã¯23âã«äžæ
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åç©ãïŒæééæµãããããŠ10âã«å·åŽãããExample 7 Preparation of trans 2-carboxy-3-azabicyclo[3.1.0]hexane via the corresponding ethyl ester 4.01 Kg (30 mol) of N-chlorosuccinimide are suspended in 12.5 kg of diethyl ether, and 3
- 2.08Kg (25mol) of azabicyclo[3.1.0]hexane was added over 80 minutes. Maintain the temperature within the range of 11 to 22°C during the addition and then 18 to 20°C.
The temperature was maintained within this range for an additional 2 hours. The reaction mixture is then filtered and added to a solution of 1.2 Kg (30 mol) of sodium hydroxide in ethanol for 10 min under a nitrogen blanket.
It was added in 2 hours at a temperature of .degree. The temperature rose to 23°C and in the next hour to 38°C. The mixture was then refluxed for 6 hours and cooled to 10°C.
液äœã·ã¢ã³åæ°ŽçŽ 844ïœïŒ31.25ã¢ã«ïŒã30åé
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ããåŸãããæ··åç©ãéãããããŠæ¬¡ã«â10ãª
ããïŒïŒâã®æž©åºŠã«ç¶æãããç¡æ°Žå¡©åæ°ŽçŽ 7.3
KgïŒ200ã¢ã«ïŒãå«ãç¡æ°Žãšã¿ããŒã«22.5ã«20
åéã§æ·»å ããããã®æ®µéã§ãïŒâã¢ã¶ãã·ã¯ã
ã3.1.0ããããµã³50ã¢ã«ãã補é ããæŽã«ïŒãã
ãã®ãã©ã³ã¹ïŒâã·ã¢ãâïŒâã¢ã¶ãã·ã¯ã
ã3.1.0ããããµã³æº¶æ¶²ããåå¿æ··åç©ã«æ·»å ã
ãã次ã«ãšãŒãã«ãçå»ãããããŠæ··åç©ãïŒæ
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ã«ããã 844 g (31.25 moles) of liquid hydrogen cyanide were added over 30 minutes and stirring continued for a further hour at room temperature. The resulting mixture was filtered and then anhydrous hydrogen chloride maintained at a temperature of -10 to +2°C7.3
Kg (200 mol) of absolute ethanol 22.5 to 20
Added within minutes. At this stage, an additional batch of trans 2-cyano-3-azabicyclo[3.1.0]hexane solution prepared from 50 moles of 3-azabicyclo[3.1.0]hexane was also added to the reaction mixture. The ether was then distilled off and the mixture was refluxed for 4 hours and then cooled to -5°C. Anhydrous ammonia was passed through the reaction mixture for 2 hours to bring the pH to 10.0.
I made it.
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ã§ã¹ããªããã³ã°ããã The reaction mixture was filtered and the solvent was stripped off on a rotary evaporator.
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70ïŒ
ã§ããããšã瀺ãã 5.42 Kg of 2-ethoxycarbonyl-3-azabicyclo[3.1.0]hexane were obtained, which was shown by NMR to be 99% chemically pure and to contain 96% trans isomer. This is based on 3-azabicyclo[3.1.0]hexane, and the through yield is
Indicates that it is 70%.
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ïŒâãšããã·ã«ã«ããã«âïŒâã¢ã¶ãã·ã¯ã
ã3.1.0ããããµã³8.3KgïŒ53.3ã¢ã«ïŒããæ°Ž83äž
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ž217mlã«éæµäžïŒæéã§æ·»å ãããå ç±
ãæŽã«ïŒ1/2æéç¶ãããã®éã«ãšã¿ããŒã«ãç
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ãŒã«ã§ã次ã«ãããµã³ã§æŽæ»ãããããŠé¢šä¹Ÿã
ãã This production was repeated several times. 8.3 Kg (53.3 mol) of the prepared trans-2-ethoxycarbonyl-3-azabicyclo[3.1.0]hexane were added to 217 ml of concentrated hydrochloric acid in 83 ml of water under reflux for 1 hour. Heating was continued for an additional 21/2 hours, during which time the ethanol was distilled off. Water is then removed from the reaction mixture in a rotary evaporator.
Stripping was performed until crystals formed. Isopropyl alcohol was added and the resulting precipitate was filtered and the solid residue was washed with isopropyl alcohol then hexane and air dried.
çæç©ã¯ïŒâã«ã«ããã·âïŒâã¢ã¶ãã·ã¯ã
ã3.1.0ããããµã³5.08KgïŒ40ã¢ã«ïŒã§ããã®98ïŒ
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ã«ãšã¹ãã«ãåºã«ããŠ75ïŒ
ã®åçã§ããã The product was 5.08Kg (40mol) of 2-carboxy-3-azabicyclo[3.1.0]hexane, 98% of which
was the trans isomer. This is a 75% yield based on the corresponding ethyl ester.
æŽæ¶²ããã³æ¶²ããæŽã«1.20Kgã®ïŒâã«ã«ãã
ã·âïŒâã¢ã¶ãã·ã¯ãã3.1.0ããããµã³ãåŸã
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ããŠããã An additional 1.20 kg of 2-carboxy-3-azabicyclo[3.1.0]hexane was obtained from the washing liquid and the liquid. It had a trans:cis ratio of 33:65.
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ã瀺ãããExample 8 Preparation of 2-cyano-3-azabicyclo[3.1.0]hexane via oxidation of 3-azabicyclo[3.1.0]hexane 1 g of 3-azabicyclo[3.1.0]hexane
(0.012 mol), manganese dioxide 5g (0.057 mol)
and gasoline with a boiling range of 40-60°C was stirred at room temperature for 4 hours. Add sodium sulfate;
The mixture was then allowed to stand for a further 4 hours and then filtered. Thin layer chromatography showed the presence of a trimer of 3-azabicyclo[3.1.0]hex-2-ene.
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ã3.1.0ããããµã³ã§ãã€ãã Then 3 ml (0.024 mol) of trimethylsilyl cyanide were added and the mixture was stirred at room temperature under nitrogen atmosphere for 20 hours. The solution became cloudy and some solid precipitated. 10 ml of water was added and the mixture was stirred for 1 hour. The aqueous layer was separated and washed with diethyl ether, and the combined organic phases were dried over sodium sulfate, filtered, and boiled down. 1.05 g of straw colored oil was obtained. 80% of this product is 2
-cyano-3-azabicyclo[3.1.0]hexane, and 20% was unreacted 3-azabicyclo[3.1.0]hexane.
Claims (1)
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ããŠãããäžè¬åŒïŒ XCN ïŒåŒäžïŒžã¯åèšã®æå³ãæããïŒ ã®ã·ã¢ã³åç©ãšåå¿ãããããšãç¹åŸŽãšããæ¹
æ³ã[Claims] 1. General formula: (In the formula, R 1 is a hydrogen atom, or unsubstituted or 1
represents an alkyl group substituted with one or more alkoxy groups, and R 2 , R 3 , R 4 , R 5 , R 6 and R 7 may be the same or each represents a hydrogen atom or an alkyl, aryl, aralkyl or alkaryl group, which may be different, and which is unsubstituted or substituted with one or more alkoxy groups, and X is a hydrogen atom, an organic acyl group or (representing a trialkylsilyl group), the general formula: (wherein R 1 to R 7 have the abovementioned meanings) and/or its trimer are reacted with a cyanide of the general formula: XCN (wherein X has the abovementioned meanings). how to. 2. Process according to claim 1 , characterized in that starting materials are used in which R 1 to R 7 each represent a hydrogen atom or an alkyl group having up to 4 carbon atoms. 3. Process according to claim 2, characterized in that starting materials are used in which R 1 to R 7 each represent a hydrogen atom. 4.Cyanide reactants are used in which X represents a hydrogen atom, an alkanoyl or aroyl group, or a trialkylsilyl group having up to 4 carbon atoms in each alkyl group. - The method described in any of the paragraphs in Section 3. 5. Process according to claim 4, characterized in that a cyanide reactant is used in which 5 X represents a hydrogen atom, a benzoyl group or a trimethylsilyl group. 6. The method of claim 5, wherein the cyanide reactant is hydrogen cyanide. 7. The method according to any one of claims 1 to 6, wherein the reaction temperature is within the range of 0 to 60°C. 8. The method according to claim 7, characterized in that the reaction temperature is in the range of 10 to 30°C. 9 Claims 1 to 8 characterized in that the cyanide reactant is used in an excess of up to 5 times
The method described in any of the sections. 10 General formula (In the formula, R 1 is a hydrogen atom, or unsubstituted or 1
represents an alkyl group substituted with one or more alkoxy groups, and R 2 , R 3 , R 4 , R 5 , R 6 and R 7 may be the same or each represents a hydrogen atom or an alkyl, aryl, aralkyl or alkaryl group unsubstituted or substituted with one or more alkoxy groups, and X is a hydrogen atom, an organic acyl group or (representing a trialkylsilyl group), the general formula: (wherein R 1 to R 7 have the above-mentioned meanings) is directly oxidized or N-chlorinated or N-brominated and then dehydrohalogenated, and the general formula: A compound of the formula : A method characterized by causing a reaction.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB7842282 | 1978-10-27 |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5559166A JPS5559166A (en) | 1980-05-02 |
JPS6232188B2 true JPS6232188B2 (en) | 1987-07-13 |
Family
ID=10500654
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP13710579A Granted JPS5559166A (en) | 1978-10-27 | 1979-10-25 | Pyrrolidine derivative and its manufacture |
Country Status (4)
Country | Link |
---|---|
JP (1) | JPS5559166A (en) |
CA (1) | CA1117128A (en) |
DK (1) | DK451379A (en) |
ZA (1) | ZA795723B (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7309717B2 (en) * | 2003-06-17 | 2007-12-18 | Schering Corporation | Process and intermediates for the preparation of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3,1,0]hexane-2-carboxylates or salts thereof |
WO2007075790A1 (en) | 2005-12-22 | 2007-07-05 | Schering Corporation | Process for the preparation of 6, 6-dimethyl-3-azabicyclo-[3.1.0]-hexane compounds and enantiomeric salts thereof |
US20110092716A1 (en) * | 2007-11-28 | 2011-04-21 | Kwok Daw-Long | Dehydrohalogenation process for the preparation of intermediates useful in providing 6,6-dimethyl-3-azabicyclo-[3.1.0]- hexane compounds |
JP2011525533A (en) * | 2008-06-24 | 2011-09-22 | ã³ãã¯ã·ã¹ïŒ ã€ã³ã³ãŒãã¬ã€ããã | A biocatalytic method for the preparation of substantially stereoisomerically pure fused bicyclic proline compounds |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5511588A (en) * | 1978-07-06 | 1980-01-26 | Shell Int Research | Derivative of 33azabicyclo*3*1*0*hexane and its manufacture |
-
1979
- 1979-09-17 CA CA000335722A patent/CA1117128A/en not_active Expired
- 1979-10-25 JP JP13710579A patent/JPS5559166A/en active Granted
- 1979-10-25 ZA ZA00795723A patent/ZA795723B/en unknown
- 1979-10-25 DK DK451379A patent/DK451379A/en not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5511588A (en) * | 1978-07-06 | 1980-01-26 | Shell Int Research | Derivative of 33azabicyclo*3*1*0*hexane and its manufacture |
Also Published As
Publication number | Publication date |
---|---|
ZA795723B (en) | 1980-10-29 |
DK451379A (en) | 1980-04-28 |
CA1117128A (en) | 1982-01-26 |
JPS5559166A (en) | 1980-05-02 |
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