JPH0592958A - Method for producing (+)-n-formyl-1-(4-methoxyphenylmethylene)-1,2,3,4,5,6,7,8-octahydroisoquinoline - Google Patents
Method for producing (+)-n-formyl-1-(4-methoxyphenylmethylene)-1,2,3,4,5,6,7,8-octahydroisoquinolineInfo
- Publication number
- JPH0592958A JPH0592958A JP3286090A JP28609091A JPH0592958A JP H0592958 A JPH0592958 A JP H0592958A JP 3286090 A JP3286090 A JP 3286090A JP 28609091 A JP28609091 A JP 28609091A JP H0592958 A JPH0592958 A JP H0592958A
- Authority
- JP
- Japan
- Prior art keywords
- binap
- complex
- ruthenium
- catalyst
- formyl
- 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.)
- Granted
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 15
- FJHQLTDBSGWURB-UHFFFAOYSA-N 1-[(4-methoxyphenyl)methylidene]-3,4,5,6,7,8-hexahydroisoquinoline-2-carbaldehyde Chemical compound C1=CC(OC)=CC=C1C=C1C(CCCC2)=C2CCN1C=O FJHQLTDBSGWURB-UHFFFAOYSA-N 0.000 title description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N phosphine group Chemical group P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 11
- 229910052718 tin Inorganic materials 0.000 claims abstract description 10
- 229910052782 aluminium Inorganic materials 0.000 claims abstract description 8
- 229910052719 titanium Inorganic materials 0.000 claims abstract description 8
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 5
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims description 26
- YBYCJQQRZPXLHU-UHFFFAOYSA-N 1,2,3,4,5,6,7,8-octahydroisoquinoline Chemical compound C1CNCC2=C1CCCC2 YBYCJQQRZPXLHU-UHFFFAOYSA-N 0.000 claims description 9
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims 1
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 claims 1
- 239000003054 catalyst Substances 0.000 abstract description 38
- GTBPUYSGSDIIMM-UHFFFAOYSA-N phosphane;ruthenium Chemical compound P.[Ru] GTBPUYSGSDIIMM-UHFFFAOYSA-N 0.000 abstract description 23
- 238000006243 chemical reaction Methods 0.000 abstract description 20
- 230000003287 optical effect Effects 0.000 abstract description 12
- 239000002994 raw material Substances 0.000 abstract description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 abstract description 7
- 150000001875 compounds Chemical class 0.000 abstract description 5
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 abstract description 3
- 230000000954 anitussive effect Effects 0.000 abstract description 3
- 229940124584 antitussives Drugs 0.000 abstract description 3
- 229960001985 dextromethorphan Drugs 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 17
- 238000000034 method Methods 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical group C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 230000003197 catalytic effect Effects 0.000 description 10
- 229910052703 rhodium Inorganic materials 0.000 description 10
- 239000010948 rhodium Substances 0.000 description 10
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 10
- -1 4- Methoxyphenylmethylene Chemical group 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 229910052751 metal Inorganic materials 0.000 description 8
- 239000002184 metal Substances 0.000 description 8
- 239000000758 substrate Substances 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000002841 Lewis acid Substances 0.000 description 6
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 6
- 239000012327 Ruthenium complex Substances 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 150000007517 lewis acids Chemical class 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000011701 zinc Substances 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- FJHQLTDBSGWURB-PDGQHHTCSA-N (1z)-1-[(4-methoxyphenyl)methylidene]-3,4,5,6,7,8-hexahydroisoquinoline-2-carbaldehyde Chemical compound C1=CC(OC)=CC=C1\C=C/1C(CCCC2)=C2CCN\1C=O FJHQLTDBSGWURB-PDGQHHTCSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 150000003303 ruthenium Chemical class 0.000 description 4
- 229910052707 ruthenium Inorganic materials 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000010936 titanium Substances 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- 102100026009 NF-kappa-B inhibitor zeta Human genes 0.000 description 3
- 101710115530 NF-kappa-B inhibitor zeta Proteins 0.000 description 3
- 238000011914 asymmetric synthesis Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- VJFARDWQCMLCGT-UHFFFAOYSA-N 1,2,3,4,4a,5-hexahydroisoquinoline Chemical compound C1C=CC=C2CNCCC21 VJFARDWQCMLCGT-UHFFFAOYSA-N 0.000 description 2
- AOBQMWZNCPVXEM-UHFFFAOYSA-N 3,4,5,6,7,8-hexahydroisoquinoline Chemical compound C1CN=CC2=C1CCCC2 AOBQMWZNCPVXEM-UHFFFAOYSA-N 0.000 description 2
- 229910020366 ClO 4 Inorganic materials 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 235000002597 Solanum melongena Nutrition 0.000 description 2
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 2
- IOPQYDKQISFMJI-UHFFFAOYSA-N [1-[2-bis(4-methylphenyl)phosphanylnaphthalen-1-yl]naphthalen-2-yl]-bis(4-methylphenyl)phosphane Chemical group C1=CC(C)=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC(C)=CC=1)C=1C=CC(C)=CC=1)C1=CC=C(C)C=C1 IOPQYDKQISFMJI-UHFFFAOYSA-N 0.000 description 2
- SDATYEQBQJQQSZ-UHFFFAOYSA-N [Sn].C(C)N(CC)CC Chemical compound [Sn].C(C)N(CC)CC SDATYEQBQJQQSZ-UHFFFAOYSA-N 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 150000003797 alkaloid derivatives Chemical class 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000004696 coordination complex Chemical class 0.000 description 2
- 230000006198 deformylation Effects 0.000 description 2
- 238000006344 deformylation reaction Methods 0.000 description 2
- 125000005610 enamide group Chemical group 0.000 description 2
- 239000011982 enantioselective catalyst Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- WJIBZZVTNMAURL-UHFFFAOYSA-N phosphane;rhodium Chemical compound P.[Rh] WJIBZZVTNMAURL-UHFFFAOYSA-N 0.000 description 2
- 239000012264 purified product Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 150000003283 rhodium Chemical class 0.000 description 2
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- 239000011592 zinc chloride Substances 0.000 description 2
- 235000005074 zinc chloride Nutrition 0.000 description 2
- KMKBEESNZAPKMP-UHFFFAOYSA-N Biphenylindanone a Chemical compound CC=1C(C)=C2C(=O)C(C3CCCC3)CC2=CC=1OCC(C=1)=CC=CC=1C1=CC=C(C(O)=O)C=C1 KMKBEESNZAPKMP-UHFFFAOYSA-N 0.000 description 1
- WMVSVUVZSYRWIY-UHFFFAOYSA-N [(4-benzoyloxyiminocyclohexa-2,5-dien-1-ylidene)amino] benzoate Chemical compound C=1C=CC=CC=1C(=O)ON=C(C=C1)C=CC1=NOC(=O)C1=CC=CC=C1 WMVSVUVZSYRWIY-UHFFFAOYSA-N 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- MKXZASYAUGDDCJ-CGTJXYLNSA-N levomethorphan Chemical compound C([C@H]12)CCC[C@@]11CCN(C)[C@@H]2CC2=CC=C(OC)C=C21 MKXZASYAUGDDCJ-CGTJXYLNSA-N 0.000 description 1
- 229950004990 levomethorphan Drugs 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 239000007858 starting material Substances 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
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Other In-Based Heterocyclic Compounds (AREA)
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、各種有機合成反応、特
に不斉水素化反応などの触媒として用いられるルテニウ
ム−ホスフィン錯体に関するものである。FIELD OF THE INVENTION The present invention relates to a ruthenium-phosphine complex used as a catalyst for various organic synthetic reactions, especially asymmetric hydrogenation reactions.
【０００２】[0002]
【従来の技術】従来、多くの遷移金属錯体が有機合成反
応の触媒として使用されている。特に貴金属錯体は高価
ではあるが、安定で取扱いが容易であるため、これを触
媒として使用する多くの合成研究がなされており、特
に、不斉合成すなわち不斉異性化反応、不斉水素化反応
などに用いられる不斉触媒について多くの報告がなされ
ている。特にロジウム金属と光学活性な第三級ホスフィ
ンによる金属錯体は不斉水素化反応の触媒として良く知
られており、たとえば、２，２′−ビス（ジフエニルホ
スフィノ）−１，１′−ビナフチル（以下、ＢＩＮＡＰ
という）を配位子としたロジウム−ホスフィン触媒が報
告されている（特開昭５５−６１９３７号公報）。2. Description of the Related Art Conventionally, many transition metal complexes have been used as catalysts for organic synthetic reactions. In particular, noble metal complexes are expensive, but since they are stable and easy to handle, many synthetic studies using them as catalysts have been carried out. In particular, asymmetric synthesis, that is, asymmetric isomerization reaction, asymmetric hydrogenation reaction Many reports have been made on asymmetric catalysts used for such purposes. In particular, a metal complex of a rhodium metal and an optically active tertiary phosphine is well known as a catalyst for an asymmetric hydrogenation reaction, and for example, 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl. (Hereafter, BINAP
, A rhodium-phosphine catalyst has been reported (JP-A-55-61937).
【０００３】また、ロジウム錯体に比べて、ルテニウム
錯体に関する報告は少ないが、ＢＩＮＡＰ及び２，２′
−ビス（ジ−ｐ−トリルホスフィノ）−１，１′−ビナ
フチル（以下、Ｔ−ＢＩＮＡＰという）を配位子とした
Ｒｕ2Ｃｌ4（ＢＩＮＡＰ）2（ＮＥｔ3）（以下、Ｅｔは
エチル基を表わす）、Ｒｕ2Ｃｌ4（Ｔ−ＢＩＮＡＰ）2
（ＮＥｔ3）のルテニウム錯体が発表されている（Ikari
yaら；J. Chem.Soc., Chem. Commun.,（１９８５）ｐ．
９２２）。また、Ｒｕ（Ｏ2ＣＨ3）2（ＢＩＮＡＰ）の
ルテニウム錯体を用いたアリルアルコールの不斉水素化
反応（Noyoriら；J.Am.Chem. Soc.,１０９（１９８７）
ｐ．１５９６）及びイソキノリン型アルカロイドの不斉
水素化反応（Noyoriら；J.Am.Chem. Soc.,１０８（１９
８６）ｐ．７１１７）が発表されている。また、［Ｒｕ
（ＢＩＮＡＰ）］Ｘ2（ここにおけるＸは、ＣｌＯ4，Ｂ
Ｆ6またはＰＦ6を表わす）は、H.TakayaらによりJ. Or
g. Chem.,５２（１９８７）ｐ．３１７４−３１７６に
発表されている。しかしながら、これらのルテニウム錯
体は、触媒活性及びその持続性について充分であるとは
言えない。Although there are few reports about ruthenium complexes as compared with rhodium complexes, BINAP and 2,2 '
- bis (di -p- tolylphosphino) -1,1'-binaphthyl (hereinafter referred to as T-BINAP) Ru 2 Cl 4 which was used as a ligand (BINAP) 2 (NEt 3) (hereinafter, Et represents an ethyl group Representation), Ru 2 Cl 4 (T-BINAP) 2
A ruthenium complex of (NEt 3 ) has been announced (Ikari
ya et al; J. Chem. Soc., Chem. Commun., (1985) p.
922). Further, asymmetric hydrogenation reaction of allyl alcohol using a ruthenium complex of Ru (O 2 CH 3 ) 2 (BINAP) (Noyori et al .; J. Am. Chem. Soc., 109 (1987).
p. 1596) and an asymmetric hydrogenation reaction of an isoquinoline type alkaloid (Noyori et al .; J. Am. Chem. Soc., 108 (19
86) p. 7117) has been announced. In addition, [Ru
(BINAP)] X 2 (where X is ClO 4 , B
F 6 or PF 6 ) is described by H. Takaya et al. In J. Or.
g. Chem., 52 (1987) p. 3174-3176. However, these ruthenium complexes are not sufficient in terms of catalytic activity and their durability.
【０００４】[0004]
【発明が解決しようとする課題】ロジウム金属はすぐれ
た錯体触媒用の金属であるが、生産地及び生産量が限ら
れており、その価格も高価なものであり、これを触媒と
して用いる場合にはその製品価格中に占めるロジウムの
価格の割合が大きくなり、商品の製造原価に影響を与え
る。これに対しルテニウム金属はロジウム金属に比して
安価であり、工業的に有利な触媒として期待されるが、
反応の精密化及び応用の点で問題が残されている。従っ
て、安価で、活性度が高く、かつ持続性があり、しかも
不斉反応における高い不斉収率、すなわち生成物の光学
純度の高いものを得ることのできる触媒が要求されてい
た。Rhodium metal is an excellent metal for a complex catalyst, but its production site and production amount are limited, and its price is also high. When it is used as a catalyst, Will increase the ratio of the price of rhodium to the product price, which will affect the manufacturing cost of the product. On the other hand, ruthenium metal is cheaper than rhodium metal and is expected as an industrially advantageous catalyst,
Problems remain with respect to reaction refinement and application. Therefore, there has been a demand for a catalyst that is inexpensive, has high activity, is durable, and can obtain a high asymmetric yield in an asymmetric reaction, that is, a product with high optical purity.
【０００５】[0005]
【課題を解決するための手段】本発明者はこのような工
業界の要請にこたえるべく研究を重ねた結果、錯体中の
配位子に光学活性をもたないものを用いれば一般合成触
媒として用いることができ、またこの配位子に光学活性
を有するものを用いれば不斉合成触媒として用いること
ができ、しかも触媒活性度が高い新規なルテニウム錯体
を見出し、ここに本発明を完成した。Means for Solving the Problems As a result of repeated research to meet the demands of the industry, the present inventor has found that if a ligand in the complex having no optical activity is used, it can be used as a general synthetic catalyst. A novel ruthenium complex which can be used, and which can be used as an asymmetric synthesis catalyst by using an optically active ligand, and has a high catalytic activity was found, and the present invention was completed here.
【０００６】すなわち、本発明は、一般式（３） ［Ｒｕ（Ｒ−ＢＩＮＡＰ）ＭＣｌk］lＸm （３） 〔式中、Ｒ−ＢＩＮＡＰは式（４）Namely, the present invention has the general formula (3) [Ru (R- BINAP) MCl k] l X m (3) wherein, R-BINAP formula (4)
【０００７】[0007]
【化４】 [Chemical 4]
【０００８】で表わされる三級ホスフィンを意味し、Ｒ
は水素原子またはメチル基を意味し、ＭはＺｎ，Ａｌ，
ＴｉまたはＳｎを意味し、ＸはＮ（Ｃ2Ｈ5）3またはＣ
Ｈ3ＣＯ 2を意味し、ＸがＮ（Ｃ2Ｈ5）3の場合、ｌが
２、ｍが１であり、かつＭがＺｎのときはｋが４、Ａｌ
のときはｋが５、ＴｉまたはＳｎのときはｋが６であ
り、ＸがＣＨ3ＣＯ2の場合、ｌが１、ｍが２であり、か
つＭがＺｎのときはｋが２、Ａｌのときはｋが３、Ｔｉ
またはＳｎのときはｋが４である〕で表わされるルテニ
ウム−ホスフィン錯体を提供するものである。A tertiary phosphine represented by
Means a hydrogen atom or a methyl group, M is Zn, Al,
Means Ti or Sn, and X is N (C2HFive)3Or C
H3CO 2Means that X is N (C2HFive)3Then l is
2, m is 1, and when M is Zn, k is 4, Al
When k is 5, k is 6 when Ti or Sn
And X is CH3CO2If, l is 1, m is 2,
When M is Zn, k is 2, when Al is k, 3 is Ti,
Or k is 4 when Sn]
An um-phosphine complex is provided.
【０００９】本発明の新規なルテニウム−ホスフィン錯
体（３）は、Ｒｕ2Ｃｌ4（Ｒ−ＢＩＮＡＰ）2ＮＥｔ3あ
るいはＲｕ（ＣＨ3ＣＯ2）2（Ｒ−ＢＩＮＡＰ）を原料
として製造することができる。The novel ruthenium-phosphine complex (3) of the present invention can be produced from Ru 2 Cl 4 (R-BINAP) 2 NEt 3 or Ru (CH 3 CO 2 ) 2 (R-BINAP) as a raw material. it can.
【００１０】原料のＲｕ2Ｃｌ4（Ｒ−ＢＩＮＡＰ）2Ｎ
Ｅｔ3は、Ikariya ら；J. Chem.Soc., Chem. Commun.,
（１９８５）ｐ．９２２、及び特開昭６１−６３６９０
号で開示されている方法により得ることができる。すな
わち、ルテニウムクロライドとシクロオクタ−１，５−
ジエン（以下、ＣＯＤと略す）をエタノール溶液中で反
応させることにより得られる［ＲｕＣｌ2（ＣＯＤ）］n
１モルと、Ｒ−ＢＩＮＡＰ １．２モルをトリエチル
アミン４モルの存在下、トルエン、エタノール等の溶媒
中で加熱反応させることにより得られる。The raw material Ru 2 Cl 4 (R-BINAP) 2 N
Et 3 is described by Ikariya et al .; J. Chem. Soc., Chem. Commun.,
(1985) p. 922, and JP-A-61-63690.
Can be obtained by the method disclosed in No. That is, ruthenium chloride and cycloocta-1,5-
[RuCl 2 (COD)] n obtained by reacting a diene (hereinafter abbreviated as COD) in an ethanol solution
It can be obtained by reacting 1 mol of R-BINAP (1.2 mol) with 4 mol of triethylamine in a solvent such as toluene or ethanol by heating.
【００１１】得られたＲｕ2Ｃｌ4（Ｒ−ＢＩＮＡＰ）2
ＮＥｔ3と、塩化亜鉛、塩化アルミニウム、四塩化チタ
ン、四塩化スズのうちより選ばれたルイス酸の１種と
を、塩化メチレンのごとき溶媒中で、１０〜２５℃の温
度で２〜２０時間反応せしめた後、溶媒を留去し、乾固
すれば本発明のルテニウム−ホスフィン錯体が得られ
る。The obtained Ru 2 Cl 4 (R-BINAP) 2
NEt 3 and one of Lewis acids selected from zinc chloride, aluminum chloride, titanium tetrachloride and tin tetrachloride in a solvent such as methylene chloride at a temperature of 10 to 25 ° C. for 2 to 20 hours. After the reaction, the solvent is distilled off and the residue is dried to obtain the ruthenium-phosphine complex of the present invention.
【００１２】もう一つの原料のＲｕ（ＣＨ3ＣＯ2）
2（Ｒ−ＢＩＮＡＰ）は、さきに本発明者らが出願した
特願昭６１−１０８８８８号の方法により得られる。す
なわち、上記方法により得られるＲｕ2Ｃｌ4（Ｒ−ＢＩ
ＮＡＰ）2ＮＥｔ3を原料とし、これと酢酸ソーダをメタ
ノール、エタノール、ｔ−ブタノール等のアルコール溶
媒中で、約２０〜１１０℃の温度で３〜１５時間反応さ
せた後、溶媒を留去して、エーテル、エタノール等の溶
媒で目的の錯体を抽出した後、乾固すれば粗製の錯体が
得られる。更に酢酸エチル等で再結晶して精製品を得る
ことができる。Ru (CH 3 CO 2 ) as another raw material
2 (R-BINAP) can be obtained by the method of Japanese Patent Application No. 61-108888 filed by the present inventors. That is, Ru 2 Cl 4 (R-BI obtained by the above method
NAP) 2 NEt 3 is used as a raw material, and this and sodium acetate are reacted in an alcohol solvent such as methanol, ethanol, or t-butanol at a temperature of about 20 to 110 ° C. for 3 to 15 hours, and then the solvent is distilled off. The target complex is extracted with a solvent such as ether or ethanol, and then dried to obtain a crude complex. Further, a purified product can be obtained by recrystallization from ethyl acetate or the like.
【００１３】得られたＲｕ（ＣＨ3ＣＯ2）2（Ｒ−ＢＩ
ＮＡＰ）と、上記のルイス酸の１種を、塩化メチレンの
ごとき溶媒中で、１０〜２５℃の温度で２〜２０時間反
応せしめた後、溶媒を留去し、乾固すれば本発明のルテ
ニウム−ホスフィン錯体が得られる。The obtained Ru (CH 3 CO 2 ) 2 (R-BI
NAP) and one of the above Lewis acids are reacted in a solvent such as methylene chloride at a temperature of 10 to 25 ° C. for 2 to 20 hours, and then the solvent is distilled off to dryness. A ruthenium-phosphine complex is obtained.
【００１４】以上の製造法において、光学活性なＲ−Ｂ
ＩＮＡＰを使用することにより、これに対応する光学活
性な性質を有するルテニウム−ホスフィン錯体を得るこ
とが出来る。In the above production method, optically active RB
By using INAP, it is possible to obtain a ruthenium-phosphine complex having an optically active property corresponding thereto.
【００１５】かくして得られる本発明のルテニウム−ホ
スフィン錯体は不斉水素化反応等の触媒として優れた性
能を有するものである。The thus obtained ruthenium-phosphine complex of the present invention has excellent performance as a catalyst for asymmetric hydrogenation reactions and the like.
【００１６】例えば、（Ｚ）−Ｎ−アシル−１−（４−
メトキシフェニルメチレン）−３，４，５，６，７，８
−ヘキサヒドロイソキノリンなどのエナミドの不斉水素
化において、日本化学会春季年会昭和６１年４月２日Ｚ
１１１Ｌ４３に発表されているＲｕ（ＣＨ3ＣＯ2）
2（ＢＩＮＡＰ）錯体では、不斉収率は高い（９８％ｅ
ｅ）が、触媒活性は基質／触媒＝１００である。これに
対して、本発明のルテニウム−ホスフィン錯体は非常に
高い触媒活性を示し、基質に対し１／３００〜１／２０
００モル濃度の錯体で反応が速やかに進行し、生成する
水素化物は、ほぼ１００％の選択性で目的物を与えると
いう優れた点を有する。また生成する光学活性アミドの
光学純度は、９０〜９５％となり工業的触媒として非常
に優れた成績を示す。For example, (Z) -N-acyl-1- (4-
Methoxyphenylmethylene) -3,4,5,6,7,8
-In the asymmetric hydrogenation of enamides such as hexahydroisoquinoline, the Chemical Society of Japan Spring Annual Meeting April 2, 1986 Z
Ru (CH 3 CO 2 ) announced in 111L43
In the case of the 2 (BINAP) complex, the asymmetric yield is high (98% e
e), the catalytic activity is substrate / catalyst = 100. On the other hand, the ruthenium-phosphine complex of the present invention exhibits a very high catalytic activity and is 1/300 to 1/20 of the substrate.
The reaction proceeds rapidly with the complex at a concentration of 00 mol, and the resulting hydride has an excellent point of providing the target product with selectivity of almost 100%. The optically active amide thus produced has an optical purity of 90 to 95%, which is extremely excellent as an industrial catalyst.
【００１７】[0017]
【実施例】次に実施例及び使用例によって、本発明を詳
しく説明する。EXAMPLES The present invention will be described in detail with reference to examples and usage examples.
【００１８】実施例１ ［Ｒｕ（（−）−Ｔ−ＢＩＮＡＰ）ＳｎＣｌ6］2ＮＥｔ
3（ビス〔ルテニウム（２，２′−ビス（ジ−ｐ−トリ
ルホスフィノ）−１，１′−ビナフチル）ヘキサクロロ
チン〕トリエチルアミン）の合成：Ｒｕ2Ｃｌ4（（−）
−Ｔ−ＢＩＮＡＰ）2ＮＥｔ3０．５２ｇ（０．３ミリモ
ル）を８０mlのシュレンク管に入れ、充分窒素置換を行
ってから、塩化メチレン２０mlと、ＳｎＣｌ4 ０．１
６ｇ（０．６ミリモル）を加え、室温にて１５時間かき
混ぜた。反応終了後、減圧下で塩化メチレンを留去し
て、乾固したところ、濃褐色の［Ｒｕ（（−）−Ｔ−Ｂ
ＩＮＡＰ）ＳｎＣｌ6］2ＮＥｔ3 ０．６８ｇを得た。
収率１００％。 元素分析値：Ｃ102Ｈ95Ｃｌ12ＮＰ4Ｓｎ2Ｒｕ2 Ｐ Ｃ Ｈ Ｃｌ 実測値（％） ５．９１ ５３．４８ ４．３６ １７．５６ 理論値（％） ５．３３ ５２．７２ ４．１２ １８．３１ 機器分析値は次の通りである。すなわち、31Ｐ核磁気共
鳴スペクトル（以下、 31ＰＮＭＲと略す）は、ブルッカ
ー社製ＡＭ４００型装置（１６１MHz ）を用いて測定
し、化学シフトは８５％リン酸を外部標準として測定し
た。31 ＰＮＭＲ（ＣＤＣｌ3）δｐｐｍ：１４．１４（ｄ，
Ｊ＝４１．７Hz） ６２．５７（ｄ，Ｊ＝４１．７Hz）Example 1 [Ru ((-)-T-BINAP) SnCl]6]2NEt
3(Bis [ruthenium (2,2'-bis (di-p-tri
Ruphosphino) -1,1'-binaphthyl) hexachloro
[Tin] triethylamine): Ru2ClFour((-)
-T-BINAP)2NEt30.52g (0.3 millimo
In a 80-mL Schlenk tube and replace it thoroughly with nitrogen.
Then, 20 ml of methylene chloride and SnClFour 0.1
Add 6 g (0.6 mmol) and stir at room temperature for 15 hours.
mixed. After the reaction was completed, the methylene chloride was distilled off under reduced pressure.
When it was evaporated to dryness, it was dark brown [Ru ((-)-TB
INAP) SnCl6]2NEt3 0.68 g was obtained.
Yield 100%. Elemental analysis value: C102H95Cl12NPFourSn2Ru2 P C H Cl actual measurement value (%) 5.91 53.48 4.36 17.56 theoretical value (%) 5.33 52.72 4.12 18.31 instrumental analysis values are as follows. That is,31P nuclear magnetic
Sound spectrum (hereinafter, 31Abbreviated as PNMR)
-Measurement using AM400 type device (161MHz)
However, the chemical shift was measured using 85% phosphoric acid as an external standard.
It was31 PNMR (CDCl3) Δppm: 14.14 (d,
J = 41.7 Hz) 62.57 (d, J = 41.7 Hz)
【００１９】実施例２ ［Ｒｕ（（−）−ＢＩＮＡＰ）ＡｌＣｌ3］（ＣＨ3ＣＯ
2）2（〔ルテニウム（２，２′−ビス（ジフェニルホス
フィノ）−１，１′−ビナフチル）トリクロロアルミニ
ウム〕ジアセテート）の合成：Ｒｕ（ＣＨ3ＣＯ2）
2（（−）−ＢＩＮＡＰ）０．６３ｇ（０．７５ミリモ
ル）を８０mlのシュレンク管に入れ、充分窒素置換を行
ってから、塩化メチレン１０mlを加え溶解させた。Ａｌ
Ｃｌ3 ０．１ｇ（０．７５ミリモル）を８０mlのシュ
レンク管に入れ、充分窒素置換を行ってから、塩化メチ
レン２０mlを加え、さらに上記で調製した、Ｒｕ（ＣＨ
3ＣＯ2）2（（−）−ＢＩＮＡＰ）の塩化メチレン溶液
を加え、１５時間かき混ぜた。反応終了後、減圧下で塩
化メチレンを留去して、乾固したところ、濃褐色［Ｒｕ
（（−）−ＢＩＮＡＰ）ＡｌＣｌ3］（ＣＨ3ＣＯ2）2
０．７３ｇを得た。収率１００％。 元素分析値：Ｃ48Ｈ38Ｏ4Ｐ2Ｃｌ3ＡｌＲｕ Ｐ Ｃ Ｈ Ｃｌ 実測値（％） ６．１７ ６０．０７ ４．３８ １１．１６ 理論値（％） ６．３５ ５９．１２ ３．９３ １０．６０31 ＰＮＭＲ（ＣＤＣｌ3）δｐｐｍ：１４．１６（ｄ，
Ｊ＝４１．５Hz） ６２．５６（ｄ，Ｊ＝４１．５Hz）Example 2 [Ru ((-)-BINAP) AlCl 3 ] (CH 3 CO
2) 2 ([ruthenium (2,2'-bis (diphenylphosphino) -1,1'-binaphthyl) trichloroacetic aluminum Synthesis of diacetate): Ru (CH 3 CO 2)
0.63 g (0.75 mmol) of 2 ((-)-BINAP) was put into an 80 ml Schlenk tube, and after sufficiently replacing with nitrogen, 10 ml of methylene chloride was added and dissolved. Al
0.1 g (0.75 mmol) of Cl 3 was put into a Schlenk tube of 80 ml, and the atmosphere was sufficiently replaced with nitrogen. Then, 20 ml of methylene chloride was added, and Ru (CH
A methylene chloride solution of 3 CO 2 ) 2 ((−)-BINAP) was added, and the mixture was stirred for 15 hours. After completion of the reaction, methylene chloride was distilled off under reduced pressure and the residue was dried to give a dark brown color [Ru
((-) - BINAP) AlCl 3] (CH 3 CO 2) 2
0.73 g was obtained. Yield 100%. Elemental analysis: C 48 H 38 O 4 P 2 Cl 3 AlRu P C H Cl Found (%) 6.17 60.07 4.38 11.16 Theoretical value (%) 6.35 59.12 3.93 10.60 31 PNMR (CDCl 3 ) δ ppm: 14.16 (d,
J = 41.5Hz) 62.56 (d, J = 41.5Hz)
【００２０】実施例３〜１６ 原料のＲ−ＢＩＮＡＰ及びルイス酸の種類を変えたほか
は、実施例３〜９は上記実施例１の方法に従い、実施例
１０〜１６は実施例２の方法に従い、それぞれの錯体を
合成した。得られた錯体の分析値を表１、表２及び表３
に示すExamples 3 to 16 Examples 3 to 9 follow the method of Example 1 above, and Examples 10 to 16 follow the method of Example 2 except that the raw materials R-BINAP and Lewis acid are changed. , And each complex was synthesized. The analytical values of the obtained complex are shown in Table 1, Table 2 and Table 3.
Shown in
【００２１】[0021]
【表１】 [Table 1]
【００２２】[0022]
【表２】 [Table 2]
【００２３】[0023]
【表３】 [Table 3]
【００２４】使用例１ （Ｚ）−Ｎ−ホルミル−１−（４−メトキシフェニルメ
チレン）−３，４，５，６，７，８−ヘキサヒドロイソ
キノリンの不斉水素化：USE EXAMPLE 1 Asymmetric hydrogenation of (Z) -N-formyl-1- (4-methoxyphenylmethylene) -3,4,5,6,7,8-hexahydroisoquinoline:
【００２５】[0025]
【化５】 [Chemical 5]
【００２６】あらかじめ乾燥し、アルゴン置換した枝付
ナスフラスコに、触媒として［Ｒｕ（（−）−Ｔ−ＢＩ
ＮＡＰ）ＳｎＣｌ6］2ＮＥｔ3 １８．８mg（０．００
８１ミリモル）を計りとり、脱気した無水メタノール４
０mlを加えた溶液を、室温で水素下２時間撹拌した。一
方、（Ｚ）−Ｎ−ホルミル−１−（４−メトキシフェニ
ルメチレン）−３，４，５，６，７，８−ヘキサヒドロ
イソキノリン５１６mg（１．８２ミリモル）を脱気した
無水メタノール２０mlに加えた溶液を別途調製した。触
媒溶液から４．３０ml（基質（モル）／触媒（モル）＝
１０００／１）を取り、基質溶液に混ぜオートクレーブ
に移し、水素気圧３５kg／cm2、７５℃で４７時間撹拌
した。撹拌終了後、減圧濃縮し、シリカゲルカラムクロ
マトグラフィーで精製して、（＋）−Ｎ−ホルミル−１
−（４−メトキシフェニルメチレン）−１，２，３，
４，５，６，７，８−オクタヒドロイソキノリン５２０
mgを得た。収率１００％。このものの旋光度は〔α〕D
25＋２２．６（ｃ＝１．１７、メタノール）であった。
光学純度は、脱ホルミル化後、生成物を２，３，４，６
−テトラ−Ｏ−アセチル−β−Ｏ−グリコピラノシルイ
ソシアネートと反応させ、逆相ＨＰＬＣ分析を行って不
斉収率を決定した結果、９８％ｅｅであった。各スペク
トルデータを次に示す。1 HNMR(400MHZ, CDCl3) δppm:1.68(m, 4H), 1.90(m,4
H), 2.20(m, 2H),2.64(dd, J=10.4, 13.9Hz, 0.6H), 2.
90(m, 2.4H),3.31(dd, J=6.6, 12.9Hz,0.4H), 3.58(d,
J=9.9Hz, 0.6H),3.77(s, 3H), 4.37(dd, J=6.7, 12.9H
z,0.6H), 4.68(broad s, 0.4H),6.80(m,2H), 6.99(m,
0.6H), 7.05(m, 0.4H),7.39(s, 0.6H),7.92(s, 0.4H)13 CNMR(100MHz, CDCl3)δppm:22.7, 22.8, 22.9, 27.7,
29.7, 30.0,30.8, 33.4, 36.3, 37.6, 40.4, 53.2, 5
5.2, 60.4, 60.8, 113.6,114.1, 127.77, 127.84, 128.
9, 129.8, 130.0, 130.2, 130.4, 158.2,158.4, 160.8,
161.1 UV(CH3OH)nm : 220, 277, 284 MS : m/e 285[Ru ((-)-T-BI] as a catalyst was placed in a branch eggplant flask that had been previously dried and purged with argon.
NAP) SnCl 6] 2 NEt 3 18.8mg (0.00
81 mmol) was weighed and degassed anhydrous methanol 4
The solution, to which 0 ml was added, was stirred at room temperature under hydrogen for 2 hours. On the other hand, 516 mg (1.82 mmol) of (Z) -N-formyl-1- (4-methoxyphenylmethylene) -3,4,5,6,7,8-hexahydroisoquinoline was added to 20 ml of degassed anhydrous methanol. The added solution was prepared separately. 4.30 ml from catalyst solution (substrate (mol) / catalyst (mol) =
1000/1) was taken, mixed with the substrate solution and transferred to an autoclave, and stirred at 75 ° C. for 47 hours under hydrogen pressure of 35 kg / cm 2 . After completion of stirring, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain (+)-N-formyl-1.
-(4-Methoxyphenylmethylene) -1,2,3
4,5,6,7,8-octahydroisoquinoline 520
to obtain mg. Yield 100%. The optical rotation of this product is [α] D
It was 25 +22.6 (c = 1.17, methanol).
The optical purity of the product was 2, 3, 4, 6 after the deformylation.
-Tetra-O-acetyl- [beta] -O-glycopyranosyl isocyanate was reacted and reverse phase HPLC analysis was performed to determine the asymmetric yield, which was 98% ee. Each spectrum data is shown below. 1 HNMR (400MH Z , CDCl 3 ) δppm: 1.68 (m, 4H), 1.90 (m, 4
H), 2.20 (m, 2H), 2.64 (dd, J = 10.4, 13.9Hz, 0.6H), 2.
90 (m, 2.4H), 3.31 (dd, J = 6.6, 12.9Hz, 0.4H), 3.58 (d,
J = 9.9Hz, 0.6H), 3.77 (s, 3H), 4.37 (dd, J = 6.7, 12.9H
z, 0.6H), 4.68 (broad s, 0.4H), 6.80 (m, 2H), 6.99 (m,
0.6H), 7.05 (m, 0.4H), 7.39 (s, 0.6H), 7.92 (s, 0.4H) 13 CNMR (100MHz, CDCl 3 ) δppm: 22.7, 22.8, 22.9, 27.7,
29.7, 30.0, 30.8, 33.4, 36.3, 37.6, 40.4, 53.2, 5
5.2, 60.4, 60.8, 113.6, 114.1, 127.77, 127.84, 128.
9, 129.8, 130.0, 130.2, 130.4, 158.2, 158.4, 160.8,
161.1 UV (CH 3 OH) nm: 220, 277, 284 MS: m / e 285
【００２７】使用例２〜１６ 使用例１と同様な反応操作により、実施例２〜１６で得
られたルテニウム−ホスフィン錯体を用いて（Ｚ）−Ｎ
−ホルミル−１−（４−メトキシフェニルメチレン）−
３，４，５，６，７，８−ヘキサヒドロイソキノリンの
不斉水素化反応を行い、（＋）−Ｎ−ホルミル−１−
（４−メトキシフェニルメチレン）−１，２，３，４，
５，６，７，８−オクタヒドロイソキノリンの製造を行
った結果を表４に示す。Use Examples 2 to 16 Using the ruthenium-phosphine complex obtained in Examples 2 to 16 in the same reaction procedure as in Use Example 1, (Z) -N.
-Formyl-1- (4-methoxyphenylmethylene)-
Asymmetric hydrogenation reaction of 3,4,5,6,7,8-hexahydroisoquinoline is carried out to obtain (+)-N-formyl-1-
(4-Methoxyphenylmethylene) -1,2,3,4
Table 4 shows the results of the production of 5,6,7,8-octahydroisoquinoline.
【００２８】[0028]
【表４】 [Table 4]
【００２９】[0029]
【発明の効果】本発明は、新規なルテニウム−ホスフィ
ン錯体を提供するものであり、この錯体は、各種有機合
成反応、特に不斉水素化反応などの触媒としてすぐれた
性能を示し、オレフィンの選択的水素化ならびに触媒活
性についても工業的にすぐれた成績を示し、且つ従来の
ロジウム系触媒などに比し、安価に作られ、製品の価格
引下げに貢献することのできる工業的価値の高いもので
ある。INDUSTRIAL APPLICABILITY The present invention provides a novel ruthenium-phosphine complex, which exhibits excellent performance as a catalyst for various organic synthetic reactions, especially asymmetric hydrogenation reactions, and is a preferred olefin. It also has excellent industrial hydrogenation and catalytic activity results, is cheaper than conventional rhodium-based catalysts, etc., and has a high industrial value that can contribute to price reduction of products. is there.
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【手続補正書】[Procedure amendment]
【提出日】平成３年１１月６日[Submission date] November 6, 1991
【手続補正１】[Procedure Amendment 1]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】発明の詳細な説明[Name of item to be amended] Detailed explanation of the invention
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【発明の詳細な説明】Detailed Description of the Invention
【０００１】[0001]
【産業上の利用分野】本発明は、鎮咳薬デキストロメト
ルファンの合成中間体として有用な（＋）−Ｎ−ホルミ
ル−１−（４−メトキシフェニルメチレン）−１，２，
３，４，５，６，７，８−オクタヒドロイソキノリンの
製造方法に関するものである。TECHNICAL FIELD The present invention relates to (+)-N-formyl-1- (4-methoxyphenylmethylene) -1,2, which is useful as a synthetic intermediate for the antitussive drug dextromethorphan.
The present invention relates to a method for producing 3,4,5,6,7,8-octahydroisoquinoline.
【０００２】[0002]
【従来の技術】従来、多くの遷移金属錯体が有機合成反
応の触媒として使用されている。特に貴金属錯体は高価
ではあるが、安定で取扱いが容易であるため、これを触
媒として使用する多くの合成研究がなされており、特
に、不斉合成すなわち不斉異性化反応、不斉水素化反応
などに用いられる不斉触媒について多くの報告がなされ
ている。特にロジウム金属と光学活性な第三級ホスフィ
ンによる金属錯体は不斉水素化反応の触媒として良く知
られており、たとえば、２，２′−ビス（ジフェニルホ
スフィノ）−１，１′−ビナフチル（以下、ＢＩＮＡＰ
という）を配位子としたロジウム−ホスフィン触媒が報
告されている（特開昭５５−６１９３７号公報）。2. Description of the Related Art Conventionally, many transition metal complexes have been used as catalysts for organic synthetic reactions. In particular, noble metal complexes are expensive, but since they are stable and easy to handle, many synthetic studies using them as catalysts have been carried out. In particular, asymmetric synthesis, that is, asymmetric isomerization reaction, asymmetric hydrogenation reaction Many reports have been made on asymmetric catalysts used for such purposes. In particular, a metal complex of a rhodium metal and an optically active tertiary phosphine is well known as a catalyst for an asymmetric hydrogenation reaction. For example, 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl ( Below, BINAP
, A rhodium-phosphine catalyst has been reported (JP-A-55-61937).
【０００３】また、ロジウム錯体に比べて、ルテニウム
錯体に関する報告は少ないが、ＢＩＮＡＰ及び２，２′
−ビス（ジ−ｐ−トリルホスフィノ）−１，１′−ビナ
フチル（以下、Ｔ−ＢＩＮＡＰという）を配位子とした
Ｒｕ2Ｃｌ4（ＢＩＮＡＰ）2（ＮＥｔ3）（以下、Ｅｔは
エチル基を表わす）、Ｒｕ2Ｃｌ4（Ｔ−ＢＩＮＡＰ）2
（ＮＥｔ3）のルテニウム錯体が発表されている（Ikari
yaら；J. Chem.Soc., Chem. Commun.,（１９８５）ｐ．
９２２）。また、Ｒｕ（Ｏ2ＣＨ3）2（ＢＩＮＡＰ）の
ルテニウム錯体を用いたアリルアルコールの不斉水素化
反応（Noyoriら；J.Am.Chem. Soc.,１０９（１９８７）
ｐ．１５９６）及びイソキノリン型アルカロイドの不斉
水素化反応（Noyoriら；J.Am.Chem. Soc.,１０８（１９
８６）ｐ．７１１７）が発表されている。また、［Ｒｕ
（ＢＩＮＡＰ）］Ｘ2（ここにおけるＸは、ＣｌＯ4，Ｂ
Ｆ6またはＰＦ6を表わす）は、H.TakayaらによりJ. Or
g. Chem.,５２（１９８７）ｐ．３１７４−３１７６に
発表されている。しかしながら、これらのルテニウム錯
体は、触媒活性及びその持続性について充分であるとは
言えない。Although there are few reports about ruthenium complexes as compared with rhodium complexes, BINAP and 2,2 '
- bis (di -p- tolylphosphino) -1,1'-binaphthyl (hereinafter referred to as T-BINAP) Ru 2 Cl 4 which was used as a ligand (BINAP) 2 (NEt 3) (hereinafter, Et represents an ethyl group Representation), Ru 2 Cl 4 (T-BINAP) 2
A ruthenium complex of (NEt 3 ) has been announced (Ikari
ya et al; J. Chem. Soc., Chem. Commun., (1985) p.
922). Further, asymmetric hydrogenation reaction of allyl alcohol using a ruthenium complex of Ru (O 2 CH 3 ) 2 (BINAP) (Noyori et al .; J. Am. Chem. Soc., 109 (1987).
p. 1596) and an asymmetric hydrogenation reaction of an isoquinoline type alkaloid (Noyori et al .; J. Am. Chem. Soc., 108 (19
86) p. 7117) has been announced. In addition, [Ru
(BINAP)] X 2 (where X is ClO 4 , B
F 6 or PF 6 ) is described by H. Takaya et al. In J. Or.
g. Chem., 52 (1987) p. 3174-3176. However, these ruthenium complexes are not sufficient in terms of catalytic activity and their durability.
【０００４】[0004]
【発明が解決しようとする課題】ロジウム金属はすぐれ
た錯体触媒用の金属であるが、生産地及び生産量が限ら
れており、その価格も高価なものであり、これを触媒と
して用いる場合にはその製品価格中に占めるロジウムの
価格の割合が大きくなり、商品の製造原価に影響を与え
る。これに対しルテニウム金属はロジウム金属に比して
安価であり、工業的に有利な触媒として期待されるが、
反応の精密化及び応用の点で問題が残されている。従っ
て、安価で、活性度が高く、かつ持続性があり、しかも
不斉反応における高い不斉収率、すなわち生成物の光学
純度の高いものを得ることのできる触媒が要求されてい
た。一方、（＋）−Ｎ−ホルミル−１−（４−メトキシ
フェニルメチレン）−１，２，３，４，５，６，７，８
−オクタヒドロイソキノリンは、鎮咳薬として用いられ
るデキストロメトルファンの合成中間体として有用であ
り、これは一般に（Ｚ）−Ｎ−ホルミル−１−（４−メ
トキシフェニルメチレン）−３，４，５，６，７，８−
ヘキサヒドロイソキノリンを不斉水素化して合成されて
いる。しかし、従来の不斉水素化反応の不斉収率、得ら
れた生成物の光学純度は未だ充分満足できるものではな
かった。Rhodium metal is an excellent metal for a complex catalyst, but its production site and production amount are limited, and its price is also high. When it is used as a catalyst, Will increase the ratio of the price of rhodium to the product price, which will affect the manufacturing cost of the product. On the other hand, ruthenium metal is cheaper than rhodium metal and is expected as an industrially advantageous catalyst,
Problems remain with respect to reaction refinement and application. Therefore, there has been a demand for a catalyst that is inexpensive, has high activity, is durable, and can obtain a high asymmetric yield in an asymmetric reaction, that is, a product with high optical purity. On the other hand, (+)-N-formyl-1- (4-methoxyphenylmethylene) -1,2,3,4,5,6,7,8
-Octahydroisoquinoline is useful as a synthetic intermediate for dextromethorphan used as an antitussive, which is generally (Z) -N-formyl-1- (4-methoxyphenylmethylene) -3,4,5,5. 6,7,8-
It is synthesized by asymmetric hydrogenation of hexahydroisoquinoline. However, the asymmetric yield of the conventional asymmetric hydrogenation reaction and the optical purity of the obtained product have not been sufficiently satisfactory.
【０００５】[0005]
【課題を解決するための手段】本発明者はこのような工
業界の要請にこたえるべく研究を重ねた結果、触媒活性
度が高い新規なルテニウム錯体を用いて不斉水素化を行
えば、高選択率かつ高純度で（＋）−Ｎ−ホルミル−１
−（４−メトキシフェニルメチレン）−１，２，３，
４，５，６，７，８−オクタヒドロイソキノリンを製造
することができることを見出し、ここに本発明を完成し
た。本発明の製造方法は次の反応式で示される。Means for Solving the Problems As a result of repeated research aimed at meeting the demands of the industry, the present inventor has found that if asymmetric hydrogenation is carried out using a novel ruthenium complex having a high catalytic activity, a high (+)-N-formyl-1 with high selectivity and high purity
-(4-Methoxyphenylmethylene) -1,2,3
It was found that 4,5,6,7,8-octahydroisoquinoline can be produced, and the present invention has been completed here. The production method of the present invention is represented by the following reaction formula.
【０００６】[0006]
【化４】 [Chemical 4]
【０００７】[0007]
【化５】 [Chemical 5]
【０００８】で表わされる三級ホスフィンを意味し、Ｒ
は水素原子またはメチル基を意味し、ＭはＺｎ，Ａｌ，
ＴｉまたはＳｎを意味し、ＸはＮ（Ｃ2Ｈ5）3またはＣ
Ｈ3ＣＯ 2を意味し、ＸがＮ（Ｃ2Ｈ5）3の場合、ｌが
２、ｍが１であり、かつＭがＺｎのときはｋが４、Ａｌ
のときはｋが５、ＴｉまたはＳｎのときはｋが６であ
り、ＸがＣＨ3ＣＯ2の場合、ｌが１、ｍが２であり、か
つＭがＺｎのときはｋが２、Ａｌのときはｋが３、Ｔｉ
またはＳｎのときはｋが４である〕すなわち、本発明は
式（２）で表わされる（Ｚ）−Ｎ−ホルミル−１−（４
−メトキシフェニルメチレン）−３，４，５，６，７，
８−ヘキサヒドロイソキノリンを、一般式（３）で表わ
されるルテニウム−ホスフィン錯体の存在下、不斉水素
化することを特徴とする式（１）で表わされる（＋）−
Ｎ−ホルミル−１−（４−メトキシフェニルメチレン）
−１，２，３，４，５，６，７，８−オクタヒドロイソ
キノリンの製造方法を提供するものである。A tertiary phosphine represented by
Means a hydrogen atom or a methyl group, M is Zn, Al,
Means Ti or Sn, and X is N (C2HFive)3Or C
H3CO 2Means that X is N (C2HFive)3Then l is
2, m is 1, and when M is Zn, k is 4, Al
When k is 5, k is 6 when Ti or Sn
And X is CH3CO2If, l is 1, m is 2,
When M is Zn, k is 2, when Al is k, 3 is Ti,
Or when k is 4 when Sn], that is, the present invention
(Z) -N-formyl-1- (4) represented by formula (2)
-Methoxyphenylmethylene) -3,4,5,6,7,
8-hexahydroisoquinoline is represented by the general formula (3).
Hydrogen in the presence of a ruthenium-phosphine complex
(+) − Represented by the equation (1), which is characterized by
N-formyl-1- (4-methoxyphenylmethylene)
-1,2,3,4,5,6,7,8-octahydroiso
A method for producing quinoline is provided.
【０００９】本発明において用いられるルテニウム−ホ
スフィン錯体（３）は、Ｒｕ2Ｃｌ4（（−）−Ｒ−ＢＩ
ＮＡＰ）2ＮＥｔ3あるいはＲｕ（ＣＨ3ＣＯ2）
2（（−）−Ｒ−ＢＩＮＡＰ）を原料として製造するこ
とができる。The ruthenium-phosphine complex (3) used in the present invention is Ru 2 Cl 4 ((-)-R-BI.
NAP) 2 NEt 3 or Ru (CH 3 CO 2 ).
2 ((-)-R-BINAP) can be used as a starting material.
【００１０】原料のＲｕ2Ｃｌ4（（−）−Ｒ−ＢＩＮＡ
Ｐ）2ＮＥｔ3は、Ikariya ら；J. Chem.Soc., Chem. Co
mmun.,（１９８５）ｐ．９２２、及び特開昭６１−６３
６９０号で開示されている方法により得ることができ
る。すなわち、ルテニウムクロライドとシクロオクタ−
１，５−ジエン（以下、ＣＯＤと略す）をエタノール溶
液中で反応させることにより得られる［ＲｕＣｌ2（Ｃ
ＯＤ）］n １モルと、（−）−Ｒ−ＢＩＮＡＰ １．
２モルをトリエチルアミン４モルの存在下、トルエン、
エタノール等の溶媒中で加熱反応させることにより得ら
れる。The raw material Ru 2 Cl 4 ((-)-R-BINA
P) 2 NEt 3 is described by Ikariya et al .; J. Chem. Soc., Chem. Co.
mmun., (1985) p. 922, and JP-A-61-63.
It can be obtained by the method disclosed in No. 690. That is, ruthenium chloride and cycloocta-
Obtained by reacting 1,5-diene (hereinafter abbreviated as COD) in an ethanol solution [RuCl 2 (C
OD)] n 1 mol and (-)-R-BINAP 1.
2 mol of toluene in the presence of 4 mol of triethylamine,
It is obtained by heating and reacting in a solvent such as ethanol.
【００１１】得られたＲｕ2Ｃｌ4（（−）−Ｒ−ＢＩＮ
ＡＰ）2ＮＥｔ3と、塩化亜鉛、塩化アルミニウム、四塩
化チタン、四塩化スズのうちより選ばれたルイス酸の１
種とを、塩化メチレンのごとき溶媒中で、１０〜２５℃
の温度で２〜２０時間反応せしめた後、溶媒を留去し、
乾固すればルテニウム−ホスフィン錯体（３）が得られ
る。The obtained Ru 2 Cl 4 ((-)-R-BIN
AP) 2 NEt 3 and one of Lewis acids selected from zinc chloride, aluminum chloride, titanium tetrachloride and tin tetrachloride.
Seeds in a solvent such as methylene chloride at 10 to 25 ° C.
After reacting at the temperature of 2 to 20 hours, the solvent is distilled off,
The ruthenium-phosphine complex (3) can be obtained by drying.
【００１２】もう一つの原料のＲｕ（ＣＨ3ＣＯ2）
2（（−）−Ｒ−ＢＩＮＡＰ）は、さきに本発明者らが
出願した特願昭６１−１０８８８８号の方法により得ら
れる。すなわち、上記方法により得られるＲｕ2Ｃｌ
4（（−）−Ｒ−ＢＩＮＡＰ）2ＮＥｔ3を原料とし、こ
れと酢酸ソーダをメタノール、エタノール、ｔ−ブタノ
ール等のアルコール溶媒中で、約２０〜１１０℃の温度
で３〜１５時間反応させた後、溶媒を留去して、エーテ
ル、エタノール等の溶媒で目的の錯体を抽出した後、乾
固すれば粗製の錯体が得られる。更に酢酸エチル等で再
結晶して精製品を得ることができる。Ru (CH 3 CO 2 ) as another raw material
2 ((-)-R-BINAP) is obtained by the method of Japanese Patent Application No. 61-108888 filed by the present inventors. That is, Ru 2 Cl obtained by the above method
4 ((−)-R-BINAP) 2 NEt 3 is used as a raw material, and this is reacted with sodium acetate in an alcohol solvent such as methanol, ethanol, or t-butanol at a temperature of about 20 to 110 ° C. for 3 to 15 hours. After that, the solvent is distilled off, the target complex is extracted with a solvent such as ether or ethanol, and then dried to obtain a crude complex. Further, a purified product can be obtained by recrystallization from ethyl acetate or the like.
【００１３】得られたＲｕ（ＣＨ3ＣＯ2）2（（−）−
Ｒ−ＢＩＮＡＰ）と、上記のルイス酸の１種を、塩化メ
チレンのごとき溶媒中で、１０〜２５℃の温度で２〜２
０時間反応せしめた後、溶媒を留去し、乾固すればルテ
ニウム−ホスフィン錯体（３）が得られる。The obtained Ru (CH 3 CO 2 ) 2 ((-)-
R-BINAP) and one of the above Lewis acids in a solvent such as methylene chloride at a temperature of 10 to 25 ° C. for 2 to 2
After reacting for 0 hour, the solvent is distilled off and the residue is dried to give a ruthenium-phosphine complex (3).
【００１４】かくして得られるルテニウム−ホスフィン
錯体（３）は不斉水素化反応等の触媒として優れた性能
を有するものである。The ruthenium-phosphine complex (3) thus obtained has excellent performance as a catalyst for asymmetric hydrogenation reactions and the like.
【００１５】ルテニウム−ホスフィン錯体（３）を触媒
として用いる化合物（２）の不斉水素化反応は、後記実
施例に示すように通常の不斉水素化反応と同様にして実
施することができる。すなわち、例えば無水メタノール
等の溶媒中、化合物（２）に対し１／３００〜１／２０
００モル程度のルテニウム−ホスフィン錯体（３）を加
え水素化すればよい。The asymmetric hydrogenation reaction of the compound (2) using the ruthenium-phosphine complex (3) as a catalyst can be carried out in the same manner as a usual asymmetric hydrogenation reaction as shown in Examples below. That is, for example, 1/300 to 1/20 with respect to the compound (2) in a solvent such as anhydrous methanol.
The ruthenium-phosphine complex (3) in an amount of about 100 mol may be added and hydrogenated.
【００１６】（Ｚ）−Ｎ−アシル−１−（４−メトキシ
フェニルメチレン）−３，４，５，６，７，８−ヘキサ
ヒドロイソキノリンなどのエナミドの不斉水素化におい
て、日本化学会春季年会昭和６１年４月２日Ｚ１１１Ｌ
４３に発表されているＲｕ（ＣＨ3ＣＯ2）2（ＢＩＮＡ
Ｐ）錯体では、不斉収率は高い（９８％ｅｅ）が、触媒
活性は基質／触媒＝１００である。これに対して、本発
明に用いられるルテニウム−ホスフィン錯体（３）は非
常に高い触媒活性を示し、基質に対し１／３００〜１／
２０００モル濃度の錯体で反応が速やかに進行し、生成
する水素化物は、ほぼ１００％の選択性で目的物を与え
るという優れた点を有する。また生成する光学活性アミ
ドの光学純度は、９０〜９５％となり工業的触媒として
非常に優れた成績を示す。尚、本発明において用いられ
るルテニウム−ホスフィン錯体（３）の配位子である
（−）−Ｒ−ＢＩＮＡＰのかわりに、その光学異性体で
ある（＋）−Ｒ−ＢＩＮＡＰを配位子とする一般式
（５） ［Ｒｕ（（＋）−Ｒ−ＢＩＮＡＰ）ＭＣｌk］lＸm （５） 〔式中、Ｒ−ＢＩＮＡＰ，Ｍ，Ｘ，ｋ，ｌ及びｍは前記
と同じ意味を示す〕で表わされるルテニウム−ホスフィ
ン錯体を用いて、本発明と同様の方法で（Ｚ）−Ｎ−ホ
ルミル−１−（４−メトキシフェニルメチレン）−３，
４，５，６，７，８−ヘキサヒドロイソキノリンを不斉
水素化すれば、（−）−Ｎ−ホルミル−１−（４−メト
キシフェニルメチレン）−１，２，３，４，５，６，
７，８−オクタヒドロイソキノリンを得ることができる
が、この化合物を合成中間体として得ることができるレ
ボメトルファンは、鎮痛、呼吸抑制及び鎮咳作用を有す
る麻薬である。In the asymmetric hydrogenation of enamides such as (Z) -N-acyl-1- (4-methoxyphenylmethylene) -3,4,5,6,7,8-hexahydroisoquinoline, the Chemical Society of Japan Spring Annual meeting April 2, 1986 Z111L
Ru (CH 3 CO 2 ) 2 (BINA
In the P) complex, the asymmetric yield is high (98% ee), but the catalytic activity is substrate / catalyst = 100. On the other hand, the ruthenium-phosphine complex (3) used in the present invention has a very high catalytic activity and is 1/300 to 1/1 / the substrate.
The reaction proceeds rapidly with a complex having a concentration of 2000 mol, and the resulting hydride has an excellent point of giving the target product with a selectivity of almost 100%. The optically active amide thus produced has an optical purity of 90 to 95%, which is extremely excellent as an industrial catalyst. Instead of (-)-R-BINAP which is a ligand of the ruthenium-phosphine complex (3) used in the present invention, (+)-R-BINAP which is its optical isomer is used as a ligand. formula (5) [Ru ((+ ) - R-BINAP) MCl k] l X m (5) wherein, R-BINAP, M, X , k, l and m are as defined above] In the same manner as in the present invention, a ruthenium-phosphine complex represented by (Z) -N-formyl-1- (4-methoxyphenylmethylene) -3,
Asymmetric hydrogenation of 4,5,6,7,8-hexahydroisoquinoline yields (-)-N-formyl-1- (4-methoxyphenylmethylene) -1,2,3,4,5,6. ，
Levomethorphan, which makes it possible to obtain 7,8-octahydroisoquinoline, but obtains this compound as a synthetic intermediate, is a drug having analgesic, respiratory depressant and antitussive effects.
【００１７】[0017]
【実施例】次に参考例及び実施例によって、本発明を詳
しく説明する。The present invention will be described in detail with reference to Reference Examples and Examples.
【００１８】参考例１ ［Ｒｕ（（−）−Ｔ−ＢＩＮＡＰ）ＳｎＣｌ6］2ＮＥｔ
3（ビス〔ルテニウム（２，２′−ビス（ジ−ｐ−トリ
ルホスフィノ）−１，１′−ビナフチル）ヘキサクロロ
チン〕トリエチルアミン）の合成：Ｒｕ2Ｃｌ4（（−）
−Ｔ−ＢＩＮＡＰ）2ＮＥｔ3０．５２ｇ（０．３ミリモ
ル）を８０mlのシュレンク管に入れ、充分窒素置換を行
ってから、塩化メチレン２０mlと、ＳｎＣｌ4 ０．１
６ｇ（０．６ミリモル）を加え、室温にて１５時間かき
混ぜた。反応終了後、減圧下で塩化メチレンを留去し
て、乾固したところ、濃褐色の［Ｒｕ（（−）−Ｔ−Ｂ
ＩＮＡＰ）ＳｎＣｌ6］2ＮＥｔ3 ０．６８ｇを得た。
収率１００％。 元素分析値：Ｃ102Ｈ95Ｃｌ12ＮＰ4Ｓｎ2Ｒｕ2 Ｐ Ｃ Ｈ Ｃｌ 実測値（％） ５．９１ ５３．４８ ４．３６ １７．５６ 理論値（％） ５．３３ ５２．７２ ４．１２ １８．３１ 機器分析値は次の通りである。すなわち、31Ｐ核磁気共
鳴スペクトル（以下、 31ＰＮＭＲと略す）は、ブルッカ
ー社製ＡＭ４００型装置（１６１MHz ）を用いて測定
し、化学シフトは８５％リン酸を外部標準として測定し
た。31 ＰＮＭＲ（ＣＤＣｌ3）δｐｐｍ：１４．１４（ｄ，
Ｊ＝４１．７Hz） ６２．５７（ｄ，Ｊ＝４１．７Hz）Reference Example 1 [Ru ((-)-T-BINAP) SnCl]6]2NEt
3(Bis [ruthenium (2,2'-bis (di-p-tri
Ruphosphino) -1,1'-binaphthyl) hexachloro
[Tin] triethylamine): Ru2ClFour((-)
-T-BINAP)2NEt30.52g (0.3 millimo
In a 80-mL Schlenk tube and replace it thoroughly with nitrogen.
Then, 20 ml of methylene chloride and SnClFour 0.1
Add 6 g (0.6 mmol) and stir at room temperature for 15 hours.
mixed. After the reaction was completed, the methylene chloride was distilled off under reduced pressure.
When it was evaporated to dryness, it was dark brown [Ru ((-)-TB
INAP) SnCl6]2NEt3 0.68 g was obtained.
Yield 100%. Elemental analysis value: C102H95Cl12NPFourSn2Ru2 P C H Cl actual measurement value (%) 5.91 53.48 4.36 17.56 theoretical value (%) 5.33 52.72 4.12 18.31 instrumental analysis values are as follows. That is,31P nuclear magnetic
Sound spectrum (hereinafter, 31Abbreviated as PNMR)
-Measurement using AM400 type device (161MHz)
However, the chemical shift was measured using 85% phosphoric acid as an external standard.
It was31 PNMR (CDCl3) Δppm: 14.14 (d,
J = 41.7 Hz) 62.57 (d, J = 41.7 Hz)
【００１９】参考例２ ［Ｒｕ（（−）−ＢＩＮＡＰ）ＡｌＣｌ3］（ＣＨ3ＣＯ
2）2（〔ルテニウム（２，２′−ビス（ジフェニルホス
フィノ）−１，１′−ビナフチル）トリクロロアルミニ
ウム〕ジアセテート）の合成：Ｒｕ（ＣＨ3ＣＯ2）
2（（−）−ＢＩＮＡＰ）０．６３ｇ（０．７５ミリモ
ル）を８０mlのシュレンク管に入れ、充分窒素置換を行
ってから、塩化メチレン１０mlを加え溶解させた。Ａｌ
Ｃｌ3 ０．１ｇ（０．７５ミリモル）を８０mlのシュ
レンク管に入れ、充分窒素置換を行ってから、塩化メチ
レン２０mlを加え、さらに上記で調製した、Ｒｕ（ＣＨ
3ＣＯ2）2（（−）−ＢＩＮＡＰ）の塩化メチレン溶液
を加え、１５時間かき混ぜた。反応終了後、減圧下で塩
化メチレンを留去して、乾固したところ、濃褐色［Ｒｕ
（（−）−ＢＩＮＡＰ）ＡｌＣｌ3］（ＣＨ3ＣＯ2）2
０．７３ｇを得た。収率１００％。 元素分析値：Ｃ48Ｈ38Ｏ4Ｐ2Ｃｌ3ＡｌＲｕ Ｐ Ｃ Ｈ Ｃｌ 実測値（％） ６．１７ ６０．０７ ４．３８ １１．１６ 理論値（％） ６．３５ ５９．１２ ３．９３ １０．６０31 ＰＮＭＲ（ＣＤＣｌ3）δｐｐｍ：１４．１６（ｄ，
Ｊ＝４１．５Hz） ６２．５６（ｄ，Ｊ＝４１．５Hz）Reference Example 2 [Ru ((-)-BINAP) AlCl 3 ] (CH 3 CO
2) 2 ([ruthenium (2,2'-bis (diphenylphosphino) -1,1'-binaphthyl) trichloroacetic aluminum Synthesis of diacetate): Ru (CH 3 CO 2)
0.63 g (0.75 mmol) of 2 ((-)-BINAP) was put into an 80 ml Schlenk tube, and after sufficiently replacing with nitrogen, 10 ml of methylene chloride was added and dissolved. Al
0.1 g (0.75 mmol) of Cl 3 was put into a Schlenk tube of 80 ml, and the atmosphere was sufficiently replaced with nitrogen. Then, 20 ml of methylene chloride was added, and Ru (CH
A methylene chloride solution of 3 CO 2 ) 2 ((−)-BINAP) was added, and the mixture was stirred for 15 hours. After completion of the reaction, methylene chloride was distilled off under reduced pressure and the residue was dried to give a dark brown color [Ru
((-) - BINAP) AlCl 3] (CH 3 CO 2) 2
0.73 g was obtained. Yield 100%. Elemental analysis: C 48 H 38 O 4 P 2 Cl 3 AlRu P C H Cl Found (%) 6.17 60.07 4.38 11.16 Theoretical value (%) 6.35 59.12 3.93 10.60 31 PNMR (CDCl 3 ) δ ppm: 14.16 (d,
J = 41.5Hz) 62.56 (d, J = 41.5Hz)
【００２０】参考例３〜１６ 原料のＲ−ＢＩＮＡＰ及びルイス酸の種類を変えたほか
は、参考例３〜９は上記参考例１の方法に従い、参考例
１０〜１６は参考例２の方法に従い、それぞれの錯体を
合成した。得られた錯体の分析値を表１、表２及び表３
に示すReference Examples 3 to 16 Reference Examples 3 to 9 follow the method of Reference Example 1 above, and Reference Examples 10 to 16 follow the method of Reference Example 2 except that the kinds of the raw materials R-BINAP and Lewis acid are changed. , And each complex was synthesized. The analytical values of the obtained complex are shown in Table 1, Table 2 and Table 3.
Shown in
【００２１】[0021]
【表１】 [Table 1]
【００２２】[0022]
【表２】 [Table 2]
【００２３】[0023]
【表３】 [Table 3]
【００２４】実施例１ （Ｚ）−Ｎ−ホルミル−１−（４−メトキシフェニルメ
チレン）−３，４，５，６，７，８−ヘキサヒドロイソ
キノリンの不斉水素化：Example 1 Asymmetric hydrogenation of (Z) -N-formyl-1- (4-methoxyphenylmethylene) -3,4,5,6,7,8-hexahydroisoquinoline:
【００２５】[0025]
【化６】 [Chemical 6]
【００２６】あらかじめ乾燥し、アルゴン置換した枝付
ナスフラスコに、触媒として［Ｒｕ（（−）−Ｔ−ＢＩ
ＮＡＰ）ＳｎＣｌ6］2ＮＥｔ3 １８．８mg（０．００
８１ミリモル）を計りとり、脱気した無水メタノール４
０mlを加えた溶液を、室温で水素下２時間撹拌した。一
方、（Ｚ）−Ｎ−ホルミル−１−（４−メトキシフェニ
ルメチレン）−３，４，５，６，７，８−ヘキサヒドロ
イソキノリン５１６mg（１．８２ミリモル）を脱気した
無水メタノール２０mlに加えた溶液を別途調製した。触
媒溶液から４．３０ml（基質（モル）／触媒（モル）＝
１０００／１）を取り、基質溶液に混ぜオートクレーブ
に移し、水素気圧３５kg／cm2、７５℃で４７時間撹拌
した。撹拌終了後、減圧濃縮し、シリカゲルカラムクロ
マトグラフィーで精製して、（＋）−Ｎ−ホルミル−１
−（４−メトキシフェニルメチレン）−１，２，３，
４，５，６，７，８−オクタヒドロイソキノリン５２０
mgを得た。収率１００％。このものの旋光度は〔α〕D
25 ＋２２．６（ｃ＝１．１７、メタノール）であっ
た。光学純度は、脱ホルミル化後、生成物を２，３，
４，６−テトラ−Ｏ−アセチル−β−Ｏ−グリコピラノ
シルイソシアネートと反応させ、逆相ＨＰＬＣ分析を行
って不斉収率を決定した結果、９８％ｅｅであった。各
スペクトルデータを次に示す。1 HNMR(400MHZ, CDCl3) δppm:1.68(m, 4H), 1.90(m,4
H), 2.20(m, 2H),2.64(dd, J=10.4, 13.9Hz, 0.6H), 2.
90(m, 2.4H),3.31(dd, J=6.6, 12.9Hz,0.4H), 3.58(d,
J=9.9Hz, 0.6H),3.77(s, 3H), 4.37(dd, J=6.7, 12.9H
z,0.6H), 4.68(broad s, 0.4H),6.80(m,2H), 6.99(m,
0.6H), 7.05(m, 0.4H),7.39(s, 0.6H),7.92(s, 0.4H)13 CNMR(100MHz, CDCl3)δppm:22.7, 22.8, 22.9, 27.7,
29.7, 30.0,30.8, 33.4, 36.3, 37.6, 40.4, 53.2, 5
5.2, 60.4, 60.8, 113.6,114.1, 127.77, 127.84, 128.
9, 129.8, 130.0, 130.2, 130.4, 158.2,158.4, 160.8,
161.1 UV(CH3OH)nm : 220, 277, 284 MS : m/e 285[Ru ((-)-T-BI] as a catalyst was placed in a branch eggplant flask that had been previously dried and purged with argon.
NAP) SnCl 6] 2 NEt 3 18.8mg (0.00
81 mmol) was weighed and degassed anhydrous methanol 4
The solution, to which 0 ml was added, was stirred at room temperature under hydrogen for 2 hours. On the other hand, 516 mg (1.82 mmol) of (Z) -N-formyl-1- (4-methoxyphenylmethylene) -3,4,5,6,7,8-hexahydroisoquinoline was added to 20 ml of degassed anhydrous methanol. The added solution was prepared separately. 4.30 ml from catalyst solution (substrate (mol) / catalyst (mol) =
1000/1) was taken, mixed with the substrate solution and transferred to an autoclave, and stirred at 75 ° C. for 47 hours under hydrogen pressure of 35 kg / cm 2 . After completion of stirring, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain (+)-N-formyl-1.
-(4-Methoxyphenylmethylene) -1,2,3
4,5,6,7,8-octahydroisoquinoline 520
to obtain mg. Yield 100%. The optical rotation of this product is [α] D
It was 25 +22.6 (c = 1.17, methanol). The optical purity of the product was 2,3 after deformylation.
The reaction was carried out with 4,6-tetra-O-acetyl-β-O-glycopyranosyl isocyanate and reverse phase HPLC analysis was carried out to determine the asymmetric yield. As a result, it was 98% ee. Each spectrum data is shown below. 1 HNMR (400MH Z , CDCl 3 ) δppm: 1.68 (m, 4H), 1.90 (m, 4
H), 2.20 (m, 2H), 2.64 (dd, J = 10.4, 13.9Hz, 0.6H), 2.
90 (m, 2.4H), 3.31 (dd, J = 6.6, 12.9Hz, 0.4H), 3.58 (d,
J = 9.9Hz, 0.6H), 3.77 (s, 3H), 4.37 (dd, J = 6.7, 12.9H
z, 0.6H), 4.68 (broad s, 0.4H), 6.80 (m, 2H), 6.99 (m,
0.6H), 7.05 (m, 0.4H), 7.39 (s, 0.6H), 7.92 (s, 0.4H) 13 CNMR (100MHz, CDCl 3 ) δppm: 22.7, 22.8, 22.9, 27.7,
29.7, 30.0, 30.8, 33.4, 36.3, 37.6, 40.4, 53.2, 5
5.2, 60.4, 60.8, 113.6, 114.1, 127.77, 127.84, 128.
9, 129.8, 130.0, 130.2, 130.4, 158.2, 158.4, 160.8,
161.1 UV (CH 3 OH) nm: 220, 277, 284 MS: m / e 285
【００２７】実施例２〜１６ 実施例１と同様な反応操作により、参考例２〜１６で得
られたルテニウム−ホスフィン錯体を用いて（Ｚ）−Ｎ
−ホルミル−１−（４−メトキシフェニルメチレン）−
３，４，５，６，７，８−ヘキサヒドロイソキノリンの
不斉水素化反応を行い、（＋）−Ｎ−ホルミル−１−
（４−メトキシフェニルメチレン）−１，２，３，４，
５，６，７，８−オクタヒドロイソキノリンの製造を行
った結果を表４に示す。Examples 2 to 16 Using the ruthenium-phosphine complex obtained in Reference Examples 2 to 16 by the same reaction procedure as in Example 1, (Z) -N was obtained.
-Formyl-1- (4-methoxyphenylmethylene)-
Asymmetric hydrogenation reaction of 3,4,5,6,7,8-hexahydroisoquinoline is carried out to obtain (+)-N-formyl-1-
(4-Methoxyphenylmethylene) -1,2,3,4
Table 4 shows the results of the production of 5,6,7,8-octahydroisoquinoline.
【００２８】[0028]
【表４】 [Table 4]
【００２９】[0029]
【発明の効果】本発明の製造方法に用いられる新規なル
テニウム−ホスフィン錯体は、各種有機合成反応、特に
不斉水素化反応などの触媒としてすぐれた性能を示し、
オレフィンの選択的水素化ならびに触媒活性についても
工業的にすぐれた成績を示し、且つ従来のロジウム系触
媒などに比し、安価に作られ、製品の価格引下げに貢献
することのできる工業的価値の高いものである。従っ
て、このルテニウム−ホスフィン錯体を用いれば、高選
択率かつ高収率で（＋）−Ｎ−ホルミル−１−（４−メ
トキシフェニルメチレン）−１，２，３，４，５，６，
７，８−オクタヒドロイソキノリンを製造することがで
きる。INDUSTRIAL APPLICABILITY The novel ruthenium-phosphine complex used in the production method of the present invention exhibits excellent performance as a catalyst for various organic synthesis reactions, especially asymmetric hydrogenation reactions,
It also has excellent industrial performance in the selective hydrogenation of olefins and catalytic activity, and is manufactured at a lower cost than conventional rhodium-based catalysts and has an industrial value that contributes to the price reduction of products. It is expensive. Therefore, by using this ruthenium-phosphine complex, (+)-N-formyl-1- (4-methoxyphenylmethylene) -1,2,3,4,5,6 is obtained with high selectivity and high yield.
7,8-Octahydroisoquinoline can be prepared.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.5 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ｃ０７Ｆ 15/00 Ａ 9049−4Ｈ ─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 5 Identification code Internal reference number FI technical display area C07F 15/00 A 9049-4H
Claims (1)
シフェニルメチレン）−３，４，５，６，７，８−ヘキ
サヒドロイソキノリンを、次の一般式（３） ［Ｒｕ（（−）−Ｒ−ＢＩＮＡＰ）ＭＣｌk］lＸm （３） 〔式中、Ｒ−ＢＩＮＡＰは式（４） 【化２】 で表わされる三級ホスフィンを意味し、Ｒは水素原子ま
たはメチル基を意味し、ＭはＺｎ，Ａｌ，ＴｉまたはＳ
ｎを意味し、ＸはＮ（Ｃ2Ｈ5）3またはＣＨ3ＣＯ 2を意
味し、ＸがＮ（Ｃ2Ｈ5）3の場合、ｌが２、ｍが１であ
り、かつＭがＺｎのときはｋが４、Ａｌのときはｋが
５、ＴｉまたはＳｎのときはｋが６であり、ＸがＣＨ3
ＣＯ2の場合、ｌが１、ｍが２であり、かつＭがＺｎの
ときはｋが２、Ａｌのときはｋが３、ＴｉまたはＳｎの
ときはｋが４である〕で表わされるルテニウム−ホスフ
ィン錯体の存在下、不斉水素化することを特徴とする次
の式（１） 【化３】 で表わされる（＋）−Ｎ−ホルミル−１−（４−メトキ
シフェニルメチレン）−１，２，３，４，５，６，７，
８−オクタヒドロイソキノリンの製造方法。1. The following formula (2):(Z) -N-formyl-1- (4-methoxy) represented by
Cyphenylmethylene) -3,4,5,6,7,8-hex
Sahydroisoquinoline is represented by the following general formula (3) [Ru ((−)-R-BINAP) MClk]lXm (3) [wherein R-BINAP is represented by the formula (4):Means a tertiary phosphine represented by
Or methyl group, M is Zn, Al, Ti or S
means n, and X is N (C2HFive)3Or CH3CO 2Mean
Taste, X is N (C2HFive)3In case of, l is 2 and m is 1
And when M is Zn, k is 4, and when Al is k,
5, when Ti or Sn, k is 6 and X is CH3
CO2In the case of, 1 is 1, m is 2, and M is Zn.
When k is 2, when Al is k is 3, Ti or Sn
Then k is 4] ruthenium-phosph
Characterized by asymmetric hydrogenation in the presence of a tin complex
Formula (1) ofRepresented by (+)-N-formyl-1- (4-methoxy)
Cyphenylmethylene) -1,2,3,4,5,6,7,
A method for producing 8-octahydroisoquinoline.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3286090A JPH0670016B2 (en) | 1991-10-31 | 1991-10-31 | Method for producing (+)-N-formyl-1- (4-methoxyphenylmethylene) -1,2,3,4,5,6,7,8-octahydroisoquinoline |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3286090A JPH0670016B2 (en) | 1991-10-31 | 1991-10-31 | Method for producing (+)-N-formyl-1- (4-methoxyphenylmethylene) -1,2,3,4,5,6,7,8-octahydroisoquinoline |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62224288A Division JPH0667947B2 (en) | 1987-09-08 | 1987-09-08 | Ruthenium-phosphine complex |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0592958A true JPH0592958A (en) | 1993-04-16 |
| JPH0670016B2 JPH0670016B2 (en) | 1994-09-07 |
Family
ID=17699813
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3286090A Expired - Fee Related JPH0670016B2 (en) | 1991-10-31 | 1991-10-31 | Method for producing (+)-N-formyl-1- (4-methoxyphenylmethylene) -1,2,3,4,5,6,7,8-octahydroisoquinoline |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0670016B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997003052A1 (en) * | 1995-07-11 | 1997-01-30 | Lonza Ag | Process for preparing optically active 1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline |
-
1991
- 1991-10-31 JP JP3286090A patent/JPH0670016B2/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997003052A1 (en) * | 1995-07-11 | 1997-01-30 | Lonza Ag | Process for preparing optically active 1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline |
| US5892044A (en) * | 1995-07-11 | 1999-04-06 | Lonza Ltd. | Process for preparing optically active 1-(p-methoxybenzyl)-1,2,3,4,5,3,7,8-octahydroisoquinoline |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0670016B2 (en) | 1994-09-07 |
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