JPH0466471B2 - - Google Patents
Info
- Publication number
- JPH0466471B2 JPH0466471B2 JP60116484A JP11648485A JPH0466471B2 JP H0466471 B2 JPH0466471 B2 JP H0466471B2 JP 60116484 A JP60116484 A JP 60116484A JP 11648485 A JP11648485 A JP 11648485A JP H0466471 B2 JPH0466471 B2 JP H0466471B2
- Authority
- JP
- Japan
- Prior art keywords
- threo
- group
- formyl
- serine
- formula
- 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 - Lifetime
Links
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 9
- 238000006460 hydrolysis reaction Methods 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 230000007062 hydrolysis Effects 0.000 claims description 8
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 3
- CGFKQGRKHSOMHZ-VIFPVBQESA-N (2s)-2-(n-formylanilino)-3-hydroxypropanoic acid Chemical class OC[C@@H](C(O)=O)N(C=O)C1=CC=CC=C1 CGFKQGRKHSOMHZ-VIFPVBQESA-N 0.000 claims 1
- CFCNTIFLYGKEIO-UHFFFAOYSA-N 2-isocyanoacetic acid Chemical compound OC(=O)C[N+]#[C-] CFCNTIFLYGKEIO-UHFFFAOYSA-N 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 59
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 150000001875 compounds Chemical class 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- ANSUDRATXSJBLY-VKHMYHEASA-N methyl (2s)-2-amino-3-hydroxypropanoate Chemical compound COC(=O)[C@@H](N)CO ANSUDRATXSJBLY-VKHMYHEASA-N 0.000 description 7
- GKCXXDSWWDWUHS-BYPYZUCNSA-N ethyl (2s)-2-amino-3-hydroxypropanoate Chemical compound CCOC(=O)[C@@H](N)CO GKCXXDSWWDWUHS-BYPYZUCNSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- -1 amino compound Chemical class 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- WTBFLCSPLLEDEM-JIDRGYQWSA-N 1,2-dioleoyl-sn-glycero-3-phospho-L-serine Chemical class CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCC\C=C/CCCCCCCC WTBFLCSPLLEDEM-JIDRGYQWSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 4
- FPULFENIJDPZBX-UHFFFAOYSA-N ethyl 2-isocyanoacetate Chemical compound CCOC(=O)C[N+]#[C-] FPULFENIJDPZBX-UHFFFAOYSA-N 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- XDDLXZHBWVFPRG-UHFFFAOYSA-N 3,4-bis(phenylmethoxy)benzaldehyde Chemical compound C=1C=CC=CC=1COC1=CC(C=O)=CC=C1OCC1=CC=CC=C1 XDDLXZHBWVFPRG-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 150000003935 benzaldehydes Chemical class 0.000 description 3
- QXWYKJLNLSIPIN-JGVFFNPUSA-N droxidopa Chemical compound OC(=O)[C@@H](N)[C@H](O)C1=CC=C(O)C(O)=C1 QXWYKJLNLSIPIN-JGVFFNPUSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 239000007859 condensation product Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 229960002179 ephedrine Drugs 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- GZLRNTMXOXBIRR-HMTLIYDFSA-N (2s)-2-amino-3-[3,4-bis(phenylmethoxy)phenyl]-3-hydroxypropanoic acid Chemical compound C=1C=CC=CC=1COC1=CC(C(O)[C@H](N)C(O)=O)=CC=C1OCC1=CC=CC=C1 GZLRNTMXOXBIRR-HMTLIYDFSA-N 0.000 description 1
- RXFFQBYNCVPZGL-UHFFFAOYSA-N 1,2,3,4,5,5a,8,9-octahydropyrido[1,2-b]diazepine Chemical compound N1CCCCC2C=CCCN21 RXFFQBYNCVPZGL-UHFFFAOYSA-N 0.000 description 1
- RBNBFXRIYVDZBU-UHFFFAOYSA-N 2,3-bis(phenylmethoxy)benzaldehyde Chemical compound C=1C=CC=CC=1COC=1C(C=O)=CC=CC=1OCC1=CC=CC=C1 RBNBFXRIYVDZBU-UHFFFAOYSA-N 0.000 description 1
- 125000003504 2-oxazolinyl group Chemical group O1C(=NCC1)* 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- RYTSFSLVJDNOHI-UHFFFAOYSA-N 3,4-bis(methoxymethoxy)benzaldehyde Chemical compound COCOC1=CC=C(C=O)C=C1OCOC RYTSFSLVJDNOHI-UHFFFAOYSA-N 0.000 description 1
- JSHLOPGSDZTEGQ-UHFFFAOYSA-N 3-methoxy-4-phenylmethoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC=C1OCC1=CC=CC=C1 JSHLOPGSDZTEGQ-UHFFFAOYSA-N 0.000 description 1
- NEAYIABCUAOVAD-UHFFFAOYSA-N 4,5-dihydro-1,3-oxazole-4-carboxylic acid Chemical compound OC(=O)C1COC=N1 NEAYIABCUAOVAD-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical class O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- IIDNACBMUWTYIV-VIFPVBQESA-N benzyl (2s)-2-amino-3-hydroxypropanoate Chemical compound OC[C@H](N)C(=O)OCC1=CC=CC=C1 IIDNACBMUWTYIV-VIFPVBQESA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000020176 deacylation Effects 0.000 description 1
- 238000005947 deacylation reaction Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- CRXFROMHHBMNAB-UHFFFAOYSA-N methyl 2-isocyanoacetate Chemical compound COC(=O)C[N+]#[C-] CRXFROMHHBMNAB-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229940081310 piperonal Drugs 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 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
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
【発明の詳細な説明】
産業上の利用分野
本発明により提供される化合物〔〕は医薬の
分野で有用な各種の薬理活性を有する化合物、特
にスレオ−３−（３，４−ジヒドロキシフエニル）
セリン（以下スレオ−DOPSと称す）を製造する
際の合成中間体として有用である。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The compound [ ] provided by the present invention is a compound having various pharmacological activities useful in the pharmaceutical field, particularly threo-3-(3,4-dihydroxyphenyl).
It is useful as a synthetic intermediate in the production of serine (hereinafter referred to as threo-DOPS).
従来の技術
スレオ−DOPSおよびその関連化合物は生体内
の重要な生理活性アミンであるカテコールアミン
類の前駆体になり得るものとされ、またそれ自身
循環器系あるいは中枢神経系に対してある種の薬
理作用を有することが知られている（特開昭50−
49252号、特開昭54−138537号、特開昭56−
104815号公報）。またDOPS誘導体を医薬として
使用する場合、そのＬ−光学活性体がより有用で
あることが知られている（特開昭52−125630号、
特開昭55−20747号公報）。Prior Art Threo-DOPS and its related compounds are thought to be precursors of catecholamines, which are important physiologically active amines in living organisms, and they themselves have certain pharmacological effects on the circulatory system or central nervous system. It is known to have the effect
No. 49252, JP-A-54-138537, JP-A-56-
Publication No. 104815). Furthermore, when using DOPS derivatives as medicines, it is known that the L-optically active form thereof is more useful (Japanese Patent Application Laid-open No. 125630/1989,
(Japanese Patent Application Laid-open No. 55-20747).
従来、スレオ−DOPSおよび近縁誘導体はベン
ズアルデヒド類にグリシンを縮合させる
Erlenmyer法により製造されてきた〔Chem.Ber.
第52巻1734頁（1919）、J.Am.Chem.Soc.第76巻
1322頁（1954）〕。またそのＬ−光学活性体はスレ
オ−DOPSのアミノ基をベンジルオキシカルボニ
ル基で保護した後光学分割し、ついで還元条件下
に該保護基を脱離することによつて製造されてき
た（特開昭54−36233号公報）。 Traditionally, threo-DOPS and related derivatives condense glycine to benzaldehydes.
It has been produced by the Erlenmyer method [Chem.Ber.
Vol. 52, p. 1734 (1919), J.Am.Chem.Soc. Vol. 76
1322 pages (1954)]. In addition, the L-optically active form of threo-DOPS has been produced by protecting the amino group with a benzyloxycarbonyl group, optically resolving it, and then removing the protecting group under reducing conditions (Unexamined Japanese Patent Publication No. Publication No. 54-36233).
発明が解決しようとする問題点
前掲の従来のスレオ−DOPSの製造法について
言えば、高価な原料であるベンズアルデヒド類を
過剰に使用する点、さらには該製造法によつて得
られる反応生成物がスレオ体とエリスロ体との混
合物になるためこれらを分離しなければならない
点など、工業的にスレオ体を効率よくかつ安価に
製造するためには、不適合な点があつた。加え
て、Ｌ−スレオ−DOPSの製造に際しては、アミ
ノ基を保護し、光学分割後、該アミノ基を脱離し
なければならないというような煩雑な操作を必要
とする点で、非効率的であつた。Problems to be Solved by the Invention Regarding the conventional method for producing threo-DOPS mentioned above, there are problems in that benzaldehydes, which are expensive raw materials, are used in excess, and that the reaction products obtained by this method are There were some incompatibilities in industrially producing threo isomers efficiently and at low cost, such as the fact that they were a mixture of threo isomers and erythro isomers, which had to be separated. In addition, the production of L-threo-DOPS is inefficient and requires complicated operations such as protecting the amino group and removing the amino group after optical resolution. Ta.
以上、本発明は公知の方法によるスレオ−
DOPS、そのＬ−光学活性体およびその関連化合
物の製造法の問題点を解決しうる、工業的に価値
の高い合成中間体およびその製造法を提供するも
のである。 As described above, the present invention provides
The object of the present invention is to provide an industrially valuable synthetic intermediate and a method for producing the same, which can solve problems in the production method for DOPS, its L-optically active form, and related compounds.
問題点を解決するための手段
本発明者らはかねてよりDOPSおよびその近縁
誘導体の簡便な製造法を検討していたが、後記式
〔〕で表わされるＮ−ホルミル誘導体が対応す
るアルデヒドとイソシアノ酢酸エステルとの反応
およびそれに続く部分加水分解により、高率で、
しかも一義的にスレオ体のみとして得られること
を発見した。さらに発明者らは化合物〔〕が光
学活性アミンにより容易に光学分割され、しか
も、該ホルミル基が緩和な酸性条件下に容易に脱
離されることから、化合物〔〕が光学活性スレ
オ−DOPSの有用な合成中間体となることを見い
出し、本発明を完成させた。Means for Solving the Problems The present inventors have been studying a simple method for producing DOPS and its closely related derivatives for some time. By reaction with acetate esters and subsequent partial hydrolysis, in high
Moreover, I discovered that it can be uniquely obtained only as a thread typeface. Furthermore, the inventors found that the compound [] is easily optically resolved by an optically active amine, and the formyl group is easily eliminated under mild acidic conditions. The present inventors have discovered that the present invention can be used as a synthetic intermediate, and have completed the present invention.
すなわち本発明は、一般式
（式中R1およびR2は同一または異なつてもよい
低級アルキル基、低級アルコキシアルキル基、ア
ラルキル基もしくは両者が互いに連結してメチレ
ン基を示し、R3は水素原子、低級アルキル基ま
たはアラルキル基を示す）で表わされる新規なス
レオ−Ｎ−ホルミルフエニルセリン誘導体および
その製造法を提供するものである。 That is, the present invention is based on the general formula (In the formula, R 1 and R 2 are a lower alkyl group, a lower alkoxyalkyl group, an aralkyl group, which may be the same or different, or both are linked to each other to represent a methylene group, and R 3 is a hydrogen atom, a lower alkyl group, or an aralkyl group. The present invention provides a novel threo-N-formylphenylserine derivative represented by the following formula and a method for producing the same.
本発明化合物〔〕について、さらに詳細に説
明すれば、式中の各記号の定義において低級とい
う語は炭素数１ないし５個の直鎖または分枝状の
炭素鎖を意味する。したがつて低級アルキル基と
はメチル基、エチル基、ｎ−プロピル基、イソプ
ロピル基、ｎ−ブチル基、イソブチル基などを、
また低級アルコキシアルキル基とはメトキシメチ
ル基、エトキシメチル基などを意味する。またア
ラルキル基とは芳香環に任意の置換基を有してい
てもよいベンジル基、フエネチル基もしくはナフ
チルメチル基などである。 To explain the compound of the present invention in more detail, in the definition of each symbol in the formula, the term "lower" means a straight or branched carbon chain having 1 to 5 carbon atoms. Therefore, lower alkyl groups include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, etc.
Further, the lower alkoxyalkyl group means a methoxymethyl group, an ethoxymethyl group, etc. Further, the aralkyl group includes a benzyl group, a phenethyl group, a naphthylmethyl group, etc., which may have an arbitrary substituent on the aromatic ring.
本発明により提供される一般式〔〕の化合物
の具体例を挙げれば以下のものがあげられる。 Specific examples of the compound of general formula [] provided by the present invention include the following.
(1) スレオ−Ｎ−ホルミル−３−（３，４−ジベ
ンジルオキシフエニル）セリン
(2) スレオ−Ｎ−ホルミル−３−（３，４−ジベ
ンジルオキシフエニル）セリン メチルエステ
ル
(3) スレオ−Ｎ−ホルミル−３−（３，４−ジベ
ンジルオキシフエニル）セリン エチルエステ
ル
(4) スレオ−Ｎ−ホルミル−３−（３，４−ジベ
ンジルオキシフエニル）セリン ベンジルエス
テル
(5) スレオ−Ｎ−ホルミル−３−（３，４−ジメ
トキシフエニル）セリン
(6) スレオ−Ｎ−ホルミル−３−（３，４−ジメ
トキシフエニル）セリン メチルエステル
(7) スレオ−Ｎ−ホルミル−３−（３，４−ジメ
トキシフエニル）セリン エチルエステル
(8) スレオ−Ｎ−ホルミル−３−（３，４−ジメ
トキシメチルオキシフエニル）セリン
(9) スレオ−Ｎ−ホルミル−３−（３，４−ジメ
トキシメチルオキシフエニル）セリン メチル
エステル
(10) スレオ−Ｎ−ホルミル−３−（３，４−ジメ
トキシメチルオキシフエニル）セリン エチル
エステル
(11) スレオ−Ｎ−ホルミル−３−（３−メトキ
シ−４−ベンジルオキシフエニル）セリン
(12) スレオ−Ｎ−ホルミル−３−（３−メトキ
シ−４−ベンジルオキシフエニル）セリン メ
チルエステル
(13) スレオ−Ｎ−ホルミル−３−（３−メトキ
シ−４−ベンジルオキシフエニル）セリン エ
チルエステル
(14) スレオ−Ｎ−ホルミル−３−（３−メトキ
シ−４−ベンジルオキシフエニル）セリン ベ
ンジルエステル
(15) スレオ−Ｎ−ホルミル−３−（３，４−メ
チレンジオキシフエニル）セリン
(16) スレオ−Ｎ−ホルミル−３−（３，４−メ
チレンジオキシフエニル）セリン メチルエス
テル
(17) スレオ−Ｎ−ホルミル−３−（３，４−メ
チレンジオキシフエニル）セリン エチルエス
テル
ただし、本発明はこれらの代表例により限定さ
れるものではない。また、式〔〕で表わされる
化合物は光学活性体あるいはラセミ体として存在
することができ、本発明はこれら光学異性体の全
てを包含する。(1) Threo-N-formyl-3-(3,4-dibenzyloxyphenyl)serine (2) Threo-N-formyl-3-(3,4-dibenzyloxyphenyl)serine methyl ester (3) ) Threo-N-formyl-3-(3,4-dibenzyloxyphenyl)serine ethyl ester (4) Threo-N-formyl-3-(3,4-dibenzyloxyphenyl)serine benzyl ester (5 ) threo-N-formyl-3-(3,4-dimethoxyphenyl)serine (6) threo-N-formyl-3-(3,4-dimethoxyphenyl)serine methyl ester (7) threo-N-formyl -3-(3,4-dimethoxyphenyl)serine ethyl ester (8) threo-N-formyl-3-(3,4-dimethoxymethyloxyphenyl)serine (9) threo-N-formyl-3-( 3,4-dimethoxymethyloxyphenyl)serine methyl ester (10) threo-N-formyl-3-(3,4-dimethoxymethyloxyphenyl)serine ethyl ester (11) threo-N-formyl-3-( 3-methoxy-4-benzyloxyphenyl)serine (12) threo-N-formyl-3-(3-methoxy-4-benzyloxyphenyl)serine methyl ester (13) threo-N-formyl-3-( 3-methoxy-4-benzyloxyphenyl)serine ethyl ester (14) threo-N-formyl-3-(3-methoxy-4-benzyloxyphenyl)serine benzyl ester (15) threo-N-formyl-3 -(3,4-methylenedioxyphenyl)serine (16) threo-N-formyl-3-(3,4-methylenedioxyphenyl)serine methyl ester (17) threo-N-formyl-3-( 3,4-methylenedioxyphenyl) serine ethyl ester However, the present invention is not limited to these representative examples. Further, the compound represented by the formula [] can exist as an optically active form or a racemic form, and the present invention includes all of these optical isomers.
本発明によれば一般式〔〕の化合物は次の方
法により製造される。すなわち、一般式
（式中R1およびR2は前記の意味を有する）で表
わされるアルデヒドと一般式
CN−CH2−COOR 〔〕
（式中Ｒは低級アルキル基またはアラルキル基を
示す）で表わされるイソシアノ酢酸エステルとを
塩基の存在下に反応させ、ついで部分加水分解す
ることにより式〔〕のＮ−ホルミル体が得られ
る。 According to the present invention, the compound of general formula [] is produced by the following method. That is, the general formula (In the formula, R 1 and R 2 have the above-mentioned meanings) and an isocyanoacetic ester represented by the general formula CN-CH 2 -COOR [] (In the formula, R represents a lower alkyl group or an aralkyl group) The N-formyl compound of the formula [] is obtained by reacting these in the presence of a base and then partially hydrolyzing them.
本発明の第一工程の反応は、通常適当な溶媒中
塩基の存在下に実施され、その際使用される塩基
としては水素化ナトリウムなどの金属アルカリ、
ナトリウムメトキシド、ナトリウムエトキシドな
どの金属アルコキシド、水酸化ナトリウム、水酸
化カリウムなどの水酸化アルカリ、シアン化ナト
リウム、シアン化カリウムなどのシアン化アルカ
リ、炭酸ナトリウム、炭酸カリウムなどの炭酸ア
ルカリあるいはトリエチルアミン、１，８−ジア
ザビシクロ〔５，４，０〕ウンデセンなどの有機
アミン類などを挙げることができる。また、溶媒
としては例えばメタノール、エタノールの如き低
級アルカノール、テトラヒドロフラン、ジオキサ
ン、ジメチルホルムアミド、ベンゼンなどが適宜
使用される。反応温度および反応時間は特に限定
されないが、生成物の安定性などを考慮し、好ま
しくは−20℃ないし50℃付近、0.5ないし20時間
である。 The reaction in the first step of the present invention is usually carried out in a suitable solvent in the presence of a base, and the bases used at that time include metal alkalis such as sodium hydride,
Metal alkoxides such as sodium methoxide and sodium ethoxide, alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali cyanides such as sodium cyanide and potassium cyanide, alkali carbonates such as sodium carbonate and potassium carbonate, or triethylamine, 1. Examples include organic amines such as 8-diazabicyclo[5,4,0]undecene. Further, as the solvent, for example, lower alkanols such as methanol and ethanol, tetrahydrofuran, dioxane, dimethylformamide, benzene, etc. are used as appropriate. The reaction temperature and reaction time are not particularly limited, but considering the stability of the product, etc., they are preferably around -20°C to 50°C and 0.5 to 20 hours.
上記反応で生成した縮合成積体は単離精製後ま
たは単離精製せずに次工程の加水分解に供せられ
る。すなわち単離せずに加水分解を実施するに
は、前工程の反応液あるいは溶媒留去後の残留物
を例えば水、含水メタノール、含水エタノール、
含水アセトンなどの適当な溶媒に混和し、これに
塩酸、硫酸などの鉱酸、あるいはギ酸、酢酸など
の有機酸を作用させる。また単離精製して加水分
解を行なう場合は、前工程の反応液から、例えば
溶媒留去後の抽出あるいは再結晶などの普通の分
離手段により、一般式
（式中R1、R2およびＲは前記の意味を有する）
で表わされる２−オキサゾリン−４−カルボン酸
エステル体を単離し、これを前記と同様な酸性条
件下で加水分解を行なえばよい。なお、加水分解
反応の際、同時にエステル部分の加水分解を行な
うことができ、この場合には、例えば縮合生成物
に始めた含水溶媒中で水酸化アルカリを作用さ
せ、次いで酸によりオキサゾリン環を開環させる
などの方法が取られる。 The condensation product produced in the above reaction is subjected to the next step of hydrolysis after isolation and purification or without isolation and purification. That is, in order to perform hydrolysis without isolation, the reaction solution from the previous step or the residue after solvent distillation can be mixed with water, aqueous methanol, aqueous ethanol, etc.
It is mixed with a suitable solvent such as aqueous acetone, and treated with a mineral acid such as hydrochloric acid or sulfuric acid, or an organic acid such as formic acid or acetic acid. In addition, when performing hydrolysis by isolation and purification, the general formula (In the formula, R 1 , R 2 and R have the above meanings)
The 2-oxazoline-4-carboxylic acid ester represented by is isolated and hydrolyzed under the same acidic conditions as described above. Note that during the hydrolysis reaction, the ester moiety can be hydrolyzed at the same time. In this case, for example, the condensation product is treated with an alkali hydroxide in a starting water-containing solvent, and then the oxazoline ring is opened with an acid. Methods such as ringing are used.
かくして生成した目的化合物〔〕は、例えば
濃縮、抽出、カラムクロマト、再結晶等の通常の
分離手段により適宜取得される。 The thus produced target compound [ ] can be appropriately obtained by conventional separation means such as concentration, extraction, column chromatography, recrystallization, and the like.
ところで本発明化合物〔〕に見られるような
Ｎ−アシル型フエニルセリン誘導体の加水分解に
よるアシル基の除去は、そのもの自身あるいは生
成物が脱離条件下に不安定であるため困難とされ
ており、このため、アミノ基の保護基としてアシ
ル基を選択する場合には、還元条件下に除去が可
能なベンジルオキシカルボニル基などを選ぶ必要
があつた。しかし上記反応により得られる式
〔〕の化合物のホルミル基は塩酸、硫酸等の鉱
酸あるいはｐ−トルエンスルホン酸、トリフルオ
ロメタンスルホン酸等の有機酸の存在下、加水分
解により容易に脱離可能である。この反応は、一
般に希薄な酸の存在下、０ないし50℃、１ないし
10時間という緩和な条件下に実施されるため、不
安定な置換基等の存在にもかかわらず、目的のア
ミノ体の収量は通常きわめて良好である。 By the way, it is difficult to remove the acyl group by hydrolysis of N-acyl phenylserine derivatives as seen in the compound of the present invention [] because the product itself or the product is unstable under elimination conditions. Therefore, when selecting an acyl group as a protecting group for an amino group, it was necessary to select a benzyloxycarbonyl group or the like that can be removed under reducing conditions. However, the formyl group of the compound of formula [] obtained by the above reaction can be easily removed by hydrolysis in the presence of a mineral acid such as hydrochloric acid or sulfuric acid or an organic acid such as p-toluenesulfonic acid or trifluoromethanesulfonic acid. be. This reaction is generally carried out in the presence of dilute acid at 0 to 50°C.
Since the reaction is carried out under mild conditions of 10 hours, the yield of the desired amino compound is usually very good despite the presence of unstable substituents.
また式〔〕の化合物の中でR3＝Ｈのカルボ
ン酸は、窒素がアシル化されたアミノ酸であるた
め、光学活性アミンとジアステレオマーの塩を形
成し、その結果、光学分割の基質として利用する
ことができる。本化合物を中間体とする光学分割
法は、目的のアミノ酸を一且アシル化後光学分割
し、次いで脱アシル化する従来法に比べて非常に
効率的であり、その後の脱アシル化が容易なこと
を考慮すれば光学活性スレオ−DOPSの経済的か
つ工業的製法を提供するものである。 Furthermore, in the compound of formula [], the carboxylic acid with R 3 = H is an amino acid whose nitrogen is acylated, so it forms a diastereomeric salt with an optically active amine, and as a result, it can be used as a substrate for optical resolution. can be used. The optical resolution method using this compound as an intermediate is much more efficient than the conventional method in which the target amino acid is single-acylated, optically resolved, and then deacylated, and the subsequent deacylation is easy. Taking this into consideration, the present invention provides an economical and industrial method for producing optically active threo-DOPS.
作 用
一般式〔〕で表わされる適当なベンズアルデ
ヒド誘導体と、一般式〔〕で表わされるイソシ
アノ酢酸エステルとを反応させ、ついで部分加水
分解を施すことにより、一般式〔〕で表わされ
る本発明の化合物のスレオ体が特異的に高収率で
得られる。さらに、この化合物の光学分割および
ホルミル基の脱離は容易におこなえるため、医薬
として有用なスレオ−DOPSのＬ−光学活性体が
高収率で得られる。Effect The compound of the present invention represented by the general formula [] can be produced by reacting a suitable benzaldehyde derivative represented by the general formula [] with an isocyanoacetic acid ester represented by the general formula [], and then subjecting it to partial hydrolysis. The threo isomer is specifically obtained in high yield. Furthermore, since the optical resolution of this compound and the elimination of the formyl group can be easily performed, an L-optically active form of threo-DOPS useful as a pharmaceutical can be obtained in high yield.
実施例
以下に実施例および参考例を挙げ、本発明を具
体的に説明する。EXAMPLES The present invention will be specifically described below with reference to Examples and Reference Examples.
実施例 １
イソシアノ酢酸メチルエステル3.11ｇをベンゼ
ン100mlに溶解し、５〜10℃で冷却撹拌下50％水
素化ナトリウム0.30ｇ、次いで５分後に３，４−
ジベンジルオキシベンズアルデヒド10.0ｇを加え
る。室温で２時間撹拌後50％水素化ナトリウム
0.24ｇを追加し、さらに３時間撹拌を続ける。Example 1 3.11 g of isocyanoacetic acid methyl ester was dissolved in 100 ml of benzene, and 0.30 g of 50% sodium hydride was added under cooling and stirring at 5 to 10°C. After 5 minutes, 3,4-
Add 10.0 g of dibenzyloxybenzaldehyde. 50% sodium hydride after stirring for 2 hours at room temperature
Add 0.24 g and continue stirring for an additional 3 hours.
氷冷後撹拌下に酢酸15mlを滴下し、次いでメタ
ノール30mlを加えて減圧下に溶媒を留去する。残
渣を含水メタノールから再結晶すると、スレオ−
Ｎ−ホルミル−３−（３，４−ジベンジルオキシ
フエニル）セリンメチルエステル10.8ｇ（収率
79.0％）mp150〜152℃が得られる。 After cooling on ice, 15 ml of acetic acid was added dropwise while stirring, then 30 ml of methanol was added, and the solvent was distilled off under reduced pressure. When the residue is recrystallized from aqueous methanol, threo-
N-formyl-3-(3,4-dibenzyloxyphenyl)serine methyl ester 10.8g (yield
79.0%) mp150-152℃ is obtained.
IR νKBr naxcm-1：3400−2870、1740、1665、1590、
1270
NMRδ（d6−DMSO）：3.59（3H、ｓ）、4.55（1H、
d.d、Ｊ＝8.1Hz、2.8Hz）、5.05（1H、br、ｓ）、
5.05（4H、ｓ）、6.80−7.20（3H、ｍ）、7.37
（10H、ｓ）、7.92（1H、ｓ）、8.27（1H、ｄ、Ｊ
＝8.1Hz）
上記で得られたスレオ−Ｎ−ホルミル−３−
（３，４−ジベンジルオキシフエニル）セリンメ
チルエステル4.00ｇをジオキサン40mlに懸濁し、
室温撹拌下2N水酸化ナトリウム水溶液5.0mlを加
えて１時間半撹拌を続ける。IR ν KBr nax cm -1 : 3400−2870, 1740, 1665, 1590,
1270 NMRδ( d6 -DMSO): 3.59 (3H, s), 4.55 (1H,
dd, J=8.1Hz, 2.8Hz), 5.05 (1H, br, s),
5.05 (4H, s), 6.80−7.20 (3H, m), 7.37
(10H, s), 7.92 (1H, s), 8.27 (1H, d, J
= 8.1Hz) Threo-N-formyl-3- obtained above
Suspend 4.00 g of (3,4-dibenzyloxyphenyl) serine methyl ester in 40 ml of dioxane,
While stirring at room temperature, add 5.0 ml of 2N aqueous sodium hydroxide solution and continue stirring for 1.5 hours.
反応終了後酢酸10mlを加えて酸性とし、減圧留
去後残渣を含水アセトンから再結晶すると、スレ
オ−Ｎ−ホルミル−３−（３，４−ジベンジルオ
キシフエニル）セリン2.68ｇ（収率74.2％）
mp168〜170℃（dec.）が得られる。 After the reaction was completed, 10 ml of acetic acid was added to make it acidic, and after distillation under reduced pressure, the residue was recrystallized from aqueous acetone to give 2.68 g of threo-N-formyl-3-(3,4-dibenzyloxyphenyl)serine (yield 74.2). %)
mp168-170℃ (dec.) is obtained.
IR νKBr naxcm-1：3300−2700、1760、1625、1535、
1625、1030、
NMRδ（d6−DMSO）：4.54（1H、ｄ、ｄ、Ｊ＝
9.4Hz、2.8Hz）、5.1（1H、ｍ）、5.10（4H、ｓ）、
6.9−7.4（3H、ｍ）、7.39（10H、ｓ）、7.99（1H、
ｓ）、8.19（1H、ｄ、Ｊ＝9.4Hz）
実施例 ２
エタノール30mlにイソシアノ酢酸エチルエステ
ル1.13ｇと３，４−ジベンジルオキシベンズアル
デヒド3.18ｇを懸濁し、シアン化ナトリウム0.07
ｇを加えて室温で５時間反応させる。IR ν KBr nax cm -1 : 3300−2700, 1760, 1625, 1535,
1625, 1030, NMRδ ( d6 -DMSO): 4.54 (1H, d, d, J=
9.4Hz, 2.8Hz), 5.1 (1H, m), 5.10 (4H, s),
6.9−7.4 (3H, m), 7.39 (10H, s), 7.99 (1H,
s), 8.19 (1H, d, J = 9.4Hz) Example 2 Suspend 1.13 g of isocyanoacetic acid ethyl ester and 3.18 g of 3,4-dibenzyloxybenzaldehyde in 30 ml of ethanol, and add 0.07 g of sodium cyanide.
g and react at room temperature for 5 hours.
氷冷撹拌下に酢酸10mlを滴下し、次いで１時間
後に水10mlを加えて氷室に一夜放置する。 10 ml of acetic acid is added dropwise while stirring under ice cooling, and after 1 hour, 10 ml of water is added and the mixture is left in an ice room overnight.
析出晶を取し、結晶を含水エタノールで洗浄
後乾燥すると、スレオ−Ｎ−ホルミル−３−（３，
４−ジベンジルオキシフエニル）セリンエチルエ
ステル3.86ｇ（収率86.0％）mp156〜157℃が得ら
れる。 The precipitated crystals were collected, washed with aqueous ethanol, and dried to give threo-N-formyl-3-(3,
3.86 g (yield: 86.0%) of 4-dibenzyloxyphenyl) serine ethyl ester, mp 156-157°C, is obtained.
IR νKBr naxcm-1：3350−2870、1730、1665、1605、
1590
NMRδ（d6−DMSO）：1.16（3H、ｔ、Ｊ＝７Hz）、
4.10（2H、ｑ、Ｊ＝７Hz）、4.56（1H、ｄ、ｄ、
Ｊ＝4.1Hz、8.5Hz）、5.11（4H、ｓ）、5.80（1H、
ｄ、Ｊ＝４Hz）、6.9、7.3（3H、ｍ）、7.40
（10H、ｓ）、8.00（1H、ｓ）、8.82（1H、ｄ、Ｊ
＝8.5Hz）
実施例 ３
３，４−ジベンジルオキシベンズアルデヒド
0.96ｇとイソシアノ酢酸エチルエステル0.34ｇを
エタノール10mlに懸濁し、この中にシアン化ナト
リウム0.02ｇを添加して室温で３時間撹拌する。IR ν KBr nax cm -1 : 3350−2870, 1730, 1665, 1605,
1590 NMRδ ( d6 -DMSO): 1.16 (3H, t, J=7Hz),
4.10 (2H, q, J=7Hz), 4.56 (1H, d, d,
J=4.1Hz, 8.5Hz), 5.11 (4H, s), 5.80 (1H,
d, J=4Hz), 6.9, 7.3 (3H, m), 7.40
(10H, s), 8.00 (1H, s), 8.82 (1H, d, J
=8.5Hz) Example 3 3,4-dibenzyloxybenzaldehyde
0.96 g and 0.34 g of ethyl isocyanoacetate are suspended in 10 ml of ethanol, 0.02 g of sodium cyanide is added thereto, and the mixture is stirred at room temperature for 3 hours.
減圧下にエタノールを留去し、残渣を酢酸エチ
ルに溶解後水洗し、無水硫酸ナトリウムで乾燥す
る。乾燥剤を別後減圧下に酢酸エチルを留去す
ると、５−（３，４−ジベンジルオキシフエニル）
−４−エトキシカルボニル−２−オキサゾリンが
淡黄色の油状物として得られる。 Ethanol is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. After removing the desiccant, ethyl acetate was distilled off under reduced pressure to obtain 5-(3,4-dibenzyloxyphenyl).
-4-Ethoxycarbonyl-2-oxazoline is obtained as a pale yellow oil.
IR νneat naxcm-1：3090、1735、1620、1605、1260
NMRδ（CDCl3）：1.28（3H、ｔ、Ｊ＝７Hz）、4.19
（2H、ｑ、Ｊ＝７Hz）、4.44（1H、ｄ、ｄ、Ｊ
＝2.2Hz、7.9Hz）、5.30（4H、ｓ）、5.47（1H、
ｄ、Ｊ＝7.9Hz）、6.91（1H、ｄ、Ｊ＝2.2Hz）、
6.8−7.3（3H、ｍ）、7.25（10H、ｓ）
上記で得られたオキサゾリン体をエタノール30
mlに溶解し、酢酸５mlおよび水10mlを加えて氷室
に一夜放置する。IR ν neat nax cm -1 : 3090, 1735, 1620, 1605, 1260 NMR δ (CDCl 3 ): 1.28 (3H, t, J=7Hz), 4.19
(2H, q, J = 7Hz), 4.44 (1H, d, d, J
=2.2Hz, 7.9Hz), 5.30 (4H, s), 5.47 (1H,
d, J = 7.9Hz), 6.91 (1H, d, J = 2.2Hz),
6.8−7.3 (3H, m), 7.25 (10H, s) The oxazoline compound obtained above was mixed with ethanol 30
ml, add 5 ml of acetic acid and 10 ml of water, and leave in an icebox overnight.
析出晶を取し、含水エタノールで洗浄後乾燥
すると、実施例２で得られた化合物1.14ｇ（収率
84.0％）mp156〜157℃が得られる。 The precipitated crystals were collected, washed with aqueous ethanol, and dried, resulting in 1.14 g of the compound obtained in Example 2 (yield:
84.0%) mp156-157℃ is obtained.
実施例 ４
イソシアノ酢酸エチルエステル2.50ｇを無水ベ
ンゼン50mlに溶解し、氷冷撹拌下50％水素化ナト
リウム0.21ｇ、次いで３，４−ジメトキシメチル
オキシベンズアルデヒド5.00ｇを加えて室温で４
時間撹拌する。Example 4 2.50 g of isocyanoacetic acid ethyl ester was dissolved in 50 ml of anhydrous benzene, and 0.21 g of 50% sodium hydride was added under ice-cooling and stirring, followed by 5.00 g of 3,4-dimethoxymethyloxybenzaldehyde.
Stir for an hour.
酢酸10mlおよびエタノール10mlを加えて１時間
撹拌後、溶媒を減圧留去し、残渣を含水エタノー
ルから再結晶すると、スレオ−Ｎ−ホルミル−３
−（３，４−ジメトキシメチルオキシフエニル）
セリンエチルエステル3.37ｇ（収率42.7％）
mp136〜138℃が得られる。 After adding 10 ml of acetic acid and 10 ml of ethanol and stirring for 1 hour, the solvent was distilled off under reduced pressure and the residue was recrystallized from aqueous ethanol to give threo-N-formyl-3.
-(3,4-dimethoxymethyloxyphenyl)
Serine ethyl ester 3.37g (yield 42.7%)
mp136-138℃ is obtained.
IR νKBr naxcm-1：3350−2825、1725、1655、1515、
1475、1440
NMRδ（d6−DMSO）：1.14（3H、ｔ、Ｊ＝7.0
Hz）、3.35（6H、ｓ）、4.04（2H、ｒ、Ｊ＝7.0
Hz）、4.46（1H、ｄ、ｄ、Ｊ＝3.9Hz、8.4Hz）、
4.97（1H、ｄ、Ｊ＝3.9Hz）、5.09（4H、ｓ）、69
−7.1（3H、ｍ）、7.88（1H、ｓ）、8.22（1H、ｄ、
Ｊ＝8.4Hz）
実施例 ５
ピペロナール1.35ｇ、イソシアノ酢酸エチルエ
ステル1.13ｇおよびシアン化ナトリウム0.06ｇを
エタノール15mlに加え、室温で３時間撹拌する。IR ν KBr nax cm -1 : 3350−2825, 1725, 1655, 1515,
1475, 1440 NMRδ ( d6 -DMSO): 1.14 (3H, t, J=7.0
Hz), 3.35 (6H, s), 4.04 (2H, r, J=7.0
Hz), 4.46 (1H, d, d, J = 3.9Hz, 8.4Hz),
4.97 (1H, d, J = 3.9Hz), 5.09 (4H, s), 69
−7.1 (3H, m), 7.88 (1H, s), 8.22 (1H, d,
J=8.4Hz) Example 5 1.35 g of piperonal, 1.13 g of isocyanoacetic acid ethyl ester and 0.06 g of sodium cyanide are added to 15 ml of ethanol and stirred at room temperature for 3 hours.
反応後に撹拌下酢酸３mlおよび水10mlを加え氷
室に一夜放置すると結晶が析出する。 After the reaction, 3 ml of acetic acid and 10 ml of water were added with stirring, and the mixture was left in an ice chamber overnight to precipitate crystals.
生成物を取し、エタノールで洗浄後乾燥する
と、スレオ−Ｎ−ホルミル３−（３，４−メチレ
ンジオキシフエニル）セリンエチルエステル1.75
ｇ（収率69.2％）mp136〜138℃が得られる。 The product was taken, washed with ethanol, and dried to give threo-N-formyl 3-(3,4-methylenedioxyphenyl)serine ethyl ester 1.75
g (yield 69.2%) mp 136-138°C is obtained.
IR νKBr naxcm-1：3380、3250、1730、1660、1500、
1260、1030
NMRδ（d6−DMSO）：1.16（3H、ｔ、Ｊ＝7.0
Hz）、4.11（2H、ｔ、Ｊ＝7.0Hz）、4.50（1H、
ｄ、ｄ、Ｊ＝10Hz、3.0Hz）、5.03（1H、ｔ、Ｊ
＝3.0Hz）、5.80（1H、ｄ、Ｊ＝3.0Hz）、5.95
（2H、ｓ）、6.80（2H、ｓ）、6.94（1H、ｓ）、
7.96（1H、ｓ）、8.29（1H、ｄ、Ｊ＝10Hz）
上記エステル体0.54ｇをジオキサン８mlに加
え、室温撹拌下に2N水酸化ナトリウム1.1mlを滴
下後３時間撹拌を続ける。IR ν KBr nax cm -1 : 3380, 3250, 1730, 1660, 1500,
1260, 1030 NMRδ ( d6 -DMSO): 1.16 (3H, t, J=7.0
Hz), 4.11 (2H, t, J=7.0Hz), 4.50 (1H,
d, d, J = 10Hz, 3.0Hz), 5.03 (1H, t, J
= 3.0Hz), 5.80 (1H, d, J = 3.0Hz), 5.95
(2H, s), 6.80 (2H, s), 6.94 (1H, s),
7.96 (1H, s), 8.29 (1H, d, J = 10Hz) Add 0.54 g of the above ester to 8 ml of dioxane, add 1.1 ml of 2N sodium hydroxide dropwise with stirring at room temperature, and continue stirring for 3 hours.
反応終了後酢酸１mlを加えて酸性とし、減圧濃
縮後残渣を含水アセトンから再結晶すると、スレ
オ−Ｎ−ホルミル−３−（３，４−メチレンジオ
キシフエニル）セリン0.32ｇ（収率65.8％）
mp187〜189℃（dec.）が得られる。 After the reaction was completed, 1 ml of acetic acid was added to make it acidic, and after concentration under reduced pressure, the residue was recrystallized from aqueous acetone to give 0.32 g of threo-N-formyl-3-(3,4-methylenedioxyphenyl)serine (yield 65.8%). )
mp187-189℃ (dec.) is obtained.
IR νKBr naxcm-1：3560、3250、2975、1660、1620、
1400、1265
NMRδ（d6−DMSO）：4.29（1H、ｄ、ｄ、Ｊ＝10
Hz、3.0Hz）、4.99（1H、ｄ、Ｊ＝3.0Hz）、5.95
（2H、ｓ）、6.76（2H、ｓ）、6.89（1H、ｓ）、
7.35（1H、br.s）、7.67（1H、ｄ、Ｊ＝10Hz）、
7.96（1H、ｓ）
実施例 ６
実施例１の３，４−ジベンジルオキシベンズア
ルデヒドに代えて４−ベンジルオキシ−３−メト
キシベンズアルデヒド2.42ｇを用い、他は実施例
１と同様に処理すると、スレオ−Ｎ−ホルミル−
３−（４−ベンジルオキシ−３−メトキシフエニ
ル）セリンメチルエステル2.37ｇ（収率66.0％）
mp130〜132℃が得られる。IR ν KBr nax cm -1 : 3560, 3250, 2975, 1660, 1620,
1400, 1265 NMRδ ( d6 -DMSO): 4.29 (1H, d, d, J=10
Hz, 3.0Hz), 4.99 (1H, d, J = 3.0Hz), 5.95
(2H, s), 6.76 (2H, s), 6.89 (1H, s),
7.35 (1H, br.s), 7.67 (1H, d, J=10Hz),
7.96 (1H, s) Example 6 When 2.42 g of 4-benzyloxy-3-methoxybenzaldehyde was used in place of 3,4-dibenzyloxybenzaldehyde in Example 1, and the other conditions were the same as in Example 1, threo -N-formyl-
3-(4-benzyloxy-3-methoxyphenyl)serine methyl ester 2.37g (yield 66.0%)
mp130-132℃ is obtained.
IR νKBr naxcm-1：3360、3240、1735、1660、1500、
1255
NMRδ（d6−DMSO）：3.60（3H、ｓ）、3.77（3H、
ｓ）、4.35（1H、d.d、Ｊ＝9.0Hz、3.0Hz）、5.10
（1H、ｍ）、5.04（2H、ｓ）、6.95（2H、ｓ）、
7.06（1H、ｓ）、7.36（5H、ｓ）、7.91（1H、ｓ）、
8.23（1H、ｄ、Ｊ＝9.0Hz）
参考例 １
実施例１で得られたスレオ−Ｎ−ホルミル−３
−（３，４−ジベンジルオキシフエニル）セリン
メチルエステル5.00ｇをジオキサン50mlと2N水
酸化ナトリウム水溶液７mlに懸濁し、氷冷下１時
間撹拌する。IR ν KBr nax cm -1 : 3360, 3240, 1735, 1660, 1500,
1255 NMRδ ( d6 -DMSO): 3.60 (3H, s), 3.77 (3H,
s), 4.35 (1H, dd, J=9.0Hz, 3.0Hz), 5.10
(1H, m), 5.04 (2H, s), 6.95 (2H, s),
7.06 (1H, s), 7.36 (5H, s), 7.91 (1H, s),
8.23 (1H, d, J = 9.0Hz) Reference example 1 Threo-N-formyl-3 obtained in Example 1
5.00 g of -(3,4-dibenzyloxyphenyl)serine methyl ester is suspended in 50 ml of dioxane and 7 ml of 2N aqueous sodium hydroxide solution, and stirred for 1 hour under ice cooling.
反応液に3N塩酸50mlを加えて50℃の水浴上３
時間加熱し、次いで減圧下に溶媒を留去する。残
渣を熱エタノール50mlで２回抽出し、抽出物を活
性炭で処理後、18％塩化水素−エタノール20mlを
加えて一夜氷室に放置する。 Add 50ml of 3N hydrochloric acid to the reaction solution and place on a water bath at 50°C.
Heat for an hour and then evaporate the solvent under reduced pressure. The residue was extracted twice with 50 ml of hot ethanol, and the extract was treated with activated charcoal, then 20 ml of 18% hydrogen chloride-ethanol was added, and the mixture was left in an ice chamber overnight.
析出晶を取し、結晶をエタノールで洗浄後乾
燥すると、スレオ−３−（３，４−ジベンジルオ
キシフエニル）セリン塩酸塩3.86ｇ（収率78.2
％）mp156〜158℃（dec.）が得られる。 The precipitated crystals were collected, washed with ethanol, and dried to give 3.86 g of threo-3-(3,4-dibenzyloxyphenyl)serine hydrochloride (yield: 78.2
%) mp156-158℃ (dec.) is obtained.
参考例 ２
実施例１で得られたスレオ−Ｎ−ホルミル−３
−（３，４−ジベンジルオキシフエニル）セリン
メチルエステル400ｇをジオキサン40mlと3N塩酸
40mlの混液に溶解し、40℃の水浴上10時間加温す
る。Reference Example 2 Threo-N-formyl-3 obtained in Example 1
-(3,4-Dibenzyloxyphenyl)serine methyl ester 400g with dioxane 40ml and 3N hydrochloric acid
Dissolve in 40 ml of mixed solution and heat on a 40°C water bath for 10 hours.
減圧下に溶液を留去し、残渣を含水メタノール
から再結晶すると、スレオ−３−（３，４−ジベ
ンジルオキシフエニル）セリンメチルエステル塩
酸塩3.85ｇ（収率94.9％）mp148〜151℃（dec.）
が得られる。 The solution was distilled off under reduced pressure, and the residue was recrystallized from aqueous methanol to give 3.85 g (yield 94.9%) of threo-3-(3,4-dibenzyloxyphenyl) serine methyl ester hydrochloride (yield 94.9%), mp 148-151°C. (dec.)
is obtained.
参考例 ３
実施例３で得られたスレオ−Ｎ−ホルミル−３
−（３，４−ジベンジルオキシフエニル）セリン
2.10ｇをエタノール80mlに加熱溶解し、この中に
エタノール８mlに溶解したｌ−エフエドリン0.48
ｇを加えて氷室に一夜放置する。Reference Example 3 Threo-N-formyl-3 obtained in Example 3
-(3,4-dibenzyloxyphenyl)serine
Dissolve 2.10 g in 80 ml of ethanol by heating, and add 0.48 l-efedrin dissolved in 8 ml of ethanol.
Add g and leave it in an icebox overnight.
析出晶を取し、エタノールで洗浄後乾燥する
と、ｌ−スレオ−Ｎ−ホルミル−３−（３，４−
ジベンジルオキシフエニル）セリンのｌ−エフエ
ドリン塩1.26ｇ、mp152〜155℃（dec.）が得ら
れる。 The precipitated crystals were collected, washed with ethanol, and dried to give l-threo-N-formyl-3-(3,4-
1.26 g of l-ephedrin salt of dibenzyloxyphenyl)serine, mp 152-155°C (dec.) is obtained.
上記で得られたエフエドリン塩を30倍量の酢酸
エチルに懸濁し、氷冷下に10倍量の2N塩酸を加
えて液が透明になるまで撹拌する。 Suspend the efuedrin salt obtained above in 30 times the amount of ethyl acetate, add 10 times the amount of 2N hydrochloric acid under ice cooling, and stir until the liquid becomes transparent.
酢酸エチル層を分取し、水洗後無水硫酸ナトリ
ウムで乾燥する。減圧下に溶媒を留去し、残渣を
ｎ−ヘキサンから再結晶すると、ｌ−スレオ−Ｎ
−ホルミル−３−（３，４−ジベンジルオキシフ
エニル）セリン0.83ｇ（収率39.5％）mp142〜144
℃（dec.）〔α〕20°D−28.6（ジオキサン、Ｃ＝1.0）
が得られる。 The ethyl acetate layer is separated, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from n-hexane to give l-threo-N
-Formyl-3-(3,4-dibenzyloxyphenyl)serine 0.83g (yield 39.5%) mp142-144
°C (dec.) [α] 20 ° D −28.6 (dioxane, C=1.0)
is obtained.
IR νKBr naxcm-1：3300−2900、1760、1625、1535、
1450、1380、1250、1140
NMRδ（d6−DMSO）：4.52（1H、d.d、Ｊ＝9.5Hz、
3.0Hz）、5.05（1H、ｍ）、5.10（4H、ｓ）、6.9−
7.5（3H、ｍ）、7.39（10H、ｓ）、7.98（1H、ｓ）、
8.19（1H、ｄ、Ｊ＝9.5Hz）
上記のｌ−ホルミル体1.52ｇをジオキサン15ml
と3N塩酸15mlに懸濁し、40℃で３時間加温撹拌
する。IR ν KBr nax cm -1 : 3300−2900, 1760, 1625, 1535,
1450, 1380, 1250, 1140 NMRδ ( d6 -DMSO): 4.52 (1H, dd, J=9.5Hz,
3.0Hz), 5.05 (1H, m), 5.10 (4H, s), 6.9−
7.5 (3H, m), 7.39 (10H, s), 7.98 (1H, s),
8.19 (1H, d, J = 9.5Hz) 1.52g of the above l-formyl compound was added to 15ml of dioxane.
and 15 ml of 3N hydrochloric acid, and stirred at 40°C for 3 hours.
溶媒を減圧留去し、残渣を熱エタノール15mlで
２回抽出後、抽出液を合わせ活性炭処理する。活
性炭を去後、液を10mlまで濃縮し、35％塩酸
15mlを添加して氷室に一夜放置する。 The solvent was distilled off under reduced pressure, the residue was extracted twice with 15 ml of hot ethanol, and the extracts were combined and treated with activated carbon. After removing the activated carbon, concentrate the liquid to 10ml and add 35% hydrochloric acid.
Add 15ml and leave in an icebox overnight.
析出晶を取し、含水エタノールで洗浄後乾燥
すると、ｄ−３−（３，４−ジベンジルオキシフ
エニル）セリン塩酸塩1.35ｇ（収率87％）mp146
〜148℃（dec.）〔α〕28 D＝＋5.5（Ｃ＝1.0、EtOH）
が得られる。 The precipitated crystals were collected, washed with aqueous ethanol, and dried to yield 1.35 g (yield 87%) of d-3-(3,4-dibenzyloxyphenyl) serine hydrochloride.mp146
~148℃ (dec.) [α] 28 D = +5.5 (C = 1.0, EtOH)
is obtained.
上記のｄ−アミノ酸0.88ｇをジオキサン10mlと
水５mlの混液に溶解し、氷冷撹拌下炭酸水素ナト
リウムを加えてPH3.5に調整する。 0.88 g of the above d-amino acid was dissolved in a mixture of 10 ml of dioxane and 5 ml of water, and the pH was adjusted to 3.5 by adding sodium hydrogen carbonate while stirring under ice cooling.
沈殿する遊離アミノ酸を取し、乾燥後酢酸10
mlとメタノール10mlの混液に溶かし、５％Pd−
C0.1ｇの存在下常圧で３時間接触還元する。 Take the precipitated free amino acids and dry them with acetic acid for 10 minutes.
ml and methanol 10ml, 5% Pd-
Catalytic reduction was carried out for 3 hours at normal pressure in the presence of 0.1 g of C.
触媒を別後、溶媒を減圧留去し、残渣を含水
メタノールから再結晶すると、ｄ−スレオ−３−
（３，４−ジヒドロキシフエニル）セリン0.30ｇ
（収率81％）mp230〜232℃（dec.）〔α〕20 D＋417°
（Ｃ＝1.0、1N HCl）が得られる。 After removing the catalyst, the solvent was distilled off under reduced pressure and the residue was recrystallized from aqueous methanol to give d-threo-3-
(3,4-dihydroxyphenyl)serine 0.30g
(Yield 81%) mp230-232℃ (dec.) [α] 20 D +417°
(C=1.0, 1N HCl) is obtained.
参考例 ４
ｌ−エフエドリンに代えてｄ−エフエドリンを
使用し、他は参考例３と同様な処理を行なうと、
ｌ−スレオ−３−（３，４−ジヒドロキシフエニ
ル）セリンmp227〜229℃（dec.）〔α〕20 D−42.1°
（Ｃ＝1.0、1N HCl）が得られる。Reference Example 4 Using d-ephedrin instead of l-ephedrin and performing the same treatment as in Reference Example 3, except for the following:
l-Threo-3-(3,4-dihydroxyphenyl)serine mp227-229℃ (dec.) [α] 20 D -42.1°
(C=1.0, 1N HCl) is obtained.
参考例 ５
実施例６で得られたスレオ−Ｎ−ホルミル−３
−（４−ベンジルオキシ−３−メトキシフエニル）
セリンメチルエステル2.15ｇをジオキサン25mlに
懸濁し、氷冷撹拌下2N水酸化ナトリウム水溶液
3.2mlを加えて45分間撹拌すると透明な溶液が得
られる。この液に3N塩酸28mlを加えて50℃の水
浴上３時間加温し、次いで反応液を減圧下に〜10
mlまで濃縮後、濃縮液を活性炭処理する。2N水
酸化ナトリウムでPH4.5に調整後、析出晶を取
し、水およびメタノールで洗浄後乾燥すると、ス
レオ−３−（４−ベンジルオキシ−３−メトキシ
フエニル）セリン1.51ｇ（収率79.5％）mp160〜
162℃が得られる。Reference Example 5 Threo-N-formyl-3 obtained in Example 6
-(4-benzyloxy-3-methoxyphenyl)
Suspend 2.15 g of serine methyl ester in 25 ml of dioxane, and add a 2N aqueous sodium hydroxide solution while stirring on ice.
Add 3.2 ml and stir for 45 minutes to obtain a clear solution. 28 ml of 3N hydrochloric acid was added to this solution, heated on a 50°C water bath for 3 hours, and then the reaction solution was heated under reduced pressure for ~10 min.
After concentrating to ml, the concentrate is treated with activated carbon. After adjusting the pH to 4.5 with 2N sodium hydroxide, the precipitated crystals were collected, washed with water and methanol, and dried to give 1.51 g of threo-3-(4-benzyloxy-3-methoxyphenyl)serine (yield 79.5). %) mp160~
162℃ is obtained.
発明の効果
本発明の合成中間体を経由する製造法により医
薬として有用なＬ−スレオ−DOPSおよびそれら
の近縁誘導体を、工業的に安価で、かつ大量に製
造できるので、本発明は、Ｌ−スレオ−DOPS類
の医薬としての利用面で多大なる貢献をなすもの
である。Effects of the Invention Since L-threo-DOPS and its related derivatives useful as pharmaceuticals can be produced industrially at low cost and in large quantities by the production method via synthetic intermediates of the present invention, the present invention -Threo- This will make a significant contribution to the medicinal use of DOPS.
Claims (1)
低級アルキル基、低級アルコキシアルキル基、ア
ラルキル基もしくは両者が互いに連結してメチレ
ン基を示し、R3は水素原子、低級アルキル基ま
たはアラルキル基を示す）で表わされるスレオ−
Ｎ−ホルミルフエニルセリン誘導体。 ２ 一般式 （式中R1およびR2は同一または異なつてもよい
低級アルキル基、低級アルコキシアルキル基、ア
ラルキル基もしくは両者が互いに連結してメチレ
ン基を示す）で表わされるアルデヒドと、一般式 CN−CH2−COOR 〔〕 （式中Ｒは低級アルキル基またはアラルキル基を
示す）で表わされるイソシアノ酢酸エステルとを
塩基の存在下に反応させ、ついで部分加水分解す
ることを特徴とする一般式 （式中R1およびR2は前記の意味を有し、R3は水
素原子、低級アルキル基またはアラルキル基を示
す）で表わされるスレオ−Ｎ−ホルミルフエニル
セリン誘導体の製法。[Claims] 1. General formula (In the formula, R 1 and R 2 are a lower alkyl group, a lower alkoxyalkyl group, an aralkyl group, which may be the same or different, or both are linked to each other to represent a methylene group, and R 3 is a hydrogen atom, a lower alkyl group, or an aralkyl group. )
N-formylphenylserine derivative. 2 General formula (In the formula, R 1 and R 2 may be the same or different lower alkyl group, lower alkoxyalkyl group, aralkyl group, or both are linked to each other to represent a methylene group) and the general formula CN-CH 2 A general formula characterized by reacting an isocyanoacetate represented by -COOR [] (in the formula R represents a lower alkyl group or an aralkyl group) in the presence of a base, followed by partial hydrolysis. A method for producing a threo-N-formylphenylserine derivative represented by the formula (wherein R 1 and R 2 have the above-mentioned meanings, and R 3 represents a hydrogen atom, a lower alkyl group, or an aralkyl group).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60116484A JPS61275254A (en) | 1985-05-31 | 1985-05-31 | N-formylphenylserine derivative and production thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60116484A JPS61275254A (en) | 1985-05-31 | 1985-05-31 | N-formylphenylserine derivative and production thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61275254A JPS61275254A (en) | 1986-12-05 |
| JPH0466471B2 true JPH0466471B2 (en) | 1992-10-23 |
Family
ID=14688251
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP60116484A Granted JPS61275254A (en) | 1985-05-31 | 1985-05-31 | N-formylphenylserine derivative and production thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61275254A (en) |
-
1985
- 1985-05-31 JP JP60116484A patent/JPS61275254A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61275254A (en) | 1986-12-05 |
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