WO2001034557A1 - Procede de production de derives d'enaminone cycliques optiquement actifs - Google Patents
Procede de production de derives d'enaminone cycliques optiquement actifs Download PDFInfo
- Publication number
- WO2001034557A1 WO2001034557A1 PCT/JP2000/007876 JP0007876W WO0134557A1 WO 2001034557 A1 WO2001034557 A1 WO 2001034557A1 JP 0007876 W JP0007876 W JP 0007876W WO 0134557 A1 WO0134557 A1 WO 0134557A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- derivative
- cyclic
- cycloalkyl
- optically active
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/20—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/6574—Esters of oxyacids of phosphorus
- C07F9/65742—Esters of oxyacids of phosphorus non-condensed with carbocyclic rings or heterocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/6574—Esters of oxyacids of phosphorus
- C07F9/65744—Esters of oxyacids of phosphorus condensed with carbocyclic or heterocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Definitions
- the present invention relates to a method for producing an optically active cyclic enaminonone derivative, which is a synthetic raw material for producing a medicine, a pesticide and the like.
- the enaminone derivative is a compound useful as a synthetic raw material for producing pharmaceuticals, agricultural chemicals, and the like. The same applies to the case where a drug or an agricultural chemical is manufactured stereoselectively using this enaminone derivative as a synthetic raw material compound. If an optically active derivative is used from the beginning, the optical isomer is resolved in the subsequent step. A decrease in yield can be avoided, and manufacturing costs can be significantly reduced.
- enaminone derivatives are susceptible to amino group substitution and exchange under acidic conditions due to their enaminone partial structure, and are more inefficient than ordinary organic bases such as alkylamines, monoarylamines, heterocyclic bases and alkyloids. It is stable. For these reasons, there have been few reports that the enaminone derivative could be optically resolved with an optically active acid, and at present there has been no sufficient study.
- the optically isomeric mixture of the chiral cyclic enaminonone derivative obtained using the compound as a raw material can be used.
- the other optical isomer can be converted back into the cyclic 1,3-diketone derivative having a symmetric plane as a raw material.
- a method for producing an optically active cyclic enaminone derivative comprising optically resolving a mixture of optical isomers of a cyclic enaminonone derivative using a highly acidic optical resolving agent,
- R Q to R 1Q each independently represent a hydrogen atom or a substituent (however, R 1 and R 2 are not the same, and R 3 and R 4 and R 5 and R 6 are the same at the same time, Wherein R 7 and R 8 and R 9 and R 1G are not the same at the same time.)
- R 1 and R 2 are as defined above, (7) wherein the partial structure (A) is represented by the following formula (A-2):
- R 3 , R 4 , R 5 and R 6 are as defined above.
- R 3 and R 4 of the compound represented by the formula (A-2) in which the partial structure (A) is represented by the formula (A-2) are each independently a hydrogen atom or a 5- or 6-membered aromatic group which may be substituted.
- R 5 and R 6 are each independently a hydrogen atom, a halogen, a linear or branched aliphatic hydrocarbon group which may be substituted, or a substituted or unsubstituted homocyclic or heterocyclic group.
- R 3 and R 4 of the compound represented by the formula (A-2) in which the partial structure (A) is represented by the formula (A-2) are each independently a hydrogen atom or a 5- or 6-membered aromatic group which may be substituted.
- R 7 to R 1Q are as defined above.
- optical resolving agent is an optically active sulfonic acid derivative or a sulfamic acid derivative.
- the optical resolving agent is an optically active phosphoric acid derivative. Or the production method according to 11,
- R 3 and R 4 each independently represent a hydrogen atom or an optionally substituted 5- or 6-membered aromatic homo- or heterocyclic ring (however, R 3 and R 4 are not the same)
- cyclic 1,3-diketone derivative having a plane of symmetry refers to a compound having a surface in which, when the cyclic 1,3-diketone derivative is divided into two, the divided portions are mirror images of each other. If the compound satisfying this condition, the production method of the present invention Among these compounds, preferred compounds to which the production method of the present invention can be applied include compounds represented by the following formula (I):
- the “substituent” in RQ or R 1 Q includes a halogen atom, a linear or branched aliphatic hydrocarbon group which may be substituted, a hydroxy group which may be substituted, Optionally substituted mercapto group, optionally substituted amino group, optionally substituted imidoyl group, optionally substituted amidino group, nitro group, cyano group, esterified or amidified Carboxyl group, optionally substituted sulfonyl group, carboxylic acid-derived acyl group, sulfonic acid-derived acyl group, sulfinic acid-derived acyl group, and optionally substituted aromatic or non-aromatic group. And an optionally substituted aromatic or non-aromatic heterocyclic group.
- the “halogen atom” includes, for example, fluorine, chlorine, bromine, iodine and the like, and preferably chlorine, bromine and the like.
- linear or branched aliphatic hydrocarbon group examples include an alkyl group, an alkenyl group, and an alkynyl group.
- alkyl group examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n- Xyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl, n-heptyl, 1-methylheptyl, 1-ethylhexyl , N- octyl, 1-methylheptyl, nonyl and so on.
- Al Kill group and the like preferably lower - a (C ⁇ 6) alkyl.
- alkenyl group examples include vinyl, aryl, isopropyl, 2-methylaryl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl- 1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2- C 2 _ 6 alkenyl groups such as hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like.
- alkynyl group examples include ethynyl, 1-propynyl, 2-propenyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2 - to hexynyl, the 3-key Shin Il, hexynyl to 4-, C 2 of hexynyl, etc., to 5 - include 6 alkynyl group.
- linear or branched aliphatic hydrocarbon group may further, for example eight androgenic atom; a lower (C, - 6) alkoxy group, C 3 _ 6 cycloalkyl O alkoxy group, Ari Ruokishi group optionally substituted hydroxy group and the like; lower ((: preparative 6) alkylthio group, C 3 _ 6 cycloalkylthio group, an optionally substituted main mercapto group such as ⁇ Li one thio group; a lower (C ⁇ ) alkyl, lower ((: 6) alkoxy, C 3 - 6 a cycloalkyl, hydroxy, force Rubamoiru, phenyl, phenylene Lou lower (C ⁇ ) alkyl, lower (C ⁇ Arukanoiru, C 3 - 6 cycloalkyl one carbonyl, Benzoyl, Eniru C 2 _ 6 Arukanoiru, lower (C ⁇ one 6) alkoxy one
- substituted hydroxy groups further include, for example, an octogen atom; a linear or branched aliphatic hydrocarbon group such as an alkyl group, an alkenyl group, and an alkynyl group; a lower (C ⁇ e) alkoxy group; C 3 6 cycloalkyl O alkoxy group, an optionally substituted hydroxy group such as Ariruokishi group; a lower (( ⁇ _ 6) alkylthio groups, C 3 6 consequent Roarukiruchio group, may be substituted, such as Ariruchio group mercapto group; low grade (Ji ⁇ alkyl, lower (C ⁇ e) alkoxy, C 3 6 cycloalkyl, hydroxy sheet, the force Rubamoiru, phenyl, phenylene Lou lower (C alkyl, lower (C ⁇ 6) Arukanoiru, C 3 _ 6 cycloalkyl - carbonyl, Benzoiru, pheny
- Bok 6 alkyl sulfonyl Le a lower (C ⁇ ) alkoxy sulfonyl, C 3 6 cycloalkyl O carboxymethyl sulfonyl, phenylene Lou alkoxysulfonyl, sulfamoyl, lower (C ⁇ ) alkyl aminosulfonyl, C 3 _ 6 cycloalkyl aminosulfonyl, phenylene Lou
- Examples of the “optionally substituted mercapto group” include not only a free mercapto group but also a lower (C 6 ) alkylthio group (methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec. butylthio, tert Puchiruchio, cyclohexylthio etc.
- substituted mercapto groups further include, for example, a halogen atom; a linear or branched aliphatic hydrocarbon group such as an alkyl group, an alkenyl group, and an alkynyl group; a lower (C ⁇ 6 ) alkoxy group; 3 _ 6 cycloalkyl O alkoxy group, an optionally substituted hydroxy group such as Ariruokishi group; a lower (Cn) alkylthio groups, C 3 6 consequent Roarukiruchio group, an optionally substituted mercapto group such as Ariruchio group; Low Grade ( ⁇ _ 6) alkyl, lower (c Bok 6) alkoxy, c 3 - 6 cycloalkyl, hydroxy sheet, the force Rubamoiru, phenyl, phenyl - lower (C ⁇ - 6) alkyl, lower (C ⁇ e) Arukanoiru, c 3 _ 6 cycloalkyl one carbony
- the “optionally substituted amino group” includes not only a free amino group but also lower (C ⁇ 16 ) alkyl (methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
- Lower (C 6 ) alkoxy (methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, etc.
- C 6 cycloalkyl (cyclopropyl, cyclobutyl, consequent opening pentyl, cyclohexyl, etc.) hydroxy, force Rubamoiru, phenyl, Hue sulfonyl - lower (C ⁇ ) alkyl (benzyl, phenethyl, 3-phenylpropyl, 4 one Phenylbutyl, etc.), lower (C alkanols (formyl, acetyl, pio) Le, Puchiriru, isobutyryl, valeryl, pivaloyl, etc.), C 3 _ link port alkyl one carbonyl (cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexyl-carbonyl cyclohexane, etc.), Benzoiru, phenylene Lou C 2 _ 6 Arukanoiru ( Phenylacetyl, phenyl
- cyclic amino group optionally being.
- two of such substituents may form a cyclic amino group together with the nitrogen atom.
- Examples of such a cyclic amino group include pyrrolidino, piperidino, morpholino, and thiomorpholino. .
- substituted amino groups further include, for example, a halogen atom; a linear or branched aliphatic hydrocarbon group such as an alkyl group, an alkenyl group, and an alkynyl group; a lower (C ⁇ ) alkoxy group; C 3 - 6 cycloalkyl O alkoxy group, an optionally substituted hydroxy group such as Ariruokishi group; a lower (C ⁇ ) alkylthio groups, C 3 - 6 cycloalkyl alkylthio, mercapto substituted such Ariruchio group Groups; lower (C ⁇ 6 ) alkyl, lower (Cu) alkoxy, C 3 _ 6 cycloalkyl, hydroxy, carbamoyl, phenyl, phenyl lower (C ⁇ ) alkyl, lower (C ⁇ ) alkenyl, C 3 _ 6 cycloalkyl - carbonyl, Benzoiru, phenylene Lou C 2 _
- Honiru C 3 - 6 cycloalkyl aminosulfonyl, phenylene Lou al kills aminosulfonyl, cyclic aminosulfonyl, nitroxy alkylamino Nosuruhoniru may sulfonyl group which may be substituted, such as ⁇ two Reno sulfonyl; Low grade (g alkyl one .
- substituted imidoyl groups and substituted amidino groups further include, for example, a halogen atom; a linear or branched aliphatic hydrocarbon group such as an alkyl group, an alkenyl group, and an alkynyl group; ⁇ ) alkoxy group, C 3 - 6 cycloalkyl Okishi group, an optionally substituted hydroxy group such as Ariruokishi groups; lower E - 6) alkylthio group, C 3 _ 6 cycloalkylthio group, a substituted such Ariruchio group Tei also mercapto group; a lower ((: preparative alkyl, lower (C ⁇ 6) alkoxy, C 3 - 6 cycloalkyl, hydroxy, force Rubamoiru, phenyl, phenylene Lou lower (C 6) alkyl, lower (C ⁇ 6 ) Arukanoiru, C 3 _ 6 cycloalkyl - carbonyl, Benzoir
- an amino group which may be substituted such groups; lower (C ⁇ ) alkyl, lower (C ⁇ 6) alkoxy, C 3 _ 6 cycloalkyl, optionally substituted with ⁇ reel such imidoyl group or an amidino group; Nitro group; cyano group; lower alkoxycarbonyl group, aryloxycarbonyl group, aralkyloxycarbonyl group, etc.
- N- disubstituted force Luba carbamoyl group a lower (C Bok 6) alkylsulfonyl, C 3 _ 6 cycloalkyl alkylsulfonyl, phenyl - C alkylsulfonyl , lower (C ⁇ e) alkoxysulfonyl, C 3 _ 6 cycloalkyl O carboxymethyl sulfonyl, phenylene Lou C e alkoxysulfonyl, sulfamoyl, lower (C i _ 6) alkyl ⁇ amino sulfonyl, C 3 - 6 cycloalkyl aminosulfonyl , Phenyl alcohol, aminoaminosulfonyl, cyclic aminosulfonyl, nitroxyalkylaminosulfonyl, Nilinosulfonyl, etc.
- An optionally substituted sulfonyl group a lower (C ⁇ ) alkyl mono-alkenyl, alkenyl group derived from a carboxylic acid such as C 3 _ 6 cycloalkyl monocarbonyl, benzoyl; a lower (c alkyl sulfonyl, 3 _ 6 cycloalkyl sulfonyl, Ashiru group derived from sulfonic acids such as phenylalanine sulfonyl, lower (c ⁇ ) alkyl sulfinyl, C 3 _ 6 cycloalkyl ⁇ Ruki Rusuru alkylsulfonyl, Ashiru group derived from sulfinic acid, such as Hue Nils sulfinyl; cyclo A saturated or unsaturated alicyclic hydrocarbon group such as an alkyl group, a cycloalkenyl group or a cycloalkenyl group; a monocycl
- Examples of the “carboxyl group that may be esterified” of the “carboxyl group that may be esterified or amidated” include, in addition to a free carboxyl group, for example, a lower alkoxycarbonyl group, an aryloxycarbonyl group, And an aralkyloxycarbonyl group.
- Examples of the lower alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyl C ⁇ 6 alkoxy groups such as oxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl, etc., for example, cyclopropoxycarbonyl, cyclobutyloxycarbonyl
- cycloalkyl alkoxycarbonyl such as downy Nji Ruo alkoxycarbonyl, phenyl such as phenyl O alkoxycarbonyl - C E _ 6 alkoxycarbonyl, such as 2 two preparative port key shell butoxycarbonyl, 3-two Toro alkoxy Nitoroki such propoxycarbonyl C.
- Preparative 6 alkoxycarbonyl and the like among which methoxycarbonyl, such alkoxycarbonyl groups such as ethoxycarbonyl, propoxycarbonyl are preferred.
- ⁇ reels O alkoxycarbonyl group for example, phenoxyethanol carbonyl, 1 one naphthoxycarbonyl, C 7 _ 1 2 Ariruokishi force such as 2 one naphthoxycarbonyl Luponyl groups and the like are preferred.
- aralkyloxycarbonyl group examples include benzyloxycarbonyl and phenethyloxycarbonyl.
- ⁇ Lal Kill O propoxycarbonyl sulfonyl group (for example C 6 _ i. Ariru such as single C _ 4 alkoxycarbonyl) is preferred.
- esterified carboxyl group further, for example, eight androgenic atom; ⁇ alkyl group, an alkenyl group, linear or branched aliphatic carbon hydrocarbon group and alkynyl group; a lower (C Bok 6) alkoxy groups, C 3 - 6 cycloalkyl O alkoxy group, Ariru Okishi optionally substituted hydroxy group such as a group; a lower (C ⁇ - alkylthio group, C 3 - 6 cycloalkylthio group, such as ⁇ Li one thio group optionally substituted Melka -but group; a lower (( ⁇ _ 6) alkyl, lower (C ⁇ 6) alkoxy, c 3 - 6 cycloalkyl, hydroxy, force Rubamoiru, phenyl, phenylene Lou lower (C ⁇ 6) alkyl, lower (C ⁇ e) Arukanoiru, C 3 - 6 cycloalkyl - carbony
- Alkylsulfonyl, c 3 _ 6 cycloalkyl sulfonyl, lower (c ⁇ ) alkoxy sulfonyl and 1 to 2 identical or different may be substituted by an amino group selected from phenylalanine sulfonyl like or two substituents, There optionally substituted amino group such as a cyclic amino group taken together with the nitrogen atom; a lower (C ⁇ 6) alkyl Le, lower (C alkoxy, C 3 _ 6 cycloalkyl, optionally substituted with Ariru etc.
- alkylaminosulfonyl ⁇ two Reno sulfonyl optionally substituted scan even if Ruhoniru group and the like; a lower (C ⁇ ) alkyl one carbonyl (Arukanoiru), C 3 - 6 cycloalkyl one carbonyl, Ashiru derived from a carboxylic acid such as Benzoiru group; a lower (C preparative 6) alkylsulfonyl, C 3 - 6 cycloalkylsulfonyl, Ashiru group derived from sulfonic acids such as phenylalanine sulfonyl; lower (C alkylsulfinyl, C 3 - 6 consequent opening alkylsulfinyl, Hue Nils sulfinyl etc.
- a saturated or unsaturated alicyclic hydrocarbon group such as a cycloalkyl group, a cycloalkenyl group, or a cycloalkenyl group; a monocyclic or condensed polycyclic aromatic group such as an aryl group A hydrocarbon group; a 5- or 6-membered aromatic monocyclic heterocyclic group, and an 8- to 12-membered aromatic condensed heterocyclic group;
- One or three identical or different substituents selected from the above may be substituted at the replaceable positions.
- Examples of the “amidated carboxyl group” include a rubamoyl group, an N-monosubstituent rubamoyl group, and an N, N-disubstituted rubamoyl group.
- the N-monosubstituted rubamoyl group means a rubamoyl group having one substituent on the nitrogen atom, and examples of the substituent include lower alkyl groups (eg, methyl, ethyl, propyl, isopropyl, butyl, etc.). , isobutyl, t er t-butyl, alkyl cyclohexyl, etc., to pentyl, etc.), a cycloalkyl group (e.g.
- Ariru group e.g. Phenyl, 1-naphthyl, 2-naphthyl and the like; aryl and the like; an aralkyl group (for example, C 7 ⁇ such as benzyl and phenethyl; aralkyl, preferably a phenyl and a trialkyl); No.
- Preferred N-mono-lower (C n) alkyl rubamoyls include, for example, methyl carbamoyl, ethyl carbamoyl, propyl rubamoyl, isopropyl rubamoyl, butyl carbamoyl, isobutyl carbamoyl, sec-butyl carbamoyl, tert-butyl carbamoyl,
- the N, N-disubstituted rubamoyl group means a rubamoyl group having two substituents on a nitrogen atom, and one example of the substituent is the aforementioned “N-monosubstituted rubamoyl”.
- substituents in the group " include those similar to the substituents in the group ", as the other example, such as lower alkyl groups (e.g. methyl, Echiru, propyl, isopropyl, heptyl, t -. heptyl, pentyl, the hexyl etc. Bok 6 alkyl group etc.), C 3 - 6 cycloalkyl group (e.g.
- cyclopropyl, cyclobutyl, cyclohexyl, etc. cyclopentyl, cyclohexylene
- Ararukiru groups e.g. benzyl, phenethyl etc., preferably phenylene root C DOO 4 alkyl group
- the two substituents may form a cyclic amino group together with the nitrogen atom.
- the cyclic amino group may be, for example, 1-azetidinylcarbonyl, 1-1 Pyrrolidinyl carbonyl, piperidino carbonyl, morpholino carbonyl, 1-piperazinyl carbonyl and a lower alkyl group at the 4-position (e.g.
- alkyl group such as benzyl
- an aralkyl group eg, a C 7 _ 1 C
- aralkyl group such as benzyl and phenethyl
- an aryl group eg, ceyl such as phenyl, 1-naphthyl, 2-naphthyl
- preferred C 3 - the 6 cycloalkyl force Rubamoiru eg consequent opening propyl force Rubamoiru, cycloalkyl Petit carbamoyl, cyclopentyl carba model I le, carboxy carbamoyl like cyclohexane, preferred phenylene Lou alkyl Cal Bamoiru, for example base Nji
- Preferred nitroxy C alkylaminocarbonyl, such as rucarbamoyl and phenethylcarbamoyl are, for example, 2-dioxyshethylcarbamoyl, 3-nitroxypropyl-capillum, etc.
- Preferred cyclic aminocarbonyl are, for example, morpholinocarbonyl, Peridinocarbonyl, pyrrolidinocarbonyl, thiomorpholinocarbonyl and the like can be mentioned. Also, anilinocarbon and the like can be exemplified.
- amidated carboxyl groups further include, for example, a halogen atom; Kill group, an alkenyl group, linear or branched aliphatic hydrocarbon group such as an alkynyl group; a lower (C ⁇ ) alkoxy group, C 3 6 cycloalkyl O alkoxy group, substituted such Ariruo alkoxy group which may be hydroxy group; a lower (C ⁇ ) alkylthio group, C 3 _ 6 cycloalkylthio group, an optionally substituted Melka but-groups such Ariruchio group; a lower (C ⁇ ) alkyl, lower (C ⁇ ) alkoxy, C 3 6 cycloalkyl, hydroxy, carbamoyl, phenyl, phenyl lower (C ⁇ e) alkyl, lower (C 6) alkanol, C 3 _ 6 cycloalkyl carbonyl, benzoyl, phenyl-C 2 _ 6 alkanol,
- Lal kill O alkoxycarbonyl group Carboxyl group which may be stealized; lower alkyl, cycloalkyl, aryl, aralkyl, aromatic or non-aromatic
- An N-mono-substituted or N-disubstituted lubamoyl group which may be substituted with 1 or 2 same or different groups selected from an aromatic homocyclic group, an aromatic or a non-aromatic heterocyclic group;
- C i _ 6) ⁇ alkylsulfonyl, C 3 _ 6 cycloalkyl sulfonyl, phenylene Lou alkyl sulfonyl, lower (C ⁇ alkoxysulfonyl, C 3 6 cycloalkyl O alkoxy scan Ruhoniru, phenylene Lou ( ⁇ _ 6 alkoxysulfonyl, sulfamoyl, lower (Ji ⁇ - 6) alkylaminosulf
- sulfonyl group for example, lower (C- 6 ) alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl) , t er t - butylsulfonyl, pentylsulfonyl, hexyl sulfonyl, etc.), C 3 _ 6 cycloalkyl alkylsulfonyl (e.g.
- cyclopropyl aminosulfonyl cyclobutylamino scan Ruhoniru, cyclopentyl aminosulfonyl, cyclohexyl aminosulfonyl cyclohexane, etc.
- phenylene Lou Bok 6 alkylaminosulfonyl (e.g. downy Njiruaminosuru Honiru, full energy chill aminosulfonyl, etc.), cyclic aminosulfonyl (e.g.
- Horinosuruhoniru Piberi Dinosulfonyl, pyrrolidinosulfonyl, thiomorpholinosulfonyl, etc.
- nitroxyalkylaminosulfonyl eg, 2-nitroxicetylaminosulfonyl, 3-nitroxypropylaminosulfonyl, etc.
- anilinosulfonyl eg, 2-nitroxicetylaminosulfonyl, 3-nitroxypropylaminosulfonyl, etc.
- the "Ashiru group derived from a carboxylic acid" for example, lower (Ji Bok 6) alkyl one local Boniru (Arukanoiru) (e.g. formyl, Asechiru, propionyl, Puchiriru, Isopuchiriru, valeryl, pivaloyl, etc.), C 3 - 6 cycloalkyl one Carbonyl (eg, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), benzoyl and the like.
- lower (Ji Bok 6) alkyl one local Boniru (Arukanoiru) (e.g. formyl, Asechiru, propionyl, Puchiriru, Isopuchiriru, valeryl, pivaloyl, etc.), C 3 - 6 cycloalkyl one Carbonyl (e
- sulfonic group derived from sulfonic acid examples include, for example, lower trialkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, to Kishirusuruhoniru etc.), C 3 _ 6 cycloalkyl alkylsulfonyl (e.g.
- cyclopropylsulfonyl cyclo butylsulfonyl, cyclopentylsulfonyl, Kishirusuruhoniru cyclohexane, etc.
- phenylalanine sulfonyl and the like.
- Examples of the “sulfinic acid-derived acyl group” include lower (C ⁇ ) alkylsulfinyl (eg, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl) , tert- butylsulfinyl, pentyl Luz sulfide two Le, hexyl-sulfinyl, etc.), C 3 - 6 cycloalkyl alkylsulfinyl (e.g.
- cyclo-propyl-sulfinyl cycloalkyl Petit Rusuru alkylsulfonyl, cycloalkyl pentylsulfamoyl off Iniru, hexyl-sulfinyl, etc. cyclohexane), phenyl Sulfinyl and the like.
- acyl groups specifically exemplified as described above further include, for example, a halogen atom; a linear or branched chain such as an alkyl group, an alkenyl group, and an alkynyl group.
- An aliphatic hydrocarbon group a lower (C 1-6 ) alkoxy group, a C 3 _ 6 cycloalkyloxy group, an optionally substituted hydroxy group such as an aryloxy group; a lower ((: tri 6 ) alkylthio group , C 3 _ 6 cycloalkylthio group, an optionally substituted mercapto group such as Ariruchio group; a lower (C ⁇ e) alkyl, lower (Cu) alkoxy, C 3 _ 6 consequent opening alkyl, hydroxy, force Rubamoiru, phenyl , phenylene Lou lower (C preparative 6) ⁇ alkyl, lower (C ⁇ e) Arukanoiru, C 3 _ 6
- Wakashi Ku is different may be substituted N- monosubstituted or N, N- disubstituted force Rubamoi Le group; a lower (C ⁇ ) alkylsulfonyl, C 3 _ 6 cycloalkyl sulfonyl, phenylene Lou alkylsulfonyl, lower (C ⁇ - e) alkoxysulfonyl, C 3 _ 6 a cycloalkyl O carboxymethyl sulfonyl, phenylene Lou alkoxysulfonyl, sul Famoiru, lower (Ji alkylaminosulfonyl, C 3 _ 6 cycloalkyl amino Nosuruhoniru, phenyl - alkylaminosulfonyl, cyclic Aminosuruho sulfonyl, nitroxy ( ⁇ _ 6 alkylaminosulfonyl, ⁇ two Ren
- the “aromatic or non-aromatic homocyclic group” includes, for example, a saturated or unsaturated alicyclic hydrocarbon group such as a cycloalkyl group, a cycloalkenyl group, a cycloalkenyl group and the like, and a monocyclic or condensed polycyclic group. etc. Ariru groups such cyclic aromatic hydrocarbon group, the Shikuroa alkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl cyclo, heptyl cyclohexane, Shikurookuchiru, C 3 _ 9 consequent opening alkyl such as cyclononyl is No.
- Examples of the cycloalkenyl group include 2-cyclopentene-1-yl, 3-cyclopentene-1-yl, 2-cyclohexene-1-yl, 3-cyclohexene-1-yl, and 1-cyclohexene-1-yl. Shikurobuten one 1 - I le, 1 Shiku port-pentene - 1-I le, etc. C 3 - 6 cycloalkenyl group and the like.
- Examples of the cycloalkenyl group include C 4, such as 2,4-cyclopentene-1-yl, 2,4-cyclohexanediene-1-yl, and 2,5-cyclohexanediene-1-yl. — 6 cycloalkanegenyl group and the like.
- the Ariru group eg if phenyl, 1 one-naphthyl, 2 _ naphthyl, anthryl, Fuenantoriru, etc.
- C 6 _ 1 4 Ariru group such as ⁇ Senafuchireniru like.
- a 5- or 6-membered aromatic or non-aromatic homocyclic group which may be substituted is preferable, and a 5- or 6-membered aromatic homocyclic group is particularly preferable.
- aromatic heterocyclic ring of the “aromatic or non-aromatic heterocyclic group” examples include, as an atom (ring atom) constituting a ring system, a heteroatom selected from an oxygen atom, a sulfur atom, a nitrogen atom, and the like.
- Aromatic heterocycles containing at least one (preferably one to three, more preferably one to two) of three (preferably one to two) are exemplified.
- aromatic monocyclic heterocyclic groups for example, furyl, chenyl, piperyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imimi Pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4 5- to 6-membered aromatic monocyclic heterocyclic groups such as —thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.
- aromatic monocyclic heterocyclic groups for example, furyl, chenyl, piperyl, oxazolyl, isoxazolyl, thiazolyl, isothiazo
- aromatic condensed heterocyclic groups eg, benzofuranyl, isobenzofuranyl, benzochenyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothia
- Examples thereof include an 8- to 12-membered fused aromatic heterocyclic group.
- a 5- or 6-membered aromatic or non-aromatic heterocyclic group which may be substituted is preferable, and a 5- or 6-membered aromatic heterocyclic group is particularly preferable.
- non-aromatic heterocyclic group for example, as a ring-forming atom (ring atom), 1 to 3 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom (preferably 1 to 2
- a saturated or unsaturated non-aromatic heterocyclic ring (aliphatic heterocyclic ring) containing at least one (preferably 1 to 4, and more preferably 1 to 2) of oxylanyl, azetidinyl, Saturated or unsaturated 3- to 8-membered (preferably 5- to 6-membered) compounds such as oxenilyl, ceylilyl, lipidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, etc.
- Saturated (preferably saturated) non-aromatic heterocyclic group Aliphatic heterocyclic group).
- a nitrogen atom constituting the ring may be oxidized, and when the ring is a nitrogen-containing aromatic heterocyclic ring having a hydroxyl group as a substituent such as 2-oxypyridine, ⁇
- a nitrogen-containing aromatic complex ring having an oxo group such as pyridone (which is equivalent in chemical structure to a nitrogen-containing aromatic heterocyclic ring having a hydroxyl group as a substituent);
- the above substituent may be present on the nitrogen atom of the ring.
- aromatic or non-aromatic homocyclic groups and “aromatic or non-aromatic heterocyclic groups” further include, for example, a halogen atom; a linear or branched group such as an alkyl group, an alkenyl group, and an alkynyl group.
- 1 or 2 selected may be the same or different and may be substituted with N-moso substitution or Other N, N-disubstituted force Rubamoiru group; a lower (Cn) alkylsulfonyl, C 3 "6 cyclo alkylsulfonyl, phenylene Lou C Bok 6 alkylsulfonyl, a lower (C ⁇ ) alkoxy sulfonyl, C 3 - 6 cycloalkyl alkyl O carboxymethyl sulfonyl, phenylene Lou _ 6 alkoxysulfonyl, sulfamoyl, lower (C alkylaminosulfonyl, C 3 _ 6 cycloalkyl aminosulfonyl, phenylene Lou alkylamino sulphonyl, cyclic aminosulfonyl, nitroxy Ji Bok 6 alkylaminosulfonyl Sulfonyl groups which may
- R 1 to R 4 R 7 and R 8 of the compound represented by the formula (I) are as described above.
- a halogen atom a linear or branched aliphatic hydrocarbon group which may be substituted, a hydroxy group which may be substituted, An optionally substituted mercapto group, an optionally substituted diamino group, an optionally substituted imidoyl group, an optionally substituted amidino group, a nitro group, a cyano group, an esterified or amidated group
- R D , R 5 , R 6 , R 9 and R 1 Q can be widely selected from the above-mentioned “substituents”, but are preferably a halogen atom or an optionally substituted straight chain. And a branched or branched aliphatic hydrocarbon group, an optionally substituted hydroxy group, and an optionally substituted mercapto group, and particularly preferably a hydrogen atom.
- Specific examples of the cyclic 1,3-pin derivative having a symmetry plane particularly preferably used in the production method of the present invention are as follows.
- the cyclic 1,3-diketone derivative having a symmetry plane and the chiral cyclic enaminonone derivative used in the production method of the present invention each have a tautomer, and all of these tautomers are present. It is included in the scope of the present invention.
- one of the carbonyl groups of the diketone of the cyclic 1,3-diketone derivative having a plane of symmetry of the present invention represented by the formula (I) is aminated to give the formula (II-11) and
- the mixture of optical isomers of the chiral cyclic enaminone derivative represented by (II-12) is shown below.
- a desired optically active cyclic enaminonone derivative is optically resolved from the optical isomer mixture, and the resulting optically active isomer, for example, the formula (I1-1) is derived as a raw material for synthesis into a target drug.
- the cyclic 1,3 having a symmetry plane represented by the formula (I) used as an initial raw material in the present invention is obtained.
- -Diketone derivatives can be obtained.
- Ammonia, ammonium acetate acetate, ammonium chloride, ammonium sulfate or other aminating agents selected from aminating agents) are converted to a solvent inert to the reaction, for example, methanol, ethanol, benzene, toluene, toluene, dichloromethane, dichloromethane. 1,2-dichloroethane, tetrahydrofuran, getyl ether, hexane, ethyl acetate, dimethylformamide, etc., or a mixed solvent thereof, preferably an alcoholic solvent such as ethanol, at about 0 ° C.
- a solvent inert to the reaction for example, methanol, ethanol, benzene, toluene, toluene, dichloromethane, dichloromethane. 1,2-dichloroethane, tetrahydrofuran, getyl ether, hexane, ethyl
- a cyclic 1,3-diketone derivative having a symmetry plane as a raw material for example, a compound represented by the formula (I)
- a compound represented by the formula (I) has a substituent which is affected by the above amination reaction, it is necessary to always carry out the above treatment as necessary.
- the substituent can be protected by a method.
- an optical resolving agent preferably a highly acidic optical resolving agent
- the optical resolving agent having a high acidity those having a dissociation constant pKa in water of about 4 or less, preferably about 110 to about 3 are used.
- an optically active phosphoric acid derivative, an optically active sulfamic acid derivative and an optically active sulfonic acid derivative are preferred.
- optically active phosphoric acid derivative for example,
- ring A represents a benzene ring which may have a substituent
- R la and R 2a each represent a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, or represents an alkoxy group or a nitro group which may have a group
- R 1 a and R 2a has the combined such connexion which may have a substituent C 2 _ 6 alkylene or location substituent Represents an optionally substituted methylenedioxy, and * represents an asymmetric center.
- ring A 1 and ring A 2 each represent an aromatic ring which may have a substituent.
- B is a good C 6 _ 1 4 7 aryl group which may have a substituent
- a hydroxyl group R lb was or hydrogen atom
- R 2 b is hydrogen atom
- R 3b represents a hydrogen atom or a hydrocarbon group which may have a substituent
- n represents 0 or 1.
- ring C is substituted with one or two substituents selected from a hydrocarbon group which may have a substituent, a carboxyl group which may be esterified or amidated, and a cyano group.
- substituents selected from a hydrocarbon group which may have a substituent, a carboxyl group which may be esterified or amidated, and a cyano group.
- 1-phenylethylsulfamic acid 1-phenyl-12- ( ⁇ -tolyl) ethylsulfamic acid, 1- (1-naphthyl) ethylsulfuric acid Famic acid, 2-phenylpyrrolidine-1-sulfonic acid, 2-benzylpyrrolidin-1-sulfonic acid, 3-phenylpyrrolidine-1-sulfonic acid, 2- (4-methoxyphenyl) piperidine-1-sulfonic acid And the like.
- optically active sulfonic acid derivative examples include camphor 10-sulfonic acid, 3-bromocamphor-8-sulfonic acid, 1-phenylenesulfonic acid, 1-phenylpropanesulfonic acid, and the like.
- the optically active sulfamic acid derivative exemplified here can be easily obtained, for example, according to the method described in J. Org. Chem. 23, pi 133 (1958).
- the “aromatic ring” of the “optionally substituted aromatic ring” represented by ring A 1 and ring A 2 includes, for example, a benzene ring, a naphthalene ring and a phenanthrene ring.
- a 3 ring, A 4 ring, A 5 ring and A 6 ring each represent a benzene ring which may have a substituent. And the like, or an optically active form of the compound or a salt thereof.
- a ring may be respectively to no A 1 ring A 6 ring and B have one or two substituents at any position, as the substituent, for example, have a substituent
- Examples of the lower alkyl group which may have a substituent include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.
- these alkyl groups include c 2 _ 5 alkanols (eg, acetyl, propionyl, etc.), carboxyl, and alkoxy 4 Examples include those substituted by carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, etc.).
- a lower alkoxy group eg, methyloxy, ethyloxy, n-propyloxy, isoprop
- a lower alkylthio group unsubstituted thiol groups as thiol group that may have the substituent (e.g., methylthio, Echiruchio, C physician 4 alkylthio group such as propylthio), lower Arukanoiruchio group (eg, Asechiruchio , C E _ 4 Arukanoiruchio such as propionic two Lucio), and the like.
- substituent e.g., methylthio, Echiruchio, C physician 4 alkylthio group such as propylthio
- lower Arukanoiruchio group eg, Asechiruchio , C E _ 4 Arukanoiruchio such as propionic two Lucio
- Examples of the amino group which may have a substituent include an unsubstituted amino group, for example, a lower alkylamino group (eg, a 4-alkylamino group such as methylamino, ethylamino, propylamino, etc.), a di-lower alkylamino group (eg, Jimechiruamino, di C E _ 4 Arukiruamino such Jechiruamino), C E _ 4 alkanoate noisy Rua amino group (e.g., Asetoamido and propionamide), and the like.
- a lower alkylamino group eg, a 4-alkylamino group such as methylamino, ethylamino, propylamino, etc.
- a di-lower alkylamino group eg, Jimechiruamino, di C E _ 4 Arukiruamino such Jechiruamino
- As the Ashiru group e.g. Arukanoiru group (e.g., formyl; Asechiru, (Bok 6 Arukanoiru such flop port Pioniru), an alkylsulfonyl group (e.g., methylstyrene Ruhoniru, C i 4 alkylsulfonyl such Echirusuruhoniru), ⁇ Li Monosulfonyl group (eg, benzenesulfonyl, p-toluenesulfonyl, etc.), optionally substituted rubamoyl group (eg, methylcarbamoyl, ethylcarbamoy) Or dimethylcarbamoyl, dimethylcarbamoyl, etc.
- Arukanoiru group e.g., formyl; Asechiru, (Bok 6 Arukanoiru such flop port Pioniru)
- Alkyl Ichiriki Rubamoiru group for example phenylene carbamoyl, mono- such Jifuenirukaru Bamoiru or di one C 6 4 Ariru - force Rubamoiru, Tatoebaben di carbamoyl, mono- and di benzylcarbamoyl or di C 7 6 ⁇ La alkyl Ichiriki Rubamoiru Group), a sulfamoyl group which may have a substituent (eg,
- halogen atom examples include fluorine, chlorine, bromine, and iodine.
- the optionally substituted methylenedioxy group is substituted on two adjacent carbon atoms of the benzene ring.
- the methylenedioxy group include an unsubstituted methylenedioxy group and a methylenedioxy group such as a halogen atom (eg, , A fluorine atom, a chlorine atom, a bromine atom, iodine), a nitro group, a hydroxyl group, an amino group and the like.
- a ring, halogen, ( ⁇ _ 6 alkyl and ( ⁇ was 1 or selected from alkoxy groups benzene ring which may have a two substituents are preferred.
- a ring is especially Mu ⁇ conversion And those having 1 or 2 chlorine atoms or methoxy groups as substituents are preferred, and the substitution positions are 2-position, 4-position and 2,4-position.
- B represents a C 6 _ 14 aryl group (phenyl group, naphthyl group) which may have one or two substituents selected from nitro, halogen atom, —6 alkyl group and C 6 alkoxy group. preferable.
- Examples of the “optionally substituted hydrocarbon group” in the substituents of R la , R 2a , R 2b , R 3b and the ring C include unsubstituted (: 4 alkyl groups such as methyl, ethyl and propyl). other groups, halogen atoms in these alkyl groups, nitro, Shiano, CI_ 4 Arukanoiru (eg, Asechiru, propionyl etc.), carboxyl, hydroxyl group, alkoxy (e.g., methoxy, ethoxy, propoxy, etc.), ( ⁇ _ 4 alkoxycarbonyl Kishi carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, etc.
- Examples of the halogen atom represented by R la and R 2a include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
- No replacement of R 1 a and R 2a is if represents an alkylene group which may have a together a connexion substituent group, the alkylene group that may have the substituent 2 -C 6 other alkylene (dimethylene, trimethylene, tetramethylene, pentamethylene) of, for example, in any position of these alkylene, lower alkyl group (e.g., methylation, Echiru, CI_ 4 alkyl, such as propyl), lower alkoxy (e.g. , Methoxy, ethoxy, propoxy, etc.), hydroxyl, amino, nitro, halogen (eg, fluorine, chlorine, bromine, iodine) It may have one or two substituents.
- lower alkyl group e.g., methylation, Echiru, CI_ 4 alkyl, such as propyl
- lower alkoxy e.g. , Methoxy, ethoxy, propoxy, etc.
- hydroxyl amino
- R 1 a and R 2 a when both of R 1 a and R 2 a are each methyltransferase group, and both include the case shown tetramethylene group bonded with each other.
- the ⁇ carboxyl group which may be esterified '' represented by R 2b and the ⁇ carboxyl group which may be esterified or amidated '' in the substituent of the ring C include the above-mentioned R Q to R 1G
- R Q to R 1G
- substituents as those described in detail in “Substituent” can be used.
- the above compound may form a salt with a metal (eg, sodium, potassium, calcium, etc.) or ammonium ion, and when it has a basic group, an acid addition salt ,
- a metal eg, sodium, potassium, calcium, etc.
- an acid addition salt eg, inorganic acid salts (eg, hydrochloride, sulfate, hydrobromide, phosphate, etc.), organic acid salts (eg, acetate, trifluoroacetate, succinate, maleate, fumarate) , Propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate, etc.).
- inorganic acid salts eg, hydrochloride, sulfate, hydrobromide, phosphate, etc.
- organic acid salts eg, acetate, trifluoroacetate, succinate, maleate, fumarate
- Propionate cit
- optical resolution in the production method of the present invention is carried out by reacting an optical isomer mixture of a cyclic enaminone derivative with an organic solvent inert to the reaction, for example, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, and the like.
- organic solvent inert for example, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, and the like.
- Alcohols such as acetonitrile; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; lactams such as N-methylpyrrolidone; ketones such as acetone and methylethyl ketone; Esters such as ethyl and methyl acetate; carboxylic acids such as formic acid and acetic acid; aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran and diisopropyl pyrether; halogenated hydrocarbons such as methylene chloride; Dissolved in a solvent appropriately selected from dimethyl sulfoxide and the like; 0.5 to 5 equivalents, preferably about 0.5 to 2 equivalents of the highly acidic optical resolving agent is added and the mixture is heated at about 0 ° C.
- the cooling temperature for precipitating the salt is, for example, preferably in the range of about 120 to 20 ° C.
- concentration of the organic solvent may be carried out, for example, by dissolving the optically active cyclic enaminone derivative and the optical resolving agent in the organic solvent, and then distilling off the organic solvent under reduced pressure until a part or a sufficient amount of the crystalline salt is precipitated.
- a cyclic enaminone derivative and an optical resolving agent are dissolved by heating in ethanol, and then ethyl acetate is dropped to crystallize.
- the crystalline salt of the optically active cyclic enaminonone derivative and the optical resolving agent obtained by the above method can be subjected to recrystallization by a conventional method, if necessary. Further, if necessary, the resulting product can be obtained as a desired optically active cyclic enaminone derivative or a salt thereof by treating with an inert solvent in a solvent inert to the reaction. Specifically, for example, the crystalline salt is partitioned between an organic solvent such as ethyl acetate, tetrahydrofuran, and methyl ethyl ketone, and an aqueous alkali solution such as sodium hydroxide to obtain a free cyclic enaminonone derivative.
- an organic solvent such as ethyl acetate, tetrahydrofuran, and methyl ethyl ketone
- an aqueous alkali solution such as sodium hydroxide
- the obtained optically active cyclic enaminonone derivative can be isolated as a desired salt by further treating with an inorganic acid or an organic acid.
- the salt include hydrochloride, hydrobromide, sulfate, nitrate, phosphate, methanesulfonate, toluenesulfonate, 1-phenylethylsulfamate and the like. be able to.
- a desired optically active cyclic enaminone derivative is isolated from the mixture of optical isomers as a salt with the optical resolving agent, and then the remaining optically active cyclic enaminone derivative is hydrolyzed.
- the 1,3-diketone derivative having a symmetry plane which is a raw material compound, can be recovered.
- the hydrolysis treatment carried out here may be carried out in accordance with a usual acid hydrolysis reaction. For example, about 0.1 to 100 equivalents, preferably about 0.1 to 100 equivalents of an optically active cyclic enaminone derivative or a salt thereof.
- an inorganic or organic acid such as an acid selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, and toluenesulfonic acid.
- Water or an organic solvent capable of dissolving in water and water for example, an appropriate solvent selected from alcohols such as methanol and ethanol, and ketones such as acetone.
- the cyclic 1,3-diketon derivative having a plane of symmetry used as a raw material in the production method of the present invention is known per se and can be easily obtained as a commercial product. More specifically c which can be easily obtained by converting, when partial structures (a) is a compound represented by the formula (A- 2), the method of publicly known, for example, J. Am Chem. so, 72 , 1645 (1950) and the like, and some compounds can also be easily obtained as commercial products.
- the partial structure (A) is a compound represented by the formula (A-1) or (A-3), for example, 2,3-dimethylmaleic anhydride, 2,3-diphenylmaleic anhydride, 3,4 Easily obtained from commercially available compounds such as 1,5,6-tetrahydrofluoric anhydride, 2,3-bis (2,4,5-trimethyl-3-phenyl) maleic anhydride by a combination of known reactions Can be.
- optically active cyclic enaminonone derivative obtained by the production method of the present invention is useful as a synthetic raw material or a synthetic intermediate for producing an optically active drug or agricultural chemical.
- optically active cyclic enaminonone derivative obtained by the production method of the present invention is useful as a synthetic raw material or a synthetic intermediate for producing an optically active drug or agricultural chemical.
- An optically active cyclic enaminone derivative represented by is produced by the same method as described in Examples 1 to 4 described below, and further, in the same manner as in Reference Examples 1 to 2 described below, H 2 N NH.
- optically active cyclic enaminonone derivative represented by is produced by a method similar to the method described in Example 5 described later, and further, a reference example described later is prepared. In the same way as ⁇ 9,
- the compound is useful as a Na + / H + exchange inhibitor such as a drug for preventing or treating ischemic heart disease or a drug for preventing or treating heart failure (see W ⁇ 99 / 4224).
- Example 2 The compound obtained in Example 2 (1 g), a 1: 1 mixed solvent of ethyl acetate and methyl ethyl ketone (20 ml) and an aqueous solution of sodium hydroxide IN (20 ml) were mixed, and the mixture was stirred at room temperature for about 1 hour. Stirred. After confirming that the solid was completely dissolved, the organic layer was washed with saturated saline (20 ml) and dried over magnesium sulfate (lg). The solvent was distilled off under reduced pressure, and the powder obtained was dried in vacuo to give the title compound (0.52 g, yield 99.2%).
- Example 3 The compound (12 g) obtained in Example 3 was dissolved in ethanol (120 ml), and toluene (36 Om 1), 1,1-dimethoxy-13-butaneone (7.2 g) and sodium methoxide (3 . 7 g) was added and the mixture was heated under reflux for 2 hours. After cooling to room temperature, water (60 ml) was added and the mixture was stirred, and the organic layer was separated. After the aqueous layer was washed with toluene (60 ml), the organic layers were combined, washed with saturated saline (50 ml), and concentrated under reduced pressure.
- the obtained residue was dissolved in ethanol (130 ml), aminoguanidine hydrochloride (3.23 g) and concentrated hydrochloric acid (8.5 ml) were added, and the mixture was heated under reflux for 3.5 hours.
- the residue obtained by concentrating the reaction solution under reduced pressure was dissolved in water (100 ml), adjusted to pH 9 with an 8 M aqueous sodium hydroxide solution, and then extracted with 2-butanone (165 m and 65 ml). The organic layers were combined, washed with a saturated saline solution (65 ml), and the solvent was distilled off under reduced pressure.
- an optically active cyclic enaminone derivative useful as a raw material for synthesizing stereospecific drugs, agricultural chemicals, and the like, and a 1,3-diketone derivative having a symmetry plane as a precursor thereof are wasted. And it can be manufactured efficiently.
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU13030/01A AU1303001A (en) | 1999-11-10 | 2000-11-09 | Process for the production of optically active cyclic enaminone derivatives |
CA002390921A CA2390921A1 (en) | 1999-11-10 | 2000-11-09 | Process for the production of optically active cyclic enaminone derivative |
EP00974856A EP1229019A4 (en) | 1999-11-10 | 2000-11-09 | METHOD FOR THE PRODUCTION OF OPTICALLY ACTIVE, CYCLIC ENAMINONE DERIVATIVES |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP11/319991 | 1999-11-10 | ||
JP31999199 | 1999-11-10 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2001034557A1 true WO2001034557A1 (fr) | 2001-05-17 |
Family
ID=18116536
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2000/007876 WO2001034557A1 (fr) | 1999-11-10 | 2000-11-09 | Procede de production de derives d'enaminone cycliques optiquement actifs |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1229019A4 (ja) |
AU (1) | AU1303001A (ja) |
CA (1) | CA2390921A1 (ja) |
WO (1) | WO2001034557A1 (ja) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3848030A (en) * | 1971-03-18 | 1974-11-12 | Richardson Merrell Spa | Optical isomers of binaphthyl-phosphoric acids |
US4814477A (en) * | 1984-10-24 | 1989-03-21 | Oce-Nederland B.V. | Dioxaphosphorinanes, their preparation and use for resolving optically active compounds |
WO1999042442A1 (fr) * | 1998-02-20 | 1999-08-26 | Takeda Chemical Industries, Ltd. | Derives d'aminoguanidine hydrazone, procedes de production, et medicaments a base de ces derives |
EP0950418A2 (en) * | 1998-04-14 | 1999-10-20 | Takeda Chemical Industries, Ltd. | Composition for preventing or treating ischemic disease |
-
2000
- 2000-11-09 AU AU13030/01A patent/AU1303001A/en not_active Abandoned
- 2000-11-09 EP EP00974856A patent/EP1229019A4/en not_active Withdrawn
- 2000-11-09 WO PCT/JP2000/007876 patent/WO2001034557A1/ja not_active Application Discontinuation
- 2000-11-09 CA CA002390921A patent/CA2390921A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3848030A (en) * | 1971-03-18 | 1974-11-12 | Richardson Merrell Spa | Optical isomers of binaphthyl-phosphoric acids |
US4814477A (en) * | 1984-10-24 | 1989-03-21 | Oce-Nederland B.V. | Dioxaphosphorinanes, their preparation and use for resolving optically active compounds |
WO1999042442A1 (fr) * | 1998-02-20 | 1999-08-26 | Takeda Chemical Industries, Ltd. | Derives d'aminoguanidine hydrazone, procedes de production, et medicaments a base de ces derives |
EP0950418A2 (en) * | 1998-04-14 | 1999-10-20 | Takeda Chemical Industries, Ltd. | Composition for preventing or treating ischemic disease |
Non-Patent Citations (2)
Title |
---|
RAMESH NAMAKKAL G. ET AL.: "Enantioselective synthesis of 4-acetylaminocyclopent-2-en-1-ols from tricyclo(5.2.1.0(2,6))decenyl enaminones. Precursors for 5'-norcarbocyclic nucleosides and related antiviral compounds", J. ORG. CHEM., vol. 61, no. 10, 1999, pages 3635 - 3641, XP002936533 * |
See also references of EP1229019A4 * |
Also Published As
Publication number | Publication date |
---|---|
EP1229019A4 (en) | 2004-08-18 |
CA2390921A1 (en) | 2001-05-17 |
EP1229019A1 (en) | 2002-08-07 |
AU1303001A (en) | 2001-06-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
RU2346945C2 (ru) | Производные n-гетероциклилметилбензамидов, их получение и их применение в терапии | |
JPH0748340A (ja) | スルホンアミド誘導体 | |
KR20040027878A (ko) | 아미딘 유도체의 제조 방법 | |
WO2015006875A1 (en) | Process for the preparation of substituted pyrimidines | |
EP3643308B1 (en) | Coumarin-like cyclic compound as mek inhibitor and use thereof | |
JPH11322721A (ja) | 環式4―オキソアミジンの製造方法 | |
WO2006128389A1 (fr) | Derives de purine | |
CN115160321B (zh) | 一种伐地那非类似物及其合成方法和应用 | |
JP2005320249A (ja) | 2−アミノピラジン誘導体の製造方法 | |
WO2001034557A1 (fr) | Procede de production de derives d'enaminone cycliques optiquement actifs | |
EP2643308B1 (en) | Process for the preparation of taurolidine and its intermediates thereof | |
EP1476441B1 (en) | A method of eliminating sulfone analog in the synthesis of pyridine-benzimidazole sulfoxides | |
JP2651912B2 (ja) | イミダゾール誘導体、それらの製造法及び薬剤としての使用 | |
RU2228929C2 (ru) | Способ получения 3s-3-амино-3-пиридилпропионовой кислоты и ее производных и промежуточное вещество | |
HUT55390A (en) | Process for producing quinoline derivatives and pharmaceutical compositions containing them | |
JPH10182635A (ja) | 光学活性ピペリジン誘導体及びその製造方法 | |
JP2001199906A (ja) | 光学活性環状エナミノン誘導体の製造法 | |
JP2676113B2 (ja) | 安定な結晶性の塩およびそれを含有するトロンボキサン受容体拮抗剤 | |
WO2002060873A1 (en) | 3-(3-amidinophenyl)-5-[({[1-(1-(-iminoethyl)-4-piperidyl}amino)methyl]benzoic acid dihydrochloride and process for preparing the same | |
EP3440064B1 (en) | Process for preparing oxathiazin-like compounds | |
JP4166266B2 (ja) | 置換芳香族化合物の製造法および製造中間体 | |
JP2019532111A (ja) | (3S,4S)−テトラヒドロフラン−3−イル 4−イソプロピル−6,7−ジヒドロ−3H−イミダゾ[4,5−c]ピリジン−5(4H)−カルボキシラートの製造方法 | |
JPH08239381A (ja) | 安定なベンズイミダゾール誘導体金属塩の溶媒和物及びその製造法並びにそれを含有する抗潰瘍剤 | |
CN117769547A (zh) | 3-芳氧基-3-五元杂芳基-丙胺类化合物的制备方法 | |
KR820001449B1 (ko) | 퀴나졸린 유도체의 제조방법 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AU AZ BA BB BG BR BY BZ CA CN CR CU CZ DM DZ EE GD GE HR HU ID IL IN IS JP KG KR KZ LC LK LR LT LV MA MD MG MK MN MX NO NZ PL RO RU SG SI SK TJ TM TR TT UA US UZ VN YU ZA |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 10129707 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2390921 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2000974856 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 2000974856 Country of ref document: EP |
|
NENP | Non-entry into the national phase |
Ref country code: JP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 2000974856 Country of ref document: EP |