Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/12—Radicals substituted by oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/56—Ring systems containing three or more rings
  • C07D209/80—[b, c]- or [b, d]-condensed
  • C07D209/82—Carbazoles; Hydrogenated carbazoles
  • C07D209/88—Carbazoles; Hydrogenated carbazoles 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 carbon atoms of the ring system

Definitions

• the present invention is concerned with a novel process for the preparation of heterocyclic indene analogs, especially with the preparation of 4-hydroxycarbazole or N- protected 4-hydroxycarbazole.
• These compounds may be used as a building block for pharmaceutically active compounds, e.g. l-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxy- phenoxy) ethyl] amino] -2-propanol (carvedilol).
• This compound is known in the art and is described for example in EP 0004920. It is especially useful for prophylaxis and treatment of heart- and circulatory diseases like, for example, hypertension, coronary heart failure, angina pectoris and the like.
• the present invention refers to a process for the preparation of heterocyclic indene analogs of formula (I)
• R l and R 2 are independently selected from hydrogen or lower-alkyl; or R 1 and R 2 together with the ring carbon atoms to which they are attached form a monovalent carbocyclic or a phenyl ring, wherein the said monovalent carbocyclic or phenyl ring may optionally be substituted by halogen, lower- alkyl or lower-alkoxy;
• X is O, S or N-Z
• Z is an amino protecting group selected from SO 2 R a , NMe 2 , CO 2 R b and CON(R c ) 2 ;
• R a is lower-alkyl or aryl
• R b and R c are lower-alkyl
• R is lower-alkyl, aryl or aralkyl and R , R and X are as defined above;
• R 4 is lower-alkyl or aryl and R , R and X are as defined above;
• cyclocarbonylation refers to an introduction of a carbonyl group coupled to the formation of an aromatic cyclic ring structure.
• transition metal compound refers to a metal-phosphine complex compound wherein the term metal refers to Pd, Pt, Ru, Co, Rh or Ni, preferably Pd.
• ligand refers to phosphine, arsine or stibine derivatives, preferable phosphine derivatives, of general formulae P(R 5 )(R 6 )(R 7 ), (R 5 )(R 6 )P-(X)-P(R 5 )(R 0 ), As(R 5 )(R 6 )(R 7 ) or Sb(R 5 )(R 6 )(R 7 ), preferably P(R 5 )(R 6 )(R 7 ), wherein R 5 , R 6 , and R 7 are defined below.
• alkyl refers to a branched or straight chain monovalent alkyl radical of one to nine carbon atoms (unless otherwise indicated).
• lower-alkyl refers to a branched or straight chain monovalent alkyl radical of one to four carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, i-butyl, n-butyl, t-butyl and the like.
• alkoxy alone or in combination, signifies a group of the formula alkyl-O- in which the term “alkyl” has the significance given above.
• alkoxy radicals are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.butoxy and tert.butoxy, preferably methoxy and ethoxy.
• aryl refers to a monovalent carbocyclic aromatic radical, e.g. phenyl or naphthyl, optionally substituted, independently, with halogen, lower-alkyl, lower-alkoxy, lower-alkylenedioxy, carboxy, trifluoromethyl and the like.
• aralkyl refers to a residue -CH 2 -aryl wherein the term aryl is as defined above.
• alkylenedioxy refers to C ⁇ _ 3 -alkyl-dioxy groups, such as methylene- dioxy, ethylenedioxy or propylenedioxy.
• halogen refers to fluorine, chlorine, and bromine.
• the present invention refers to a process for the preparation of compounds of formula (I)
• R . 1 a __ndJ r R2 are independently selected from hydrogen or lower-alkyl; or R 1 and R together with the ring carbon atoms to which they are attached form a monovalent carbocyclic or phenyl ring, wherein the said monovalent carbocyclic or phenyl ring may optionally be substituted by halogen, lower- alkyl or lower-alkoxy;
• X is O, S or N-Z
• Z is an amino protecting group selected from SO 2 R a , NMe , CO 2 R and CON(R c ) 2 ;
• R a is lower-alkyl or aryl
• R and R c are lower-alkyl
• R 3 is lower-alkyl, aryl or aralkyl and R 1 , R 2 and X are as defined above;
• R 4 is lower-alkyl or aryl and R , R and X are as defined above;
• lower-alkyl residues R 1 and R are methyl, ethyl, n-propyl and isopropyl, with methyl being preferred.
• Preferred monovalent carbocyclic rings formed by substituents R 1 and R together with the ring carbon atoms to which they are attached are cyclopentenyl, cyclohexenyl and cycloheptenyl, preferably cyclohexenyl. Such rings may be substitued by lower-alkyl, such as methyl and ethyl.
• the most preferable monovalent carbocyclic ring formed by substituents R 1 and R together with the ring carbon atoms to which they are attached is unsubstituted cyclohexenyl.
• a phenyl residue formed by R 1 and R 2 together with the ring carbon atoms to which they are attached may be substituted by halogen, lower-alkyl or lower-alkoxy, preferably by chloro, bromo, methyl or methoxy. Most preferably, R and R 2 together with the ring carbon atoms to which they are attached form an unsubstituted phenyl ring.
• aryl residues in substituent R are phenyl and phenyl substituted by halogen or lower alkyl, preferably unsubstituted phenyl.
• Preferable aralkyl residue R 3 is benzyl, optionally substituted by halogen or lower alkyl.
• aralkyl residue R 3 is unsubstituted benzyl.
• lower-alkyl residues R 3 are methyl, ethyl, n-propyl, isopropyl and t-butyl, with methyl being preferred.
• R depends on the anhydride used in the cyclocarbonylation reaction.
• lower-alkyl residues are methyl, ethyl, n-propyl, isopropyl and t-butyl, with methyl being preferred!
• An example of aryl residues is phenyl. Such phenyl residue may be substituted by halogen, lower-alkyl or lower-alkoxy, preferably by chloro, bromo, methyl or methoxy.
• aryl residue R 4 is unsubstituted phenyl.
• lower-alkyl residues R a , R and R c are methyl, ethyl, n-propyl, isopropyl and t-butyl, with methyl being preferred.
• aryl residues R d are phenyl and naphthyl. Such rings may be substituted by halogen or lower-alkyl, preferably by chloro, methyl, ethyl or isopropyl. More preferably, aryl residue R a is phenyl, substituted by halogen or lower-alkyl, preferably by chloro, methyl, ethyl or isopropyl. Most preferred aryl residue R a is phenyl.
• the present invention relates to a cyclocarbonylation process as described above, wherein R 1 and R 2 together with the ring carbon atoms to which they are attached form a phenyl ring, R is methyl or phenyl, X is N-Z, Z is an amino protecting group as defined above, preferably a group of the formula SO 2 R a wherein R a is phenyl.
• the cyclocarbonylation reaction is carried out in the presence of a base, an anhydride and a catalyst comprising a transition metal compound and a ligand.
• Transition metal compounds useful for the process of the present invention comprise salts of Pd, Pt, Ru, Co, Rh or Ni and also includes Pd/C.
• the use of transition metal compounds as catalysts has been described for example in Matsuzaka et al. (1988) J.
• transition metal compounds are salts of palladium, e.g.
• Pd(OAc) 2) Pd 2 dba 3 , PdCl 2 , Pd 2 Cl 2 ( ⁇ -allyl) 2 , PdCl 2 (NCMe) 2 , [Pd(NCMe) 4 ](BF 4 ) 2 , and most preferably Pd(OAc) 2 .
• the mentioned catalysts are known in the art (e.g. US Patent No. 5,380,861; "Carbonylation, Direct Synthesis of Carbonyl Compounds", H.M. Colquhoun, D.J. Thompson, MN. Trigg, Plenum Press, 1991) and/or are commercially available (e.g. from Fluka, Buchs, Switzerland or Strem Chemicals, Kehl, Germany).
• the ligand of the transition metal compound in the catalyst may be selected from a group consisting of phosphine, arsine or stibine derivatives, preferably phosphine derivatives of general formulae P(R 5 )(R 6 )(R 7 ), (R 5 )(R 6 )P-(Y)-P(R 5 )(R 6 ), As(R 5 )(R 6 )(R 7 ) or Sb(R 5 )(R 6 )(R 7 ), preferably P(R 5 )(R 6 )(R 7 ), wherein Y, R 5 , R 6 , and R 7 are defined below.
• Suitable ligands are chiral and non-chiral mono- and diphosphorus compounds for example described in Houben-Weyl, "Methoden der organischen Chemie", vol. El, page 106 et seq. Georg Thieme Verlag Stuttgart, 1982, and Aspects Homog. Catal., 4, 145-202 (1981), especially those of the formulae
• R 5 , R and R each independently are -s-alkyl, cyclohexyl, benzyl, naphthyl, 2- or 3-pyrrolyl, 2- or 3-furyl, 2- or 3-thiophenyl, 2- or 3- or 4-pyridyl, phenyl or phenyl which is substituted by C ⁇ _ 4 -alkyl, .
• Y is binaphthyl, 6,6'-dimethyl- or 6,6'-dimethoxybiphenyl-2,2 , -diyl, or one of the groups -(CH 2 ) n -, - CH 2 CH 2 -P(C 6 H 5 )- CH 2 CH 2 -,
• n is a number of 1 - 8.
• Suitable phosphorus ligands are triphenylphosphine and the ligands shown in Scheme 1.
• TROPP-Ph Preferred phosphorus ligands are triphenylphosphine
• the most preferred phosphorus ligand is triphenylphosphine.
• the preparation of a transition metal complex is explained in more detail for the corresponding palladium-phosphine complex:
• the palladium-phosphine complex compound is conveniently formed in situ from a palladium component and a phosphine ligand.
• These palladium components is for example metallic palladium, which is optionally supported on a carrier material such as carbon, or a complex or a salt of 0-, 2- or 4-valent palladium such as palladium-bis(dibenzylideneacetone), palladium chloride, palladium acetate and the like.
• the phosphorus ligand/transition metal compound ratio amounts to about 0.1 : 1 to 100 : 1, preferably to about 6 : 1 to 15 : 1.
• Suitable phosphine ligands are for example chiral and non-chiral mono- and diphosphorus compounds such as are described in Houben-Weyl, Methoden der organischen Chemie, volume El, page 106 et. seq. Georg Thieme Verlag Stuttgart, 1982, and Aspects Homog. Catal., 4, 145 - 202 (1981), especially those described above.
• palladium-phosphine complex compound palladium-(II) chloride or palladium-(II) acetate
• palladium-dichloro-bis(acetonitrile) and triarylphosphine may be used.
• the process of the present invention comprises the use of bases for the cyclocarbonylation reaction like tertiary bases such as tri-alkyl-amines, di-alkyl-aryl- amines, pyridines, alkyl-N-piperidines, and for example inorganic bases such as NaOH, KOH or salts of carbonic acids.
• bases for the cyclocarbonylation reaction like tertiary bases such as tri-alkyl-amines, di-alkyl-aryl- amines, pyridines, alkyl-N-piperidines, and for example inorganic bases such as NaOH, KOH or salts of carbonic acids.
• examples are (alkyl) 3 amines, e.g. triethylamine, ethyl-di- isopropyl-amine, pyridine, N-methyl-piperidine, sodium hydrogen carbonate, potassium hydrogen carbonate, di-sodium carbonate, etc.
• the preferred base is triethyl
• anhydrides in connection with the present invention are acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, pivalic anhydride, benzoic anhydride etc.
• the preferred anhydrides are acetic anhydride and benzoic anhydride.
• Solvents for the above reaction are known to skilled persons.
• Preferred solvents are aromatic solvents, e.g. toluene, xylene, benzene, halogenated hydrocarbons, e.g. CH 2 C1 2 , nitriles, e.g.
• acetonitrile e.g. ethylacetate
• amides e.g. DMF
• ether e.g. THF
• dioxane e.g. TMU
• sulfoxides e.g. DMSO
• the preferred solvent is toluene.
• reaction conditions for the above carbonylation reaction can vary to a certain extent.
• the temperature can vary between 40°C and 170°C, preferably between 60 - 120°C, and most preferably the reaction is performed at about 90°C.
• the substrate/catalyst ratio (mol/mol; S/Pd) amounts to 1 to 10000, preferably 100 to 5000, more preferably 100 to 1500 and most preferably 100 to 1000.
• the above mentioned phosphorus ligand/transition metal compound ratio (mol/mol; P/Pd) amounts to 0.1 : 1 to 100 : 1, preferably 6 : 1 to 15 : 1.
• the upper limit for the carbon monoxide (CO) pressure is only limited by the specification of the autoclave used.
• the carbonylation reaction would work even with a CO pressure of 1 bar.
• the CO pressure is about 20 to 70 bar, more preferably 35 to 60 bar.
• the "crude” compound of formula (II) can be used for the preparation of the compound of formula (I).
• a preparation of a crude material is performed by collecting a compound of formula (II), e.g. acetic acid l-(l-benzenesulfonyl- lH-indol-2-yl)-allyl ester, with an organic solvent and drying without further purification.
• the preparation of this material is exemplified in Examples 2 and 3, Example 5 shows the use of the crude starting material for the preparation of a compound of formula (I).
• the cyclocarbonylation reaction is followed by saponification.
• Conditions for saponification reactions are known in the art and described for example in "Practical Organic Chemistry", A.I. Vogel, Longmans Ed., 1967, p. 390 - 393.
• the saponification is carried out in a biphasic mixture of aqueous sodium hydroxide and toluene or in an homogeneous mixture of sodium methylate in methanol.
• R 1 , R 2 and X are as defined above; with a reagent of the formula vinyl-metal-X with -metal-X being -MgCl, -MgBr, -Mgl or -Li, followed by reaction with an acid derivative selected from a group consisting of (R 3 -CO) 2 O, or R 3 -(CO)-Hal, wherein R 3 is as defined above and Hal is CI or Br.
• the compounds of formula (II) may be prepared by reaction of compounds of formula (VI)
• R 1 , R 2 and X are as defined above and M is -MgCl, -MgBr, -Mgl or -Li; with acrolein, followed by reaction with an acid derivative selected from a group consisting of (R 3 -CO) 2 O or R 3 -(CO)-Hal, wherein R3 is as defined above and Hal is CI or Br.
• Compounds of formula (VI) are commercially available or can be prepared from compounds of formula (Via) or compounds of formula (VIb)
• N-protected 4- hydroxycarbazole can be prepared by a cyclocarbonylation reaction as described above starting from a compound of above formula (II), wherein R 1 and R 2 together with the ring carbon atoms to which they are attached form a phenyl ring, R 3 is as defined above , X is N-Z and Z is an amino protecting group selected from SO 2 R a , NMe 2) CO 2 R and CON(R c ) 2 (with R a , R b and R c being as defined above), in the presence of an anhydride and a base as defined above, followed by saponification.
• N-protected 4-hydroxycarbazole can be converted to 4-hydroxycarbazole by deprotection as described below.
• 4- Hydroxycarbazole and N-protected 4-hydroxycarbazole are useful for the preparation of pharmaceutically active substances, e.g. l-(9H-carbazol-4-yloxy)-3-[[2-(2- methoxyphenoxy)ethyl] amino] -2-propanol (carvedilol) and optionally salts thereof.
• a process for the preparation of this compound has been described for example in European Patent Application EP 0 004920.
• this compound may be prepared according to the following processes:
• a compound of above formula (I), wherein R 1 and R 2 together with the ring carbon atoms to which they are attached form a phenyl ring, X is N-Z and Z is an amino protecting group selected from SO 2 R a , NMe 2 , CO 2 R b and CON(R c ) 2 (with R a , R b and R c being as defined above), may be converted into a compound of formula (VII)
• reaction with benzyl- [2-(2-methoxy-phenoxy]-ethyl- amine.
• the reaction may be performed in organic solvents like ethanol, methanol, isopropanol, THF and DMF, preferably with ethanol.
• the temperature can vary between 40 and 140°C, with a preferred temperature between 60-90°C.
• Hydrogenation of the compound of formula IX reveals l-(9H-carbazol-4-yloxy)-3- [[2-(2-methoxyphenoxy)ethyl] amino] -2-propanol (carvedilol) of formula (X).
• the reaction may be performed in organic solvents like ethanol, methanol, isopropanol and THF, preferably with methanol.
• the pressure of hydrogen can vary between 1 bar and 50 bar pressure, with a preferred hydrogen pressure between 1 to 10 bar.
• the temperature can vary between 20°C and 100°C, with a preferred temperature between 40- 60°C.
• Another embodiment of the present invention relates to a process for the preparation of l-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2- propanol comprising: a) cyclocarbonylation of acetic acid l-(l-benzenesulfonyl-lH-indol-2-yl)allyl ester or benzoic acid l-(l-benzenesulfonyl-lH-indol-2-yl)-allyl ester to give acetic acid 9-benzenesulfonyl-9H-carbazol-4-yl ester; b) saponification of acetic acid 9-benzenesulfonyl-9H-carbazol-4-yl ester to give
• 4-hydroxy-carbazole (XI) may be converted into a compound of formula (XII) by reaction with epichlorohydrin under basic conditions.
• the reaction may be performed in polar organic solvents like THF, DMF or DMSO, preferably without a solvent in a great surplus of epichlorohydrin.
• Basic compounds are for example sodium carbonate, potassium carbonate, sodium hydride, potassium hydroxide and sodium hydroxide, preferably sodium hydroxide.
• the temperature can vary between 20°C and 100°C, with a preferred temperature between 40- 60°C.
• reaction by reaction with benzyl- [2-(2-methoxy-phenoxy]-ethyl-amine.
• the reaction may be performed in organic solvents like ethanol, methanol, isopropanol, THF and DMF, preferably with ethanol.
• the temperature can vary between 40 and 140°C, with a preferred temperature between 60-90°C.
• This reaction may be performed as described above.
• Another embodiment of the present invention relates to a process for the preparation of l-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2- propanol comprising: a) cyclocarbonylation of acetic acid l-(l-benzenesulfonyl-lH-indol-2-yl)allyl ester or benzoic acid l-(l-benzenesulfonyl-lH-indol-2-yl)-allyl ester to give acetic acid 9-benzenesulfonyl-9H-carbazol-4-yl ester; b) saponification of acetic acid 9-benzenesulfonyl-9H-carbazol-4-yl ester to give 9-benzenesulfonyl-9H-carbazol-4-ol; c) deprotection of 9-benzenesulfonyl
• the present invention relates to the use of any of the above processes for the preparation of l-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)- ethyl] -amino] -2-propanol and optionally salts thereof.
• R is hydrogen, acetyl or benzoyl
• Example 1 l-( l-Benzenesulfonyl-lH-indol-2-yl)-allyl alcohol 10.3 g (40 mmol) of l-(phenylsulfonyl)indole (synthesized analogous to T. Sakamoto; Y. Kondo; N. Takazawa; H. Yamanaka; J.Chem.Soc.Perkin Trans.1; 16; 1996; 1927-1934) in 110 ml tetrahydrofuran were cooled to -20°C. To the stirred solution 30 ml of 1,6 M n- butyllithium were added at -20°C within 20 min.
• the resulting suspension was warmed to 10°C and stirred at 10°C for 4 hours.
• the mixture was again cooled to -20°C and a solution of 3.4 g acrolein (61 mmol) in 20 ml THF was added dropwise within 20 min at - 20°C.
• the solution was stirred at 20°C for 16 hours.
• 150 ml water was added dropwise, the mixture was vigorously stirred for 10 min.
• the phases were separated, and the water phase was extracted with 3 x 100 ml of methyl-t-butyl-ether.
• the combined organic phases were washed with 100 ml of brine, dried on sodium sulfate and rotary evaporated (35°C, 20 mbar).
• the residue was purified by liquid chromatography (eluent toluene/ethyl acetate 6:1), the pure fractions were collected and rotary evaporated (40°C/15 mbar).
• a 1 1 3-necked glass flask equipped with a magnetic stirrer, a thermometer and a nitrogen inlet was charged with 23.6 g of 9-benzenesulfonyl-9H-carbazol-4-ol (73 mmol) and 236 ml of epichlorohydrin (3.0 mol) and to the resulting solution 236 ml of a 5 N sodium hydroxide solution was added in one portion at 20°C.
• the temperature of the oil bath was increased to 45°C, the temperature inside increased slowly to 55°C, and after 30 min the temperature inside was at 45°C.
• the stirring was continued for 3 h.
• the ethanol was rotary evaporated (T bath 40°C, 20 mbar) and the crude material purified by liquid chromatography (eluent toluene/ethyl acetate 4:1), the pure fractions were collected and rotary evaporated (40°C/15 mbar).
• the phases were separated and the toluene phase was washed 3 times with 25 ml of water.
• the organic phase was rotary evaporated (40°C/15 mbar) and the residue was crystallized with 9 ml ethanol.
• the product was filtered under suction and washed twice with 3 ml cold ethanol. The substance was dried at 50°C for 12 h.
• Example 15 l- ⁇ Benzyl-[2-(2-methoxy-phenoxy)-ethyl]-amino ⁇ -3-(9H-carbazol-4-yloxy)-propan-2-ol 35.0 g of benzyl- [2-(2-methoxy-phenoxy)-ethyl]-amine (136 mmol) were dissolved in 225 ml ethanol. To the stirred solution 30.1 g of 4-oxiranylmethoxy-9H-carbazole (126 mmol) were added and the mixture was heated under reflux for 15 h. The boiling solution was treated with 3 g of activated carbon for 30 min. The activated carbon was filtered off in the heat, and washed with 20 ml ethanol. The solution was stirred for 3 h at room temperature and next 5 h at 0°C. The product was filtered under suction and washed twice with 10 ml cold ethanol. The substance was dried at 50°C for 12 h
• Example 16 l-(9H-carbazol-4-yloxy)-3-[2-(2-methoxy-phenoxy)-ethylamino]-propan-2-ol (carvedilol) 10 g of l- ⁇ Benzyl-[2-(2-methoxy-phenoxy)-ethyl]-amino ⁇ -3-(9H-carbazol-4-yloxy)- propan-2-ol (20 mmol) were dissolved in 80 ml methanol. 1 g of Pd-C (10%) were added and the suspension was warmed to 50°C. The mixture was hydrogenated at normal pressure for about 7 hours.
• the Pd-catalyst was filtered under suction and washed with 25 ml of hot methanol. 80 ml of methanol were distilled off and the residue was cooled to 0°C and hold at this temperature for 6 h. The product was filtered and washed twice with 3 ml cold methanol. The substance was dried at 60°C for 12 h.

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  • 2002-01-22 MX MXPA03006606A patent/MXPA03006606A/es not_active Application Discontinuation
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