Patent Application
20210380569
The invention relates to a process for the preparation of optically enriched isoxazoline compounds of formula I
wherein
wherein the shown enantiomer has at least 80% ee;
by oxo-Michael addition of hydroxyl amine or its salt to an enone of formula II,
wherein the variables have the meanings given for formula I, in the presence of a catalyst of formula III
wherein X is a counteranion;
and a base.
The isoxazoline active compounds I wherein group A is A1, A2, or A3, and their pesticidal activity are generally known from WO 2005/085216, WO 2007/026965, WO 2009/00289, WO 2011/067272, WO 2012/120399, WO 2014/090918, WO 2016/102482, and WO 2018/197466. Compounds of formula I with group A4 are valuable intermediates for the synthesis of formula I active compounds.
WO 2009/063910, WO 2012/156400, WO 2013/069731, WO 2014/79937, and WO 2014/79941 describe asymmetric syntheses of some isooxazoline compounds of formula I by using cinchona alkaloid-based phase-transfer catalysts. The processes require relatively high catalyst loadings and yield enantiomeric excesses of formula I compounds which still leave room for improvement.
Objective task for the invention therefore is providing an economical, industrially applicable manufacturing process for optically enriched compounds of formula I. This task is achieved by the process defined in the outset. The presence of a catalyst III as defined herein in the reaction of compound II ensures a quick and complete transformation at moderate temperatures.
Formula III catalyst is described in the art for enantioselective Michael addition reactions of cyclic esters with Michael acceptor to form C—C bonds (cf. Tetrahedron: Asymmetry 2009, 20, 2651-2654; Tetrahedron: Asymmetry 2010, 21, 2872-2878; Tetrahedron: Asymmetry 2012, 23, 176-180).
In the invention this catalyst is used in asymmetric Oxa-Michael addition of hydroxyl amine with an enone to form an enantioselective C—O bond. The process yields formula I compounds in good yield with at least 80% ee by using low catalyst loadings.
The reaction of an enone of formula II, wherein the variables have the meanings given in the outset, with hydroxyl amine or its salt is usually carried out at temperatures of from −30° C. to 35° C., preferably from −10° C. to 0° C., in an inert solvent, in the presence of catalyst of formula III. The formula III catalyst is known from Tetrahedron: Asymmetry 2009, 20,2651-2654.
Suitable solvents are preferably water immiscible solvents, such as aliphatic hydrocarbons such as pentane, hexane, cyclohexane, and petrol ether, aromatic hydrocarbons such as toluene, o-, m-, and p-xylene, halogenated hydrocarbons such as methylene chloride, dichloroethane, and chloroform, ethers such as diethylether, diisopropylether, tert.-butyl-methylether, anisole, and ketones such as methyl ethyl ketone, diethyl ketone, and tert.-butyl methyl ketone, alcohols such as, n-propanol, n-butanol, preferably halogenated hydrocarbons such as methylene chloride, dichloroethane, and chloroform. It is also possible to use mixtures of the solvents mentioned.
Suitable bases are in general, inorganic compounds, such as alkali metal and alkaline earth metal hydroxides, such as LiOH, NaOH, KOH and Ca(OH)2, alkali metal and alkaline earth metal oxides, such as Li2O, Na2O, CaO, and MgO, and alkaline earth metal carbonates, such as Li2CO3, Na2CO3, K2CO3 and CaCO3, and also alkali metal bicarbonates, such as NaHCO3, moreover organic bases, e.g. tertiary amines, such as trimethylamine, triethylamine (NEt3), diisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine, and also bicyclic amines, such as DBU (1,8-Diazabicyclo(5.4.0)undec-7-ene) and DBN (1,5-Diazabicyclo[4.3.0]non-5-ene). Particular preference is given to alkali metal and alkaline earth metal hydroxides, such as LiOH, NaOH, KOH, and Ca(OH)2, such as NaOH, and KOH.
The bases are generally employed in catalytic amounts; however, they can also be used in equimolar amounts or in excess. Under certain conditions an excess up to 10 mol equivalents of compound II may be advantageous.
For practical reasons hydroxylamine is preferably used in the form of an aqueous solution, alternatively as acid addition salt, such as halogenide or sulfate, preferably halogenide, particularly as HCl addition salt.
Hydroxylamine is generally employed in equimolar amounts; however, it can also be used in excess. Under certain conditions an excess up to 10 mol equivalents of compound II may be advantageous.
The catalyst III is used in 0.01 to 0.5, preferably 0.01 to 0.2, particularly about 0.02 to 0.1 mol equivalents of compound II. The starting materials are generally reacted with one another in equimolar amounts. In terms of yield, it may be advantageous to employ an excess of hydroxyl amine, based on II.
Starting materials of formula II required for preparing the compounds I are commercially available or known from the literature or can be prepared as outlined above, or in accordance with the literature cited.
In case group A in formula I is different from group A in the envisaged final isooxazoline active compound the cyclisation as described in the outset yields in an intermediate compound of formula Ia, which corresponds to formula I. The intermediate Ia is transformed to the active compound in a subsequent reaction step.
If in compounds la group A is A1 or A3 different from group A in the envisaged final active compounds I, the process also comprises the amidation of Ia with an appropriate amine IV under conditions known in the art, e.g. WO2004/22536.
In case in formula II group A is A1 which is COOR9 or CON(R5)R6, wherein R5 and R6 are as defined for formula I, and preferably are H or C1-C6-alkyl, and R9 is H or a leaving group, the reaction yields intermediate compounds Ia′. Compounds of formula I can be prepared by reacting carboxylic acids or acid derivatives of formula Ia′ with an amine of formula IV in an amidation reaction.
In formula Ia′ the variables are as defined for formula I, and A is A1 C(O)Y, wherein
The amidation reaction is preferably carried out by direct reaction with the amine IV, or by prior transformation of carboxylic acids of formula Ia′ (compounds of formula Ia with Y being OH) with oxalyl chloride [(COCl)2] or thionylchloride (SOCl2) to the corresponding acid chlorides of formula Ib, followed by reaction with an amine of formula IV. The reaction is preferably carried out in the presence of an organic base such as, NEt3, N-ethyl-N,N-diisopropylamine, pyridine, or substituted pyridines such as collidine or lutidine. Optionally a nucleophilic catalyst such as 4-(N,N-dimethylamino)pyridine (“DMAP”) can be employed in the reaction. Suitable solvents are halogenated hydrocarbons such as, dichloromethane, chloroform, and chlorobenzene, or polar aprotic solvents such as THF, 1,4-dioxane, and N,N-dimethylformamide (DMF), or aromatic hydrocarbons such as benzene, toluene, o-, m-, and p-xylene, or mixtures thereof. The transformation is usually carried out at temperatures from −40° C. to 100° C., preferably from 0° C. to 30° C. The starting materials are generally reacted with one another in equimolar amounts. In terms of yield, it may be advantageous to employ an excess of IV, based on Ia.
Compounds of formula Ia′, or formula I compounds with A being A1 can be obtained from compound wherein A is A4 being halogen, such as bromine or iodine (formula Id).
This transformation is usually carried out at temperatures of from 50° C. to 115° C., preferably from 75° C. to 110° C., in an inert solvent, in the presence of a base and a catalyst [cf. WO 2012/059441].
Compounds of formula I with A being A3 can preferably be prepared by reduction of nitrils of formula Ia wherein A is A4 being cyano (formula Ia″) to the corresponding amine of formula Ic, and subsequent acylation of Ic with a carboxylic acid derivative of formula V. In formula Ia″ the variables are as defined for formula I.
The reduction of Ia″ to Ic is usually carried out at temperatures of from −10° C. to +110° C., preferably from 0° C. to +60° C., in an inert solvent, in the presence of a base, a reducing agent and a catalyst [cf. JP 2010235590].
Suitable solvents are aliphatic hydrocarbons such as pentane, hexane, cyclohexane, and petrol ether, aromatic hydrocarbons such as toluene, o-, m-, and p-xylene, halogenated hydrocarbons such as methylene chloride, chloroform, and chlorobenzene, ethers such as diethylether, diisopropylether, TBME, dioxane, anisole, and THF, nitrils such as acetonitrile, and propionitrile, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, and tert.-butanol, moreover water; preferably alcohols, ethers, and water. It is also possible to use mixtures of the solvents mentioned.
Suitable bases are, in general, inorganic compounds, such as alkali metal and alkaline earth metal hydroxides, such as LiOH, NaOH, KOH, and Ca(OH)2, alkali metal and alkaline earth metal oxides, such as Li2O, Na2O, CaO, and MgO, alkali metal and alkaline earth metal hydrides, such as LiH, NaH, KH, and CaH2, alkali metal and alkaline earth metal carbonates, such as Li2CO3, Na2CO3, K2CO3 and CaCO3, and also alkali metal bicarbonates, such as NaHCO3, moreover organic bases, e.g. tertiary amines, such as trimethylamine, NEt3, diisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine, and also bicyclic amines, such as DBU and DBN. Particular preference is given to alkali metal and alkaline earth metal carbonates and alkali metal bicarbonates, such as NaHCO3.
The bases are generally employed in catalytic amounts; however, they can also be used in equimolar amounts or in excess.
Suitable catalysts are nickel carbonyl, Raney nickel or nickel dichloride.
Suitable reducing agents are hydrogen gas, or alkali metal hydrides such as sodium borohydride or lithium borohydride.
The starting materials are generally reacted with one another in equimolar amounts. In terms of yield, it may be advantageous to employ an excess of V, based on Ic.
The acylation is usually carried out at temperatures of from −10° C. to 110° C., preferably from 0° C. to 60° C., in an inert solvent, in the presence of a base and a catalyst [cf. Organic Letters, 18(23), 5998-6001, 2016].
Suitable solvents are aliphatic hydrocarbons such as pentane, hexane, cyclohexane, and petrol ether, aromatic hydrocarbons such as toluene, o-, m-, and p-xylene, halogenated hydrocarbons such as methylene chloride, chloroform, and chlorobenzene, ethers such as diethylether, diisopropylether, TBME, dioxane, anisole, and THF, nitrils such as acetonitrile, and propionitrile, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, and tert.-butanol, moreover water; preferably halogenated hydrocarbons and aromatic hydrocarbons. It is also possible to use mixtures of the solvents mentioned.
Suitable bases are, in general, inorganic compounds, such as alkali metal and alkaline earth metal hydroxides, such as LiOH, NaOH, KOH and Ca(OH)2, alkali metal and alkaline earth metal oxides, such as Li2O, Na2O, CaO, and MgO, alkali metal and alkaline earth metal hydrides, such as LiH, NaH, KH, and CaH2, alkali metal and alkaline earth metal carbonates, such as Li2CO3, Na2CO3, K2CO3 and CaCO3, and also alkali metal bicarbonates, such as NaHCO3, moreover organic bases, e.g. tertiary amines such as trimethylamine, triethylamine, diisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines such as collidine, lutidine and 4-dimethylaminopyridine, and also bicyclic amines. Particular preference is given to alkali metal and alkaline earth metal carbonates and alkali metal bicarbonates, such as
NaHCO3. The bases are generally employed in catalytic amounts; however, they can also be used in equimolar amounts, in excess or, if appropriate, as solvent.
Suitable catalysts are e.g. 4-N,N-dimethyl aminopyridine, DBU (1,8-Diazabicyclo(5.4.0)un-dec-7-ene), pyridine, DBN; catalytic NaI, KI, LI to activate acid chloride to acid iodide.
The starting materials are generally reacted with one another in equimolar amounts. In terms of yield, it may be advantageous to employ an excess of V, based on Ic.
The reaction mixtures are worked up in a customary manner, for example by mixing with water, separating the phases and, if appropriate, chromatographic purification of the crude products. Some of the intermediates and end products are obtained in the form of colourless or slightly brownish viscous oils which are purified or freed from volatile components under reduced pressure and at moderately elevated temperature. If the intermediates and end products are obtained as solids, purification can also be carried out by recrystallization or digestion.
However, if the synthesis yields mixtures of isomers, a separation is generally not necessarily required since in some cases the individual isomers can be interconverted during work-up for use or during application (for example under the action of light, acids or bases). Such conversions may also take place after use, for example in the treatment of plants in the treated plant, or in the harmful fungus to be controlled.
Furthermore, in one embodiment the invention relates to a process for the manufacture of compounds of formula I comprising the steps of reacting formula II with hydroxy amine or its salt, and amidation Ia′ to the final active compounds I.
The organic moieties mentioned in the above definitions of the variables are—like the term halogen—collective terms for individual listings of the individual group members. The prefix Cn-Cm indicates in each case the possible number of carbon atoms in the group.
The term “halogen” denotes in each case fluorine, bromine, chlorine, or iodine, in particular fluorine, chlorine, or bromine.
The term “alkyl” as used herein and in the alkyl moieties of alkylamino, alkylcarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl and alkoxyalkyl denotes in each case a straight-chain or branched alkyl group having usually from 1 to 10 carbon atoms, frequently from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, more preferably from 1 to 3 carbon atoms. Examples of an alkyl group are methyl (“Me”), ethyl (“Et”), n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl, tert-butyl (“tBu”), n-pentyl, and n-hexyl.
The term “haloalkyl” as used herein and in the haloalkyl moieties of haloalkylcarbonyl, haloalkoxycarbonyl, haloalkylthio, haloalkylsulfonyl, haloalkylsulfinyl, haloalkoxy and haloalkoxyalkyl, denotes in each case a straight-chain or branched alkyl group having usually from 1 to 10 carbon atoms, frequently from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms.
The term “alkoxy” as used herein denotes in each case a straight-chain or branched alkyl group which is bonded via an oxygen atom and has usually from 1 to 10 carbon atoms, frequently from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.
The term “alkoxyalkyl” as used herein refers to alkyl usually comprising 1 to 10, frequently 1 to 4, preferably 1 to 2 carbon atoms, wherein 1 carbon atom carries an alkoxy radical usually comprising 1 to 4, preferably 1 or 2 carbon atoms as defined above.
The term “haloalkoxy” as used herein denotes in each case a straight-chain or branched alkoxy group having from 1 to 10 carbon atoms, frequently from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms, in particular fluorine atoms.
The term “carbocycle” or “carbocyclyl” includes in general a 3- to 12-membered, preferably a 3- to 8-membered or a 5- to 8-membered, more preferably a 5- or 6-membered mono-cyclic, non-aromatic ring comprising 3 to 12, preferably 3 to 8 or 5 to 8, more preferably 5 or 6 carbon atoms. Preferably, the term “carbocycle” covers cycloalkyl and cycloalkenyl groups as defined above.
The term “heterocycle” or “heterocyclyl” includes in general 3- to 12-membered, preferably 5- or 6-membered, in particular 6-membered monocyclic heterocyclic non-aromatic radicals. The heterocyclic non-aromatic radicals usually comprise 1, 2 or 3 heteroatoms selected from N, O and S as ring members, wherein S-atoms as ring members may be present as S, SO or SO2.
The term “hetaryl” includes monocyclic 5- or 6-membered heteroaromatic radicals comprising as ring members 1, 2, or 3 heteroatoms selected from N, O and S.
With respect to the variables, the particularly preferred embodiments of the intermediates correspond to those of the compounds of the formula I.
In a particular embodiment, the variables of the compounds of the formula I have the following meanings, these meanings, both on their own and in combination with one another, being particular embodiments of the compounds of formula I.
The process is particularly suitable for compounds II wherein A is selected from A1, A2, and A3.
In the compounds of the inventive process R1 is preferably fluoromethyl, in particular CF3.
The phenyl ring in formula I and its sub formulae, bearing the R2n substitution is preferably a group P
R2a is preferably selected from F, Cl, Br, CF3, and OCF3.
R2b and R2c are independently preferably selected from H, F, Cl, Br, CF3, and OCF3.
Particularly preferred is each one of the following combinations of R2a, R2b, and R2c wherein each line of Table A denotes a substitution pattern of the phenyl ring P bearing the R2a, R2b, and R2c moieties.
Groups A-8, A-9, and A-11 are more preferred patterns in formula I and its sub formulae compounds. A-11 is particularly preferred.
R3 is preferably H, halogen, or CH3.
In a preferred embodiment G1 and G2 represent each CR3, particularly G1 is CH and G2 is C—Cl, or C—CH3.
In another embodiment G1 and G2 represent each CR3, wherein the two R3 form a five- or sixmembered saturated carbocyclic ring, or a dihydrofurane.
In another embodiment G1 and G2 together form a sulfur atom.
A preferred embodiment relates to the process for obtaining compounds I wherein A is A1.
The catalyst III is used preferably in an amount of 0.1-100 mol %, more preferred in 0.5-50 mol %, particularly in 1-20 mol % relative to formula II compounds.
The nature of the counteranion X− in formula III catalyst is of minor importance. For practical reasons it is usually selected from halogen (preferably Cl, Br), BF4, PF6, C1-C10-alkylsulfonate, benzenesulfonate, or methylbenzenesulfonate. Particularly preferred III is used as dibromide.
The processes for obtaining compounds I wherein A is A1 start preferably from compounds of formula II wherein A is C(═O)Y, and Y is OR9, preferably OH, or C1-C4-alkoxy, or NR5R6, wherein R5 and R6 are H or C1-C4-alkyl, preferably Y is NH2 or NHCH3. Particularly preferred A group in compounds I and its intermediates is an C1-C4-alkylester, such as C(═O)OCH3.
In A1 the variables R5 and R6 have preferably following meanings:
Another embodiment relates to the process for obtaining compounds I wherein A is A2, preferably wherein Q-Z is % —CH2—O—*, and R4 is C1-C4-alkylcarbonyl wherein the terminal C-atom of the alkyl is substituted with S(O)n-C1-C4-alkyl.
Another embodiment relates to the process for obtaining compounds I wherein A is A3, preferably CH2—NR5C(═O)R6, wherein R5 is H or CH3, and R6 is H, C1-C6-alkyl, C2-C6-alkenyl, which groups are substituted with one or more same or different R8, wherein R8 is as defined and preferred above.
Compounds I and its sub formulae wherein A is A4 are intermediates in the inventive process.
Compounds wherein A is A4 are preferred intermediates. In one embodiment A4 is cyano. In another embodiment A4 is halogen, preferably Br, or I.
The process is particularly suitable for synthesis of following active compounds of formula I, which correspond to formulae I.A, and I.B, resp., wherein the variables are as defined and preferred above:
wherein W is CH or O; and
wherein p is 1 or 2; Rx5 is H or CH3, and Rx6 is C1-C6-alkyl, C1-C4-haloalkyl, C3-C6-alkenyl, C3-C6-alkynyl, which groups may be substituted with C(═O)ORa1, C(═O)N(Ra2)Ra3, CH═NORa1, and phenyl, benzyl, which rings are unsubstituted or substituted with halogen, C1-C4-alkyl, or C1-C4-haloalkyl; wherein Ra1 is C1-C6-alkyl, Ra2 and Ra3 are each H or C1-C6-alkyl, C1-C6-haloalkyl, C2-C4-alkenyl, C2-C4-alkynyl;
preferably Rx6 is CH3, C2H5, CH2(CH3)2, CH2CH═CH2, CH2CF3, CH2CH2CF3, CH2C6H5, or CH2C(═O)OCH3.
The process is furthermore particularly suitable for synthesis of following active compounds 1.1, 1.2, 1.3, 1.4, 1.5, and 1.6 of formula I which are known in the art (cf. WO 2011067272; WO 2005085216; WO 200900289; WO 2014090918; WO 2007026965; WO 2012120399):
Accordingly, the process is furthermore particularly suitable for synthesis of compounds of formula I, wherein
Such compounds represent formula Ia.
Particularly preferred are intermediate compounds of formula Ia, which represents formula I wherein R1 is CF3, and the variables have the meanings as shown in Table I.1, wherein each compound corresponds to one line.
The following examples illustrate the invention.
With appropriate modification of the starting materials, the procedures given in the synthesis description were used to obtain further compounds I. The compounds obtained in this manner are listed in the table that follows, together with physical data.
The products shown below were characterized by melting point determination, by NMR spectroscopy or by the masses ([m/z]) or retention time (RT; [min.]) determined by HPLC-MS or HPLC spectrometry.
HPLC-MS=high performance liquid chromatography-coupled mass spectrometry;
HPLC method A: Shimadzu LC2010, Column: Waters XBridge C18, 150 mm*4.6 mm ID*5μ; Mobile Phase: A: water+0.1% TFA; B: acetonitrile+0.1% TFA; Temperature: 400° C.; Gradient: 10% B to 100% B in 5 min; 100% B 2 min; 10% B 3 min; Flow: 1.4 ml/min; Run Time: 10 min; PDA detector.
HPLC method B: Shimadzu LC2010, Column: CHIRALPAK AD-RH, 150 mm*4.6 mm*5μ; Mobile Phase: A: water+0.1% TFA; B: acetonitrile+0.1% TFA; Temperature: 400° C.; Gradient: 65% B to 100% B in 12 min; 100% B 1 min; 35% B 7 min; Flow: 1.4 ml/min; Run Time: 20 min; PDA detector.
a) According to the invention with catalyst (R)-[1-[[10-[[2-[(R)-hydroxy-(6-methoxy-4-quinolyl)methyl]-5-vinyl-quinuclidin-1-ium-1-yl]methyl]-9-anthryl]methyl]-5-vinyl-quinuclidin-1-ium-2-yl]-(6-methoxy-4-quinolyl)methanol dibromide (III-Br2)
A round bottom glass flask was charged with 1 g (1 eq) of N-[[4-[(E)-3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2,3-dihydrobenzofuran-7-yl]methyl]propenamide in 20 ml of DCE, the reaction mass was cooled to 0° C. and III-Br2 0.103 g (0.05 eq) was added. The reaction mass was stirred at 0° C. for 30 min. A premixed solution of 0.7 ml (5 eq) 50% NH2OH solution in 2.5 ml (6 eq) of 20% NaOH was added dropwise in 90 mins and reaction mass was stirred at 0° C. for 5-6 hrs. After complete consumption of educts, water was added, and organic phase separated. Organic layer was washed with 6M HCl and water and evaporation of organic layer yielded 0.98 g (95.1% yield) of the title compound (99% HPLC purity, 92:8 S:R).
1H-NMR (500 MHz, CDCl3): 1.12-1.18 (t, 3H, J=7.5 Hz), 2.19-2.26 (q, 2H, J=7.8 Hz), 3.43-3.50 (m, 2H), 3.67-3.73 (dd, 1H, J=17 Hz), 4.06-4.12 (dd, 1H, J=17.1 Hz), 4.41-4.43 (d, 2 H, J=6 Hz), 4.63-4.69 (t, 2H, J=8.7 Hz), 6.03 (bs, 1H), 6.67-6.79 (d, 1H, J=7.8 Hz), 7.13-7.16 (d, 1H, J=7.8 Hz), 7.57-7.59 (d, 2H, 6Hz)
b) Comparison with (R)-[1-(9-anthrylmethyl)-5-vinyl-quinuclidin-1-ium-2-yl]-(6-methoxy-4-quinolyl)methanol chloride (PTC-1)
Analogously to Example 1, except replacement of the catalyst by 0.061 g (0.05 eq) of PTC-1 were obtained 0.75 g (72.8% yield) of the title compound (99.8% HPLC purity & 84:16 S:R).
Analogously to the protocol described in Example 1, isocycloseram was obtained
a) With III-Br2: Enantiomeric ratio at isoxazoline=95:5 (S:R), 82% yield;
b) With PTC-1: Enantiomeric ratio at isoxazoline=81:19 (S:R), 81% yield.
| Number | Date | Country | Kind |
|---|---|---|---|
| 18204501.3 | Nov 2018 | DE | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2019/079324 | 10/28/2019 | WO | 00 |
