Title of Invention

A PROCESS FOR THE PREPARATION OF 2-PHENYL-2-HYDROXY-N [2-(3-ALKOXY-4-HYDROXYPHENYL)-ETHYL] -ACETAMIDES

Abstract The present invention concerns a novel process for the preparation of 2-phenyl-2-hydroxy-N-[2-(3-alkoxy-4-hydroxyphenyl)-ethyl]-acetamides of the formula (I), wherein R<sub>1</sub> is alkyl, R<sub>2</sub> and R<sub>3</sub> are each independently hydrogen or alkyl, and R<sub>4</sub> is optionally substituted aryl or optionally substituted heteroaryl, which process comprises reacting a 2-(3-alkoxy-4-hydroxyphenyl)-ethylamine of the formula (II), wherein R<sub>1</sub> R<sub>2</sub> and R<sub>3</sub> are as defined above with a &#945; -hydoxycarboxylic acid ester of the formula (III) or a dioxolanone of the formula (III)a, wherein R<sub>4</sub>, is as defined above, and R<sub>5,</sub> R<sub>6</sub> and R<sub>7</sub> independently of each other are lower alkyl. The compounds of formula (I) are important intermediates for a novel group of fungicides derived from mandelic acid amides.
Full Text

Process for Preparation of g-Hydroxvcarboxylic Acid Amides
The present invention relates to a process for the production of a-hydroxycarboxylic acid amides which are valuable intermediates for the production of fungicidally active compounds. The present invention further relates to novel intermediates used in the process according to the invention.
The a-hydroxycarboxylic acid amides which can be produced by the process according to the present invention may be used as intermediates for fungicidally active phenyl-propargylether derivatives which are described, for example, in WO 01/87822. These fungicidally active phenyl-propargylether derivatives correspond to the formula la

wherein
Ri is hydrogen, alkyl, cycloalkyi or optionally substituted aryl,
Ri and Rm are each independently hydrogen or alkyl,
Rive is alkyl,
Rg, Rive. Rio, and Rvm are each independently hydrogen or alkyl,
Rick is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally
substituted alkynyl,
Rx is optionally substituted aryl or optionally substituted heteroaryl, and
Z is halogen, optionally substituted aryloxy, optionally substituted alkoxy, optionally
substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted arylthio,
optionally substituted alkylthio, optionally substituted alkenylthio, optionally substituted
alkynyl thio, optionally substituted alkylsulfinyl, optionally substituted alkenylsulfinyl,,
optionally substituted alkynylsulfinyl, optionally substituted alkylsulfonyl, optionally
substituted alkenylsulfonyl or optionally substituted alkynylsulfonyl,
including the optical isomers thereof and mixtures of such isomers.
In WO 01/87822 a variety of methods for the preparation of the compounds of the above formula la have been described with reference to reaction schemes 1 to 4 a which are briefly discussed below.


This reaction scheme comprises two altemative methods. According to the first alternative an acid of formula (1) or a carboxy-activated derivative of an acid of formula (1) is reacted with an amine of formula (2) to obtain a carboxylic acid amide of the formula (3), which is further reacted with a compound of the formula (4) to form a compound of the formula I. Alternatively, an amine of the formula (5) is reacted with an acid of the formula (2) to obtain a compound of the formula 1. The two alternatives are based on the same types of reaction and are only distinguished by the order of the reaction steps involved.


According to this scheme compounds of subformula la are prepared starting from N-formyl-2-(4-hydroxyphenyl)-ethylamine (6) which is etherified with compound (4) to compound (7) the N-formyl group of which is converted into a isonitrile group as shown in compound (8). Isonitrile (8) is reacted with ketone (9) in the presence of acid (10) to a-hydroxy acid ester (11) which is hydrolysed to a'hydroxyacid amide (12), which compound can also be obtained directly from isO nitrile (8) or from N-formyl compound (7) by reaction with ketone (9). The a-hydroxylase amide (12) is then reacted with compound (13) to form the compound of the subformula la which compound can alternatively be obtained by reacting either compound (15) or compound (15a) with hydroxy-compound (14).


According to this method a dioxolanone (16) which can be obtained by reacting the corresponding a-hydroxyacid with acetone in the presence of a strong acid is alkylated to form a dioxolanone (17) or the corresponding a-hydroxyacid (18) is then reacted with substituted 2-phenylethylamine (5) to obtain a compound (12).

According to this method a a-hydroxyacid (18a), which can be obtained either by chlorinating a ketone (19) in acetic acid and hydrolyzing the a, -dichloroketone (20) or by transforming an aldehyde (21) into the corresponding cyanohydrins (22) and hydrolyzing of the •

latter, is reacted with a ketone (23) to form a dioxolanone (16a). The dioxolanone (16a) thus obtained is then reacted with a 2-(4-hydroxyphenyl)-ethylamine (24) to obtain carboxylic acid amide (25) which is di-etherified with compound (26) to obtain a compound of the subformula lb.
In view of the excellent fungicidal activity of the phenyi-propargyiether derivatives of the above formula la there exists a need for a process for their preparation which is suitable to be performed on an industrial scale. Since the processes contemplated in the hitherto unpublished co-pending international application PCT/EP01/05530 are not satisfactory for that purpose it is the object of the present invention to provide a process for the preparation of intermediates which can be easily transformed into the phenyl-propargylether derivatives of the above formula la.
According to the present invention it is suggested to prepare 2-phenyl-2-hydroxy-N-[2-(3-alkoxy-4-hydroxyphenyl)-ethyl]-acetamide of the formula I

wherein Ri , R2 and R3 are as defined above with a a-hydoxycarboxylic acid ester of the formula III or a dioxolanone of the formula Ilia


wherein R4 is as defined above, and R5, Re and R7 independently of each other are lower alkyl.
According to a one embodiment the process is carried out in the absence of a solvent at a temperature at or above the melting temperature of the reaction mixture. The process according to the present invention is advantageously carried out by intimately mixing a 2-(3-alkoxy-4-hydroxyphenyl)-ethylamine of the formula II with a a-hydroxycarboxylic acid ester of the formula III and heating the mixture to a temperature within the range from the melting temperature of the reaction mixture and a temperature of up to +100°C above the melting temperature of the reaction mixture. Preferably the reaction is carried out at a temperature within the range of from the melting temperature and a temperature of -i-50°C above the melting temperature of the reaction mixture, and most preferably at a temperature of from the melting temperature and a temperature of +20°C above the melting temperature of the reaction mixture.
The a-hydroxycarboxylic acid ester of the formula III or Ilia and the 2-(3-alkoxy-4-hy-droxyphenyl)-ethylamine of the formula II may be used in a molar ratio of from 1 : 2, preferably 1 : 1,2. Most preferably the a-hydroxycarboxylic acid ester of the formula III and the 2-(3-alkoxy-4-hydroxyphenyl)-ethylamine of the formula II are used in equimolar amount. According to a preferred embodiment the reaction of a 2-(3-alkoxy-4-hydroxyphe-nyl)-ethylamine of the formula II in the absence of a solvent to a 2-aryl-2-hydroxy-N-[2-(3-alkoxy-4-hydroxyphenyl)-ethyl]-acetamide is carried out with an a-hydroxycarboxylic acid ester of the formula 111.
As a rule the reaction can be carried out in the absence of a catalyst. However, if acidic impurities are present, such as traces of the carboxylic acid of the ester used, a base can be advantageously added to the reaction mixture in order to complete the reaction. Suitable bases are, for example, tertiary amines, such as triethylamine.
As a rule the molten product obtained by the process according to the present invention can be immediately used for the further conversion into a compound of the formula la. If necessary, the molten product can be dissolved in an organic solvent and purified by crystallization and/or extraction. Further, it is possible, to dissolve the product in an aqueous base,

such as sodium hydroxide or potassium hydroxide, and further reacting the corresponding phenolate salt formed in a two-phase system in the presence of a phase transfer catalyst. In comparison to the previously described process in which a solvent is used, the process according to the invention is advantageous in that a considerably shorter reaction time is needed. Further, the yield per volume of the process according to the invention is higher than in the previously described process and the conversion to the desired a-hydroxycar-boxylic acid amide of the formula I is practically quantitative.
According to another embodiment the reaction of a 2-(3-alkoxy-4-hydroxyphenyl)- ethyl-amine of the formula II with a a-hydroxycarboxylic acid ester of the formula III or Ilia is carried out in the presence of an inert solvent and in the presence of an organic or inorganic base at a temperature within the range of from -SOX to +200°C. Suitable solvents are, for example, aromatic and aliphatic or halogenated optionally haloge-nated hydrocarbons, ethers, alcohols and nitriles. Especially suitable solvents are chlorohy-drocarbons, such as dichloromethane or chlorobenzene, hydrocarbons, such as n-hexane, cyclohexane or toluene, ethers, such as diethyl ether, tert-butyl-methyl ether, dioxane or tetrahydrofuran, alcohols, such as methanol, ethanol, propanol, isopropanol or sec-butanol. Mixtures of the afore-mentioned solvents can also be used.
Suitable organic bases are, for example, triethylamine, N,N-isopropyl-ethylamine, pyridine, N-ethylpiperidine and N-methylmorpholine. Examples for suitable inorganic bases are sodium carbonate and potassium carbonate.
Within the temperature range of from -80X to +200°C the range of 0°C to +140°C is preferred.
The reaction of a 2-(3-alkoxy-4-hydroxyphenyl)- ethylamine of the formula II to a 2-aryl-2-hy-
dory -N-[2-(3-alkoxy-4-hydroxyphenyl)-ethyl]-acetamide of the formula I in the presence of
an inert solvent is preferably carried out with a dioxolanone compound of the formula Ilia.
The dioxolanones of the formula Ilia are novel compounds and are, therefore, also a part of
the present inventive concept. |
The dioxolanones of the formula Ilia may be obtained by reacting an a-hydroxyacid of the formula IV

wherein R4 is as defined for formula I, in the presence of a strong acid with a ketone of the formula V


wherein R5 and Re are each independently of each other lower alkyl. Suitable strong acids are hydrochloric acid, sulfuric acid, benzene sulfonic acid, methane sulfonic acid, and nitric acid, with sulfuric acid being preferred. Lower alkyl groups R5 and Re contain 1 to 4 carbon atoms. Preferably R5 and Re represent methyl or ethyl and most preferably methyl.
In the above definition of the formula I aryl includes aromatic hydrocarbon rings like phenyl, naphthyl, anthracenyl, phenanthrenyl and biphenyl like 1,3-biphenyl and 1,4-biphenyl, with phenyl being preferred. The same definition applies where aryl is part of aryloxy or arylthio. Heteroaryl stands for aromatic ring systems comprising mono-, bi- or tricyclic systems wherein at least one oxygen, nitrogen or sulfur atonics present as a ring member. Examples are furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazolyl, indolyl, benzothienyl, benzofuranyl, benzimidazolyl, imidazolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, quinolinyl and naphthyridinyl.
The above aryl and heteroaryl groups may be optionally substituted. This means that they may carry one or more identical or different substituents. Normally not more than three substituents are present at the same time. Examples of substituents of aryl or heteroaryl groups are: alkyl, alkenyl, alkynyl, cycloalkyi, cycloalkyl-alkyi, phenyl and phenyl-alkyi, it being possible in turn for all of the preceding groups-to carry one or more identical or different halogen atoms; alkoxy; alkenyloxy; alkynyloxy; alkoxyalkyl; haloalkoxy, alkylthio; haloalkylthio; alkylsulfonyl; formyl; alkanoyl; hydroxy; halogen; cyano; nitro; amino; alkyla-mino; dialkylamino; carboxyl; alkoxycarbonyl; alkenyloxycarbonyl; or alkynyloxycarbonyl. Typical examples include 4-chlorophenyl, 4-bromophenyl, 3,4-dichlorophenyl, 4-chloro-3-flu-orophenyl, 3-chloro-4-fluorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-propargyloxyphenyl, 1-naphthyl, 2-naphthyl, 4-biphenylyl, 4'-chloro-4-biphenylyl, 5-chloro-thien-2-yl, 5-methyl-thien-2-yl, 5-methyl-fur-2-yl, 5.6,7,8-tetrahydro-1-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl, 3,4-dioxomethylenyl-phenyl, 3,4-dioxoethylenyl-phenyl, 6-benzothienyl, 7-benzothienyl, 3-methylphenyl, 4-fluorophenyl, 4-ethenylphenyl, 4-ethynylphenyl, 4-propylphenyl, 4-isopro-pylphenyl, 4-tert-butylphenyl, 4-ethoxyphenyl, 4-ethynyloxyphenyl, 4-phenoxyphenyl,
4-methylthiophenyl, 4-methylsulfonylphenyl, 4-cyanophenyl, 4-nitrophenyl, 4-methoxycarbo-nyl-phenyl, 3-bromophenyl, 3-chlorophenyl, 2-chlorophenyl, 2,4-dichlorophenyl, 3,4,5-tri-chlorophenyl, 3,4-difluorophenyl, 3,4-dibromophenyl, 3,4-dimethoxyphenyl, 3,4-dime-thylphenyl, 3-chloro-4-cyanophenyl, 4-chloro-3-cyanophenyl, 3-bromo-4-methylphenyl, 4-methoxy-3-methylphenyl, 3-fluoro-4-methoxyphenyl, 4-chloro-3-methylphenyl, 4-chloro-3-trifluoromethyl-phenyl, 4-bromo-3-chlorophenyl, 4-tnfluoromethylphenyl, 4-trifluorometh-oxyphenyl, 4'methoxyphenyl, 4'-methyl-4-biphenylyl, 4'-trifluoromethyl-4-biphenylyl, 4'-bromo-4-biphenylyl, 4'-cyano-4-biphenylyl, 3'4'-dichloro-4-biphenylyl, etc. Again, the same optional substituent may be present where aryl is part of aryloxy or arylthio. Optionally substituted alkyl groups may carry one or more substituents selected from halogen, alkyl, alkoxy, alkylthio, cycloalkyi, phenyl, nitro, cyano, hydroxy, mercapto, alkylcarbonyl or alkoxycarbonyl. This also applies where alkyl is part of another substituent like alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl.
Preferably, the number of substituents is no more than three with the exception of halogen, where the alkyl groups may be perhalogenated.
In the above definitions "halogen" includes fluorine, chlorine, bromine and iodine. The alkyl radicals may be straight-chain or branched. This applies also to the alkyl parts of other alkyl-containing groups.
Depending upon the number of carbon atoms mentioned, alkyl on its own or as part of another substituent is to be understood as being, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the isomers thereof, for example isopropyl, isobutyl, tert-butyl or sec-butyl, isopentyl otter-pentyl. Cycloalkyi is, depending upon the number of carbon atoms mentioned, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclo octyl.
Depending upon the number of carbon atoms mentioned, alkenyl as a group or as a structural element of other groups is to be understood as being, for example -CH=CH2, -CH2*CH=CH2, -CH=CH-CH3, -CH2-CH=CH-CH3, -CH2-CH2-CH=CH2, -CH2-CH(CH3)-CH=CH2, -CH2-C(CH3)=CH2, -CH=CH-(CH2)2-CH3, -CH2-CH2-CH=CH-CH3, -CH2-CH2-C(CH3)=CH-CH3, -CH(CH3)-CH2-CH=CH-CH3, -CH2-CH2-CH=CH-CH2-CH3, -CH=CH-(CH2)3-CH3, -CH2-CH2-CH=C(CH3)-CH3, -CH2-CH2-CH=C(CH3)-CH2-CH3, -C(CH3)=CH2, -CH(CH3)-CH=CH2, -CH(CH3)-CH=CH-CH3, -CH(CH3)-CH2-CH=CH2, -CH2-CH(CH3)-C(CH3)=CH2, -CH2-C(CH3)=CH-CH3, -C(CH3)=CH-(CH2)2-CH3, -CH(CH3)-CH2-C(CH3)=CH-CH3, -CH(CH3)-(CH2)2-CH=CH2, -C(CH3)=CH-(CH2)3-CH3,

-CH(CH3)-CH2-CH=CH-CH2-CH3, -(CH2)3-CH=CH2. -C(CH3)=CH-CH3, -CH(CH3)-CH2-C(CH3)=CH-CH3, or -CH(CH3)-CH2-CH=CH-CH2-CH3 . Alkynyl as a group or as a structural element of other groups is, for example -C=CH,-CH2-C=CH, -CHC-CH3, -CH2-C=C-CH3, -CH2-CH2-C=CH, -C=C-CH2-CH3, -CH2-CH(CH3)-CaCH, -C=C-(CH2)2-CH3, -CH2-CH2-C=C-CH3, -CH(CH3)-CH2-C=C-CH3, -CH2-CH2-C=C-CH2-CH3, -C=C-(CH2)3-CH3, -C=C-(CH2)4-CH3, -CH(CH3)-C=CH, -CH(CH3)-C=C-CH3, -CH(C2H5)-CHC-CH3, -CH(CH3)-CH2-C=CH, -CH(CH3)-(CH2)2-C=CH, -CH(CH3)-CH2-C=C-CH2-CH3. -(CH2)3-C=CH, or -CH(CH3)-CH2-C=C-CH2-CH3, depending on the number of carbon atoms present.
A haloalkyl group may contain one or more (identical or different) halogen atoms, and for example may stand for CHCI2, CH2F, CCI3, CH2CI, CHF2, CF3, CH2CH2Br, C2CI5, CHsBr, CHCIBr, CF3CH2, etc..
The presence of at least one asymmetric carbon atom in the compounds of formula I means that the compounds may occur in optically isomeric and enantiomeric forms. As a result of the presence of a possible aliphatic C=C double bond, geometric isomerism may also occur Formula I is intended to include all those possible isomeric forms and mixtures thereof.
The optical isomers of compounds of the formula I can be prepared, for example, by reacting a 2-phenylethylamine of the formula IV with the optical isomers R- or the S-iso-mars, i.e. the (+)- or the (-)-form, of an a-hydroxycarboxylic acid in order to form the corresponding R- or S-enantiomer of a compound of the formula IV. The reaction can be advantageously carried out at room temperature in an aprotic solvent, for example dimethylforma-mide, in the presence of a catalyst, such as a quaternary phosphonium compound, for example, (benzotria2ol-1-yloxy)-tris-(dimethylamino)- phosphonium hexafluorophosphate. For example, (R)-2-hydroxy-2-(4-bromophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide, (S)-2-hydroxy-2-(4-bromophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide, (R)-2-hydroxy-2-(4-chlorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide and (S)-2-hydroxy-2-(4-chlorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide can be prepared in this manner.
Preferred subgroups of compounds of formula I are those wherein Ri is d-Chalky; or Ri is d-Chalky; or

Ri is CrC4alkyl, or
Ri is methyl or ethyl, especially methyl; or
R2 and R3 are independently of each other hydrogen or Ci-C4alkyl; or
R2 and R3 is hydrogen, methyl or ethyl, preferably methyl; or
R2 and R3 are hydrogen; or
R4 is aryl or heteroaryl, each optionally substituted with substituents selected from the group comprising alkyl, alkenyl, alkynyl, cycloalkyi, cycloalkyl-alkyi, phenyl and phenylalkyi, where all these groups may be substituted with one or more halogen atoms; alkoxy; alkenyloxy; alkynyloxy; alkoxyalkyl; haloalkoxy; alkylthio; haloalkylthio; alkylsulfonyl; formyl; alkanoyl; hydroxy; cyano; nitro; amino; alkylamino; dialkylamino; carboxyl; alkoxycarbonyl; alkenyloxycarbonyl and alkynyloxycarbonyl; or
R4 is phenyl, naphthyl or thiophenyl, each optionally substituted by one to three substituents selected from the group comprising subgroups are those wherein
Ri is alkyl; and R4 is aryl or heteroaryl, each optionally substituted by substituents selected from to group comprising alkyl, alkenyl, alkynyl, cycloalkyi, cycloalkyl-alkyi, phenyl and phenylalkyi, where all these groups may be substituted by one or several halogen; alkoxy; alkenyloxy; alkynyloxy; alkoxyalkyl; haloalkoxy; alkylthio; haloalkylthio; alkylsulfonyl; formyl; alkanoyl; hydroxy; cyano; nitro; amino; alkylamino; dialkylamino; carboxyl; alkoxycarbonyl; alkenyloxycarbonyl and alkynyloxycarbonyl; or
R2 is hydrogen; and Ri and R3 are independently


Other preferred subgroups of the compounds of formula I are those wherein
Ri is Ci-Chalky; and R2 and R3 are independently of each other hydrogen or CrC4alkyl; and R4 is aryl or heteroaryl, each optionally substituted with substituents selected from to group comprising aikyi, alkenyl, alkynyl, cycloalkyi, cycloalkyl alkyI, phenyl and phenylalkyi, where all these groups may be substituted with one or more substituents selected from the group comprising halogen; alkoxy. alkenyloxy, alkynyloxy: alkoxyalkyl; haloalkoxy; alkylthio; haloalkylthio; alkylsulfonyl; formyl; alkanoyl; hydroxy; cyano; nitro; amino; alkylamino; dial-calamine; carboxyl; alkoxycarbonyl; alkenyloxycarbonyl and alkynyloxycarbonyl; or wherein
Ri is ; and R2 and R3 is hydrogen, methyl or ethyl, preferably methyl; and
R4 is phenyl, naphthyl or biphenyl, each optionally substituted by one to three substituents selected from the group comprising
Ri is Ci-C4alkyl, and R2 and R3 is hydrogen or methyl; and
R4 is phenyl, naphthyl, thiophenyl, each optionally substituted by one to three substituents selected from the group comprising , . Preferred individual compounds are:
2-hydroxy-2-(4-bromophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide, 2-hydroxy-2-{4-chlorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide, 2-hydroxy-2-(3,4-dichlorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide, 2-hydroxy-2-biphenyl-4-yl-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,

2-hydroxy-2-naphthalen-2-yl-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
2-hydroxy-2-p-tolyl-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
2-hydroxy-2-(4-ethylphenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]- acetamide,
2-hydroxy-2-(4-trifluoromethylphenyl)-N-[2-(3-rnethoxy-4-hydroxyphenyl)-ethyl]-acetamide,
2-hydroxy-2-(4-fluorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
2-hydroxy-2-(3,4-difluorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyi]-acetamide,
2-hydroxy-2-(4-chloro-3-fluorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
2-hydroxy-2-(3-chloro-4-fluorophenyi)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetarnide.
2-hydroxy-2-(5-chlorothiophen-2-yl)-N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl]-acetamide,
2-hydroxy-2-phenyl-N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl]-acetamide, and
2-hydroxy-2-(4-methoxyphenyl)-N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl]-acetamide,
and the R- and S-enantiomers of these compounds, for example
(R)-2-hydroxy-2-(4-bromophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
(S)-2-hydroxy-2-(4-bromophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
(R)-2-hydroxy-2-(4-chlorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
(S)-2-hydroxy-2-(3,4-dichlorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
(S)-2-hydroxy-2-(4-chlorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
(R)-2-hydroxy-2-(3,4-dichlorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
(R)-2-hydroxy-2-biphenyl-4-yl-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
(S)-2-hydroxy-2-naphthalen-2-yl-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
(S)-2-hydroxy-2-biphenyl-4-yl-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
(R)-2-hydroxy-2-naphthalen-2-yl-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
(R)-2-hydroxy-2-p-tolyl-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]- acetamide,
(S)-2-hydroxy-2-(4-ethylphenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
(S)-2-hydroxy-2-p-tolyl-N-[2-(3-methoxy-4-hydroxyphenyi)-ethyl]- acetamide,
(R)-2-hydroxy-2-(4-ethylphenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]- acetamide,
(R)-2-hydroxy-2-(4-trifluorom’thylphenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-
acetamide,
(S)-2-hydroxy-2-(4-trifluoromethylphenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-
acetamide,
(R)-2-hydroxy-2-(4-fluorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
(S)-2-hydroxy-2-(4-fiuorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
(R)-2-hydroxy-2-(3,4-difluorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
(S)-2"hydroxy-2-(3,4-difluorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,

(R)-2-hydroxy-2-(4-chloro-3-fluorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
(S)-2-hydroxy-2-(4-chloro-3-fluorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
(R)-2-hydroxy-2-(3-chloro-4-fluorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide.
(S)-2-hydroxy-2-(3-chloro-4-fluorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide.
(R)-2-hydroxy-2-(5-chlorothiophen-2-yl)-N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl]-acetamide,
(S)-2-hydroxy-2-(5-chlorothiophen-2-yl)-N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl
(R)-2-hydroxy-2-phenyl-N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl]-acetamide,
(S)-2-hydroxy-2-phenyl-N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl]-acetamide,
(R)-2-hydroxy-2-(4-methoxyphenyl)-N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl]-acetonide,
and
(S)-2-hydroxy-2-(4-methoxyphenyl)-N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl]-acetamide.
The novel species of the above list have especially been prepared in the context of this
invention and thus form another embodiment thereof. Preferred species are selected from
the following group:
2-hydroxy-2-(4-bromophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
2-hydroxy-2-(4-chlorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
2-hydroxy-2-(3,4-dichlorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
2-hydroxy-2-p-tolyl-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]- acetamide,
2-hydroxy-2-(4-ethylphenyl)-N-[2-(3-metho.xy-4-hydroxyphenyl)-ethyl]-acetamide,
2-hydroxy-2-(4-trifluoromethylphenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
2-hydroxy-2-(4-fluorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
2-hydroxy-2-(3,4-difluorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
2-hydroxy-2-(4-chloro-3-fluorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
2-hydroxy-2-(3-chloro-4-fluorophehyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide.
2-hydroxy-2-(5-chlorothiophen-2-yl)-N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl]-acetamide,
2-hydroxy-2-phenyl-N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl]-acetamide, and
2-hydroxy-2-(4-methoxyphenyl)-N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl]-acetamide,
and the R- and S-enantiomers of these compounds, for example (R)-2-hydroxy-2-(4-bromophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,

(S)-2-hydroxy-2-(4-bromophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
(R)-2-hydroxy-2-(4-chiorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
(S)-2-hydroxy-2-(3,4-dichlorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
(S)-2-hydroxy-2-(4-chlorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetonide,
(R)-2-hydroxy-2-(3,4-dichlorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetum
(R)-2-hydroxy-2-p-tolyl-N-[2-(3'methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
(S)-2-hydroxy-2-p-tolyl-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyi]-acetamide,
(R)-2-hydroxy-2-(4-ethylphenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]- acetamide,
(S)-2-hydroxy-2-(4-ethylphenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]- acetamide,
(R)-2-hydroxy-2-(44rifluoromethylphenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-
acetamide,
(S)-2-hydroxy-2-(4-trifluoromethylphenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-
acetamide,
(R)-2-hydroxy-2-(4-fluorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
(S)-2-hydroxy-2-(4-fluorophenyl)-N-[2-(3-methoxy-4'hydroxyphenyl)-ethyl]-acetamide,
(R)-2-hydroxy-2-(3,4-difluorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
(S)-2-hydroxy-2-(3,4-difluorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-acetamide,
(R)-2-hydroxy-2-(4-chloro-3-fluorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-
acetamide,
(S)-2-hydroxy-2-(4-chloro-3-fluorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-
acetamide,
(R)-2-hydroxy-2-(3-chloro-4-fluorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-
acetamide.
(S)-2-hydroxy-2-(3-chloro-4-fluorophenyl)-N-[2-(3-methoxy-4-hydroxyphenyl)-ethyl]-
acetamide.
(R)-2-hydroxy-2-(5-chlorothiophen-2-yl)-N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl]-acetal’
(S)-2-hydroxy-2-(5-chlorothiophen-2-yi)-N-[2-(4-hydroxy-3-methoxyph’nyl)-ethyl]-ac’
(R)-2-hydroxy-2-phenyl-N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl]-acetamide,
(S)-2-hydroxy-2-phenyl-N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl]-acetamide,
(R)-2-hydroxy-2-(4-methoxyphenyl)-N42-(4-hydroxy-3-methoxyphenyl)-ethyl]-acetamide’
and (S)-2-hydroxy-2-(4-methoxyphenyl)-N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl]-acetamide.

The present invention further relates to processes for the preparation of 2-(3-alkoxy-4-hydroxyphenyl)-ethylamine’s of the formula IL
It is known from Japanese Patent Specification JP 55-45604 to prepare 2-(4-hydroxyphe-nyl)-nitro thanes by transforming an optionally substituted 4-hydroxybenzaldehyde with nitromethane into a corresponding 1-(4-hydroxyphenyl)-2-nitroethene and reducing the latter with a metal hydride, such as sodium borohydride or lithium aluminum hydride according to the following reaction scheme:

The 2-(4-hydroxyphenyl)-nitroethanes thus obtained are used as intermediates for the preparation of the corresponding 2-(4-hydroxyphenyl)-acetic acids. Further, it is known from Tetrahedron Letters (15) 1317-20 (1977) to prepare phenethyl-mines by reducing nitrostyrenes with sodium boron hydride to 2-phenylnitroethanes and further reducing the latter with Al/Hg in aqueous methanol. Specifically described is the reduction of 3-methoxy-4-benzyloxystyrene to 2-(3-methoxy-4-benzyloxyphenyl)-ethylamine. This reaction sequence can be described by the following reaction scheme:

From Tetrahedron Letters 51(8), 2305-24, 1993 it is further known to prepare enantio-enriched 2-aryl-alkylamines by addition of primary dialkylzinc reagents to 2-aryl-nitroolefines and subsequently reducing the 2-aryl-nitroalkanes thus obtained by catalytic hydrogenation over Pd/C or Raney-Ni.
It is further knave from Chem. Ber. 55, 3388, (1933) and 71, 2154 (1938) to prepare 2-phe-nylethylamines by reacting a substituted benzaldehyde with hydrogen cyanide to form the corresponding mandelonitrile and reducing the latter to the corresponding 2-phenylethyl-amine. The reduction is carried out by catalytic hydrogenation with platinum oxide as catalyst. The transformation of substituted mandelonitriles into the corresponding 2-phe-nylethylamines by catalytic hydrogenation with platinum oxide (Adams catalyst) is also described in J. Amer. Chem. Soc, 55, 2593 - 2597, 1933.


wherein Ri R2 and R3 are as defined above; and bi) further reacting the 2-phenyl-nitroethane derivative of the formula VII obtained in step a) with hydrogen in the presence of a catalyst to form a 2-phenylethylamine derivative of the formula II. Steps ai) and bi) are further described in detail as follows.
Step ai
Suitable reducing agents for the reduction of a nitrostyrene of the formula VI to a 2-phenyl-nitroethane of the formula VII are metal hydrides, such as sodium borohydride and lithium borohydride. Other suitable reducing agents are 2,6,dialkyl-3,5-di-alkoxycarbonyl-1,4-di-hydropyridines, particularly 2,6-dimethyl-3,5-di-ethoxycarbonyl-1,4-dihydropyridine (Hantzsch-ester). Further suitable reducing agents are boranes and trialkylborohydrides. Preferably sodium borohydride is used for the reduction of the nitrostyrene of the formula VI. For enantiomerically enriched 2-phenyl-nitroethanes of the formula VII asymmetric ,

catalysts for chiral reduction can be used. The reduction reaction is advantageously performed in a inert solvent, such as aromatic and aliphatic or halogenated hydrocarbons. Suitable solvents are chlorohydrocarbons, such as dichloromethane or chlorobenzene, hydrocarbons, such as n-hexane, cyclohexane or toluene, ethers, such as diethyl ether, tert.-butyl-methy ether, dioxane or tetrahydrofuran. alcohols, such as methanol, ethanol, propanol, isopropanol or sec. butanol. Mixtures of the afore-mentioned solvents can also be used. The reduction reaction can be performed at a temperature of from -80°C to +150°C, with temperatures within the range of -20'C to +60°C being preferred. The 2-phenyl-nitroethanes of the formula VII are novel compounds and are, therefore, also part of the present inventive concept. Step bi
Suitable catalysts for the hydrogenation of a 2-phenyl-nitroethane of the formula VII to a 2-(3-alkoxy-4-hydroxyphenyl)-ethylamine’s of the formula II are, for example, Raney-nickel, palladium on a suitable carrier, such as palladium on carbon. Further, the reduction of 2-phenyl-nitroethanes of the formula VII can also be carried out by reaction with hydrogen donors, such as hydrazine. The reduction reaction is advantageously performed in an inert solvent, such as water or alcohols, such as methanol, ethanol, propanol, isopropanol or sec. butanol. Further suitable solvents are chlorohydrocarbons, such as dichloromethane, and chlorobenzene, hydrocarbons, such as n-hexane, cyclohexane and toluene, ethers, such as diethyl ether, tert-butyl-methyl ether, dioxane and tetrahydrofuran, carboxylic acids, such as acetic acid. Mixtures of the afore-mentioned solvents can also be used. The reduction reaction can be performed under neutral or acidic conditions. The reduction reaction can be performed at a temperature of from "20°C to +150'C, with temperatures within the range of from 0°C to -i-100°C being preferred.
The nitrostyrenes of the formula IV can be prepared by reacting a carbonyl compound of the formula VIII


wherein R3 is as defined for formula 1. This reaction can be carried out under conditions as described in Japanese Patent Specification JP 55-45604.
According to a second alternative the 2-(3-alkoxy-4-hydroxyphenyl)-ethylamine’s of the formula 11

wherein Ri and R2 are as defined above, and ba) further reacting the a-hydroxynitrile of the formula VII with hydrogen in the presence of a catalyst to form a 2-(3-alkoxy-4-hydroxyphenyl)-ethylamine of the formula II. Most of the compounds of the formula VIII are known compounds and can be prepared by conventional methods.
The reactions involved in steps ai) and bg) are further described in detail as follows: Step a’
Suitable agents for the conversion of a compound of the formula VIII into a 2-phenyl-cyanohydrin derivative of the formula IX are prussic acid (hydrogen cyanide) and any kind of salts thereof as well as reactive cyanohydrins, for example acetone cyanohydrins. The reaction is advantageously performed under neutral to acidic conditions. Suitable acids are carboxylic acids, hydrochloric acid, sulfuric acid, optionally substituted alkyl or aryl sulfonic

acids, phosphoric acid and nitric acid, with hydrochloric acid and sulfuric acid being preferred.
Optionally, the reaction can be performed in the presence of a biocatalyst to produce the optically enriched cyanohydrin derivatives of the formula VII. Optionally, the reaction can be performed in the presence of an alkylating or acylating agent, e.g. like acetyl chloride or ethyl chloroformate to yield protected 2-phenyl-cyanohydrin derivative of the formula IX. The reaction is advantageously performed in a solvent selected from water, alcohols, hydrocarbons, chorohydrocarbons, ethers and nitriles. Especially suitable solvents are alcohols, such as methanol, ethanol, propanol, isopropanol or sec. butanol, chlorohydrocarbons, such as dichloromethane or chlorobenzene, hydrocarbons, such as n-hexane, cyclohexane or toluene, ethers, such as diethyl ether, tert-butyl-methyl ether, dioxane or tetrahydrofuran, nitriles, such as acetonitrile or butyronitrile. Mixtures of the afore-mentioned solvents can also be used. If aprotic solvents are used, the reaction is advantageously performed in the presence of a phase transfer catalyst. The reaction can be performed at a temperature of from -SOX to +150°C, with temperatures within the range of -20°C to +60°C being preferred.
Step bg
Suitable catalysts for the hydrogenation of a 2-phenyl-cyanohydrin derivative of the formula IX are, for example, platinum oxide, Raney-nickel, palladium on a suitable carrier, such as palladium on carbon. The reduction reaction is advantageously performed in a inert solvent, such as water, alcohols, hydrocarbons, halogenated hydrocarbons,ethers or carboxylic acids. Especially suitable solvents are alcohols, such as methanol, ethanol, propanol, isopropanol or sec. butanol. Other suitable solvents are chlorohydrocarbons, such as dichloromethane or chlorobenzene, hydrocarbons, such as n-hexane, cyclohexane or toluene, ethers, such as diethyl ether, tert-butyl-methy ether, dioxane or tetrahydrofuran, carboxylic acids, such as acetic acid. Mixtures of the afore-mentioned solvents can also be used. The reduction reaction can be performed under neutral or acidic conditions. Suitable acids are those mentioned for step a2). The reduction reaction can be performed at a temperature of from -20°C to +150°C, with temperatures within the range of OX to +100°C being preferred. The hydrogenation can be either performed with an isolated 2-phenyl-cyanohydrin of the formula IX or in situ without isolation of the 2-phenyl-cyanohydrin of the formula I formed in step a2). Preferably, the hydrogenation is performed with in a manner such that a 2-phenyl-cyanohydrin of the formula IX is introduced portionwise into the reaction mixture in order

to minimise the formation of free hydrogen cyanide which detrimentally affects the activity of the catalyst. This equally applies to the use of an isolated 2-phenyl-cyanohydrin derivative of the formula IX and the use of a solution of the 2-phenyl-cyanohydrin derivative of the formula IX obtained in step as). The performance of the hydrogenation in this manner makes it possible to reduce the amount of catalyst. Further, the yield per volume can be increased by up to 20%.
The compounds of the formula ! are valuable intermediates which can be used for the preparation of fungicidally active compounds which represent a sub group of the compounds of the above formula la which sub group can be defined by formula lb

wherein Ri is alkyl,
R2, and R3 are each independently hydrogen or alkyl, and
R4 is optionally substituted aryl or optionally substituted heteroaryl, '
R5 is hydrogen, alkyl, cycloalkyi or optionally substituted aryl, Re and R7 are each independently of each other hydrogen or alkyl, and Z is halogen, optionally substituted aryloxy, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted arylthio, optionally substituted alkylthio, optionally substituted alkenylthio, optionally substituted alkynyl thio, optionally substituted alkylsulfinyl, optionally substituted alkenylsulfinyl, optionally substituted alkynylsulfinyl, optionally substituted alkylsulfonyl, optionally substituted alkenylsulfonyl or optionally substituted alkynylsulfonyl. and of the enantiomers thereof.
The present invention is further illustrated but in no way limited by the following examples.
E1: Preparation of 2-Phenvl-2-hvdroxv-N-[2-(4-hvdroxv-3-methoxvphenvn-ethvn-
acetamide
\_
El .1:2-(4-Bromophenvl)-2-hvdroxv-N-f2-(4-hvdroxv-3-methoxvphenvl)-ethno-acetamide by solvent process


5-(4-Bromophenyl)-2,2-diinethyl-1,3-dioxolan-4-one (15 g; 55 mmol) is dissolved in 50 ml of methanol. 4-(2-AmJnoethyl)-2-methoxyphenol hydrochloride (14 g; 69 mmol) and triethyl-mine (7 g; 69 mmol) are added and the mixture is stirred for 72 hours at room temperature. The solvent is removed in vacuum and the residue is extracted with ethyl acetate and the combined organic phases are washed with brine, dried over sodium sulfate and evaporated. to dryness. The remaining 2-{4-bromophenyl)-2-hydroxy-N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl]-acetamide is purified by chromatography on silica gel.
'H-NMR (300 MHz, CDCI3): 2.71 (t, 2H, CH2CH2), 3.54 (t, 2H, CH2CH2), 3.80 (s, 3H, OCH3), 5.39 (s, 1H, CHOH), 6.16 (bs, 1H, NH), 6.52-7.35 (m, 7H, CH aroma.).
E1.2: 2-(4-Chlorophenvl)-2-hvdroxv-N-[2-(4'hvdroxv-3-methoxvphenvl)-ethyl-acetamide

a) by solvent process
5-(4-Chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-one (5.67 g; 25 mmol) and 4-(2-aminoethyl)-2-methoxyphenol (4.39 g; 26.25 mmol) are dissolved in 31.25 g of dry dioxane. The mixture is heated to reflux (+100 °C) and the solution is stirred for 7 hours at reflux temperature. The solvent is removed in vacuum and to the residue 20 g of a 1:1 mixture of ethyl acetate and hexane is added at +70 'C whereupon a precipitate is formed. After cooling, filtering and washing the product is dried in vacuum. 7.44 g of 2-(4-chlorophenyl)-2-hydroxy-N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl]-acetamide with a purity of 91.0 % is obtained in 80.6 % yield.
'H-NMR (300 MHz, CDCI3): 2.72 (q, 2H, CH2CH2). 3.50 (m, 2H, CH2CH2), 3.82 (s, 3H, OCH3), 4.95 (s, 1H, CHOH), 6.23 (bs, 1H, NH), 6.49-7.35 (m, 7H, CH arom.).
b) by melt process
(4-Chloro-phenyl)-hydroxy-acetic acid methyl ester (10.03 g; 50 mmol) and 4-(2-ami-noethyl)-2-methoxyphenol (4.39 g; 26.25 mmol) are weighed into a 50 ml reactor. The '







'H-NMR (CDCI3) 5(ppm): 3.25 (t, 2H); 3.9 (s, 3H);4.6 (t, 2H); 5.65 (s,1 H); 6.6 - 6.75 (m, 2H); 6.8-6.9 (m,1H).
b) To sodium borohydride (1.93 g, 51.2 mmol) suspended in ethanol (15 ml) at +10 to +15°C is added a solution of 2-methoxy-4-(2-nitro-vinyl)-phenol (10.0 g, 51.2 mmol) in tetrahydrofuran (100 ml) over 1h. Thereafter the reaction mixture is stirred at room temperature for 30 minutes. Acetic acid (4 ml) in water (100 ml) is then added carefully. The resulting mixture is evaporated to at about a quarter of its volume. It is extracted with ethyl acetate (1 x 100 ml, 1 x 50 ml) washed with brine (2 x 50 ml) dried (Na2S04) and evaporated. 2-methoxy-4-(2-nitro-ethyl)-phenol (9.64 g) is obtained as an oil, which is purified by kugelrohr distillation (+150"C, 0.02 torr) yielding 7.3 g (72 %) of purified material.

To 2-methoxy-4-(2-nitro-ethyl)-phenol (2.0 g) and Raney-nickel (3.7 g) in ethanol (30 ml) is added hydrazine hydrate (3.8 g) during 30 minutes. The reaction mixture is stirred for 1 hour at room temperature. After filtration the reaction mixture is poured into water (350 ml). It is extracted with ethyl acetate (2 x 400 ml) washed with brine (2 x 50 ml) dried (Na2S04) and evaporated. 4-(2-amino-ethyl)-2-methoxy-phenol is obtained as colorless crystals. 'H-NMR (de-DMSO) 5(ppm): 2.3 - 2.4 (m, 2H together with DMSO); 2.5 (t, 2H); 2.5 - 3.6 (broad, 3H together with H2O); 3.5 (s, 3H); 6.2 - 6.6 (m. 3H).
E5: Preparation of 2-(methoxv-4-(2-aminoethvl)-chino by reduction of hydroxy-(4-hvdroxv-3-methoxvphenvn-acetonitrile

Sodium cyanide (10.2g) is dissolved in water (40 ml) and cooled to 0°C. A second solution comprising vanillin (15.5g) and ethanol (30 ml) is added at 0°C. Now, concentrated hydrochloric acid (28.5g 32%) is added to the mixture at 0 to +5°C within 30 to 45 minutes

and the dropping funnel is rinsed with water (10 ml). After confirming that the conversion has proceeded to a satisfactory level by HPLC, the mixture is worked up by extracting repeatedly with t-butyl methyl ether (3 x 50 ml). The collected organic phases are washed twice with 10% aqueous bisulfate (50 ml) and once with water (40 ml). Finally, the product solution is dried and the solvent is evaporated in vacuum to yield the crude product as a yellow oil, which crystallized on standing (mp 80-81 °C). If the already pure product needs further purification, it can be crystallized from ether/hexane (m.p82-83°C). 'H-NMR (CDCI3) 5(ppm): 3.05 (d, 1H), 3.92 (s, 3H), 5.45 (d, 1H), 5.82 (s, 1H), 6.91 -6.96 (m, 1H); 6.98-7.04 (m.2H)

A solution of hydroxy-(4-hydroxy-3-methoxy-phenyiy-acetonitrile (9.0 g) in ethanol (50 ml) is added to a mixture of 10% palladium on charcoal (0.8 g), anhydrous ethanol (100 ml) and concentrated sulfuric acid (6.7 g) over a period of 2 hours at room temperature, while hydrogen is introduced simultaneously into the reaction mixture. ‘Hydrogen addition is continued for 1 hour at room temperature. After the catalyst is removed by hot-filtration at +70°C, most of the ethanol is removed (approx. 70%) by distillation. The remainder is cooled to a temperature of O’C, at which the hydrogen sulfate of the desired amino phenol crystallizes on standing. The obtained white crystals are dissolved in 50 ml of water and the pH of the solution is adjusted to 10.5. The product precipitates during the neutralization as off-white crystals. Finally, 4-(2-amino-ethyl)-2-methoxy-phenol is collected by filtration (m.p. 156-158°C).
‘H-NMR (de-DMSO) d(ppm): 2.3 - 2.4 (m, 2H together with DMSO); 2.5 (t, 2H); 2.5 - 3.6 (broad, 3H together with H2O); 3.5 (s, 3H); 6.2 - 6.5 (m, 3H).

A solution of sodium cyanide (10.2 g) in water (50 ml) is added to a mixture of vanillin (15.5 g) and methanol (30 ml) at O’C. Concentrated hydrochloric acid (28.5 g 32%) is introduced

at 0°C to+5°C within 30 to 45 minutes. After confirming that the conversion has proceeded to a satisfactory level by HPLC, the mixture is extracted with t-butyl methyl ether (100 ml). After aqueous layer is drained, the organic phase is washed twice with 10% aqueous bisulfate (50 ml) and once with water (40 ml). The obtained crude cyanohydrin-solution is dried over sodium sulfate right after work-up. Most of the solvent is removed in vacuum and the remainder is dissolved in anhydrous, acidified methanol (50 ml). The ethanolic solution is added to a mixture of 10% palladium on charcoal 11.4g), anhydrous methanol (100 ml) and concentrated sulfuric acid (13.0 g) over a period of 1 hour at room temperature, while the mixture is kept under a pressurized hydrogen atmosphere. Hydrogen addition is continued for 3 hour at room temperature. After water (80 mi) is added, the catalyst is removed by filtration, and most of the methanol is removed by distillation. During the adjustment of the pH of the obtained solution to 10.5, the amino phenol precipitates as a sticky semisolid, which slowly crystallized on further stirring at room temperature. The crystallized product is isolated by filtration. The retained light yellow crystals are dried in vacuum (m.p. 156-158°C). ‘H-NMR (de-DMSO) d(ppm): 2.3 - 2.4 (m, 2H / DMSO); 2.5 (t, 2H); 2.5 - 3.6 (broad, 3H / H2O); 3.5 (s, 3H); 6.2 - 6.6 (m, 3H).

Method A: A 80 % solution of properly bromide in toluene (39,1 g, 0,263 mol) is
added slowly at room temperature to a mixture of 2-(4-chloro-phenyl)-2-hydroxy-N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-acetamide (35.25 g, 0,105 mol), 30 % sodium hydroxide solution (52,4 ml, 0,524 mmol) and tetrabutylammonium bromide (1,8 g) in 180 ml of dichloroethane. The reaction mixture is stirred for 16 hours at +40°C. Subsequently the mixture is evaporated and the residue is diluted with water (100 ml) and dichloroethane (100 ml). The organic phase is separated and the aqueous layer is extracted with dichloroethane. The combined organic phases are washed with brine (150 ml), dried over sodium sulfate and evaporated. The remaining oil is purified by chromatography on silica

gel (ethyl acetate / hexane 1 : 1) to yield 2-(4-chlcro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-prop-2-ynyloxy-acetamide. m.p. 90 - 92°C. ‘H-NMR (300 MHz, CDCI3): 2.42(t, 1H), 2.47(t, IH), 2.74 (t, 2H), 3.50(1, 2H), 3.79(s, 3H), 3.91 (dd, 1H, 4.14(dd, 1H), 4.69(d, 2H), 4.91 (s. IH1, 6.62 -7.29(m, 7H).
Method B:
A mixture of 2-(4-chloro-phenyl)-2-hydroxy-N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-acetamide (5.6 g), 30% potassium hydroxide solution (5.6 g), methyl-tributylammonium chloride (0.43 g) and water (9.7 g) is stirred at roan temperature. Methanesulfonic acid prop-2-ynyl ester (10 g) is added dropwise over a period of 2 hours, and stirring is continued at room temperature for further 4 hours. The mixture is allowed to separate and the aqueous phase is discarded. To the remaining organic phase a 30% potassium hydroxide solution (2.8 g), methyl-tributylammonium chloride (0.3 g) and water (2.8 g) are added and the reaction mixture is stirred at room temperature. During 1 hour the methanesulfonic acid prop-2-ynyl ester (5 g) is added. Stirring is continued for 18 hours at room temperature for 18 hours before the triethylamine (1.1 g) is added and the mixture is stirred at room temperature for another 30 minutes. Toluene (10 g) is added and the mixture is allowed to s separate. After discarding the aqueous phase the organic phase is washed with 15% hydrochloric acid. Then 10 g of acetone are added to the organic phase and it is washed with a 8.7% sodium hydrogen carbonate solution ‘3 g). The organic phase is collected and the solvent is evaporated, yielding the desired 2-{4-chloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-prop-2-ynyloxy-acetamide, which exhibits identical physic-chemical data as the product prepared by Method A is obtained.




WE CLAIM:
1. A process for the preparation of 2- envy 24ydroxy--N-[2'(S-lkoxy-4-hydroxyphenyO-ethyt]-ac6tamides of the formula I

wherein Ri is alkyI,
R2» and R3 are each independently hydrogen or alkyl.
R4 is aryl or heteroaryl, each optionally substituted with substituents selected from the group
comprising alkyl, alkenyl, alkynyl. cyckalkyl, cydoalkytalkyi, phenyl and phenylalkyi, where
all these groups may be substituted with one or more substituents sheeted from the group
comprising halogen; alkoxy; aikenykxy; atkynykxy; alkoxyalkyl; alkoxy; arylthio;
haloalkylthio; alkylsulphonyl; fomnyl; alkanoyl; hydroxy; canoe; nitro; amino; alkylamino;
dialkylamino; carboxyl; alkoxylate omit; aikenyloxycartx and
which process comprises
reacting a nitro styrene of the formula IV




WE CLAIM:
1. A process for the preparation of 2- envy 24ydroxy--N-[2'(S-lkoxy-4-hydroxyphenyO-ethyt]-ac6tamides of the formula I

wherein Ri is alkyI,
R2» and R3 are each independently hydrogen or alkyl.
R4 is aryl or heteroaryl, each optionally substituted with substituents selected from the group
comprising alkyl, alkenyl, alkynyl. cyckalkyl, cydoalkytalkyi, phenyl and phenylalkyi, where
all these groups may be substituted with one or more substituents sheeted from the group
comprising halogen; alkoxy; aikenykxy; atkynykxy; alkoxyalkyl; alkoxy; arylthio;
haloalkylthio; alkylsulphonyl; fomnyl; alkanoyl; hydroxy; canoe; nitro; amino; alkylamino;
dialkylamino; carboxyl; alkoxylate omit; aikenyloxycartx and
which process comprises
reacting a nitro styrene of the formula IV





Documents:

1061-chenp-2004-abstract.pdf

1061-chenp-2004-claims filed.pdf

1061-chenp-2004-claims granted.pdf

1061-chenp-2004-correspondnece-others.pdf

1061-chenp-2004-correspondnece-po.pdf

1061-chenp-2004-description(complete)filed.pdf

1061-chenp-2004-description(complete)granted.pdf

1061-chenp-2004-form 1.pdf

1061-chenp-2004-form 26.pdf

1061-chenp-2004-form 3.pdf

1061-chenp-2004-form 5.pdf

1061-chenp-2004-other document.pdf


Patent Number 209793
Indian Patent Application Number 1061/CHENP/2004
PG Journal Number 50/2007
Publication Date 14-Dec-2007
Grant Date 06-Sep-2007
Date of Filing 14-May-2004
Name of Patentee M/S. SYNGENTA PARTICIPATIONS AG
Applicant Address Schwarzwaldallee 215, CH-4058 Basel,
Inventors:
# Inventor's Name Inventor's Address
1 ZELLER, Martin Syngenta Crop Protection Muenchwilen AG, Breitenloh 5, CH-4333 Muenchwilen,
2 FABER, Dominik Syngenta Crop Protection Schweizerhalle AG, Rothausweg, 4133 Schweizerhalle
3 VETTIGER, Thomas Syngenta Crop Protection Schwarzwaldallee AG, Rothausweg, CH 4133
4 LAMBERTH, Clemens Syngenta Crop Protection AG, Schwarzwaldallee 215, CH-4058 Basel,
PCT International Classification Number C07C 213/02
PCT International Application Number PCT/EP2002/012844
PCT International Filing date 2002-11-15
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 0127559.3 2001-11-16 U.K.