AP57A - Pyrimidine derivatives. - Google Patents

Pyrimidine derivatives. Download PDF

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Publication number
AP57A
AP57A APAP/P/1988/000092A AP8800092A AP57A AP 57 A AP57 A AP 57A AP 8800092 A AP8800092 A AP 8800092A AP 57 A AP57 A AP 57A
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Prior art keywords
formula
carbon atoms
acid
pyrimidin
benzyl
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APAP/P/1988/000092A
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AP8800092A0 (en
Inventor
Edward Mcdonald
Roger Salmon
Alan John Whittle
Michael Gordon Hutchings
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Ici Plc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/30—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Dentistry (AREA)
  • Wood Science & Technology (AREA)
  • Plant Pathology (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Agronomy & Crop Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Pest Control & Pesticides (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyridine Compounds (AREA)

Abstract

This invention provides novel

Description

PYRIMIDINE DERIVATIVES
This invention relates to novel insectic.dally ar.d acaricidally active esters and compositions comprising them, and to novel acids and derivatives thereof useful in their preparation. The invention also relates to processe.
for preparing the novel esters, acids and derivatives and to novel compounds useful in such processes.
In a first aspect the invention provides novel compounds of formula (I):
R1 (I) and stereoisomers thereof, wherein:
'0 r! is selected from alkyl containing 1 to 6 caress atoms; alkenyl containing 2 to 8 carbon atoms; alkyn/i containing 2 to 6 carbon atoms; haloalkyi containing 1 carbon atoms; haloalkenyl containing 2 to 8 carton acorn;; and cycloalkyl containing 3 to 6 carbon atoms optional·?.
substituted by one or more substituents selected iron , containing 1 to 4 carbon atoms and halogen;
is selected from alkyl containing 1 to 8 carbo.; atoms; haloalkyi containing 1 to 4 carbon atoms; a 1 ·· .: containing 1 to 6 carbon atoms; alkylamino containxng 1 . .>
4 carbon atoms; dialkylamino containing a totai of 2 -υ i carbon atoms; halogen; cycloalkyl containing 3 to 6 care n atoms optionally substituted by one or more substituents
APO00057 bad ORIGINAL selected from halogen and alkyl confaini·?; 1 ·υ atoms; and phenyl optionally substituted witn one or :,? substituents selected from alkyl containing 1 to 4 atoms, haioalkyl containing 1 to 4 carbon atoms, dale and alkoxy containing 1 to 4 carbon atoms;
is selected from hydrogen and halogen;
R^ is the residue of an alcohol of formula R4-OH /..-.forms an insecticidal ester when combined with chrysanthemic acid, permethrin acid or cyhaloti/in acid;
and
X is selected from oxygen and sulphur;
provided that R may not represent an alpha-branched alkyl group or a cycloalkyl group when R^ represents 1me^hylethyl (i so-propyl) .
In the proviso, alpha-branched alkyl group means :,-.
alkyl group having fewer than two hydrogen substituen-; rt the carbon atom of group R which is directly at tached the pyrimidine ring in formula (I). Chrysanthen is act;
3-(2-methy1prop-l-en-l-yl)-2,20 dimethylcyclopropanecarboxylic acid, permethrin acid ; a 3( 2,2-dichloroethenyl)-2,2-dimethylcyclopropane(c. boxy 1ic acid and cyhalothrin acid is 3-(Z-2-chloro-3,3,3t r i f luor oprop-l-en-l-yl) - 2,2-dimet hylcyclopropar.eca r be .< / 3 t c acid.
Preferred compounds according to the invention are those according to formula (I) wherein R^, R2, r3 and X have any of the meanings given hereinbefore, and R“ i < selected from:
bad ORQ’NAL (i) a group of formula:
I wherein Y represents nitrogen, or carbon substituted with either of a hydrogen atom or a methyl group, Ra represents hydrogen, halogen or methyl, Rb represents phenyl, phenoxy, halophenoxy, benzyl or halogen, and Rc represents hydrogen, methyl, trifluoromethyl, cyano or ethynyl;
(ii, a group of formula:
AP000057 wherein :
Rd is selected from halogen; alkyl containing 1 to 8 carbs iO atoms; alkenyl containing 1 to 8 carbon acorns; alkynyl containing 1 to 8 carbon atoms; haloalkyl containing 1 to carbon atoms; haloalkenyl containing 1 to 6 carbon atoms; group of formula -SiR^; a group of formula -CC^R; a grouc of formula -OR; a group of formula -(CH2))-Rn where R*1 represents chlort group of formula -BR2, or a group of group of formula -CH2Ri where rep·.
.a group halogen, a group of formula -OR, a group ot fosr.la alkenyloxy containing 2 to 4 carbon atoms, alxoanyithso containing 2 to 4 carbon atoms, alxynyioxy containin'! ..
carbon atoms, alkynylthio containing 2 to 4 carbon a f a: phenyl optionally substituted with one or more halogen substituents, phenoxy optionally substituted with one or more halogen substituents, phenylthio optionally substituted with one or more halogen substituents, benzyloxy optionally substituted with one or more haio'vn substituents, a group of formula -OCOR, a group of form! 1
-OCOOR, a group of formula -O-N=CR2, a group of formula -NR2, piperidin-l-yl, pyrollidin-l-yl, N-morpholino, or cyclopropyl optionally substituted with one or more haicc substituents, wherein R represents alkyl conLs.aino 1 carbon atoms;
Re, R, r‘3 and Rh are independently selected f.om r.yc.· :: fluorine, chlorine, bromine, piper idιn-1- /1, ; > yr c 1· i ;: ., - 1 yl, alkyl containing 1 to 4 carbon atom::, alkoxy sen ·. - ;
to 4 carbon atoms, alkylthio contain:;: : 1 . a .: o atoms, and a group of formula -NR2 wherein R lecr-a··.·..1:.·· alkyl containing 1 to 4 carbon atoms;
(iii) a group of formula:
N
BAD ORIGIN M5 and (iv) a group of formula:
ch2 wherein Z is selected from oxygen and sulphur, pJ is selected from hydrogen, alkyl containing 1 to 6 caroon atoms, alkenyl containing 1 to 6 carbon atoms, alkynyl containing 1 to 6 carbon atoms, and benzyl, and Rk is selected from alkyl containing 1 to 6 carbon atoms, alkenyl containing 1 to 6 carbon atoms, alkynyl containing 1 to 6 carbon atoms, and benzyl.
^referred values of R1 in the compounds of formula (I) according to the invention include ethyl, 1-methylethy1,
1,1-dimethylethyl, 1,1-dimethylpropyl, 1,l-dimethylprop-2en-l-yl, tri fluoromethyl, cyclopropyl, 1-methylcyclopropy1,
2-methy1prop-2-en-1-y1, 2-fluoro-1,1-dimethylethyl, 2,2Ίifluoro-1,1-dimethylethyl, prop-l-en-2-y1, and prop-2-en1-yl.
AP 0 0 0 0 5 7
Preferred values of Ri include methyl, ethyl, 1methylethyl, 1,1-dimethylethyl, 1,1-dimethylprooyi, ' ri 1 iuoromethyl, 2-fluoro-1,1-dimethylethyl, 2,2-difluoro1,1-dimethylethyl, trichloromethyl, cycloptopyl, 1methylcyclopropyl, cyclohexyl, 1-methylcyclohexy1, phenyl, 2-chlorophenyl, dimethylamino'and chloro.
BAD ORIGINAL
Preferred values of include hydrogen, s '.lor: fluorine.
Preferred values of R4 include either (1) a q: : for mu la :
Rc wherein Ra is selected from hydrogen and fluorine; Rc l .selected from benzyl, phenoxy, 4-chlorophenoxy 4 bromophenoxy and 4-fluorophenoxy; Rc is selected from hydrogen, methyl, trif1uoromethyl, ethynyl and cyano; v represents nitrogen or carbon substituted with either hydrogen atom or a methyl group; or (ii) the group of formula:
wherein Rd has any of the meanings given herei rbefor .· ls selected from fluorine, chlorine, ce .rite. ,.ethyl, methoxy, ethoxy, methylthio, ethylthio and dimethylamino; fF is selected from hydrogen and fLu -, and r9 and Rh are independently selected trot! fluori.··',
BAD
chlorine, bromine, methoxy, ethoxy, methyl and ethyl.
Particularly preferred esters of focmoia (Σ) arc·. ) to the invention are those derived from the Loiloxnu or simple derivatives thereof by the processes descri;.-. ;
hereinafter:
2-(2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3dimethylbutanoic acid and stereoisomers thereof,
2-(2-(1-methylethyl)pyrimidin-5-yl]-3,3-dimerhylbutanoic acid and stereoisomers thereof,
2-[2-(1-methyl cyclopropyl)pyrimidin-5-yi]-3,3dimethylbutanoic acid and stereoisomers thereof,
2-(2-(1, 1 -dimethylpropyl)pyrimidin-5-yl]-3,3dimethylbutanoic acid and stereoisomers thereof,
2-[2-(t rifluoromethyl)pyrimidin-5-yl]-3,3-d ioe .h/ibc t . ?
acid and stereoisomers thereof,
- [ 2 - (1,1-dimethylethyl)pyr imidin-5-yl ] - 3,3-t; j methy i ce:. ;enoic acid and stereoisomers thereof,
2-[ 2-(1,1-dimethylethyl, pyrimidin-5-yl ] butan>o acic --. :
stereoisomers thereof,
0 2-[2-(dimethylamino)pyrimidin-5-yl]-3,3-dimethy1buta n.
acid and stereoisomers thereof,
- [ 2 - ( cyclopropyl) pyr imidin-5-yl ] - 3,3 -d i me t hy .1 b j 1 a no : - · · and stereoisomers thereof,
2-[ 2-phenylpy r imidi n-5-yl ]-3,3-d ime thy lbu t anoi. c acid ar. 1 25 stereoisomers thereof,
AP 0 0 0 0 5 7
BAD ORIGINAL
2- [ 2 - ( 4-methoxypneny1)pyr imidin-5-y1]-3,3-dimet h/11 :.
acid and stereoisomers thereof,
2-(2-(1,i-dimethylethyl)pyrimidin-5-yl]-3-me chyle a acid and stereoisomers thereof,
2-[2-methylpyrimidin-5-yl]-3,3-dimethylbjtanoic acic and stereoisomers thereof,
2-[2-(l-methylcyclohexyl)pyrimidin-5-yi]-3,3dimethylbutanoic acid and stereoisomers thereof,
2-[2-(2-chlorophenyl)pyrimidin-5-yl]-3,3-dimethyibutano. 10 acid and stereoisomers thereof,
2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3dimethylpentanoic acid and stereoisomers thereof,
2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]pent-4-enorc aci i and stereoisomers thereof,
2-[2-(l,l-dimethylethyl)pyrimidin-5-ylj-3,3,3trif1 joropropanoic acid and stereoisomers thereof,
-( 2 - (1,1-dimethylethyl)pyr imidin-5-y 1 ] - 2-cycloprop> 1 - ···: acid and stereoisomers thereof,
2-[2-phenylpyrimidin-5-yl]-3-methylbutanoic acid ane 20 stereoisomers thereof,
2-[ 2-(t r i fluoromethyl )pyrimidin-5-yl ]-3-methyib,i 1· t and s t - r eo : state r s thereof,
- [ 2 - (dimethyl ami no) pyr imidin-5-yl ] - 3 -me t hyl beta no i c and stereoisomers thereof,
BADORIG,nAL £
2-[2-(t r ichloromethyl)pyr imidin-5-yl]-3-methylbu tanoio a· and stereoisomers thereof,
2-[2-chloropyrimidin-5-ylJ-3-methylbutanoic acid and stereoisomers thereof,
2-[2-methylpyrimidin-5-yl]-3-methylbutanoic acid and stereoisomers thereof,
2-[2-(t r i fluoromethyl)pyrimidin-5-y1)-2-(1methylcyclopropyl)acetic acid and stereoisomers thereof,
2-(2-(1,1-dimethylethyl)pyrimidin-5-y1]-2-(ΙΙΟ methylcyclopropyl)acetic acid and stereoisomers thereof,
- [ 2 - (t r i fluoromethyl )pyrimidin-5-yl ] - 3,3-dimethylpentan·, acid and stereoisomers thereof,
-[2-(t r ichloromethyl)pyr imidin-5-yl]-3,3-d imethylbu t a t o i acid and stereoisomers thereof,
2-[ 2-ch lo r opy r imid in-5-yl ]-3,3-d ime t hy Ibu t an o-. c acid cd stereoisomers thereof, and
2-[2-(1,1-dimethylethyl)pyr imidin-5-y1]-3,3dimethylbutanethioic acid and stereoisomers thereof.
It will be appreciated that the compounds of f ' 1 are capable of existing in different isomeric forms exhibiting differing levels of insecticidal and acaro'r activity, and as mixtures of such isomers. Thus op i isomerism arises from the presence of one or mote ;h.:: ? centres xeading to the possibility of o'. itoo.oo. .
diastereoisomers. In addition the possibility of geometrical isomerism arises where a compound accordi·.: the invention contains one or more substituted alkenyl groups. All such individual isomeric forms and mixtures
ΔΡ 0 0 0 0 5 7
BAD ORIGINAL thereof, including racemic mixtures are x j f h i r. the score o ' the invent ion .
Particular examples of compounds accordmc to the invention useful as acaricides and insecticides are those set out in Table I below and stereoisomers thereof. The compounds correspond to the formula (I) and the meanings or Rl, r2, R^, r4 and X are given for each compound. In Tabl·. I, R4 is defined as a group E-01 to E-32, the meanings of which are set out as follows:
E-01 = 3-phenoxybenzyl
Ξ-02 = 1-cyano-1-(3-phenoxyphenyl) methy1
E-03 = 2-methyl-3-phenylbenzyl
E-04 = 4-methyl-2,3,5,6-tetrafluorobenzyl
E-05 = 4-( pr op-2-en-l-y 1)-2,3 , 5,6 - te t r a f 1 uor obenz y
E-06 = N-3,4,5,6-tet rahydrophtha 1 i mid-.methyl
E-07 = 1-ethynyl-l-(3-phenoxyphenyl)methy1
E-08 = 5-benzylfur-3-ylmethyl
E-09 = 6-phenoxypyrid-2-ylmethyl
E-10 = 1-cyano-1-(6-phenoxypyrid-2-yl) methy1
E-ll = 1-(6-phenoxypyrid-2-yl )ethyl
E-12 = 4-(prop-2-yn-l-yl)-2,3,5,6-tetraf1uorobenzyL
Ξ-13 = 4-(but-2-yn-l-yl)-2,3,5,6-tetrafluorobenzyI
E-14 = 4-(3-chloroprop-2-en-l-yl)-2,3,5,6-tetraE-15
E-16
E-17
E-18
E-19
E-20
E-21
E-22 fluorobenzyl
4-(methoxymethyl)-2,3,5,6-tetrafluorobenzyl
2- methoxy-4-(methoxymethyl)-3,5,6-t r i fluorc benzyl
4-benzyl-2,3,5,6-tet rafluorobenzyl
3- benzyl-4-fluorobenzyl
4- [3-(trimethylsilyl)prop-2-yn-l-yll-2,3,5, tetrafluorobenzyl
4-(2-methylprop-2-en-l-yl)-2,3,5,6-tetrafluorobenzyl
4-ethoxy-2,3,5,6-tetrafluorobenzyl
4-trimethylsilyl-2,3,5,6-tetrafluorobenzyl
E-23
E-24
E-25 5 E-26
E-27
E-28
E-29
E-30
E-31 E-32 E-33
E-34
E-35
E-36
E-37
E-38
E-39
E-40
E-41
E-42
E-43
E-44
E-45
4-(but-2-en-l-y1)-2,3,5,6-tetrafluorobenzy1 4-(2-chloroprop-2-en-l-yl)-2,3,5,6-tetrafluorobenzyl
4-fluoro-3-phenoxybenzyl
2- chloro-6-fluorobenzyl
1-cyano-1-(3-benzyl-4-f1uoropheny1) me thy1
3- phenylaminobenzyl
4- (2,3-dichloroprop-2-en-l-y1)-2,3,5,6tetrafluorobenzyl pentafluorobenzyl
1-cyano-l-(4-fluoro-3-phenoxyphenyl) methy 1 2,2,2-trifluoro-l-(6-phenoxypyr id-2-yl)ethyl
2.3.5.6- tetrafluoro-4-[4chlorobenzyloxy)methyl]benzyl
2.3.5.6- tetrafluoro-4-(hydroxymethyl)benzyl
2.3.5.6- tetrafluoro-4-[((1, Ιό imethylethyl)oxycarbony1)methoxymethyl ] benzyl
2.3.5.6- tetrafluoro-4(acetyloxymethyl) benzyl
2.3.5.6- tetrafluor0-4-(chloromethyl)benzyl
2.3.5.6- tetrafluoro-4-(n-propyl) benzyl
2.3.5.6- tetrafluoro-4(methythiomethyl)benzyl
2.3.5.6- tetrafluoro-4(ethoxycarbonyl)benzyl
2.3.5.6- tetrafluor0-4-[(Ιώβ thy le thyl Joxycarbonyl]benzyl
2.3.5.6- tetrafluoro-4-[(2,2d imethylpropanoyl)oxymethyl]benzyl
2.3.5.6- tetrafluoro-4-[(2methylpropanoyl)oxymethyl]benzyl
2.3.5.6- tetrafluoro-4-[(1methylethyl)thiomethy1]benzyl
2.3.5.6- tetrafluoro-4-[(1,1AP 0 0 0 0 5 7
E-46 dLmethylethyl)thiomethyl]benzyl 2,3,5,6-tetrafluoro-4-(N,N-
E-47 diethylami nomethyl) benzyl 2,3,5,6-tetrafluoro-4-[(piperidin-l-
5 E-48 - y 1) methyl]benzyl 2,3,5,6-tetrafluoro-4-[(N-prop-2-
E-49 ylideneamino)oxymethyl]benzyl 2,3,5,6-tetrafluoro-4-
10 E-50 - (cyclopropylmethyl) benzyl 3-(4-chlorophenoxy) benzyl
E-51 = 1-[3-(4-chlorophenoxy)pyrid-2-yl]ethyl
E-52 = 3,5-difluoro-4-methyl-2-( methyithio)benzyl
E-53 = 2,3,5,6-tetrafluoro-4-(methylthio)benzyl
E-54 = 2,3,5,6-tetrafluoro-4-(ethylthio)benzyl
15 E-55 = 2-ethoxy-4-(methoxymethyl )-3,5,6-
E-56 — trifluorobenzyl 2,3,5,6-tetrafluoro-4-(ethoxymethyl)benzyl
E-57 2-methoxy-4-(ethoxymethy1)-3,5,6-
20 E-58 tri fluorobenzyl 2-ethoxy-4-(ethoxymethyl )-3,5,6-
E-59 = trifluorobenzyl 2,3,5,6-tetrafluoro-[(Ι-
E-60 — ώβ thy let hyl) oxymethyl]benzyl 2-methoxy-4-[(1-methylethyl)oxymethyl]-
25 E-61 — 3,5,6-tr i fluorobenzyl 2-ethoxy-4-[(1-methylethyl)oxymethyl)-3,5,6
E-62 - tri fluorobenzyl 2,3,5,6-tetrafluoro-4-(phenoxymethyl) benzyl
E-63 = 2-methoxy-4-(phenoxymethyl)-3,5,6-
30 E-64 — trifluorobenzyl 2-ethoxy-4-(phenoxymethyl)-3,5,6-
k E-65 tri fluorobenzyl 2,3,5,6-tetrafluoro-4-[(2,2-
35 E-66 d ichlorocyclopropyl) methyl]benzyl 2,5, 6-tr i‘f luoro-3-methoxy-4-
(methoxymethyl,benzyl
Ε-67 2,3,5,6-tetrafluoro-4-[3(triethylsilyl)prop-l-yl]benzyl
Ε-68 = 2-methyl-3,4,5,6-tetrafluorobenzyl
Ε-69 = 2,3,5,6-tetrafluoro-4-[(prop-2-yn-lyl) thiomethyl]benzyl
AP Ο Ο Ο Ο 5 7
TABLE I
COMPOUND NO R1 R2 R3 X 1 R4
1 (CH3)3C (CH3)3c H 0 E-01
2 (CH3)3c (ch3)3c H 0 E-02
3 (CH3)3C (ch3)3c H 0 £-03
4 (οη3,3ο (ch3)3 c H 0 E-04
5 (CH3)3C (ch3)3 c H 0 E-05
6 (CH3)3C (ch3)3 c H 0 E-06
7 (CH3)3c (ch3)3 c H 0 E-07
8 (ch3,3c (CH3)3C H 0 E-08
9 (CH3)3C (ch3)3c H 0 £-09
10 (CH3)3C (ch3i3c H 0 E-i')
LI (CH3)3C (CH3)3C H 0 £-1 i
12 \CH3)3C (CH3)3C H 0 5-12
13 (CH3)3C (CH3)3C H 0 5-13
14 (CH3)3C (CH3)3C H 0 E-14
15 (ch3)3c (ch3)3c H 0 E-15
16 (ch3)3c (ch3)3c H 0 Ξ-16
17 (CH3)3C (CH3)3c H 0 E-17
18 (CH3)3C (ch3)3c H 0 ' Ξ-18
19 (ch3)3c (ch3)3c H 0 Ξ-19
20 (ch3)3c (CH3)3c H 0 £-20
21 (CH3)3c (CH3)3C H 0 Ξ-21
22 (ch3)3 c (ch3)3c H 0 L ~
23 (cH3)3C (ch3)3c H 0 2L ~ z, _>
TABLE I CONTINLTT
AP 0 0 0 0 5 7
BAD ORIGINAL
- 16 TABLE I CONTINUED
COMPOUND NO R1 R2 R3 X R4
45 46 47 48 49 50 51 52 53 54 55 56 , 57 58 59 60 61 62 63 64 65 (ch3)3c (ch3)3c (ch3)3c (CH3)3C (ch3)3c (ch3)3 c (ch3)3c (Ch’3)3C (CH3)3C (CH3)3C (CH3)3c (ch3)3c (ch3)3c (CH3)3c (CH3)3c (CH3)3c (ch3)3c (ch3)3c (ch3)3c (CH3)3c (ch3)3c cf3 cf3 cf3 cf3 cf3 CF3 cf3 cf3 CH3CH2(CH3)2C ch3ch2(ch3)2c CH3CH2(CH3)2C ch3ch2(ch3)2c CH3CH2(CH3)2C ch3ch2(ch3)2c ch3ch2(ch3)2c ch3ch2(ch3)2c ch3ch2(ch3)2c ch3ch2(ch3)2c ch3ch2(ch3)2c CH3 CH2(CH3)2C CH3 CH2(CH3^2C H H H H H H H H H H H H H H H H H H H H H 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 E-20 E-23 E-24 E-25 E-26 E-29 E-30 E-31 E-04 E-05 E-09 E-10 Ε-Π E-12 E-13 E-14 E-15 E-16 E-17 E-18 E-20
AP 0 0 0 0 5 7
TABLE I CONTINUED
COMPOUND NO R1 R2 R3 X R4
66 (ch3)3c CH3CH2(CH3)2C H E-23
67 (CH3)3C ch3ch2(ch3)2c H c E-24
68 (ch3)3c CH3CH2(CH3)2C H 0 E-25
69 (CH3)3C ch3ch2(ch3)2c H e E-26
70 (ch3)3c ch3ch2<ch3)2c H L E-29
71 (CH3)3C CH3CH2(CH3)2C H 0 E-30
72 (CH3)3C CH3CH2(CH3)2C H 0 E-31
73 (CH3)3C (ch3)2ch H c E-Os
74 (ΟΗβ)3C (CH3)2CH K 0 E-ll
75 (CH3)3C (ch3)2ch H 0 E-12
76 (ch3)3c (CH3)2CH H 0 E-I h
77 (CH3)3C cyclopropyl H 0 E-02
78 (CH3)3c cyclopropyl H 0 E·-1 ·
79 (ch3)3c cyclopropyl H c £-12
80 (ch3)3c cyclopropyl H 0 E-16
81 (ch3)3 c phenyl H 0 E-02
82 (CH3)3 c phenyl El c E-ll·
83 iCH3)3C phenyl H o E-12
84 (CH3)3 c phenyl H 0 E-16
85 (CH3)2CH CF3 H 0 E-02
86 (ch3)2ch cf3 H 0 E-ll
- 18 TABLE I CONTINUED
1 C .«POUND NO 2? R2 1 ,?3 ·'< i -, *
87 (CH3)2CH cf3 H 0
88 ('-H 3 ) 2CH cf3 0 E- if,
89 cyclopropyl W3C H 0 0.
90 cyclopropyl (ch3)3c H 0 E- l
91 cyclopropyl (CH3)jC i 0 5-17
, 32 cyclopropyl (ch3)3c ;; 1,) E- L f,
i 93 cyclocropyl CF3 j-1 0 E-0z
| 94 cyclopropyl cf3 H 0 E-l 1
; 95 cyclopropyl CF3 H 0 :-1/
96 cyclopropyl cf3 ! ί 0 r -1 -
97 l-methvlcyclopropyl (ch3)3c h 1) - J
98 i-methylcyclopropyl <ch3)3c i. E -!. L
1 99 1-methylcyclopropyl (ch3)3c 0 E-l 1
100 1-methylcyclopropyl (ch3)3c 1 i 0 * — i <·>
101 1-methylcyclopropyl cf3 o 0 -'-o:
102 1-methylcyclopropyl cf3 H ϋ E-il·
103 1-methylcyclopropyl cf3 H 0 -h.
104 1-methylcyclopropyl CF3 H 0 E-lf-
105 ch3ch2ich3)2c (ch3)3c H 0 E-ij..
106 CH3CH2(CH3)2C (ch3)3c H 0 E-l 1
107 Cn3CH2(CH3)2C (ch3)3c H 0 2-22
APO 0 0 0 5 7
BAD ORIGINAL sin
TABLE I CONTINUE?
C 'HPOUND NO 1 eF R2 R3 ;< R4
1 1 108 C H J c η £ 0- Η T -> e (ch3)3c H c L _ · -
109 OH iCH-j (CH i) -C J 4. J 4- cf3 H 0 5
110 CH 3CH2 \ <-'H 3 ) < cf3 H 0 7,-.1 J.
ILL t ΟΗ3ΟΗ;(ΟΗ3)2Ο cf3 H c 2' _ i ?
112 CH (CH3 ) CF3 H 0 1-1.6
113 (CH3)2CH phenyl H 0 0-(''5
114 (CH3)2CH cf3 H 0 0-0 6
115 (CH3)2CH (CH3)2N H 0 E-OS
116 (CH3)22H CF3 H 0 E-JS
117 <ch3)2ch CCl 3 H c 5 -0 S
113 (-3,<h Cl H 0 E-15
119 (ch3)2ck ch3 H 0 0-0 5
120 (CH3)3j ch3 H c -.
121 ^2^5 (CH3)3C H 0 .0-7 1
122 C2H5 (CH3)3c H 0 L-
123 C2H5 (CH3)3C H h E-ut
124 cyclopropyl (ch3)3c H 0 0-05
125 cyclopropyl· (ch3)3c H 0 Ξ-25
126 (CH3)3c ch3 H 0 0-04
127 (ch3)3c ch3 H 0 0-05
128 <ch3>3~ ch3 H 0 E-50
129 (ch3) -.: (ch3)2ch H f 7.-7.:
i30 (OH3)32 (CH3)2CH H 0 — 'J J
>*BAD ORIGINAL fi.
TABLE I CONTINUED
C jM.EOL'tJD NO R1 R2 R3 X 1 i
131 (ch3)3c (ch3)2ch H 0 E-l
132 (1H3)3C (ch3)2ch H 0 L -)
133 (CH3)3c cyclopropyl K 0 - Q
134 (CH 3)3C cyclopropyl H 0 1-(.1
135 (ch3)3c cyclopropyl H 0 1 L J ~' J
136 (ch3)3c cyclopropyl H 0
137 (ch3)3c 1-methylcyclopropyl u 0
138 (ΟΗ3)3Ο 1-methylcyclopropyl H 0
L39 (CH3)3C 1-methyleye1op r opy1 H 0 1 „ 1
140 tCH3)3C 1-methylcyclopropy1 K 0
141 (7H3,3C CH3CH2(CH3)2C H 0
142 (ch3)3o ch3ch2(ch3)2c ?; ΰ
L43 (0H3)3c ch3ch2(ch3)2c -·
144 (ch3)3c ch3ch2(ch3)2c 0
145 (lH3)3C CC13 H 1 0
146 (CH3)3C CC13 H 0
147 (ch3)3c CC13 H 0 E-E
148 (CH3)3C CC13 H 0 E-l
149 (ch3)3c CC13 H 0 E-l
150 (CH3)3C CC13 H 0 :l-i
151 (ch3)3c CC13 H 0 I E-1
152 (‘ H 7 ) ,C Cl c: ,-, !
Lo3 Cl 1 !
AP 0 0 0 0 5 7
BAD ORIGINAL
TABLE I CONTINUE!
C1NP< jUND NO R1 R2 R3 A
154 <'-H3>3C Cl H 0
155 (-:h3)3c Cl H 0 E-
156 <'2Hj)3C Cl H 0 : ' -
157 Cl H :)
158 - -3)3c Cl H n
159 H.n3)3C phenyl H 0
160 (Ch3)3C phenyl H 0
161 (UH3)3C phenyl H A 1-
L62 <CH3)3c phenyl H ' -
163 (CK3)3C (ch3)3c H 0
164 (8H3)3C (ch3)3c H 0
165 <ca?3c (ch3)3) H 0
156 (ch3)3c (ch3)3) H 0 L-
167 (CH3)3C (CH3)3) H 0
168 (lh3)3c (ch3)3) H c
169 (ch3)3c (ch3)3) H 0
170 (CK3)jC (ch3)3) H 0 ,· - :
171 (ch3)3c (CH3)3) H 0 1
172 ( '-H-j ) 3'_ (ch3)3) H 0 ..-1
173 (ch3)3c (ch3)3) H 0 1-1
174 ( CK ) (ch3)3) H 0 1 ~ 4
175 (CLJ3C ich3)3) H 0
17 6 ( >ih3 / 3C (CHj)3) H '1
177 (ch3)3c (CH3)3) H c> 1-1
178 (ch3)3c (ch3)3) H 0 1-1
BAD ORIGINAL
TABLE I CONTINUE'.'
! COM'-lXJND NO N R2 1 1 1
1 i 179 (CH3)3C (ch3)3c H 0 _ J J
180 1 (CH 3)3C (ch3)3c H 0 Ξ-5'i
; i8L (Cf 13 ) 3 c <ch3)3c H o L' __ r- 1
i 182 1 (CH3)3 - (ch3)3c H ,Ί 5-r- '
±33 (CK3)3c (ch3)3c H 0
164 (CH3)3C (ch3)3c f! r\ ±-’±i
185 (ch3)3c (ch3)3c H ύ N - 5 3
165 fCH3l3C (CH3)3C H 0
137 (CH3)3C (ch3)3c H 0 -:-3:
133 (C!I3)3c (ch3)3c H 0 EL -J 2
139 (CK3)3c (ch3)3c ii 0 i- _ · J
190 (CH 3)3C (ch3)3c H 0 3-3'1
191 (CH3)3C (CH3)3C H 0 F- 3 J
192 (Cn3)3C (ch3)3c H 0 ή — h ..
193 (ch3)3c (CH3)3c H 0 1-63
194 (CH3)3c (CH3)3C H 0 Ξ—54
195 (ch3)3c (CH3)3c H s E-15
196 (ch3)3c (ch3)3c H 3 ,5-3-1
197 (CH3)3C (ch3)2ch H 0 5-2 5
193 (CH3)3C (ch3)2n H 0 E-l L
199 <ch3)3c (CH3)2N H 0 5-15
200 (CH3)3c (CH3)2N H 5-52
’ ; 11 «2 J X (crij ) 3 i- cyclopropyl H 0 5-,.
202 prop-l-en-2-yl (ch3)3c H 0 E-15
203 (ch3)3c 1-methylcyclopropyl H 0 5-1
204 (CH3)3C 1-methylcyclopropyl H 0 E-z5
BAD ORIGINAL $
TABLE I CONTINUED
COMPOUND NO R2 R3 X R‘:
205 (ck3)3c ch3 H 0 e-ι :
206 (CK3)3C ch3 H 0 E-23
207 (CH3)3c 1-methylcyclohexyl H 0 E-l ?
206 (CH3)3C 2-chlorophenyl H 0 E-15
209 (ch3)3c 2-chlorophenyl H 0 E-.5
210 ch3ch2(ch3)2c (CH3)3C H 0 E-15
211 (CH2=CH)(CH3)2C (ch3)3c H 0 E-15
212 ch2=chch2 (CH3)3C H 0 :--
213 ce3 (ch3)3c H 0 E-15
214 (CH3?2CH ch3 H 0 E-15
2i6 (CH3)3C (ch3)3c H 0 E-65
217 (ch3)3c (ch3)3c H 0 E-6 6
213 (CH3)3c (ch3)3c H G E-fe'
219 (ch3)3c (ch3)3c H 0 E-6 8
220 (ch3)3c (ch3)3c H 0 E-69
221 (ch3)3c (ch3)3c H 5 E-li
222 (ch3)3c (ch3)3c H s E—30
223 (ch3)3c <ch3)3c H r'· O E.—5 i
224 (CK3)3c (ch3)2ch H 0 E-56
225 (CH3)3C (ch3)2ch H 0 E-57
226 (CH3)3C (CH3)2CH H 0 E-5S
227 prop-l-en-2-yl (CH3)3C H 0 E-04
228 prcp-l-en-2-yl (CH3)3C H 0 i -: 5
229 prop-l-en-2-yl (ch3)3c H 0 E-12
230 prop-·; -en-2-yl (ch3)3c H 0 E-16
231 prop-l-en-2-yl (ch3)3c H 0 E-56
BAD ORIGINAL
- 24 TABLE I CONTINUE!
COMPOUND NO R1 R2 r3 1 I y ! * 1 . ; r/
232 prop-l-en-2-yl (ch3)3c H 0 E-57
233 prop-l-en-2-yl (CH3)3C H 0 E-53
234 (ch3)3c 1-methylcyclopropyl H 0 E-12
235 (ch3)3c 1-met hy1eyelop r opy1 H G E-16
236 (ch3)3c 1-met hy1eye1op r opy1 H o E-56
237 (ch3)3c 1-methylcyclopropyl H 0 E-5 ’
238 (ch3)3c 1-methylcyclopropyl H 0 Cj ~ ΰ '3
239 (CH3)3C ch3 H 0 E-12
240 (CH3)3c ch3ch2(ch3)2c H 0 E-56
241 (ch3)3c ch3ch2(ch3)2c H 0 E-57
242 (CK3,3C CH3CH2(CH3)2C H E-53
243 (CH3)3C cf3 H ' 0 E-39
244 (ch3)3c cf3 H 0 E-56
245 (ch3)3c cf3 H 0 --7 iu J
246 (ch3)3c cf3 H 0 E-58
247 (ch3)3 c 1-methylcyclohexyl H 0 E-05
248 (CH3)3C 1-methylcyclohexyl H 0 E-ll
249 (ch3)3c 1-me t hy1eye1ohexy1 H 0 E-12
250 (CH3)3c 1-me t hy1eye1ohexy1 H 0 E-16
251 (ch3)3c 1-methylcyclohexyl H 0 E-27
252 (CH3)3c 1-methylcyclohexyl H 0 E-31
253 (ch3)3c 1-methylcyclohexyl Li 0 E-56
254 (ch3)3c 1-methylcyclohexyl - c, E-5 7
255 (ch3)3c 1-methylcyclohexyl H 0 E-58
APO00057
Bad
- 25 TABLE I CONTINUED
R1 R2 FJ X
CHjCH2(CH3)2C (CH3)3c H 0
CH3CH2(CH3)2C (ch3)3 c H .0 2-11
CH3CH2(CH3)2C (CH3)3c H c -: - ' 5
LH 3CH2(Ch^)2C (CH3)3C K 0 2- ; 6
CH3CH2(CH3)2C (ch3)3c H 0 - -2
(CH2=CH)(CH3)2C (ch3)3c K 0' 2- i J
(CH2=CH)(CH3)2C (ch3)3c H 0 _ __ c;
(cu2=ch)(ch3)2c (ch3)3 c H 0
(CH2=CH)(CH3)2C (ch3)3c H 0 ' “ -
(ch2=ch)(ch3)2c (ch3)3c H 0 4
(CK2=CH)(CH3)2C (ch3)3c H 0 -
(CH2=CH)(CK3)2C (CH3)3C l; η
(CH2=CH)(ch3)2c (ch3)3c H 0
(CH2=CH)(ch3)2c <ch3)3c H r
(CH2=CH)(CH3)2C (ch3)3c H c ' - <
(CH2=CH)(CH3)2C (ch3)3c ;; 0 . -'4
(CH2=CH)(CH3)2C (CH3)3c H 0 rl- :9
(CH2=CH)(CH3)2C (CH3)3C H ϋ ·· - ’ G
(CH2=CH)(CH3)2C (ch3)3c H b -
(CH2=CH)(CH3)2C (ch3)3c H 0 2 --' 6
(ch2=ch)(ch3)2c (ch3)3c H 0 2--' β
1-methylcyclopropyl (ch3)3c H (1
W')(ch3)22 (2H3)3c 'r-> 0
(CH2F)(CH3)2C (CH3)3C H 0 12 „ '
bad original
TABLE I CONTINUED
C .('POUND NO rl R2 r- ( i 1 V 1
230 (ch2f)(ch3)2c (ch3)3c 4 1 4
;.3i ί ΟΗηΕ) 1, OH 3) 2<2 (ch3)3c ί i
232 i 2H O' ,( CH3)2C (ch3)3 c 1 i It I 1 . , i i
.3 3 (,'K2F)(CHj)2C (CH3)3C H : i
.,34 i/2H2F) ( OH3)2C (ch3)3c H )
23 5 (OH3)32 (CH2F)(CH3)2C ο j π
.236 ('-H3) 3C (CH2F)(CH3)2C H J1
237 (ch3)3o (ch2f)(ch3)2c ’.J
233 (UH3)3C (CH2F)(CH3)2C H
239 <CH3)3C (CH2F)(CH3)2C 4 j
2 30 (,-h3)3c (ch2f)(ch3)2c ri '!
2)1 ( UH3 ) (CH2F)(CH3)2C ί 1 < 1 ί 1
r** ir>
o
O.
<
bad ORIGINAL $
The insecticidally and acaricid a 11y active cc-mcou· of the invention according to formula (I) wnere’t is oxygen are esters, and may be prepared from ’he corresponding alkyl esters, acids and acid rclondes o. conventional esterification processes, such as those described in (a) to (d) below, by way of example.
(a) An acid of formula ( II) :-
where Q represents the hydroxy group and R3, R2 ano rhave any of the meanings given hereinabove, may be reacted directly with an alcohol of formula R^-OH (III) where R^ has any of the meanings given hereinabove, the reaction preferably taking place in the presence of an acid catalyst, for example, dry hydrogen chloride, or a dehydrating agent, such as fci example, dicyclohexylcarbodiimide or N-ethyl-N-(3dimethylaminopropyl)carbodiimide , the latter beino particularly suitable in those cases where R3 represents Jt-butyl;
(b) An acid halide of formula (II) where Q represents a halogen atom, preferably a chlorine atom, and R3, Rz and R3 have any of the meanings given hereinabove, ma/ be reacted with an alcohol of formula (III), the reaction preferably taking place i the presence e: .base, for example, pyridine, alkali metal hydroxide or carbonate, or alkali metal alkoxide.
ba° (c) An acid of formula (II) where Q regies·-nt · ere h; : χ group or, preferably, an alkali met a 5 -J ‘-her·.- .1 , may be reacted with either (i) a hal id·.· ot iurmud; Q'-R4 (IV) wherein Q' represents a halogen atom, preferably the chlorine atom, or with a cruternary ammonium salt derived by reaction of such a halide with a tertiary amine, for example pyridine or trialkylamines such as t r iet hyl ami ne , or i,i) with compound of formula Q'-R4 wherein Q' represents U mesylate or tosylate group, and R4 has any of the meanings given hereinabove.
(d) A lower alkyl ester of formula (II) where Q represent a lower alkoxy group containing up to six carbon atoms, preferably the methoxy or ethoxy group, and F1,
R and RJ have any of the meanings given hereinabove, is heated with an alcohol of formula (III) to effec* transesterification reaction. Preferably the process is performed in the presence of a suitable catalyst, for example, an alkali metal alkoxide, su;.; as sodium methoxide, or an alkylated titanium derivative, such as tetramethyl titanate or tetraethyl titanate.
All of these conventional processes for the preparation of esters may be carried out using solvents ?-c diluents for the various reactants where appropriate, may be accelerated or lead to higher yields of producu .,u performed at elevated temperatures or in the presence o· appropriate catalysts, for example phase-transfer catalysts .
Similarly the interconversion of the acid, arid j cnloride and lower alkyl esters of fornul.t li ·..·/ performed using conventional chemical procedures for chlorination, esterification and hydrolysis.
The compounds of formula (I) wherein X is sulphur aie thioesters and may be prepared by conventional
AP0 0 0 0 5 7
BAD ORIGINAL : i f Leaf lon processes. Pa analogous to those desericed ia) and (b) above, wherein a thioal? 1H is used in place of the alcohol o. Λ namber of the preferred compound.
η. -J - .
_ . 1 7-1 r o riio j accor-i:
invention are derivatives of esters of i he for mu i a i
R3 0 F
N II \ \ /'
3— CH - C — X - CH - __ \
N --/ I ξ — /
R1 ( IA) / / F -
/,me rem , R“, R3 and X have any c1 : i O': a u \ η n 3 ' i
nereinee f : re , and may be convenient!.- · c.OOol ·
con rentiona l· alkylation, acylation eno .. 11 cC' 1
'J ' t ' eiesse?, rattier than by initial· rival! ;ed alcohol. Further detai scribed m the Examples given her· formula ( LA) are therefore usefu j compounds according tor the synthesis of id. 5 invention, the alcohols Of forma or ’ e p a red by Thus, -or a n'! a i < r i, o > o a
i. 0. e r mr' <' 1 a f e s according to f·’ a r; 7 O f oi formula pZ-bLI are well known in be prepared by methods described th Losely analogous p·.· xample, the prep' ‘
·.·... -;f' '·:!, on rvl alcohols, alkenyl· alcohols , benzyl-tetrafluorobenzyl tefrafluorobenzyl alcohols, alkylth alcohols and analogues thereof is d Patent Application No 31199; the pr<
.co
- f ? c t : a i on halomethy1-tetrafluorobenzyl alcohols is described m ue Patent No 2153819 ; the preparation of ai-;ynyltetrafluorobenzyl alcohols is described m European - a · r Application No 196156;·the preparation of phenoxya 115 tetraf luorobenzyl alcohols, alkoxyalky 1-tet raf 1 uoro-be;.- / : alcohols, and dialkylaminoalkyl-tetrafluorobenzyl aicor,.>l· is described in European Patent Application No 54360; the preparation of alkoxy-alkoxyalkyl-trifluorobenzyl alcoholis described in UK Patent Application No 2197317; the preparation of 2,6-dihalobenzyl alcohols is described in
European Patent Application No 57795; the preoaration of ' f luoro-3-benzylbenzyl alcohols is described in t'K Patent Application No 2193959 ; the preparation of 2,2 . 2-tr i flucr o
1- (6-phenoxypyrid-2-yl) ethanol is described in European:
Patent Application No 223,521; the preparation of other fluorinated benzylalcohols is described in UK Patent Application No 8726875; the preparation of (6-phenoxypyrιn
2- yl) methanols and substituted derivatives is described i: US Patent No 4,256, 893 and European Patent Application N.·
112,293, 145,661 and 145,179.
Further examples of the preparation of alcohols a · f as intermediates in the preparation of the compounds : formula (I) are given in the Examples hereinafter.
The preparation of individual isomers of fn> n ;
of formula (I) may be carried out in the same manner no described above but commencing from the corresponding individual isomers of compounds of formula If. These ~ be obtained by conventional isomer separation technics' from mixtures of isomers. Thus the various optically active species may be obtained by fractional crystallisation of salts of the acids with optically ac : amines, for example ( + )- or ( - )-alpha-me t .nyiber.ry 1 am :. . followed by regeneration of the optically pure acid. Tne optically pure isomeric form of the acid (or its equivalen* acid chloride or ester) may then be reacted with the
AP 0 0 0 0 5 7 bad original appropriate alcohol to produce a compound ol formul : ; >
the form of an individually pure isomer thereof. wn·.-';·· specific isomer is required, there exists the possib,::·/ that the residual isomer or isomer mixture rna · ,e epimerised and recycled for further isolation of the required form, thereby improving the overall yield of the requ i red isomer .
Where the compounds of Formula (I) are forned as mixtures of diastereoisomers, racemic isomer pairs can be separated by eg, h.p.l.c techniques, or, where the phyo’c·. properties of the compounds are suitable, by selective crystallisation.
The acids, acid halides and esters of formula (II) ma themselves be prepared by a number of alternative process.
The choice of process depends on the stability of individual substituents under the various reaction conditions employed in the process.
A first process, suitable for the preparation of intermediates of formula (II) wherein Q represents a h».·?· alkoxy group of formula -OR containing up to · caroou and R^ represents a primary or secondary alkyl group, provides the compounds of formula II by alkylation co compound of formula (V)
wherein R represents a lower alkyl group contain!?;
to 6 carbon atoms for example using a prim,ary jt set . .
alkyl halide of formula R^-Hal, wherein Hal represen' halogen atom, in the presence of a base such as lith; ; hexamethyldisi ly lazide . The compounds of formula (Vi
BAD
wherein R3 represents a halogen atom may be prepared by reaction of the appropriate amidine or guanid.re with a dialkyl ester of 1-formylsuccinic acid, followed by conversion of the 4-hydroxy substituent on the pyrimidine ring to halogen by standard halogenation methods, for example using phosphorus oxychloride or phosphorous oxybromide. The compounds of formula (V) where R3 represents hydrogen or fluorine may be prepared from the corresponding compounds wherein R3 represents chlorine by reduction or reaction with a fluorinating agent, such as potassium fluoride. Examples of these processes are summarised in Schemes I and II
SCHEME I
CH2-c02R ch2-co2r
NaOR hco2r ohc-ch-co2r ch2-co2r
NH
RZ--C-NH2 . HC1
AP 0 0 0 0 5 7
I NaOR
BAD ORIGINAL
N —
Reduce (eg, Zn/NH^OH)
A second process suitable for the preparation of intermediates of formula (II), where Q represents a low·-: alkoxy group of formula -OR containing up to 6 carbon atom and represents hydrogen, is of general applicability with reference to the groups R1 and R2. In this procen : ·, acetal of formula (R'0)2CH-CH2-CH(R1)-CO2R, (X) wherein A' and R both represent lower alkyl containing up co 6 carbn atoms, if reacted with phosphorus oxychloride ind a formamide selected from a dialkyl formamide wherein each alkyl group contains from 1 to 4 carbon atoms for exempli dimethylformamide), N-formylpiperidine and Nformylpyrollidine to give either a 4-alkoxy or a 4dialkylamino substituted 3-formylbut-3-enoic ester of
formula (VI) or a mixture thereof, depending on the reaction conditions:
R1
I
OHC CH-C02R \ / c
II
CHR5 (VI) where R5 represents alkoxy containing 1 to 6 carbon atoms, dialkylamino wherein each alkyl group contains 1 to 4 carbon atoms, piperidin-l-yl or pyrol1idin-l-yl, and R1 and R are as described hereinbefore. Reaction of the compounds of formula (VI) with a compound of formula R2-C;NH2)=NH, or a salt thereof, wherein R2 has any of the meanings given hereinbefore, optionally in-the presence of a base, produces the intermediates of formula (II) wherein R5 is hydrogen and Q represents a lower alkoxy group of formula OR containing up to 6 carbon atoms. These processes, and a general process for the derivation of the acetals of formula (X) are illustrated by way of example in Scheme
III. An alternative process for the preparation of appropriately substituted acetals of formula (X) wherein Rx may have any of the meanings described before other than alkenyl, alkynyl and haloalkenyl is described in Scheme IIIA for the particular case where R^ is Jt-but/l. This process gives higher yields than that described in Scheme III when R^ represents a tertiary alkyl substitutent, for • example t.-butyl or t.-pentyl.
AP ο ο η n a 7
SCHEME III ch-co2r co2r
BrCH2CH(0R')2 (R10)2CH-CH2-C-C02R NaH/DMF C02R ch3cook h2o/dmso
R1 POC13 , 4-2
OHC-C-CH-CO-,R dmf
CHR3 (VI)
R1
I (r'o)2ch-ch2-ch-co2r (X)
SCHEME I IΙΑ (CH3)3C-CH2C02C2H5 (i) LDA (ii) CH2=CHCH2Br c(ch3)3
HC(0C2H5)3/H+ I ch2=ch-ch2-ch-co2 ( i ) o3 ( i i ) PPh3 v C(CH3)3 (c2H50)2ch-ch2-ch-co2c2h5 h-c-ch2-ch-co2c2h5
Key: LDA = Lithium di-isopropylamide
-Two further processes for preparing alkyl esters and acids of formula II where R3 is hydrogen and R‘ is a tertiary alkyl group are illustrated by way of example on! in Scheme IV and V, for the case where both R1 and R2 represent t-butyl.
AP 0 0 0 0 5 7
SCHEME IV
N_ ( i )' M
N (CH J 3
-> (CH (ii) C02C2H5 c02c2h5
(ch3)3c
N
N
C(CH3)3
I
Cl } 3
C— C-C02C2Hc
(C4H9)3SnH
AIBN
N / \’ N (CH3)3C-<
C(CH3)3 ch-co2c2h5
Key: AIBN = qG JL'-azoisobutyronitrile.
SCHEME V (ch3)3c
Br ( i ) Mg (ii) (CH3)3CCHO
M (CH3)3c -//
N
CH-OH (ch3
N
C(CH3)3 ch-conh2 h2so4/h2o (i) Mesyl chloride/ pyridine (ii) NaCN v
N C(CH3)3 (CH3)3C-'\-CH-CN
NaN02/TFA
N (ch3
C(CH3)3 ch-co2h
AP 0 0 0 0 5 7
Key: Mesyl chloride = CH3SO2C1
TFA = Trifluoroacetic acid >» 39
The intermediates of formula (II) where Q represent: lower alkoxy group of formula OR, R2 represent; .tydro-j-.-r. and R1 represents a haloalkyl group may not be readily accessible by the processes described hereinbefore owing tc competing reactions at the haloalkyl group unde- certain of the reaction conditions employed. A process by which these compounds may be obtained is illustrated in Scheme VI, byway of example, for the case where R2 is trifluoromethy1.
Br i ) Mg
CF·
R2 —\ CH-C02CH3 (i) ROH/Base eg CH30H/K0H ii) CF3C0N(CH3)2
(ii) H+/H20
C=CC1-,
Key: ROH represents a lower alkanol containing from 1 to 4 carbon atoms
The choice of synthetic route used for the preparation of the intermediates of formula (II) wherein Q represents alkoxy or hydroxy will depend on the particular values of R-'·, R2 and R2 in the desired product.
The processes illustrated in Schemes I to VI provide a range of methods for which a choice may be made by one with normal skill in the art having regard to the nature an·: reactivity of the substitutents concerned. In some specific cases, variation of the conditions or reagents, or selection of a specifically appropriate synthetic route may
BAD ORIG»NAL be required to suit particular circumstances.
One such case is illustrated in Scheme VII, wherein «· represents 1,l-dimethylprop-2-en-l-yl, a sterically hindered alkenyl group'unsuitable for introduction by the methods described hereinbefore. A second case is illustrated in Scheme VIII for the preparation of compound? of formula (I) wherein R1 represents prop-l-er.-2-yl.
SCHEME VII
APO 0 0 0 5 7
Key: DCC = dicyclohexyl carbodiimide
SCHEME VIII
(CH3)2CH-PPh3 I “ -►
C-C02C2H5 n-BuLi R
C(CK3, // co2c2H (l) Na0H/H20 (ii) H+/H,0
N
2^/ V ^c(ch3)2 R
4r c 4co2r4 dcc
r //C(CH3)2 co2h (IX)
LHMDS
CH•C — CH:
CH
COoR*
Key; n-BuLi = £-butyllithum
DCC = dichclohexylcarbodiimide LHMDS - Lithium hexamethyldisilazide
BAD ORIGINAL
Further details of the processes described acove may be found in the Examples hereinafter.
Many of the intermediates used in the processes described hereinabove are believed to be novel.
Accordingly in further aspects, the invention provides a compound of formula (II):
(II)
9 Ί wherein Rx, R and RJ have any of the meanings given above and Q represents hydroxy, lower alkoxy containing from 1 to 6 carbon atoms or halogen; a compound of formula (VI):
APO00057 ohc-c-ch-co2r
II
CH (VI) where has any of the meanings given above, R represent; lower alkyl containing from 1 to 6 carbon atoms, and F3 represents alkoxy containing 1 to 6 carbon anors, diaikylamino wherein each alkyl group contains 1 to 4 carbon atoms, piperidin-l-yl or pyrollidin-l-yl; a compound of formula (VII):
BAD ORIGINAL
Ο
(VII ) wherein R2 has any of the meanings given hereinbefore; a compound of formula (VIII)
(VIII) wherein R2 has any of the meanings given herein befor· and a compound of formula (IX)
^c(ch3)2
COnR (IX) wherein R2, R3, and R^ have any of the meanings given hereinbefore. The compounds of formula (IX) have also c-e: shown to exhibit insecticidal and acaricidal activity.
The compounds of formula (I) may be used to comout . and control infestations of insect and acarine pests. The insect and acarine pests which may be combated and
BAD ORIGINAL controlled by the use of the invention compounds include those pests associated with agriculture (which term includes the growing of crops for food and fibre products, horticulture and animal husbandry), forestry, the storage of products of vegetable origin, such as fruit . grain and timber, and also those pests associated with the transmission of diseases of man and animals.
In order to apply the compounds to the locus of the pest’s they are usually formulated into compositions which include in addition to the insecticidally active ingredient or ingredients of formula (I) suitable inert ciluent or carrier materials, and/or surface active agents.
The compounds of the invention may be the sole active ingredient of the composition or they may be admixed with one or more additional active ingredients such as insecticides, insecticide synergist, herbicides, fungicides or plant growth regulators where appropriate.
Suitable additional active ingredients for inclusion in admixture with the compounds of the invention may be compounds which will broaden the spectrum of activity of the compounds of the invention or increase their persistence in the location of the pest. They may synergise the activity of the compounds of the invention o: complement the activity for example by increasing the speed of effect, improving knockdown or overcoming repellency.
Additionally multi-component mixtures of this type may help to overcome or prevent the development of resistance to individual components.
The particular insecticide, herbicide or fungicide included in the mixture will depend upon its intended utility and the type of complementary action required. Examples of suitable insecticides include the following:
AP 0 0 0 0 5 7
(a) Pyrethroids such as permethrin, esfenvalerate, deltamethrin, cyhalOthrin, biphenthrin, j
1.
i i Z fenpropathrin, cyfluthrin, tefluthrin, fish safe pyrethroids for example ethofenprox, natural pyrethrins, tetramethrin, s-bioallethrin, fenfluthrm, prallethrin and 5 ^-benzyl-3-f u r y 1 me t hy 1 - ( E ) - (1R, 3S ) 5 2,2-dimethyl-3-(2-oxothiolan-3-y1idenemethyl) cyclopropane carboxylate;
(b) Organophosphates such as profenofos, sulprofos, dichlorvos, methyl parathion, azinphos-methyl, demeton-s-methyl, heptenophos, thiometon, fenamiphos, monocrotophos, profenophos, triazophos, methamidophos, dimethoate, phosphamidon, malathion, chlorpyrifos , phosalone, fensulfothion, fonofos, phorate, phoxim, pyrimiphos-methyl, fenitrothion and diazinon;
(c) Carbamates (including aryl carbamates) such as pirimicarb, cloethocarb, carbofuran, ethiofencarb, aldicarb, thiofurox, carbosulfan, bendiocarb, fenobucarb, propoxur and oxamyl;
(d) Benzoyl ureas such as triflumuron, chlorof 1uazjron :
(e) Organic tin compounds such as cyhexatin, fenbutatin oxide, azocyclotin;
(f) Macrolides such as avermectins or milbemycins, for example such as abamectin, avermectin, and milbemycin;
(g) Hormones and synthetic mimics thereof such as juveni hormone, juvabione, ecdysones, methoprene and hydroprene.
(h) Pheromones.
BAD
(i) Organochlorine compounds such as benzene hexacnloride, DDT, chlordane or dieldrin.
In addition to the'ma jor chemical classes of insecticide listed above, other insecticides having particular targets may be employed in the mixture if appropriate for the intended utility of the mixture. For instance selective insecticides for particular crops, for example stemborer specific insecticides for use in rice such as cartap or buprofezin, can be employed.
Alternatively insecticides or acaricides specific for particular insect species/stages for example ovolarvicides such as clofentezine, amitraz, chlordimeform, flubenzimine, hexythiazox and tetradifon, motilicides such as dicofol cr propargite, adulticides such as bromopropylate, chlorobenzilate, or insect growth regulators such as hydramethylon, cyromazine, methoprene, chlorofluazuron and diflubenzuron may also be included in the compositions.
Examples of suitable insecticide synergists for use in the compositions include piperonyl butoxide, sesamex, and dodecyl imidazole.
Suitable herbicides, fungicides and plant growth regulators for inclusion in the compositions will depend upon the intended target and the effect required. An example of a rice selective herbicide which can be included is propanil, an example of a plant growth regulator for use in cotton is Pix, and examples of fungicides for use in rice include blasticides such as blasticidin-S. The choice of other ingredients to be used in mixture with the active ingredient will often be within the normal skill of the formulator, and will be made from known alternatives depending upon the total effect to ce . achieved.
The ratio of the compound of the invention to any other active ingredient in the composition will depend
APO 00 0 5 7 »1 upon a number of factors including the type of insect pests to be controlled, and the effects requipe: from the mixture. However in general, the additional active ingredient of the composition will be applied at about the rate it would usually be employed if used on its own, or at a lower rate if synergism occurs.
The compositions may be in the form of dusting powders wherein the active ingredient is mixed with a solid diluent or carrier, for example kaolin, .bentonite, kieselguhr, or talc, or they may be in the form of granules, wherein the active ingredient is absorbed in a porous granular material, for example pumice.
Alternatively the compositions may be in 'the form of liquid preparations to be used as dips, sprays or aerosols. Dips and sprays are generally aqueous dispersions or emulsions of the active ingredient in the presence of one or more known wetting agents, dispersing agents or emulsifying agents (surface active agents). Aerosol compositions may contain the active ingredient or ingredients, a propellant and an inert diluent, for example odourless kerosene or alkylated benzenes. In a preferred form, aerosol compositions may contain from 0.005% to 4% of active ingredient or ingredients, the remainder of the composition comprising a solvent, selected from odourless kerosine and alkylated benzenes, and a propellant. Aerosol compositions may optionally incorporate other additives, for example perfumes or corrosion inhibitors.
Wetting agents, dispersing agents and emulsifying agents may be of the cationic, anionic or non-ionic type. Suitable agents of the cationic type include, for example, quaternary ammonium compounds, for example cetyltrimethyl ammonium bromide. Suitable agents of the aniuitc type . include, for example, soaps, salts of aliphatic monoesters or sulphuric acid, for example sodium lauryl sulphate, bad OtW3|NW-
salts of sulphonated aromatic compounds, for example sodium dodecylbenzenesulphonate, sodium, calcium or ammonium 1ignosulphonate, or butylnaphthalene sulphonate, and a mixture of the sodium salts of diisopropyl- and triisopropylnaphthalene sulphonates. Suitable agents of the non-ionic type include, for example, the condensation products of ethylene oxide with fatty alcohols such as oleyl alcohol or cetyl alcohol, or with alkyl phenols such as octyl phenol, nonyl phenol and octyl cresol. Other non10 ionic agents are the partial esters derived from long chain fatty acids and hexitol anhydrides, the condensation products of the said partial esters with ethylene oxide, and the lecithins.
The compositions may be prepared by dissolving the active ingredient in a suitable solvent, for example, a ketonic solvent such as diacetone alcohol, or an aromatic solvent such as trimethylbenzene and optionally adding the mixture so obtained to water which may contain one or more known wetting, dispersing or emulsifying agents.
Other suitable organic solvents are dimethyl formamide, ethylene dichloride, isopropyl alcohol, propylene glycol and other glycols, diacetone alcohol, toluene, kerosene, white oil, methylnaphthalene, xylenes and trichloroethylene, N-methyl-2-pyrrolidone and tetrahydrofurfuryl alcohol (THFA).
The compositions which are to be used in the form of aqueous dispersions or emulsions are generally supplied in the form of a concentrate containing a high proportion of the active ingredient or ingredients, the said concentrate to be diluted with water before use. These concentrates are often required to withstand storage for prolonged periods and after such storage, to be capable of dilution . with water to form aqueous preparations which remain homogenous for a sufficient time to enable them to be applied by conventional spray equipment. The concentrates
APO00057 may contain 1-99% by weight of the active ingredient or ingredients. When diluted to form aqueous preparations such preparations may contain varying amounts of the active ingredient depending upon the purpose for which they are to be used. For agricultural or horticultural purposes, an aqueous preparation containing between 0.0001% and 0.1% by weight of the active ingredient is particularly useful.
In use the compositions are applied to the pests, to 10 the locus of the pests, to the habitat of the pests, or to growing plants liable to infestation by the pests, by any of the known means of applying pesticidal compositions, for example, by dusting or spraying.
The compounds of formula (I) and compositions 15 comprising them are very toxic to wide varieties of insect, acarine and other invertebrate pests, including, for example, the following:
Myzus persicae (aphids)
Aphis qossypi i (aphids)
Aphis fabae (aphids)
Meqoura viceae (aphids)
Aedes aeqypt i (mosqu i t os)
Anopheles spp. (mosquitos)
Culex spp. (mosquitos)
Dysdercus fasciatus (capsids)
Musca domestica (houseflies)
Pieris brassicae (white butterfly, larvae)
Plutella maculipennis (diamond back moth, larvae)
Phaedon cochleariae (mustard beetle)
Aonidiella spp. (scale insects)
Tr ialeuroides spp. (white flies) * Bemisia tabaci (white flies)
Blattella qermanica (cockroaches)
Periplaneta americana (cockroaches)
SP000057
Blatta or ientali s (cockroaches)
Spodoptera 1i t toralis (cotton leaf worm) Hellothis v i rescens (tobacco budworms)
Chor tlocetes termini fer a (locusts)
Diabrot ica spp. (rootworms)
Agrotis spp. (cutworms)
Chilo partellus (maize stem borers)
N1laparvata luqens (plant hoppers)
Nephotettix cinct iceps (leaf hoppers)
Panonychus ulmi (European red mite)
Panonychus citri (citrus red mite)
Tet ranychus urt icae (two-spotted spider mite) Tetranychus cinnabarinus (carmine spider mite) Phyllocoptruta oleivora (citrus rust mite)
Polyphaqotarsonemus latus (broad mite)
Brevipalpus spp. (mites)
Many of the compounds of formula (I) have shown especially high levels of activity towards tetranychid mites, such as Tet ranychus species (for Example Tetranychus urt icae) and Panonychus species (for Example Panonychus ulmi), in a variety of laboratory test systems. In particular, the compounds show high levels of activity against the egg stage as well as all older life stages of such mites. This strong acaricidal action has also been observed in field trials.
All of the compounds which have been tested have shown no cross-resistance to lambda-cyhalothrin or bifenthrin in a strain of Panonychus ulmi tolerant to lambda-cyhalothrin and bifenthrin.
The compounds of formula (I) may also be useful in combating insect and acarine pests which infest domestic • animals, such as Lucilia sericata, and ixodid ticks such as Boophilus spp., Ixodes spp., Amblyomma spp., Rhipicephalus spp. and Dermocentor spp. They are effective in combating both susceptible and resistant strains of these pests in their adult, larval and intermediate stages of growth, and may be applied to the infested host animal by topical, oral or parenteral administration.
The following Examples illustrate various aspects of this invention. In the preparation Examples the products were usually identified and characterised by means of nuclear magnetic reasonance spectroscopy and infra red spectroscopy. In each case where a product is specifically named its spectral characteristics are consistent with the assigned structure. Except where stated otherwise, exemplified compounds having one or more asymmetrically substituted carbon atoms were prepared in racemic form.
In the Examples, Gas Liquid Chromatography (GLC) retention times were determined on a Hewlett Packard 5890
Gas Chromatograph, using a Chromopak, C.P. Sil 5 C.B column of 12.5 m length and 0.2 mm internal diameter. Unless otherwise staged, the injection temperature was 100°C, and a temperature gradient of 15°C/minute employed, up to a maximum temperature of 280°C, maintained for 4 minutes.
The carrier gas was helium at a column head pressure maintained at 11 pis. Alternative injection and maximum temperature are indicated in the Examples where appropriate.
^H Nuclear Magnetic Resonance (NMR) spectrometry was performed at a frequency of 270 MHz on a Jeol FX 270 NMR spectrometer, unless otherwise indicated. 90 MHz, 60 MHz, 250 MHz and 400 MHz 1H NMR spectrometry were performed using Jeol FX 90 Q, Brucker WH90, Jeol PMX 60 SI, Brucker
WM250, and Jeol GX 400 spectrometers.
nmr spectrometry was performed on a Jeol FX90Q spectrometer at a frequency of 84.25 MHz. All NMR shift , values (S) are quoted in ppm relative to a standard (TMS or
CFClq)· In the NMR data, the following abbreviations are
ΛΡο oon«>7 used:- s= singlet, d=doublet, t=triplet, q=quartet, dd=double doublet, m=multiplet, b=broad.
Molecular Ion (M+) peaks were determined or. one of three mass spectrometers: Jeol DX 303, Kratos MS80 or Hewlett Packard HP 5992.
EXAMPLE 1
The Example illustrates the preparation of 2,Σόι methyl prop ionamidine hydrochloride.
Dry hydrogen chloride gas (ca 59 g) was passed through a solution of 2-cyano-2-methylpropane (86 g) in ethanol (60 cm2 at 0°C. The solution was kept for 60 hours at the ambient temperature (ca. 20°C), then diluted with diethyl ether (1000 cm2 and the precipitated l-ethoxy-l-imino-2,2dimethylpropane hydrochloride collected by filtration, washed on the filter with diethyl ether and dried. This precipitate was then slurried with ethanol (150 cm2 and gaseous ammonia passed into the mixture at the ambient temperature until the solid was completely dissolved.
The mixture was kept at the ambient temperature for 40 hours, diluted with diethyl ether (500 cm2) and the solid precipitate collected by filtration and dried to yield 2,2dimethylpropionamidine hydrochloride (25.75 g), melting point 192-194°C. A second crop (50.29 g) was obtained by evaporation of the filtrate.
Infra red (paraffin mull): 3300, 3100, 1680, 1520
1230, 995, 980 cm-1
EXAMPLE 2
By a procedure similar to that described in Example 1, the following compounds were prepared from the appropriate starting nitriles. In each case below, the incubation time with hydrogen chloride (to produce the intermediate iminoether) and subsequent incubation time with ammonia (to produce the amidine) are noted where they differ from those recorded in Example 1.
(i) 2-Methylpropionamidine hydrochloride from 2methylprop ionitrile
Hydrogen chloride reaction time: 18 hours (initial warming to 30°C required to initiate reaction)
Ammonia reaction time: 48 hours.
Infra red (paraffin mull): 3300, 3100, 1680 , 1520 cm-3· (ii) Cyclopropanecarboxamidine hydrochloride from cyclopropanecarbonitrile.
Hydrogen chloride reaction time: 6 days
Ammonia reaction time: 16 hours
Melting point: 55-58°C 1H NMR (CDC13) : 0.85 (m); 1.2 (m); 1.7 (m)
20« Infra red (paraffin mull) : 3400, 3200, 1650, 1460,
1380, 1310, 1150, 1040,
940 cm3-
LS 0 0 0 OdV (iii) 2,2-Dimethylbutyramidine hydrochloride from 2,2dimethyibutyronitrile.
Melting point 1 28-1 29 °C
Infra red (paraffin mull): 3350-2630, 1670, 1510, 1460,
1380, 1300, 1210, 1085 cm-1 (iv) 1-Methyicyclopropanecarboxamidine hydrochloride from 1-methylcyclopropanecarbonitr ile.
Hydrogen chloride reaction time: 1 hour
Ammonia reaction time: 48 hours 1H NMR (CDC13) : 0.84 (m, 2H); 1.16 (m, 2H); 1.26 (s,
3H); 8.40-9.00 (broad, 3H)
Infra Red (paraffin mull): 3200 (broad), 1670, 1530,
1085, 960, 890 cm'1 (v) 1-methylcyclohexylcarboxamidine hydrochloride from 115 methylcyclohexylcarbonitri le (prepared according to the method of Example 47)
270 MH2 1H NMR (d6DMS0): 1.10 (3H,s); 1.15-1.50 (8H,m); 1.85 (2H,m); 2.45 (2H,broad s); 8.35 (1H, broad s).
The following amidines were prepared according to 20 literature procedures.
(vi) 2,2,2-trifluoroethylamidine was prepared accordir. - t the procedure of W.L. Reilly and H.C. Brown J.A.C.S. 6032-34 1956.
(vii) 2-chlorobenzylamidine was procedure of E.R Biehl et 1979.
prepared according to the al J.O.C. 44 (21), 3674,
EXAMPLE 3
This Example illustrates the stages in the preparation of ethyl (RS)-2-[2-(1,1-dimethylethyl)pyrimidin-5y1]butanoate .
(i) diethyl (RS)-formylsuccinate
Ethanol (20 cm3) was added portionwise to a suspension of finely divided sodium (10.0 g) in dry toluene (100 cm3).
On completion of the addition the mixture was heated for 3.5 hours at 80°C. To the resulting yellow suspension, cooled to 20°C, was added dropwise, over a period of 1 hour, a mixture of diethyl succinate (70.0 g) and ethyl formate (35.0 g), whilst the temperature of the mixture was maintained in the range 20 to 30°C. The mixture was kept at the ambient temperature for 16 hours after which water (100 cm3) was added carefully.
The aqueous layer was separated, neutralised with 50% aqueous sulphuric acid, and extracted with diethyl ether.
The ethereal extracts were washed with water, dried over anhydrous magnesium sulphate, and concentrated by evaporation of the solvent under reduced pressure. The residual liquid (66 g) was subjected to fractional distillation under reduced pressure to obtain the desired diethyl (RS)-formylsuccinate (46.0 g), boiling range 82 to 86°C/0.53 mmHg.
» NMR spectroscopy indicated that the product exists as an approximately 1:1 mixture of keto and enol forms.
AP000057 XH NMR (CDC13) : 1.10-1.40 (m,3H); 2.90 (d, J=7Hz, 1H);
3.05 (s,in); 3.75 (t, J=7 Hz, 0.5H);
4.00 - 4.40 ( m, 4 H ) ; 7.10 (d,J=ll Hz, 0.5H);
9.92 ( s, 0.5 H); 11, .5 (d, J = 11 Hz, 0.5H) .
Infra red (liquid film) : 3300 , 2980, 1735, 1665, 1175,
1030 cm-·1·
(ii) ethyl 2-[2-(1,1-dimethylethyl)-4-hydroxypyrimidin-5yl]acetate .
A solution of sodium ethoxide obtained by dissolving sodium (6.9 g) in ethanol (120 cm^) was added portionwise to a stirred suspension of 2,2-dimethylpropionamidine hydrochloride (41.0 g) in ethanol (150 cm^). The precipitated sodium chloride was removed by filtration. Diethyl (RS)-formylsuccinate (60 g) was added dropwise to the stirred filtrate at the ambient temperature. After keeping the mixture for 16 hours it was heated to the reflux temperature for 1 hour, after which the solvent was removed by evaporation under reduced pressure to give a solid residue which was washed with petroleum ether (boiling range 60-80°C) to yield ethyl 2-(2-(1,1dimethylethyl)-4-hydroxypyrimidin-5-yl]acetate (40 g), melting point 98-102°C. A further quantity (15 g) was recovered from the petroleum ether washings by evaporation of the solvent and column chromatographic purification of the residue using a silica column and eluting with a mixture (1:1 by volume) of ethyl acetate and petroleum
ether (boiling range 60-80 °C) .
LH NMR (CDC13) : 1.27 (t, u — 7 H z , 3H) ; 1.39 (s,9H);
3.44 (s, 2H); 4. 13 (q, J=7 HZ, 2H);
7.92 (s, 1H); 12 . 5 (bs, 1H).
Infra red (liquid paraffin): 3400, 1735, 1660, 1570, 1460, 1375, 1335, 1275, 1155, 1030, 980 cm1.
(iii) ethyl 2-[2-(1,1-dimethylethyl)-4-chloropyrimidin-55 yl]acetate
Phosphorus oxychloride (30 cm3) was added portionwise to ethyl 2-[2-(1,1-dimethylethyl)-4-hydroxypyrimidin-5-yl]acetate (15.0 g). An exothermic reaction occurred and the resultant mixture was poured onto ice. After neutralisation with sodium carbonate the mixture was extracted with ethyl acetate and the extracts washed with water and dried over anhydrous magnesium sulphate. Removal of the solvent by evaporation under reduced pressure yielded ethyl 2-[2-(1,1-dimethylethyl)-4-chloropyrimidin-515 yl]acetate (11.35 g, oil, solidified on standing, m.p 4244°C) .
1H NMR (CDC13) : 1.29 (t, J=7Hz, 3H); 1.40 (s, 9H); 3.71 (s, 2H); 4.20 (q, J = 7Hz, 2H); 8.51 (S, 1H)
Infra red (liquid film): 2960, 1735, 1580, 1520, 1420,
1250, 1180, 1025, 880 cm'1 (iv) ethyl 2-[2-(1,1,-dimethylethyl)pyrimidin-5yljacetate.
A mixture of ethyl 2-[2-(1,1-dimethylethyl)-425 chloropyrimidin-5-yljacetate (18 g), toluene (180 cm3), zinc dust (36 g) and 3 molar ammonium hydroxide solution saturated with sodium chloride (180 cm3) was heated at 100°C for 120 hours. After cooling and filtering to remove the solid component the organic phase was separated, the
KP000057 aqueous phase washed with ethyl acetate and the washincs combined with the organic phase. After washing the organic phase with water and drying over anhydrous magnesium sulphate the solvents were removed by evaporation under reduced pressure and the residual oil (16 g) was subjected to purification by column chromatography using a silica column eluted with dichloromethane to yield ethyl 2-(2(1,1-dimethylethyl)pyrimidin-5-yl(acetate (12 g) as a yellow oil.
NMR (CDC13) : 1.25 (t, J=7Hz, 3H); 1.40 (s, 9H);
3.55 (s, 2H); 4.2 (q, J=7Hz, 2H);
8.6 (s, 2H)
Infra red (liquid film): 2960, 1735, 1480, 1430, 1260.
1180, 1025 cm-1
An alternative reduction procedure is described below: (reference J. Org. Chem ( 1985 ), 50 , 3408-11).
Ethyl 2-(2-(1,1-dimethylethyl) - 4-chloro-pyr imidin-5yljacetate (1.016 g) was dissolved in tetrahydrofuran (25 cm3) containing potassium carbonate (0.809 g) and 5% palladium on carbon (0.188 g, catalyst). To the stirred mixture at the ambient temperature was added in portions sodium hypophosphite (0.995 g) in water (7.3 cm3) over 5 hours .
The reaction mixture was stood overnight, filtered to remove the catalyst and the filtrate, and extracted with ethyl acetate. The organic layer was washed with water, dried (magnesium sulphate) and evaporated under reduced pressure to yield the reduced product as an oil (0.635 g), shown by spectroscopic analysis to be identical with that obtained by the process described above.
GLC Retention time: 3.76 minutes Molecular ion: 222 (v) ethyl (RS)-2-[2- (1,1-dimethyiethyl)pyrimidin-5yl]butanoate .
Lithium bis-(trimethyIsily) amide (2.5 cm2 of a 1 molar solution in dry tetrahydrofuran) was added dropwise to a solution of ethyl 2-[2-(1,1-dimethylethyl)pyrimidin-5yl]acetate (0.5 g) in dry tetrahydrofuran (10 cm2) maintained at -78°C, and the resultant solution stirred for
30 minutes at -78°C. Ethyl iodide (1.05 g) was then added dropwise, and after stirring the resultant mixture for 1 hour while maintaining the temperature at -78°C, the reaction mixture was allowed to warm to the ambient temperature. After a further fourteen hours, the reaction mixture was poured into aqueous ammonium chloride solution, and extracted with ethyl acetate. The combined organic extracts were washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent under reduced pressure.
The resulant orange oil was purified by column chromatography on silica gel using dichloromethane as eluent to give ethyl (RS)-2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-butanoate.
2H NMR (CDC13): 0.95 (3H,t); 1.20 (3H,t); 1.4 (9H,s);
1.8-2.20 (2H,m); 3.40 (lH,t); 4.20 (2H,q); 8.60 (s,2H)
GLC Retention Time: 4.37 minutes.
APn η η π ; 7
EXAMPLE 4
Ethyl 2-(2-(1,1-di'methylethyl )pyrimidin-5-yl] pent-460 enoate was prepared according to the procedure described in Example 3(v), using allyl bromide in place of ernyl iodide.
1H NMR (CDC13): 1.10 (t,3H); 1.25 (s,9H); 2.40 (m,lH); 2.70 (m,lH); 3.45 (t,lH); 4.00 (m,2H); 4.95 (m,2H); 5.55 (m,lH); 8.50 (s,2H);
IR (Liquid film): 2960, 1735, 1588, 1547, 1482, 1433,
1366, 1182, 1031, 921, 820 cm-1
GLC Retention time: 4.76 minutes.
EXAMPLE 5
This example illustrates the steps involved in the preparation of ethyl (RS)-4-dimethylamino-3-formyl-2-(lmethylethyl)-3-butenoate, ethyl (RS)-4-ethoxy-3-formyl-2(1-methylethyl)-3-butenoate and mixtures thereof.
(i) Preparation of diethyl 2-(1-methylethyl)-2-( 2,2diethoxyethyl)-malonate. (Reference Bull. Soc.
Chim. France, 1965, p 1761).
Sodium hydride (4.8 g of a 50% dispersion in oil) was washed free of oil with petroleum ether of boiling range 40-60°C, and suspended in dry dimethylformamide; the suspension was cooled to 0°C by external cooling. A solution of diethyl 2-(1-methylethyl)malonate (21.2 g) in dry dimethylformamide (25 cm^) was added in portions to the suspension and the reaction mixture was stirred at 10°C for 15 minutes, whereafter no further evolution of hydrogen could be detected. A solution of bromoacetaldehyde diethylacetal (19.7 g - commercially available from Aldrich Chemical Company Limited,· Gillingham, England) in dimethylformamide (25 cm2) was added to the reaction mixture to give a red-brown solution, which was then heated at 120-130°C for 20 hours with stirring. After cooling the reaction mixture to 0°C, an ice/water mixture (total volume 1000 cm2) was added cautiously. The product was extracted with diethyl ether (3 x 250 cm2) and the combined organic layers washed with water (2 x 300 cm2), dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent under reduced pressure. The 10 residual liquid was subjected to fractional distillation through a short Vigreux column to give diethyl 2-(l-methylethyl)-2-(2,2-diethoxyethyl)malonate (10.5 g), boiling point 94-98°C/0.1 mmHg.
XH NMR (CDC13) : 1.0 (d, 6H); 1.2 (t, 6H); 1.3 (t, 6H);
2.25 (d, 2H); 2.3 (m, 1H); 3.4 - 3.75 (m, 4H); 4.2 (m, 4H ); 4.65 (m, 1H).
Infra red (liquid film): 2990, 1730, 1230, 1120, 1070 cm1 (ii) Preparation of ethyl (RS)-4,4-diethoxy-2-(1methylethyl)butanoate
Diethyl 2-(1-methylethyl)-2-(2,2-diethoxyethyl ) malonate (60 g) was added to dimethyl sulphoxide (450 cm2) containing potassium acetate (37 g) and water (6.8 cm2). The mixture was stirred under nitrogen and heated to 130-140°C for 18 hours.
Analysis by gas liquid chromatography indicated that the reaction was 40% complete. The reaction temperature was increased to 160-170°C and heating continued for a further 18 hours.
The reaction mixture was cooled to room temperature and diluted with water (3000 cm2). The product was extracted using'diethyl ether (3 x 800 cm2) and the
APO 0 0 0 5 7 combined organic layers were washed with water (3 x 800 cm3) and dried over anhydrous magnesium sulphate. The solvent was evaporated under reduced pressure to give a brown liquid. Fractional distillation of the residue gave ethyl (RS)-4,4diethoxy-2-(1-methylethyl)butanoate (31.8 g) as a pale yellow liquid, boiling point 68-70°C/0.2 mmHg.
1H NMR (CDC13) : 0.9 (d, 6H); 1.0 (m, 9H); 1.75 (m, 1H);
1.8-2.G5 (m, 2H); 2.15 (m, 1H); 3.4-3.7 (m, 4H); 4.05-4.2 (m, 2H); 4.45 (m,lH)
Infra red (liquid film): 2990, 1730, 1375, 1180, 1120,
1060 cm-1
This compound may also be prepared by the methods described in Chemical Abstracts, 59 , 5012g (1963) and 51 12086c ( 1957) .
(iii) Preparation of ethyl { RS)-4-dimethylamino-3-formyl2- (1-methylethyl)-3-butenoate, ethyl (RS)-4-ethoxy3- formyl-2-(1-methylethyl)-3-butenoate and mixtures thereof .
To dry dimethylformamide (4.64 cm ) was added dropwise at 5°C, phosphorous oxychloride (5.50 cm3). This gave initially a viscous solution which then solidified. To this was added 1,2-dichloroethane (10 cm3) and the reaction mixture stirred at 60°C for 45 minutes to form the Vilsmeyer - Haack reagent.
A solution of ethyl (RS)-4,4-diethoxy-2-(lmethylethyl)butanoate (5 g) in 1,2-dichloroethane (10 cm3) , was added dropwise to the reaction mixture, which was then heated for a further 1 hour at 60°C.
The reaction mixture was sampled by adding an aliquot to solid potassium carbonate, diluting with water, and heating for a 5 minutes at 50-60°C. An extract using ethyl acetate as solvent was analysed by gas liquid chromatography, which indicated 30% completion of reaction.
The reaction mixture was heated for a further 1 hour 5 at 70°C, allowed to cool to the ambient temperature, then reheated for a further 1 hour at 70°C. The reaction mixture was cooled to 0°C and cautiously added to an excess of solid potassium carbonate. The slurry was cautiously diluted with ice/water and the mixture heated on a steam bath for 10 minutes. The mixture was cooled to room temperature and saturated sodium chloride solution added. The product was extracted with ethyl acetate (2 x 750 cm3), dried over anhydrous magnesium sulphate and the solvent was evaporated under reduced pressure. The residual brown liquid was placed under vacuum (0.5-1.0 mmHg) and heated to 50°C to remove volatile impurities.
The product was obtained as a brown liquid (3.4 g) and was used without further purification.
Analysis of the product by gas chromatography/mass spectroscopy showed the product to contain 68% ethyl (RS)4-dimethylamino-3-formyl-2-(l-methylethyl)-3-butenoate (I), 12% ethyl (RS)-4-ethoxy-3-formyl-2-(1-methylethyl)-3butenoate (II) and 17.5% 3-(1-methylethyl)-5-hydroxytetrahydrofuran-2-one (III) as an impurity. Ratios of I to
II were found to vary according to reaction conditions and isolation procedures, but all mixtures were found to be satisfactory for further conversion to derivatives as described in the remaining examples.
Molecular ion (Product I): 227
Molecular ion (Product II): 228
Molecular ion (Product III): 144
EXAMPLE 6
APO0 0 OS 7
Ethyl (RS)-4-dimethylamino-3-formy1-2-(1,164 dimethylethyl)-3-butenoate was prepared by the method of Example 5 from diethyl 2-(1,1-dimethylethy1)malonate. The physical data for the intermediates and final product are given be low :5 (i) Diethyl 2-(l,l-dimethylethyl)-2-{2,2diethoxyethyl)malonate ΧΗ NMR (CDC13): 1.10 (9H,s); 1.17 (6H,t); 1.3 (6H,t); 2.2 (2H,d); 3.4-3.71 (4H,m);
4.2 (4H,q); 4.75 (lH,t)
Infra Red (liquid film) 2977, 1725, 1446, 1372, 1256, 1198, 1074, 977, 867 cm'1
GLC Retention Time: 5.01 minutes.
(ii) Ethyl (RS)-4,4-diethoxy-2-(1,1-dimethylethyl) butanoate 1H NMR (CDC13 ) :
(9H,s); 1.18-1.3 (9H,m); 1.78 (lH,m); 2.0-2.1 (lH,m); 2.0530 (lH,dd); 3.4-3.8 (4H,m); 4.052 (2H,m); 4.4 (lH,m).
Infra Red (liquid film)
2975, cm’1
1729,
1478, 1372, 1347, 1064
GLC Retention Time: 2.90 minutes (iii) Ethyl (RS)-4-dirr.ethylamino-3-formyl-2-(l,ldimethylethyl)-3-butenoate as a 2:1 mixture of Z and E isomers.
1H NMR (CDCl-j): 0.94 and 1.04 (9H,2s); 1.23 (3H,t); 3.15 and 3.20 (6H,2s); 3.94-4.2 (3H,m); 6.9-7.5 (1H, broad s); 9.05-9.65 (1H, broad s).
Infra Red (liquid film) 2957, 1720, 1599, 1399, 1365,
1305, 1146, 1044, 878 cm'1 *
GLC Retention Time: 3.95 minutes
Molecular ion: 241
Spectroscopic data consistent with 2:1 mixture of Z and E isomers.
Variation of the reaction and isolation conditions may produce ethyl (RS)-4-ethoxy-3-formyl-2-(1,1-dimethylethyl) 3-butenoate in addition to the dimethylamino product.
EXAMPLE 7
AP 0 0 0 0 5 7
The Example illustrates an alternative procedure for the preparation of ethyl (RS)-4,4-diethoxy-2-(l,ldimethylethyljbutanoate.
(i) Preparation of ethyl (RS)-2-(1,1-dimethylethyl)pent4-enoate.
n Butyllithium (44 cm1 of a 2.5 molar solution in Hexane) was added to a solution of dry di-isopropylamine (14.7 cm3) in dry tetrahydrofuran (75 cm3) whilst the temperature was maintained at -40°C.
The reaction mixture was then allowed to warm to 0°C before being cooled to -70°C. A solution of etnyl 3,3, dimethylbutanoate (14.4 g) in dry tetrahydrofuran (20 cm3) 25 was then added dropwise to the reaction mixture which was maintained at -70°C. After the addition was complete, the reaction temperature was allowed to rise to -60°C for 15 minutes, before being cooled again to -70°C. A solution of allyl bromide (13.4 g) in dry tetrahydrofuran (5 cm2) was then added in portions to the reaction mixture, which was allowed to warm to the ambient temperature, and stirred for a further 16 hours.
The solvent was removed by evaporation under reduced pressure and the residual liquid was poured into water, and extracted into diethyl ether. The combined organic extracts were washed with water, dilute aqueous hydrochloric acid and water again.
The organic portion was dried over anhydrous magnesium sulphate, and concentrated by evaporation of the solvent under reduced pressure. The residual liquid was subjected to fractional distillation under reduced pressure through a Vigreux column to give ethyl (RS)-2-(l,ldimethylethyl)pent-4-enoate (14.3 g), boiling point 4950°C/0.6 mmHg.
MHz 1H NMR (CDCIj): 0.95 (9H,s); 1.20 (3H,t); 2.20 (3H,m); 4.10 (2H,q); 4.7-5.8 (3H,m).
Infra Red (Liquid film): 3083, 2966, 1729, 1641, 1477,
1369, 1346, 1151, 1028 and 915 cm-2, (ii) Preparation of ethyl (RS)-2-(1,1-dimethylethyl)-4oxobutanoate.
A stream of ozone in oxygen generated using a Pennwal type 3A 023012 ozonator was passed through a solution of . ethyl (RS)-2-(1,1,-dimethylethy1) pent-4-enoate (4.3 g) in dry dichloromethane (100 cm2) while the temperature was maintained at -40°C. When the reaction solution had taken on a pale blue colouration excess ozone was removed by the passage of oxygen through the solution. Triphenyl phosphine (20 g) was added to the cold reaction mixture, which was allowed to warm to the ambient temperature, for a period of three hours.
The solvent was removed by evaporation under reduced pressure, and replaced by petroleum ether (boiling range 40-60°C, 250 cm3) and the triturated mixture filtered. The residue was washed with a further portion of petroleum ether, and the combined filtrates concentrated by evaporation of the solvent under reduced pressure.
The residue was subjected to short path distillation through a kugelrohr apparatus to give ethyl (RS)-2-(l,ldimethylethyl)-4-oxo-butanoate (3.2 g), boiling point
100°C/2 mmHg.
270 MHzLH NMR (CDClj): 0.98 (9H,s); 1.27 (3H,t); 2.64 (2H,m); 3.00 (lH,m); 4.15 (2H,q);
9.50 (1H,S)
Infra Red (liquid film): 2966, 1726, 1477, 1370, 1216,
1187, 1157, 1096, 1027 and
924 cm-}·.
GLC Retention Time: 1.53 minutes.
(iii) Ethyl (RS)-4,4-diethoxy-2-(1,1-dimethylethyl)butanoate.
Ethyl (RS)-2-(1,1-dimethylethyl)-4-oxo-butanoate (0.57
g) was dissolved in excess triethylorthoformate and a catalytic amount of £-toluer.esulphonic acid was added.
, After stirring for 1 hour at the ambient temperature, excess triethylorthoformate was evaporated under reduced pressure to give ethyl (RS)-4,4-diethoxy-2-(1,1AP 0 0 0 0 5 7 dimethylethyl)butanoate, the spectral data of which were identical to those obtained in Example 6 (ii).
EXAMPLE 8
Ethyl (RS)-4-dimethylamino-3-formyl-2-cyclopropy1-3butenoate was prepared by the method of Example 5 from diethyl 2-cyclopropylmalonate. (Note: the preparation of
2-cyclopropylmalonate is described by Carney et al, Organic Preparations And Procedures International, Vol 5, P 25-29 (1973). The physical data for the intermediates and final product are given below:
(i) Diethyl 2-cyclopropyl-2-(2,2-diethoxyethyl)malonate.
Boiling Point: 104-110°C/0.1 mmHg XH NMR (CDC13): 0.4, 0.56 (4H,m); 1.18 (6H,t); 1.26 (6H,t); 1.42 (lH,m); 2.24 (2H,d); 3.48, 3.64 (4H,m); 4.16 (4H,m); 4.76 (lH,t).
Infra Red (liquid film) 2979, 1729, 1445, 1372, 1285,
1242, 1062, 862 cm-1.
GLC Retention Time: (50°C-280°C run): 7.04 minutes.
(ii) Ethyl (RS )-4,4-diethoxy-2-cyclopropylbutanoate.
Boiling Point 62-63°C/0.08 mmHg 1H NMR (CDC13): 0.16, 0.32 (2H,m); 0.50 (2H,m); 0.88 . (lH,m); 1.18 (6H,t); 1.26 (3H,t); 1.70,
1.88 (2H,m); 2.12 (lH,m); 3.46, 3.60 (4H,m);-4.15 (2H,m); 4.56 (lH,t).
Infra Red (liquid film): 3081, 2977, 1732, 1444, 1373, 1060, 825 cm-1.
GLC Retention Time (50°C-280°C run): 4.78 minutes.
(iii) Ethyl (RS)-4-dimethylamino-3-formyl-2-cyclopropyl-35 butenoate.
1H NMR (CDC13): 0.1, 0.24 (2H,m); 0.42, 0.64 (2H,m); 1.24 (3H,t); 1.42 (lH,m); 3.12 (6H,s); 3.44 (lH,d); 4.18 (2H,q); 6.66 (1H, broad s); 8.88 (1H, broad s).
10 Infra Red (liquid film) 3080, 2982, 2730, 1726, 1680,
1606, 1488, 1445, 1401, 1303,
1197, 1036, 911, 886, 853, 826,
727 cm Γ1.
APO00057
GCL Retention Time: (50°C-280°C run): 7.61 minutes.
Molecular ion: 225
It is believed that the spectroscopic data are consistent with the E isomer of the product.
EXAMPLE 9
This Example illustrates the preparation of ethyl (RS)-2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,320 dimethylbutanoate.
A solution of sodium ethoxide in ethanol was prepared .by the addition of sodium (0.276 g) to ethanol (20 cm^) under a nitrogen atmosphere. The solution was cooled to the ambient temperature (ca 20°C) and 2,270 dimethylpropionamidine hydrochloride (1.64 g) was added. A solution of a 1:1 mixture of ethyl (RS)-4-dimethylamino-3formyl-2-(1,1-dimethylethyl)-3-butenoate and ethyl (RS)-4ethoxy-3-formyl-2-(1,1-dimethylethyl)-3-butenoate (2.6 g prepared according to the method of Example 6) in ethanol (25 cm3) was added to the reaction mixture which was then heated at the reflux temperature for 3.5 hours. The mixture was cooled to the ambient temperature and the solvent evaporated under reduced pressure. Water (200 cm3) was added to the residue and the products extracted into diethyl acetate (2 x 150 cm3). The combined organic layers were dried over anhydrous magnesium sulphate and the solvent evaporated under reduced pressure to leave a brown oil. The crude product was purified by column chromatography on a silica gel support, eluting with dichloromethane containing 2% by volume ethyl acetate to
give the title compound (1.5 g) as a pale yellow oil.
1H NMR (CDCl-j) : 1.0 (9H (lH,s) ; ,s); 1 4.15 .25 (3H,t); 1.42 (9H,s); (2H,s).
(2H,m); 8.75
Infra Red (liquid film) 2962 , 2872 , 1732 , 1586, 1539,
1482 , 1433 , 1369 , 1333, 1200,
1149, 1036, 939 , 854, 821 cm-1
GLC Retention Time: 4.87 minutes
Molecular ion: 278
EXAMPLE 10
This Example illustrates the preparation of (RS)-2-[2(1,1-dimethylethy1)pyrimidin-5-y1]-3,3-dimethylbutanoic acid.
A solution of lithium hydroxide hydrate (0.12 g) in water (5 cm2) was added to a solution of ethyl (RS)-2-[2(1,1-dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate (0.35 g) in propan-2-ol (10 cm2) and the mixture was heated at the reflux temperature for 8 hours. Further lithium hydroxide hydrate (0.13 g) was then added and heating continued for a further 13 hours. The mixture was cooled, and concentrated by evaporation under reduced pressure.
The residue was added to aqueous sodium carbonate solution and residual ester extracted into dichloromethane (2 x 75 cm2). The aqueous layer was acidified with 2 molar aqueous hydrochloric acid solution and the acid product extracted into dichloromethane (2 x 100 cm2). The organic layers were dried over anhydrous magnesium sulphate and the solvent evaoprated under reduced pressure to give the title compounds as a low melting solid (0.22 g). The product was used without further purification.
XH NMR (CDC13): 0.89 (9H,s); 1.29 (9H,s); 3.4 (lH,s); 3.25 (1H,broad s); 8.7 (2H,s).
Infra Red (paraffin mull) Acid OH at 3100-2300 cm'1
GLC Retention Time: 5.5 minutes
Molecular ion: 250
EXAMPLE 11
The following compounds were prepared from the appropriate starting materials according to the method cf , Example 9.
(i) Ethyl (RS)-2-[2-(1-methylethyl)pyrimidin-5-yl]-3,372 dimethylbutanoate.
MHz XH NMR (CDCl-j) : 1.05 (9H,s); 1.25 (3H,2t); 1.35 (6H,d); 3.20 (lH,m); 3.35 (lH,s); 4.15 (2H,2d); 8.7 (2H,s).
(ii) Ethyl (RS)-2-[2-(N,N-dimethylamino)pyrimidin-5-yl]3,3-dimethylbutanoate.
MHz 1H NMR (CDC13): 1.0 (9H,s); 1.25 (3H,2t); 3.15 (6H,s); 4.10 (2H,2q); 8.30 (2H,s).
(iii) Ethyl (RS)-2-(2-cyclopropylpyrimidin-5-yl)-3,3dimethylbutanoate.
MHz 1H NMR (CDCl-j): 1.0 (9H,s); 1.15 (4H,m); 1.25 (3H,2t); 2.25 (lH,m); 3.30 (lH,s); 4.12 (2H,2q); 8.55 (2H,s) .
(iv) Ethyl (RS)-2-(2-phenylpyrimidin-5-yl)-3,3dimethylbutanoate.
MHz XH NMR (CDC13): 1.05 (9H,s); 1.25 (3H,t); 3.40 (1H,S); 3.15 (2H,2q); 7.40 (3H,m);
8.40 (2H,m); 8.80 (2H,s).
(v) Ethyl (RS)-2-[2-(l-methylcyclopropyl)pyrimidin-5-yl]3,3-dimethylbutanoate.
270 MHz 1H NMR (CDCl-j): 0.91 (2H,m); 1.00 (9H,s); 1.26 (3H,t); 1.35 (2H,m); 1.57 (3H,s); 3.33 (1H,S); 4.10 (2H,m); 8.65 (2H,s).
GLC Retention Time: 5.86'minutes .
(vi) Ethyl (RS)-2-(2-methylpyrimidin-5-yl)-3,3dimethylbutanoate.
MHz 1H NMR (CDCl-j): 1.00 (9H,s), 1.25 (3H,t); 2.7 (3H,s); 3.35 (lH,s); 4.2 (2K,q);
8.65 (2H,s).
GLC Retention Time: 3.98 minutes.
(vii) Ethyl (RS)-2-[2-(l,l-dimethylpropyl)-pyrimidin-5yl]-3,3-dimethylbutanoate
MHz 1H NMR (CDCI3): 1.05 (9H,s); 0.7-1.4 (8H,m); 1.4 10 (6H,m); 3.35 (lH,s); 4.2 (2H,2q);
8.8 (2H,s)
GLC Retention Time: 5.69
Molecular Ion: 292 (viii) Ethyl (RS)-2-(2-methylpyrimidin-5-yl)-315 methylbutanoate XH NMR (CDC13): 0.76 (3H,d); 1.06 (3H,d); 1.25 (3H,t);
2.28-2.44 (lH,m); 2.73 (3H,s)l 3.16 (lH,d); 4.10-4.24 (2H,m); 8.64 (2H,s) (ix) Ethyl (RS)-2-[2-(2-chlorophenyl)pyrimidin-5-y1]-3, 320 dimethylbutanoate.
MHz 1H NMR (CDC13): 1.05 (9H,s); 1.30 (3H,t); 3.45 (1H,S); 4.20 (2H,qd); 7.40 (3H,m);
. 7.80 (lH,m); 8.95 (2H,s) .
AP00005?
(x) Ethyl (RS)-2-[2-(1-methylcyclohexyl)pyrimidin-5-yl]74
3,3-dimethylbutanoate.
270 MHz XH NMR (CDC13): 1.00 (9H,s); 1.25 (3H,t); 1.27 <3H,s); 1.20-1.60 (8H,m); 2.35 (2H,m); 3.35 (lH,s); 4.15 (2H,q);
8.78 (2H,s) .
(xi) Ethyl (RS)-2-[2-(trifluoromethyl)pyrimidin-5-yl]-3,3dimethylbutanoate .
270 MHz 1H NMR (CDCl-j): 1.00 (9H,s); 1.27 (3H,t); 3.50 (1H,S); 4.20 (2H,dq), 8.98 (2H,s).
(xii) Ethyl (RS)-2-(2-phenylpyrimidin-5-yl)-3methylbutanoate
H NMR (CDC13): 0.82 (d,3H); 1.08 (d,3H); 1.30 (t,3H);
2.40 (m,1H); 3.22 (d,lH) ; 4.26 (q, 2 H ) ;
7.48 (m,3H); 8.44 (m,2H); 8.80 (S,2H)
EXAMPLE 12
The following compounds were prepared from the
appropriate starting materials according to the method of
Example 10:
(i) (RS)-2-[2-(1,1-dimethylpropyl)pyrimidin-5-yl]-3,3dimethylbutanoic acid
MHz 1H NMR (CDC13/DMSO): 0.8 (3H>t); 1.05 (9H,s); 1.5 (6H,s); 1.85 (2H,q); 3.4 (lH,s); 8.8 (2H,s) (acid OH not seen).
- 75 GLC Retention Time: 6.25 minutes.
(ii) (RS)-2-(2-methylpyrimidin-5-y1)-3,3-dimethylbutanoic acid
MHz NMR (CDCl-j): 1.05 (9H,s); 2.75 (3H,s); 3.45 5 (lH,s); 8.1 (IH, broad s); 8.8 (2H,s) .
GLC Retention Time: 4.5 minutes (iii) ( RS ) -2 - [ 2-(1-methylcyclopropyl)pyrimidin-5-y1)-3,3dimethylbutanoic acid
400 MHZ XH NMR (CDClj): 0.9 (2H,m); 1.05 (9H,s); 1.4 ‘ (2H,m); 1.55 (3H,s); 3.‘ (lH,s);
8.65 (2H,s) (acid OH not seen).
GLC Retention Time: 6.20 minutes (iv) (RS)-2-(2-cyclopropylpyrimidin-5-yl)-3,315 dimethylbutanoic acid
Infra Red (Nujol mull): 2927, 2478, 2347, 1901, 1710, 1592, 1548, 1457, 1331, 1228, i210, 1170, 1064, 912, 793, 713 and 656 cm'1
Melting Point: 146°C (v) (RS)-2-[2-(N,N-Dimetoylamino)pyrimidin-5-y1]-3,3dimethylbutanoic acid ** Infra Red (Nujol Mull): 2923, 2854, 2528, 1917, 1717, 1611, 1534, 1460, 1413, 1206, 973, 793, •711 and 659 cm -1
AP00005J
Melting Point: 164-166°C (vi) (RS )-2-(2-(1-methylethyl)pyrimidin-5-yl]-3,3dimethylbutanoic acid
Infra Red (Nujol Mull): 2931, 2857 , 2347, 1898, 1710, 1592 ,
5 1550, 1458, 1369, 1333, 1304, 1232 ,
1206 , 1171, 854, 800, 776 and 719
cm'^
Melting Point: 180°C (vii) (RS)-2-(2-phenylpyrimidin-5-yl)-3,3-dimethylbutanoic 10 acid
Infra Red (thin film): 2923, 2859, 1711, 1585, 1542, 1460, 1376, 1233, 1203, 1175, 1162, 745 and 695 cm’^·
Melting Point: 185°C (viii) (RS)-2-(2-methylpyrimidin-5-yl)-3-methylbutanoic acid
Infra Red (thin film): 2967, 1724, 1595, 1557, 1453, 1272, 1047, 751, 662 cm-1 (ix) (RS)-2-(2-(1,1-dimethylethyl)pyrimidin-5-yl]butanoic 20 acid
NMR (CDC13) : 1.0 (3H,t); 1.4 (9H,s); 1.8-2.4 ( 2 H , ~.) ;
3.5 (lH,t); 6.8 (1H,broad s); 8.65 (2K,s)
GLC Retention Time: 4.69 minutes ( x ) (RS)-2-[2-(2-chlorophenyl)pyrimidin-5-yl]-3,3dimethylbutanoic acid XH NMR (CDC13): 1.05 (9H,s); 3.45 (lH,s); 7.40 (2H,m);
7.50 (lH,m); 7.75 (lH,m); 8.95 (lH,m) (xi) (RS)-2-[2-(l-methylcyclohexyl)pyrimidin-5-yl]-3,3dimethylbutanoate
270 MHz 1H NMR (CDC13): 1.05 (9H,s); 1.25 (3H,s); 1.20-1.60 (8H,m); 2.30 (2H,m); 3.42 (lH,s); 8.78 (2H,s)
EXAMPLE 13
The Example illustrates an alternative procedure for the preparation of Ethyl (RS)-2-[2-(l,ldimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate.
(i) Preparation of Ethyl 2-oxo-2-[2-(l,ldimethylethyl)pyrimidin-5-yl]acetate
Magnesium turnings (1.9 g), a catalytic amount of iodine and dry tetrahydrofuran (50 cm3) were placed in a round-bottomed flask under an atmosphere of dry nitrogen.
A portion of a solution of 5-bromo-2-{1,1-dimethylethyl )pyrimidine (15.2 g) in dry tetrahydrofuran (50 cm3) was added to the reaction vessel and the Grignard reaction was initiated by the addition of a small portion of methyl iodide, followed by heating the reaction contents to the reflux temperature. The remainder of the pyrimidine • solution was added at such a rate so as to maintain reflux, and on completion of the addition and cessation of reaction, the so formed Grignard reagent was added to a
APO00057 solution of diethyl oxalate (20.4 g) in dry tetrahydrofuran, whilst the reaction temperature was maintained between
-10°C and -15°C. After the addition was complete, the reaction mixture was allowed to warm to the ambient temperature, at which point it was allowed to stir for 16 hours. Dilute aqueous hydrochloric acid was added to the reaction mixture which was then extracted into dichl'oromethane. The combined organic extracts were washed with water, and brine, and dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure, and short-path distillaton of the residue using a Kugelrohr apparatus gave ethyl 2-oxo-2-[2-(1,1dimethylethyl)-pyrimidin-5-yl]-acetate (9.3 g).
Boiling Point 140°C/0.08 mmHg.
MHz 1H NMR (CDC13): 1.45 (9H,s); 1.45 (3H,t); 4.45 (2H,q); 9.30 (2H,s) .
GLC Retention Time: 4.05 minutes (ii) Preparation of Ethyl (RS)-2-hydroxy-2-[2-(1,1dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate.
A 2 molar solution of (1,1-dimethylethyl) magnesium chloride in diethyl ether (5 cm2) was added in portions to a solution of ethyl 2-oxo-2-[2-(1,1dimethylethyl)pyrimidin-5-yl]acetate (2.36 g) in dry tetrahydrofuran whilst the reaction temperature was maintined at -78°C. After the addition was complete, the reaction mixture was allowed to warm to the ambient .temperature, and to stand overnight. Water was added, and the products were extracted into ethyl acetate. The combined organic extracts' were washed, and dried over anhydrous magnesium sulphate.
After removal of the solvent by evaporation under reduced pressure, the residue was subjected to column chromatography on silica gel using hexane containing 10% ethyl acetate by volume as eluent, to give ethyl (RS)-2hydroxy-2-[2-(l,l-dimethylethyl)pyrimidin-5-yl]-3,3dimethylbutanoate (0.65 g) as a colourless oil.
MHz 2H NMR (CDCIj): 1.0 (9H,s); 1.3 (3H,t); 1.4 (9H,s);
3.9 (1H, broad s); 4.4 (2H, 9.05 (2H,s) (iii) Preparation of Ethyl (RS)-2-chloro-2-[2-(1,1dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate
Thionyl chloride (0.57 g) was added dropwise to a 15 solution of thyl (RS)-2-hydroxy-2-(2-(l,ldimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate (0.2 g) and imidazole (0.32 g) in dry acetonitile (7 cm2, whilst the reaction temperature was maintained at 0°C. The mixture was allowed to warm to the ambient temperature and stirred for a period of sixteen hours, after which time it was poured into water, and extracted into dichloromethane. The combined organic extracts were washed with water, dried over anhydrous magnesium sulphate, passed through a short plug of silica, and concentrated by evaporation of the solvent under reduced pressure to give ethyl (RS)-2-chloro2-[2-(l,l-diraethylethyl)pyrimidin-5-yl]-3,3dimethylbutanoate as a yellow oil (0.15 g) .
270 MHz 2H NMR (CDCIj): 1.09 (9H,s); 1.25 (3H,t); 1.35 (9H,s); 4.25 (2H,2q); 8.85 (2H,s) .
AP 0 0 0 0 5 7 (iv) Ethyl (RS)-2-[2-(1,1-dimethy1ethy1)pyrimidin-5-y1]3,3-dimethylbutanoate
Tri-n-Butyl tin chloride (1.3 cm·3) was added to a solution of ethyl (RS)-2-chloro-2-[2-(1,15 dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate (1.4 g) and a catalytic amount of 2,2'-azobisisobutyronitrile in dry toluene (10 crP). The mixture was heated to the reflux temperature for a period of 1½ hours, after which it was cooled to the ambient temperature, poured into water, and extracted into ethyl acetate. After concentration by evaporation of the solvent under reduced pressure, the residue was subjected to column chromatography on silica gel using hexane followed by ethyl acetate as eluent to give ethyl (RS)-2-[2-(1,1-dimethyl-ethyl)pyrimidin-5-yl]15 3,3-dimethylbutanoate (1.1 g) as a pale yellow liquid, the spectral data of which were identical to those obtained for the sample generated in Example 9.
EXAMPLE 14
Ethyl (RS)-2-(2-(1,1-dimethylethyl)pyrimidin-5-ylj3,3-dimethylpentanoate was prepared from ethyl 2-oxo-220 (2-(1,1-dimethylethyl)pyrimidin-5-yl]acetate and 1,1dimethylpropyl magnesium chloride using the method described in Example 13.
NMR (CDC13): 0.92 (6H,m); 1.00 (3H,s); 1.20-1.30 (4H,m); 1.30-1.40 (lH,m); 1.42 (9H,s);
3.45 (lH,s); (4.05-4.25 (2H,m); 8.75 (2H,S)
GLC Retention Time: 5.81 minutes
EXAMPLE 15
This Example illustrates an alternative procedure for the preparation of (RS)-2-[2-(l,l-dimethylethyl)pyrimidin5-yl]-3,3-dimethylbutanoic acid.
(i) Preparation of 2,2-dimethyl-l-hydroxy-l-[2-(1,15 dimethylethyl)pyrimidin-5-yl]propanol
Magnesium turnings (0.42 g), a catalytic amount of iodine, and dry tetrahydrofuran (5 cm3) were placed in a round-bottomed flask under an atmosphere of dry nitrogen.
A portion of a solution of 5-bromo-2-(1, ΙΙΟ dimethylethyl)pyrimidine (3.1 g) in dry tetrahydrofuran (10 cm3) was added to the reaction pot, and the Grignard reaction was initiated by warming of the reaction mixture to the reflux temperature; the remainder of the pyrimidine solution was added at such a rate so as to maintain reflux.
After the addition was complete, and the reflux had subsided, the reaction mixture was cooled to 10°C, and a □ solution of pivaldehyde (1.5 cm ) in dry tetrahydrofuran (5 cm3) was slowly added.
After the addition was complete, the reaction mixture was stirred for 5 minutes, quenched with aqueous ammonium chloride solution, and extracted into ethyl acetate. The combined organic extracts were washed, dried over anhydrous magnesium sulphate, and concentrated by evaporation of the solvent under reduced pressure, to give 2,2-dfmethyl-l2 5 hydroxy-1-[2-(1,1-dimethylethyl)pyrimidin-5-yl]propan-l-ol as a pale solid.
MHz XH NMR (CDC13): 0.95 (9H,s); 1.25 (9H,s); 2.2 (1H, . broad s); 4.4 (lH,s); 8.6 (2H,s).
APO00057
GLC Retention Time; 4.07 minutes (ii) Preparation of 3,3-dimethyl-2-[2-(l,ldimethylethyl)pyrimidin-5-yl]butyronitrile (a) Methane sulphonyl chloride (0.17 cm3) was added to a solution of 2,2-dimethyl-1-[2-(1,1-dimethylethyl)pyrimidin5-yl]propan-l-ol(0.44 g) and a catalytic amount of 4dimethylaminopyridine in dry pyridine (3 cm3) was added to the mixture.
After stirring for 16 hours at the ambient temperature, the reaction solution was poured into water, extracted into ethyl acetate, and the organic fractions washed with dilute aqueous hydrochloric acid, water and brine. The organic solution was dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent under reduced pressure.
GLC Retention Time: 6.04 minutes
This intermediate mesylate was not further characterised, but immediately added to a solution of sodium cyanide (0.10 g) in dry dimethyl sulphoxide (4 cm3), and heated to 60°C for 4 hours. After cooling to the ambient temperature, the reaction mixture was diluted with water, extracted into ethyl acetate, washed with water and brine, and dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure gave 3,3dime thy1-2-(2-(1,1-dimethylethyl)pyrimidin-5yl]butyronitrile (0.25 g).
MHz }·Η NMR (CDCl-j): 1.1 (9H,s); 1.43 (9H,s); 3.55 (lH,s); 9.62 (2H,s).
» Molecular Ion: 231 (iii) An alternative process for the preparation of the butyronitrile stage (ii) is described below:
(a) Preparation of l-chloro-2,2-dimethyl-l-[2-(l,ldimethylethyl)pyrimidin-5-yl]propane
A solution of 2,2-dimethyl-l-(2-(1,15 dimethylethyl)pyrimidin-5-yl]propan-l-ol (19.37 g) in thionyl chloride (125 cm3) was heated at the reflux temperature for 30 minutes. After cooling to the ambient temperature, the excess thionyl chloride was removed by evaporation under reduced pressure, and the residue dissolved in dichloromethane and washed with aqueous sodium bicarbonate solution. After drying over anhydrous magnesium sulphate, concentration of the organic solution by evaporation of the solvent under reduced pressure gave
1-chloro-2,2-dimethyl-l-[2-(1,1-dimethylethyl)pyrimidin-515 yljpropane (20.95 g).
Infra Red (Nujol Mull): 2924, 2854, 1586, 1540, 1460, 1434, 1365, 1156, 859, 834 and 774 cm1
GLC Retention Time: 3.72 minutes (b) Preparation of 3,3-dimethyl-2-[2-(1,1-dimethyl20 ethyl)pyrimidin-5-yl]butyronitrile.
A solution of l-chloro-2,2-dimethyl-l-[2-ί1,1dimethylethyl)pyrimidin-5-ylIpropane (5.08 g> and sodium cyanide (2.07 g) in dry dimethylsulphoxide (50 cm3) was heated to 60°C, under an atmosphere of dry nitrogen for a period of 17 hours. After cooling to the ambient temperature, che solution was poured into aqueous sodium bicarbonate solution and extracted with diethyl ether, washed with brine, dried over anhydrous magnesium sulphate, and concentrated by evaporation of the solvent under
APO00057 reduced pressure. The resulting brown oil was combined with the crude product from a similar reaction and subjected to column chromatography on silica gel using dichloromethane followed by dichloromethane containing 5% by volume ethyl acetate to give 3,3-dimethyl-2-(2-(l,ldimethylethyl)pyrimidin-5-ylJbutyronitrile (7.6 g), identical in all respects to the material obtained in Example 15 (ii) above.
(iv) Preparation of (RS)-2-[2-(1,1-dimethylethyl) 10 pyrimidin-5-yl]-3,3-dimethylbutanoic acid
A solution of 3,3-dimethyl-2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]butyronitrile (13.3 g) in a mixture of concentrated sulphuric acid (100 cut) and water (20 cnr) was heated to 80°C for 2 hours.
GLC Analysis of a withdrawn sample of the mixture then showed the absence of starting material, but the presence of a new peak with retention time 6.29 minutes. The cooled reaction mixture was added dropwise to a solution of sodium nitrite (25.78 g) in water (50 cm3) at the ambient temperature.
Two hours after the addition was complete the reaction mixture was taken to pH 10 by addition of solid and aqueous sodium carbonate, and washed with ethyl acetate. The aqueous fraction was acidified to pH 4 to 5 with concentrated aqueous hydrochloric acid and extracted with chloroform, and the combined organic extracts were dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent under reduced pressure to give (RS)-2-(2-(1,1-dimethylethyl)pyrimidiη-5-y1(-3,3dimethyibutanoic acid, identical to the material generated in Example 10.
EXAMPLE 16
This Example illustrates the preparation of methyl 5 (RS)-2-(2-(1,1-dimethylethyl)pyrimidin-5-yl1-3,3,3trifluoropropionate.
(i) 2-(1,1-dimethylethyl)-5-trifluoroacetylpyrimidine
A solution of 5-bromo-2-(1,1dimethylethyl)pyrimidine (3.133 g) in dry tetrahydrofuran (5 cm^) was added in portions to a mixture of magnesium turnings (Grignard quality, 0.40 g) in tetrahydrofuran (5 cm^) and a crystal of iodine as catalyst. The reaction was stirred under a nitrogen atmosphere and the reaction allowed to warm to the reflux temperature by controlling the addition of the bromopyrimidine. When the addition was complete the mixture was stirred for a further 30 minutes. To the stirred mixture at the ambient temperature was added (in portions) dry Ν,Ν-dimethyltrifluoroacetamide (2.088g) and the reaction was stirred for an additional 1 hour after complete addition. The reaction was treated with saturated aqueous ammonium chloride solution, and extracted (twice) with ethyl acetate. The organic fractions were combined, dried (magnesium sulphate) and the solvent evaporated under reduced pressure to yield a brown oil (3.09 g). The oil was distilled (b.p ca 100°C/12mm Hg) to give a pale yellow semi solid (2.35 g). Infra Red Spectroscopy indicated this product to be the hydrate of the required ketone.
APO00057
The semi-solid (2.2 g) was mixed with phosphorous pentoxide (2.34 g), heated to 100°C and distilled from the residue under a dry nitrogen atmosphere at reduced pressure (12 mm Hg) to yield a colourless liquid (ca 1.6 g). The product was stored under dry nitrogen to avoid rehydration .
Infra Red (liquid film): 2965, 1729, 1583, 1533, 1483, 1440, 1388, 1364, 1217, 1148,
939, 822, 759, 723 cm-1.
Molecular Ion: 232
GLC Retention Time: 1.39 minutes (ii) 1,1-dichlor0-2-(2-(1,1-dimethylethyl)-pyrimidin-5yl]-3,3,3-t rifluoroprop-l-ene
2-(1,1-dimethylethy1-515 trifluoroacetylpyrimidine (0.9 g) was dissolved in dry carbon tetrachloride (15 era3) containing triphenylphosphine (2.5 g). The reaction mixture was stirred under a nitrogen atmosphere and heated at the reflux temperature for 30 hours to give a deep red-brown solution. The reaction mixture was fractioned by filtering the cooled solution through a short column of silica gel and eluting with a mixture of hexane/dichloromethane (3:1 by volume). On evaporation of the solvents the product was obtained as a colourless solid (0.9 g)
Melting Point 58°C.
. 1H NMR (CDC13): 1.45 (s,9H), 8.60 (s,2H)
GLC Retention Time: 2.60-minutes (iii) Methyl (RS)-2-[2-(l,l-dimethylethyl)pyrimidin-5-yl]3,3,3-trifluoropropionate.
l,l-dichloro-2-[2-(l,l-dimethylethyl)pyrimidin-5-yl]3,3,3-trifluoroprop-l-ene (0.40 g) was dissolved in dry methanol (10 cm2) containing potassium hydroxide (0.22 g). The reaction mixture was stirred at the ambient temperature for 5 hours.
. A sample was withdrawn from the reaction mixture, diluted with water and extracted into ethyl acetate.
GLC/MS analysis showed this to contain a mixture of (i) E and Z l-chloro-l-methoxy-2-[2-(1,1-dimethylethyl)pyrimidin5-yl]-3,3,3-trifluoroprop-l-ene (GLC Retention Time: 3.15, e
3.32 minutes, Molecular Ion: 294), (ii) l,l-dimethoxy-2-[2(1,1-dimethylethyl)pyrimidin-5-yl]-3,3,3-trifluoroprop-115 ene (GLC Retention Time: 3.67 minutes) and (iii) methyl (RS)-2-(2-(1,1,-dimethylethyl)pyrimidin-5-y11-3,3,3trifluoropropionate (GLC Retention Time: 2.64 minutes, Molecular Ion: 276).
After a further 18 hours at the ambient temperature the mixture was partially evaporated under reduced pressure (to ca 3 cm2 in volume) and acidified with concentrated hydrochloric acid to pHl. The reaction mixture was stirred at the ambient temperature for 4 hours, extracted with dichloromethane, washed with water and dried (anhydrous magnesium sulphate). The solvent was evaporated to yield an oil which was fractionated by eluting through a column of silica gel with dichloromethane/ethyl acetate (100:5 by volume). The product was obtained as a colourless oil [0.15 g].
XH NMR (CDC13): 1.40 (s,9H), 3.85 (s,3H), 4.30 (q,lH),
8.75 (s,2H)
GLC Retention Time: 2.64 minutes.
EXAMPLE 17
This Example illustrates the preparation of (RS)-2-[2(1,1-dimethylethyl)pyrimidin-5-yl] - 3,3-dimethylpent-4-enoic acid..
(i) 3-methylbut-2-en-l-yl 2-(2-(1,1dimethylethyl]pyrimidin-5-yl]acetate
Prepared according to the esterification process described in Example 19, Method 1 from 3-methylbut-2-en-lol and 2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]acetic acid 1H NMR (CDC13); 1.45 (9H,s); 1.70 (3H,s); 1.75 (3H,s); 3.60 (2H,s); 4.65 (2H,d); 5.35 (lH,m); 8.60 (2H,s)
GLC Retention Time: 5.72 minutes (ii) 2-(2-(1,1-d imethy lethy Dpyrimidin-5-yl]-3,3dimethylpent-4-enoic acid
3-methylbut-2-en-l-yl 2-(2-(1,1-dimethylethyl)pyrimidin-5-yl]acetate (0.366 g) was dissolved in dry toluene (5 cm2) containing sodium amide (0.068 g) and heated to the reflux temperature with stirring under a nitrogen atmosphere. After heating for 2\ hours the reaction was cooled to the ambient temperature and diluted with water. The organic layer was separated and the aqueous fraction re-extracted with ethyl acetate. The aqueous layer was acidified (2M HCl) and extracted with chloroform (3 times). The chloroform fractions were combined, dried (MgSO^) and evaporated under reduced pressure to give a light brown solid (0.283 g) shown by GLC analysis to contain a major component in 70% purity, identified as (RS)-2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]5 3,3-dimethylpent-4-enoic acid.
GLC Retention Time: 6.0 minutes (70%).
Molecular Ion: 262
A second component (19%) was identified as 2-(2-(1,1dimethylethyl)pyrimidin-5-yl]acetic acid.
GLC Retention Time: 4.0 minutes
EXAMPLE 18
This Example illustrates the preparation of ethyl (RS)-2-(2-chloropyrimidin-5-yl)-3-methylbutanoate.
(i) Preparation of ethyl (RS)-2-(2-aminopyrimidin-5-yl)-315 methylbutanoate
A solution of sodium methoxide (0.9 g) in ethanol (5 cm·*) was added dropwise to a stirred suspension of guanidine hydrochloride (1.58 g) and ethyl (RS)-4dimethylamino-3-formy1-2-(1-methylethyl)-3-butenoate in ethanol (10 cm·*). The reaction mixture was heated at the reflux temperature for 2 hours, then stood at the ambient temperature for 70 hours. The solvent was evaporated under reduced pressure and water added to the residue.
The reaction products were extracted into ethyl * acetate, and the combined organic layers dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure gave the title compound (1.08 g) as
APO00057 an oil which crystallised on standing.
NMR (CDC13): 0.78 (3H,d); 1.02 (3H,d); 1.23 (3H,t); 2.23 (lH,m); 2.97 (lH,d); 4.15 (2H,q); 5.23 (2H,broad s); 8.25 (2H,s).
Molecular Ion: 223 (ii) Preparation of Ethyl {RS)-2-(2-chloropyrimidin-5-yl)3-methylbutanoate and ethyl (RS)-2-(pyrimidin-2-one5-yl)-3-methybutanoate.
A solution of sodium nitrite (1.33 gm) in water (5 cm3) was added dropwise to a cooled solution of ethyl (RS)-2-(2-aminopyrimidin-5-yl)-3-methylbutanoate (1.08 g) in concentrated aqueous hydrochloric acid solution (14.5 cm3), the temperature of the reaction mixture being maintained at less than 5°C during the addition. The mixture was stirred at 0°C for 3 hours, then allowed to warm to the ambient temperature and stood for 16 hours.
The mixture was then cooled in an ice bath and neutralised by dropwise addition of aqueous potassium carbonate solution (the temperature of the mixture being maintained below 4°C). The products were extracted into dichloromethane, the organic layers being washed with water and dried over anhydrous magnesium sulphate. Removal of the solvent by evaporation under reduced pressure gave a mixture of two products which was separated by column chromotography on a silica gel support, eluting firstly with dichloromethane containing 2% by volume ethyl acetate to give ethyl (RS)-2-(2-chloropyrimidin-5-yl)-3methylbutanoate (0.27 g), Product A, and secondly with dichloromethane containing 10% by volume methanol to give » ethyl (RS)-2-(pyrimidin-2-one-5-yl)-3-methylbutanoate, (0.34 g), Product B.
PRODUCT A XH NMR (CDC13): 0.80 (3H,d); 1.08 (3H,d); 1.30 (3H,t); 1.32 (lH,m); 1.22 (lH,d); 4.16 (2H,m); 8.64 (2H,s)
Molecular ion: 242
PRODUCT B
Melting Point: 142-144°C.
Molecular ion: 296
EXAMPLE 19
This Example illustrates five alternative esterification processes for preparing the esters of formula (I) according to the invention.
METHOD 1 (dicyclohexylcarbodiimide coupling of acid and alcohol)
Preparation of 2,3,5,6-tetrafluoro-4(methoxymethy1)benzyl (RS)-2-(2-(1,115 dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate ( Compound No 15).
A solution of (RS)-2-[2-(l,l-dimethylethyl)pyrimidin5-yl]-3,3-dimethylbutanoic acid (0.1 g), 2,3,5,6tetrafluor0-4-(methoxymethyl)benzyl alcohol (0.089 g) and · 4-dimethylaminopyridine (0.002 g) in dry dichloromethane (4 cm2) was stirred at the ambient temperature (20°C) whilst
N,N'-dicyclohexylcarbodiimide (0.084 g) was added in
AP0 0 0 0 5 7 portions; the mixture was stirred for 18 hours. The solution was passed through silica gel and the silica gel eluted with, firstly, dichloromethane and, secondly a 50:1 mixture (by volume) of dichloromethane and ethyl acetate Evaporation of the solvents of the combined filtrate and eluted fractions gave the title compound (0.09 g) as a colourless oil.
XH NMR (CDC13): 1.0 (9H,S); 1.5 (9H,s); 3.4 (4H,broad s); 3.6 (2H,broad s); 5.25 (2H,q); 8.72 (2H,s).
GLC Retention Time: 8.14 minutes
Molecular ion: 456
METHOD 2 (1-ethy1-3-( dimethylami nopropyl) carbodiimide coupling of acid and alcohol)
Preparation of 2,3,5,6-tetrafluoro-4-(methoxymethyl) benzyl (RS)-2-(2-methylpyrimidin-5-yl)-3,3-dimethy1butanoate (Compound No 120).
A solution of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.276 g) in dry dichloromethane (6 cm^) was added to a stirred solution of (RS)-2-(2-methylpyrimidin-5-y1)-3,3-dimethylbutanoic acid (0.3 g) and 4-(methoxymethyl)-2,3,5,6-tetrafluorobenzylalcohol (0.33 g) containing a catalytic amount of 4-(N,N'-dimethylamino) pyridine. The stirred mixture was maintained at the ambient temperature for 2 hours, and left to stand overnight. The reaction solution was washed with water, dried over anhydrous magnesium sulphate and * concentrated by evaporation of the solvent under reduced pressure. The residue was subjected to column chromatography on silica’gel using a 1:1 (by volume) mixture of ethyl· acetate and dichloromethane as eluent to give 2,3,5,6-tetrafluoro-4-( methoxymethyl) benzyl (RS)-2-(2methylpyrimidin-5-yl)-3,3-dimethylbutanoate (0.228 g) as a yellow oil.
270 MHz LH NMR (CDCl-j): 0.99 (9H,s); 2.73 (3H,s); 3.38 (lH,s), 3.40 (3H,s); 4.58 (2H,s);
5.2 (lH,d); 5.3 (lH,d ),-8.68 (2H,s).
GLC Retention Time: 8.98 minutes
METHOD 3 (Base catalysed reaction of acid with halide, mesylate or tosylate derivative of alcohol)
Preparation of 4-fluoro-3-phenoxybenzyl (RS)-2-(2methylpyrimidin-5-yl)-3,3,-dimethylbutanoate (compound No 206 ) .
Solid potassium carbonate (0.4 g) was added to a solution of 4-fluoro-3-phenoxybenzyl bromide (0.4 g) and ( RS)-2-(2-methylpyr imidin-5-yl)-3,3-dimethylbutanoic acid (0.3 g) in acetone (20 cm3), and the mixture was stirred for a period of 6 hours. After standing for a further 2 days, the reaction mixture was filtered, the residue washed with acetone, and the combined filtrate and acetone washings concentrated by evaporation of the solvent under reduced pressure to give an orange oil. Column chromatography on silica gel using dichloromethane followed by ethyl acetate as eluent gave 4-fluoro-3-phenoxybenzyl (RS)-2-(2-methylpyr imidin-5-yl)-3,3-dimethylbutanoate (0.33 g) as an orange oil, which solidified on standing.
270 MHz NMR (CDCI3): 0.95 (9H,s); 2.72 (3H,s); 3.38 (lH,s); 4.95 (lH,d); 5.1 (lH,d);
APO00057
6.9-7.4 (8H,m); 8.67 (2H,s) .
GLC Retention Time: 11.42 minutes
METHOD 4 (Titanium alkoxide catalysed transesterification between simple alkyl ester and alcohol)
Preparation of 2,3,5,6-tetrafluoro-4-methylbenzyl (RS)-2-[2-(1,1-dimethylethyljpyrimidin-5-y1)-3,3dimethylbutanoate (compound No 4).
A mixture of ethyl (RS)-2-[2-(1,1dimethylethyl)pyr imidin-5-yl]-3,3-dimethylbutanoate (0.07 g), 2 ,-3,5,6-tetraf luoro-4-methylbenzyl alcohol (0.1 g), titanium IV ethoxide (catalytic amount) and dry toluene (2 cm3) was heated at the reflux temperature for 10 hours. After cooling, the solvent was evaporated under reduced pressure to leave a brown gum, which was purified by preparative thin layer chromatography on 20 cm x 20 cm x 0.2 cm silica gel plates, eluting with dichloromethane containing 2% by volume ethyl acetate, to give the title compound (0.05 g) as an oil which solidified on standing.
Melting Point: 91°C 1H NMR (CDC13): 1.0 (9H,s); 1.4 (9H,s); 2.28 (3H, broad s); 3.38 (lH,s); 5.18 (2H,q); 8.72 (2H,s) .
GLC Retention Time: 8.57 minutes.
Molecular ion: 426 , METHOD 5 (Reaction between acid chloride and alcohol or thioalcohol)
Preparation of 4-hydroxymethyl-2,3,4,6tetrafluorobenzyl (RS)-2-[2-(l,l-dimethylethyl)pyrimidin-5yl]-3,3-dimethylbutanthioate (compound No 196).
(RS)-2-[2(l,l-dimethylethyl)pyrimidin-5-yl]-3,35 dimethylbutanoic acid (0.20 g) was treated with thionyl chloride (2 cm3) and heated to reflux with stirring for 2.5 hours. Unreacted thionyl chloride was evaporated under reduced pressure to leave a gum containing (RS)-2-[2-(l,ldimethylethyl)pyrimidin-5-yl]-3,3-dmethylbutanoyl chloride.
The gum was dissolved in dry dichloromethane (3 cm3) and added dropwise at the ambient temperature to a stirred solution of 4-hydroxymethyl-2,3,5,6-tetrafluorobenzylmercaptan [0.181 g) in dry dichloromethane (2 cm3) containing dry triethylamine (0.1 cm3). The reaction mixture was stirred for 2 hours and further triethylamine (0.05 cm3) added. After stirring for a further 4 hours the mixture was diluted with dichloromethane and dilute hydrochloric acid. The organic layer was separated and the aqueous fraction extracted with further dichloromethane.
The organic fractions were combined, washed with water and dried over anhydrous magnesium sulphate. The solvent was evaporated under reduced pressure to yield an oil (0.30 g) .
This oil was fractionated by eluting through a bed of silica gel (Merck 7729) with (1) dichloromethane and (2) dichloromethane/ethyl acetate (100:5 by volume) to give the required thioester as a colourless solid (0.13 g).
Melting point 38-41°C.
1H NMR (CDC13): 1.0 (s,9H); 1.40 (s,9H); 2.1 (t,lH); 3.50 (S,1H); 4.20 (dd,2H); 4.80 (d,2H); 8.65 (S,2H)
GLC Retention Time: 14.36 minutes
APO 0 0 0 5 7
EXAMPLE 20
The follow;. ; esters were prepared from the appropriate starting materials acording to one of the methods described in Example 19.
(i) 2,3,5,6-tetrafluoro-4-(prop-2-yn-l-yl) benzyl (RS) — 2 — [2-(l,l-dimethylethyl)pyrimidin-5-yl]-3,3dimethylbutanoate (compound No 12) using method 1.
1H NMR (CDC13): 1.0 (9H,s); 1.4 (9H,s); 2.05 (lH,m); 3.4 (lH,s); 3.6 (2H,broad s); 5.4 (2H,q); 8.75 (2H,s) .
GLC Retention Time: 9.55 minutes
Molecular ion: 450 (ii) 2,3,5-tr i fluoro-6-methoxy-4-(methoxymethyl) benzyl (RS)-2-(2-(1,1-dimethylethyl)pyrimidin-5-y1)-3,3dimethylbutanoate (compound No 16) using method 3 or .
1H NMR (CDC13): 1.0 (9H,s); 2.4 (9H,s); 3.38 (lH,s); 3.4 (3H,s); 3.9 (3H, broad s);
4.56 (2H,broad s); 5.2 (2H,q); 8.75 (2H,s) .
GLC Retention Time: 10.3 minutes.
Molecular ion: 468 (iii) 2,3,5,6-tetrafluoro-4-(prop-2-en-l-yl)benzyl (RS)-2(2-tr i fluoromethylpyr imidin-5-yl)-3methylbutanoate.(compound No 114) using method 4.
1H NMR (CDC13): 0.8 (3H,d); 1.04 (3H,d); 2.4 (lH,m); 3.4 (3H,m); 5.08 (4H,m); 5.8 (lH,m); 8.88 (2H,s).
Molecular ion: 450 (iv) 2,3,5,6-tetrafluoro-4-(prop-2-yn-l-yl)benzyl (RS)-2( 2-tr ifluoromethylpyrimidin-5-yl)-3-methylbutanoate (compound No 87) using method 1.
1H NMR (CDC13): 0.8 (3H,d); 1.04 (3H,d); 2.06 (lH,m); 2.40 (lH,m); 3.36 (lH,d); 3.64 (2H,broad); 5.26 (2H,q); 8.86 (2H,s).
(v) 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl (RS)-2-(2trifluoromethylpyrimidin-5-yl)-3-methylbutanoate (compound No 116) using method 1.
ΣΗ NMR (CDCl-j): 0.80 (3H,d); 1.06 (3H,d); 2.04 (lH,m);
15 3.36 (lH,d); 3.41 (3H,s); 4.58 (2H,broad); 5.28 (2H,broad s); 8.88 (2H,s).
APO 0 0 0 5 ?
Molecular ion: 454 (vi) 2,3,5,6-tetrafluoro-4-(prop-2-en-l-yl)benzyl (RS)-2[2-(N,N-dimethylamino)pyrimidin-5-yl]-320 methylbutanoate (compound No 115) using method 4.
NMR (CDC13): 0.76 (3H,d); 1.00 (3H,d); 1.26 (lH,m);
3.00 (lH,d); 3.18 (6H,s); 3.48 (2H,m);
5.16 (4H,m); 5.88 (lH,m); 8.25 (2H,s).
.Molecular ion: 425 (vii) 2,3,5,6-tetrafluoro-4-(prop-2-en-l-yl)benzyl (RS) —298 (2-tr ichloromethylpyr imidin-5-yl)-3methylbutanoate (compound No 117) using method 4.
NMR (CDC13): 0.80 (3H,d); 1.02 (3H,d>; 2.40 (lH,m);
3.34 (lH,d); 3.46 (2H,m); 5.04 (4H,m);
5.88 (lH,m); 8.86 (2H,S) .
Molecular ion: 498 (viii) 4-fluoro-3-phenoxybenzyl (RS)-2-[2-(1,1dimethylethyl)pyrimidin-5-yl]-2cyclopropylacetate (compound No 125) using method 1.
1H NMR (CDCl-j): 0.16 (lH,m); 0.40 (lH,m); 0.60 (2H,m);
1.36 (lH,m); 1.41 (9H,s); 2.80 (lH,d);
5.08 (2H,d); 7.40-6.94 (8H,m); 8.66 (2H,s) .
GLC Retention Time: 10.45 minutes.
Molecular ion: 434.
(ix) (RS)-l-(6-phenoxypyrid-2-yl)ethyl (RS)-2-(2-(l,ldimethylethyl)pyr imidin-5-yl]-2-cyclopropylacetate. (compound No 90) using method 1.
XH NMR (CDC13): 0.20-0.66 (4H,m)? 1.42 (9H,s}; 1.42 (lH,m); 1.52 (3H,m); 2.84 (lH,d); 5.84 (lH,m); 6.70 (lH,t); 6.86, 6.94 (1H, 2d); 7.14 (2H,m); 7.20 (lH,m); 7.38 (2H,m);
7.60 (lH,2t); 8.68 (2H,d) •GLC Retention Time: 10.17, 10.26 minutes.
(mixture of diastereoisomers)
Molecular ion: 431.
(x) 3,5,6-trifluoro-2-methoxy-4-(methoxymethyl) benzyl (RS) —
2-(2-(1,1-dimethylethyl)pyrimidin-5-yl]-2cyclopropylacetate (compound No 92) using method 1.
5 1H NMR (CDCI3): 0.18 (lH,m); 0.46 (lH,m); 0.60 (lH,m);
0.72 (lH,m); 1.41 (9H,s); 1.44 (lH,m);
2.80 (lH,d); 3.41 (3H,s); 3.85 (3H,s);
4.59 (2H,s); 5.24 (2H,s); 8.67 (2H,s) .
GLC Retention Time: 8.95 minutes.
Molecular ion: 452 (xi) 2,3,5,6-tetrafluoro-4-(prop-2-yn-l-yl)benzyl (RS)-2[2-(1,1-dimethylethyl)pyrimidin-5-yl]-2cyclopropylacetate (compound 91) using method 1.
H NMR (CDC13) : 0.18 (lH,m); 0.44 (lH,m); 0.62 (lH,m);
0.72 (lH,m); 1.41 (1H, m) ; 1.41 (9H,s);
2.08 (lH,m); 2.82 (lH,d); 3.64 (2H,broad
s ) ; 5 .27 (2H , s); 8 .68 (2H ,s) .
AP 0 0 0 0 5 7
GLC Retention Time: 8.15 minutes.
(xii) 2,3,5,6-tetrafluoro-4-(prop-2-en-l-yl)benzyl (RS)-220 [2-(1,1-dimethylethy1)pyrimidin-5-yl]butanoate.
(compound No 123) using method 1.
1H NMR (CDC13): 0.95 (3H,t); 1.4 (9H,s); 1.85, 2.15 (2H,m); 3.45 (2H,d); 3.45 (lH,t); 5.1 (2H,2d); 5.9 (lH,m); 5.2 (2H,2d); 8.6 (2H,s).
100
GLC Retention Time: 8.26 minutes.
(xiii) 2,3,5,6-tetrafluoro-4-methyl (RS)-2-[2-(1,1dimethylethyl)pyrimidin-5-yl]butanoate (compound No 122) using method 1.
1H NMR (CDC13): 0.9 (3H,t); 1.4 (9H,s); 1.8, 2.15 (2H,m);
2.3 (3H,t); 3.45 (2H,t); 5.2 (2H,2d); 8.6 (2H,s).
GLC Retention Time: 7.52 minutes.
(xiv) (RS ) -®(-cyano-4-f luoro-3-phenoxybenzyl (RS)-2-[210 (l,l-dimethylethyl)pyrimidin-5-yl]butanoate (compound No 121) using method 1.
1H NMR (CDC13): 0.8-1.0 (3H,2t); 1.4 (9H,s); 1.8, 2.1 (2H,m); 3.5 (lH,t); 6.3 (lH,2s); 6.9-7.4 (8H,m); 8.6 (2H,2s).
GLC Retention Time: 11.26, 11.49 minutes.
Physical data consistent with 66:34 mixture of 2 diastereoisomers.
(xv) 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl (RS)-2(2-chloropyrimidin-5-yl)-3-methylbutanoate (compound 20 No 118) using method 4.
XH NMR (CDC13): 0.78 (3H,t); 1.02 (3H,t); 2.32 (lH,m);
3.20 (lH,d); 3.36 (3H,s); 4.56 (2H, broad s); 5.22 (2H,q); 8.56 (2H,s).
Molecular ion: 420
101 (xvi) 4-(Prop-2-en-l-yl)-2,3,5,6-tetrafluorobenzyl (RS)-2[2-methylpyrimidin-5-yl]-3-methylbutanoate ( compound No 119) .
XH NMR (CDC13): 0.75 (d,3H); 1.00 (d,3H); 2.35 (m,lH);
2.75 (s,3H); 3.20 (d,lH); 3.50 (m,2H);
5.05-5.30 (m,4H); 5.85-5.95 (m,lH); 8.60 (S,2H)
GLC Retention Time: 6.75 minutes (95%).
(xvii) 4-(methoxymethyl)-2,3,5,6-tetrafluoroenzyl (RS)—ΣΙ 0 (2-methylpyrimidin-5-yl)-3-methylbutanoate (compound No 214) by method 1.
1H NMR (CDC13): 0.75 (d,3H); 1.05 (d,3H); 2.35 (m,lH);
2.75 (s,3H); 3.20 (d,lH); 3.40 (s,3H);
4.60 (s,2H); 5.2-5.3 (dd,2H); 8.60 (s,2H)
GLC Retention Time: 7.04 minutes
Z SO 00OdV (xviii) 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl (RS)2-[2-(1-methylcyclopropyl)pyrimidin-5-yl]-3,3dimethylbutanoate (compound No 139) using method
2.
400 MHz ΧΗ NMR (CDC13): 0.90 (2H,m); 0.95 (9H,s); 1.35 (2H,m); 1.55 (3H,s); 3.35 (lH,s);
3.40 (3H,s); 4.60 (3H,s); 5.17 (lH,d); 5.25 (lH,d); 8.60 (2H,s)
GLC Retention Time: 10.38 minutes «
(xix) (RS)-l-(6-phenoxypyrid-2-yl)ethyl (RS)-2-[2-timet hyl cyclopropyl )pyrimidin-5-yl]-3,3102 dimethylbutanoate (compound No 203) using method .
MHz 1H NMR (CDC13): 0.90 (2H,m); 0.95 and 1.00 (9H,s);
1.35 (2H,m); 1.45 and 1.55 (3H,d);
1.58 (3H,s); 3.38 and 3.42 (S,1H);
5.8 (lH,m); 6.65-7 .65
(8H, complex ); 8.62 and 8.64 (2H,s)
GLC Retention Time: 12.31 and 12.58 minutes (mixture of diastereoisomers) (xx) RS-l-(6-phenoxypyrid-2-yl)ethyl (RS)-2-(2methylpyrimidin-5-y1)-3,3-dimethylbutanoate using method 2 (compound No 205)
400 MHz ΣΗ NMR (CDC13): 0.9 and 1.0 (9H,s); 1.45 and 1.55 (3H,d); 2.72 and 2.74 (3H,s); 3.40 and 3.43 (lH,s); 5.8 (lH,m); 6.657.7 (8H,m); 8.68 and 8.70 (2H,s)
GLC Retention Time: 11.08 and 11.28 minutes (mixture of diastereoisomers) (xxi) 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl (RS)-2[2-(1,1-dimethylpropyl)pyrimidin-5-y1)-3,3dimethylbutanoate using method 2 (compound No 61).
400 MHz 1H NMR (CDC13): 0.7 (3H,t); 0.99 (9H,s); 1.37 (6H,s); 1.80 (2H,q); 3.38 (lH,s);
3.40 (3H,s); 4.6 (2H,s); 5.15 (lH,d); 5.3 (lH,d); 8.70 (2H,s)
GLC Retention Time: 10.21 minutes
103 (xxii) (RS)-1-(6-phenoxypyrid-2-yl)ethyl (RS) —2 — [2—(1,1dimethylpropyl)pyrimidin-5-yl)-3,3dimethylbutanoate using method 2 (compound No 57)
400 MHz XH NMR (CDC13): 0.6 (3H,m); 1.85 and 1.95 (9H,s);
1.30 and 1.32 (6H,s); 1.4 and 1.5 (3H,d); 1.75 (2H,m); 3.35 and 3.38 (lH,s); 5.75 (lH,m); 6.6-7.6 (8H,m); 8.65 (2H,s)
GLC Retention Time: 12.13 and 12.34 minutes (mixture of diastereoisomers) (xxiii) 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl (RS)10 2-[2-(l-methylethyl)-pyrimidin-5-y1)-3,3dimethylbutanoate using method 1 (compound No 131)
250 MHz 1H NMR (CDCl-j): 0.95 (9H,s); 1.25 (6H,d); 3.15 (1H,septet); 3.35 (3H,s); 3.36 (1H,S); 4.50 (2H,s); 5.15 (lH,d);
5.25 (lH,d); 8.65 (2H,s) (xxiv) 4-methyl-2-thiomethyl-3,5-difluorobenzyl (RS)-2-[2(1,1-dimethylethyl)pyrimidin-5-yl)-3,3dimethylbutanoate using method 2 (compound No 182) 1H NMR (CDC13): 1.00 (s,9H); 1.40 (s,9H); 2.20 (m,3H);
2.30 (s,3H); 3.42 <S,1H); 5.24-5.36 (bq, 2H); 6.88 (bd, 1H); 8.72 (s,2H)
GLC Retention Time: 10.51 minutes (xxv) 4-(EZ-3-chloroprop-2-en-l-yl)-2,3,5,625 » tetrafluorobenzyl (RS)-2-[(1,1dimethylethyl)pyrimidin-5-yl)-3,3-dimethylbutanoate (E:Z ratio 1:2) using Method 2 (compound No 14)
APO00057
104 XH NMR (CDC13): 1.00 (s,9H); 1.40 (s,9H); 3.40 (s,lH);
3.50 , 3.70 (2d broad, 2H) ; 5.12-5.30 (bq, 2H); 5.80-6.20 (m,2H); 8.72 (s,2H)
GLC Retention Time: 10.66 minutes (E isomer) 10.73 minutes (Z isomer) (xxvi) 4-(3-(tr iethylsilyl) prop-1-yl]-2,3,5,6-tetrafluorobenzyl (RS)-2-[2-(1,1-dimethylethyl)pyrimidin-5yl]-3,3-dimethylbutanoate using method 2 (compound No 218) 1H NMR (CDC13): 0.42-0.60 (m,8H); 0.88-0.95 (m,9H); 1.00 (S,9H); 1.40 (s,9H); 1.55-1.65 (m,2H); 2.70-2.80 (m,2H); 3.40 (S,1H); 5.12-5.30 (bq, 2H); 8.72 (s,2H)
GLC Retention Time: 12.84 minutes (xxvi i) 4-(Prop-2-ylideneaminoxymethyl)-2,3,5,6tetrafluorobenzyl (RS)-2-(2-(1,1dimethylethyl)pyrimidin-5-yl]-3,3dimethylbutanoate using method 2 (compound No 178 )
NMR (CDC13): 1.00 (s,9H); 1.41 (s,9H); 1.82 (d,6H); 3.40 (s,lH); 5.14 (bs, 2H); 5.14-5.32 (bq,
2H); 8.72 (s,2H)
GLC Retention Time: 10.68 minutes (xxviii) 4-((1,1-dimethylethyl)thio]methyl-2,3,5,6tetrafluorobenzyl (RS) — 2 —[2-(1,1 — dimethylethy1)pyrimidin-5-yl]-3,3dimethylbutanoate using method 2 (compound No
105
175)
NMR (CDC13); 1.00 (S,9H); 1.40 (s,9H); 1.42 (s,9H); 3.40 (s IH ) ; 3.80 (bs, 2H);
5.12-5.30 (bq, 2H); 8.72 (s,2H)
GLC Retention Time: 11.54 minutes (xxix): 4-[(1-methylethyl) thiomethyl-2,3,5,6tetrafluorobenzyl (RS)-2-(2-(1,1dimethylethyl)pyrimidin-5-yl]-3,3dimethylbutanoate using method 2 (compound No
174) XH NMR (CDC13): 1.00 (s,9H); 1.30 (d,6H); 1.40 (s,9H);
2.82-2.96 (m,lH); 3.40 (s,lH) 3.80 (bs, 2H); 5.12-5.30 (bq, 2H); 8.72 (s,2H)
GLC Retention Time: 11.23 minutes (xxx) 4-[(piperidin-l-yl) methyl]-2,3,5,6-tetrafluorobenzy1 (RS)-2-(2-(1,1-dimethylethyl)pyrimidin-5-y1)-3,3dimethylbutanoate using method 2 (compound No 177) ΣΗ NMR (CDC13): 1.00 (s,9H); 1.32-1.44 (m,2H); 1.41 (s,9H); 1.52-1.64 (bs, 4H); 2.38-2.52 (bs,
4H); 3.40 (S,1H); 3.72-3.80 (bs, 2H);
5.12-5.32 (bq, 2H); 8.72 (s,2H)
GLC Retention Time: 11.84 minutes (xxxi) 4-((2,2-dichlorccyc iopropyl) methyl]-2,3,5,6 — tetrafluorobenzyl (RS)-2-[2-(1,125 dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate using method 2 (compound No 216)
APO 00 05 7
106 XH NMR (CDC13): 1.00 (s,9H); 1.22-1.34 (m,lH); 1.41 (s,9H);
1.60-1.66 (m,lH) 1.80-2.00 (m,lH); 2.722.84 (m,lH); 3.20-3.27 (m,lH); 3.40 (s,lH); 5.12-5.30 (bq, 2H) 8.72 (s,2H)
GLC Retention Time: 11.75 minutes (xxxii) 4-( cyclopropylmethyl)-2,3,5,6-tetrafluorobenzyl (RS)-2-[2-(l,l-dimethylethyl)pyrimidin-5-yl]-3,3aimethylbutanoate using method 2 (compound No 179) 1H NMR <CDC13): 0.25-0.3 (m,2H); 0.45-0.55 (m,2H); 1.00 (S,9H); 1.15-1.25 (m,lH); 1.40 (s,9H);
2.6-2.7 (bd, 2H); 3.40 (S,1H); 5.15-5.30 (bq, 2H) 8.75 (s, 2H)
GLC Retention Time: 10.27 minutes (xxxiii): 4-(N,N-dimethylami nomethyl )-2,3,5,615 tetrafluorobenzyl (RS)-2-[2-(1,1dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate using method 2 (compound No 176) LH NMR (CDC13): 1.00 (s,9H); 1.08 (bt, 6H); 1.41 (s,9H);
2.54 (bq, 4H); 3.40 (S,1H); 3.76 (bs, 2H);
5.10-5.30 (bq, 2H); 8.72 (s,2H)
GLC Retention Time: 10.81 minutes (xxxiv) (RS)-1-[6-(4-chlorophenoxy)pyrid-2-yl]ethyl (RS)2-(2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3dimethylbutanoate using method 2 (compound No 181) 1H NMR (CDC13): 0.94 (s); 1.01 (s); 1.42 (bs); 1.44-1.5
107
(m) ; 3.42 (bs); 5 .72-5.84 (m); 6.68-7.72
( m) ; 8.72 (bs) . Integration consistent
with 3 : 2 mixture of diastereoisomers
GLC Retention Time: 12 .47 minutes (60%) 12.72 minutes
(40%) (xxxv) 2,3,4,5,6-pentafluorobenzyl (RS)-2-[2-(l,ldimethylethyl)pyrimidin-5-yl]-3,3dimethylbutanoate using method 2 (compound No 30) :H NMR (CDC13): 1.00 (s,9H); 1.40 (s,9H); 3.45 (S,1H);
5.20 (q,2H); 8.70 (s,2H)
GLC Retention Time: 7.62 minutes (xxxvi) 4-(prop-2-en-l-y1)-2,3,5,6-tetrafluorobenzyl (RS)2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3dimethylbutanoate using method 2 (compound No 5)
15 ΣΗ NMR (CDC13; 1: 1.00 (s,9H); 1.40 (S,9H); 3.40 (S,1H);
5.10 (m,2H); 5.20 (q,2H); 5.90 (m,lH);
8.70 (s,2H)
GLC Retention Time: 9. 42 minutes
(xxxvii) 2-methyl-3,4,5,6-tetrafluorobenzyl (RS)—2—[2— 20 (l,l-dimethylethyl)pyrimidin-5-yl]-3,3dimethylbutanoate using method 2 (compound No 219) l-H NMR (CDC13): 1.00 (s,9H); 1.40 (s,9H); 2.20 (s,3H);
3.35 (S,1H); 5.15 (q,2H); 8.70 (s,2H)
GLC Retention Time: 8.46 minutes
108 (xxxviii) 4-(trimethylsilyl)-2,3,5,6-tetrafluorbenzyl (RS)-2-(2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3 dimethylbutanoate using method 2 (compound No 22 ) 1H NMR (CDC13): 0.41 (s,9H); 1.00 (s,9H); 1.40 (s,9H);
3.40 (s,H); 5.12-5.30 (bq, 2H); 8.72 (s,2H)
GLC Retention Time: 9.81 minutes (xxxix) 4-(n-propyl)-2,3,5,6-tetrafluorobenzyl (RS)—2-(2(l,l-dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate using method 2 (compound No 168) 1H NMR (CDC13): 0.95-1.00 (m,3H); 1.00 <S,9H); 1.40 (s,9H); 1.60-1.70 (m,2H); 2.70-2.75 (bt, 2H); 3.40 (S,1H); 5.12-5.30 (bq, 2H);
8.72 (s,2H)
GLC Retention Time: 9.50 minutes (93%) (xl) 4-benzyl-2,3,5,6-tetrafluorobenzyl (RS)-2-(2-(1,1dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate using method 2 (compound No 17) 1H NMR (CDC13): 1.00 (s,9H); 1.40 (s,9H); 3.40 (s,lH);
4.06 (bs, 2H); 5.12-5.30 (bq, 2H); 7.207.36 (m,5H); 8.72 (s,2H)
GLC Retention Time: 11.93 minutes , (xli) 4-(methylthio)-2,3,5,6-tetrafluorobenzyl (RS)-2[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate using method 2 (compound No 183)
109
XH NMR (CDC13; I: 1.00 (s,9H); 1.40 3.40 (s,lH); 5.20 (S,9H) ; (q,2H); 2.55 8.70 (s,3H); (S,2H)
GLC Retention Time: 9.53 minutes
(xlii, 4-fluoro-3-phenoxybenzyl (RS)-2-(2-(1,15 dimethylpropyl)pyr imidin-5-y11-3,3dimethylbutanoate using method 3 (compound No 68)
270 MHz 1H NMR (CDC13): 0.7 (3H,t); 0.95 (9H,s); 1.37 (6H,s); 1.8 (2H,q); 3.4 (lH,s);
5.0 (lH,d); 5.1 (lH,d); 7.0-7.4 (8H,m); 8.72 (2H,s)
GLC Retention Time: 12.57 minutes (xliii) 4-fluoro-3-phenoxybenzyl (RS)-2-[2-(l-methylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate using method 3 (compound No 197)
250 MHz ΧΗ NMR (CDCl-j): 0.95 (9H,s) ; 1.35 (6H,d); 3.20 (1H,septet); 3.35 (lH,s); 4.95 (lH,d); 5.10 (lH,d); 6.9-7.5 (8H,m); 8.7 (2H,s)
Melting Point: 85°C (xliv) (RS)-1-(6-phenoxypyridin-2-yl) ethyl (RS)-2-[2-(lmethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate using method 3 (compound No 74)
250 MHz 1H NMR (CDCl-j): 0.92 and 1.00 (9H,s); 1.35 and 1.36 (6H,d); 1.45 and 1.55 (3H,d); 3.25 (lH,m); 3.45 and 3.47 (s,lH); 5.80 (lH,m); 6.6-7.7 (8H,m); 8.69 and
ΛΡ0 9905 ?
110
8.70 (2H,s) (Mixture of diastereoisomers) (xlv) 4-fluoro-3-phenoxybenzyl (RS)-2-(2-(N,Ndimethy1amino)pyrimidin-5-yl]-3,3-dimethylbutanoate using method 3 (compound No 200)
250 MHz 2H NMR (CDCIj): 0.95 (9H,s); 3.18 (6H,s); 3.20 (1H,S); 4.95 (lH,d); 5.05 (lH,d); 6.9-7.4 (8H,m); 8.30 (2H,s) (xlvi) 2,3,5,6-tetrafluoro-4-(methoxymethyl) benzyl (RS)— 2-[2-(N,N-dimethylaminopyrimidin-5-yl]-3,3-
dimethylbutanoate using method 3 (compound No 199)
2H NMR (CDCIj): 0.95 (9H,s); 3.15 (6H,S); 3.20
(1H,S); 3.40 (3H,s); 4.58 (2H,s) ;
5.15 (lH,d); 5.25 (lH,d); 8.30
(2H,d)
(xlvii) (RS)-1-(6-phenoxypyrid-2-yl) ethyl (RS)-2-[2-(N,Ndimethylamino)pyrimidin-5-yl]-3,3dimethylbutanoate using method 3 (compound No 198)
250 MHz XH NMR (CDCIj): 0.95 and 1.00 (s,9H); 1.45 and
1.55 (3H,d); 3.18 and 3.19 (6H,s);
3.27 and 3.29 (lH,s); 5.75 (lH,m);
6.6-7.7 (8H,m); 8.35 and 8.37 (2H,s) • (As a mixture of diastereoisomers) (xlviii) 4-fluoro-3-phenoxybenzyl (RS)-2-(2Ill cyclopropylpyrimidin-5-y1)-3,3-dimethylbutanoate using method 3 (compound No 201)
MHz iH NMR (CDC13): 0.95 (9H,s), 1.10 (4H,m); 2.22 (lH,m); 3.35 (lH,s); 4.90 (lH,d);
5.1 (lH,d); 6.80-7.40 (8H,m); 8.50 (2H,s)
Melting Point: 92-93 °C (xlix) 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl (RS)2-(2-eye lopropylpyr imidin-5-yl)-3,310 dimethylbutanoate using method 3 (compound No 135)
250 MHz ΧΗ NMR (CDC13): 0.95 (9H,s); 1.10 (4H,m); 2.23 (lH,m); 3.35 (lH,s); 3.40 (3H,s); 4.58 (2H,s); 5.15 (lH,d); 5.25 (lH,d); 8.58 (2H,s) (1) RS-l-(6-phenoxypyrid-2-yl)ethyl (RS)-2-(2cyclopropylpyrimidin-5-yl)-3,3-dimethylbutanoate using method 3 (compound No 78)
AP000057
250 MHz ΧΗ NMR (CDCl-j): 0.95 and 1.00 (9H,s); 1.20 (4H,m);
1.45 and 1.55 (3H,d); 2.25 (lH,m);
20 3.35 and 3.39 (1H,S); 5.80 (lH,m);
6.65- •7.70 (8H, m); 8.59 and 8.60
(lH,s) (li) 3,5,6-trifluoro-2-methoxy-4-(methoxymethyl)benzyl (RS)-2-[2-(1-methylethyl)pyrimidin-5-y1)-3,325 dimethylbutanoate using method 3 (compound No 76)
250 MHZ 1H NMR (CDC13); 1.00 (9H,s); 1.25 (6H,d); 3.20 (1H, septet); 3.35 (lH,s); 3.40
112 (3H,s); 3.90 (3H,s); 4.45 (2H,s); 5.15 (lH,d); 5.25 (lH,d); 8.72 (2H,s) (lii) 2,3,5,6-tetrafluoro-4-(methoxymethyl) benzyl (RS)-2(2-phenylpyrimidin-5-yl)-3,3-dimethylbutanoate using
250 MHz (liii)
250 MHz
method 3 (compound No 161)
1H NMR (CDC13): 1.05 (9H,s); 3.40 (3H,s); 3.45
(1H, s); 4.68 (2H,s); 5.20 (lH,d);
5.30 (lH,d); 7.5 (3H,m); 8.55
( 2H, m); 8.85 (2H,s)
(RS)-1-(6-phenoxpyr id -2-yl)ethyl (RS)-2-(2-
phenylpyrimidin-5-yl) -3,3-dimethylbutanoate using
method 3 (compound No 82)
1H NMR (CDC13): 0.95 and 1.05 (9H,s); 1.48 and
1.55 (3H,d); 3.48 and 3.52 (lH,s)
5.85 (lH,m); 6.60-7.80 (HH,m);
8.45 (2H,m); 8.83 and 8.87 (2H,s)
(liv) 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl (RS)-2-[2(1,1-dimethylethyl)-pyrimid in-5-yl]-3,320 dimethylpentanoate using method 3 (compound No 210) XH NMR (CDC13): 0.90 (t,3H); 0.9 (s,3H); 1.00 (s,3H); 1.21.4 (m,2H); 1.40 (s,9H); 3.40 (s,3H); 3.50 (s,lH); 4.60 (broad s, 2H); 5.1-5.3 (m,2H); 8.7 (S,2H)
GLC Retention Time: 10.43 minutes (lv) 4-(methylthiomethyl)-2,3,5,6-tetrafluorobenzyl (RS)2-[2-(l,1-dimethy1ethyl)pyrimidin-5-y1)-3,3113 dimethylbutanoate using method 3 (compound No 169)
NMR (CDC13): 1.00 ( S,9H ) ; 1.40 (s,9H); 2.12 (S,3H);
3.40 (S,1H); 3.77 (bs, 2H); 5.12-5.30 (bq,
2H) ; 8.72 (s ,2H)
GLC Retention Time: 10.91 minutes (lvi) 4-((prop-2-yn-l-yl) thiomethyl]-2,3,5,6tetrafluorobenzyl (RS)-2-[2-(l,ldimethylethyl)pyrimidin-5-yl]-3,3-dimethylbenzoate using method 3 (compound No 220) 1H NMR (CDC13): 1.00 (s,9H); 1.40 (s,9H); 2.25 (m,lH);
3.27 (d,2H); 3.40 (S,1H); 3.97 ( bs , 2H);
5.12-5.30 (bq, 2H); 8.72 (s,2H)
GLC Retention Time: 11.57 minutes (lvii) 3-(4-chlorophenoxy)benzyl (RS)-2-(2-(1,115 dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate
APO 00 0 5 7
using method 3 (compound No 180)
1H NMR (CDC13: ): 1.00 (s,9H); 1.40 (s,9H ) ; 3.40 (S,1H);
5.10 (q,2H); 6.95 (t,3H ) ; 7.05 (d,lH);
7.30 (q,4H); 8.75 (s,2H)
20 GLC Retention Time: 13 .04 minutes
(lviii) (RS)-l-cyano-l-(3-phenoxyphenyl)methyl (RS)-2-[2(l,l-dimethylethyl)pyrimidin-5-yl]-3,3dimethylbutanoate using method 3 (compound No 2) 1H NMR (CDC13): 0.92 (s); 1.06 (s); 1.40 (m); 3.46 (m);
6.28 (s); 6.40 (s); 6.96-7.44 (m); 8.72
114 (m); (Consistent with mixture of diastereoisomers)
GLC Retention Time: 12.51 minutes and 12.78 minutes (lix) 4-(ethoxycarbonyl)-2,3,5,6-tetrafluorobenzyl (RS)2-[2-(l,1-dimethylethyl)pyrimidin-5-yl]-3,3dimethylbutanoate using method 3 (compound No 170) ΣΗ NMR (CDC13): 1.00 (s,9H); 1.36-1.44 (m,12H); 3.40 (S,1H); 4.40-4.48 (q,2H); 5.12-5.30 (bq, 2H); 8.72 (s,2H)
GLC Retention Time: 10.28 minutes (lx) 4-[(prop-2-yl)oxycarbonyl)-2,3,5,6-tetrafluorobenzyl (RS)-2-[2-(1,1-dimethylethyl)pyr imidin-5-yl)-3,3dimethylbutanoate using method 3 (compound No 171) 1H NMR (CDC13): 1.00 (s,9H); 1.36 (d, 6H); 1.42 (s,9H);
3.40 (S,1H); 5.12-5.40 (m,3H); 8.72 (s,2H)
GLC Retention Time: 10.45 minutes (lxi) 4-((4-chlorobenzyloxyJmethyl]-2,3,5,6tetrafluorobenyl (RS)-2-[2-(l,ldimethylethyl)pyrimidin-5-yl)-3,3-dimethylbutanoate
using method 3 (compound No 163)
(CDC13): 1.00 (s,9H); 1.40 (s,9H); 3 .40 (S,1H);
4.56 (s,2H); 4.66 (bs, 2H) ; 5. 12-5.30 (bq,
2H) ; 7.26-7.36 (m, 4H) ; 8.72 (s ,2H)
GLC Retention Time: 14,53 minutes
115 (lxii) (6-phenoxypyrid-2-ylJmethyl (RS)-2-[2-(l,ldimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate using method 3 (compound No 9) 1H NMR (CDC13): 1.00 (s,9H); 1.40 (s,9H); 3.45 (S,1H)
5.05-5.15 (q, 2H); 6.75-7.70 8.75 (S,2H)
GLC Retention Time: 12.00 minutes (lxiii) (RS)-1-(6-phenoxypyrid-2-yl)ethyl (RS)-2-[2(1,1-dimethylethyl)pyrimidin-5-yl]-3,310 dimethylbutanoate using method 3 (compound No 11) 1H NMR (CDC13): 0.95 (s); 1.00 (s); 1.40 (m); 1.45 (m);
1.55 (m); 3.45 (m); 5.80 (m); 6.65-7.70 (m); 8.75 (m) Consistent with 1:1 mixture of diastereoisomers
GLC Retention Time: 11.57 minutes, 11.79 minutes (lxiv) 2-chloro-6-fluorobenzyl (RS)-2-[2-(l,ldimethylethyl)pyrimidin-5-yl]-3,3dimethylbutanoate using method 3 (compound No 26) 1H NMR (CDC13): 1.00 (s,9H); 1.40 (s,9H); 3.40 (s,lH);
5.20-5.40 (q,2H); 7.00-7.36 (m,3H); 8.72 (s,2H)
GLC Retention Time: 9.26 minutes (lxv) N-3,4,5,6-tetrahydrophthalimidomethyl (RS)-2-[2’ (1,1-dimethylethyl)pyrimidin-5-yl]-3,325 dimethylbutanoate using method 3 (compound No 6)
AP000057
116 1H NMR (CDC13): 1.00 (s,9H); 1.40 (s,9H); 1.80 (m,4H);
2.36 (m,4H);3.72 (S,1H); 5.44-5.60 (q,2H); 8.72 (s,2H)
GLC Retention Time: 11.60 minutes (lxvi) 2-methyl-3-phenylbenzyl (RS)-2-[2-(1, Ιό i met hyle thy 1 )pyr imidin-5-yl]-3,3-dimethylbutanoate using method 3 (compound No 3)
NMR (CDC13) 1.00 (s,9H); 1.40 (S,9H); 2.16 (s,3H); 3.40 (s,lH); 5.12-5.24 (q,2H); 7.20-7.44 (m,8H);
8.72 (s,2H)
GLC Retention Time: 12.19 minutes (lxvii) 3-phenoxybenzyl (RS)-2-[2-(l,l,dimethylethyl)pyrimidin-5-y1)-3,3dimethylbutanoate using method 3 (compound No 1) 1H NMR (CDC13): 1.00 (s,9H); 1.40 (s,9H); 3.40 (s,lH);
5.00-5.16 (q,2H); 6.92-7.40 (m,9H); 8.72 (s,2H)
GLC Retention Time: 12.07 minutes (lxviii) 4-fluoro-3-phenoxybenzyl (RS)-2-[2-(l,ldimethylethyl)pyrimidin-5-yl]-3,3dimethylbutanoate using method 3 (compound No 25) 1H NMR (CDC13) 1.00 (S,9H); 1.40 (s,9H); 3.40 (s,lH); 4.925.12 (bq,2H); 6.92-7.36 (m,8H); 8.72 (s,2H)
GLC Retention Time: 11.97 minutes
117 (lxix) 3-benzyl-4-fluorobenzyl (RS)-2-(2-(l,ldimethylethyl)pyrimidin-5-y1)-3,3-dirr.ethylbutanoate using method 3 (compound No 18)
NMR (CDC13): 1.00 (s,9H); 1.40 (s,9H); 3.35 (s,lH);
4.00 (bs, 2H); 4.95-5.10 (bq, 2H); 6.957.30 (m,8H); 8.72 (s,2H)
GLC Retention Time: 12.00 minutes (lxx) 4-(methoxymethyl)-2,3,5,6-tetrafluorobenzyl (RS)-2[2-(l,l-dimethylethyl)pyrimidin-5-yl]pent-4-enoate using method 4 (compound No 212) 1H NMR (CDC13): 1.40 (s,9H); 2.55 (m,lH), 2.85 (m,lH);3.40 (s,3H); 3.65 (t,lH); 4.60 (broad s, 2H); 5.0-5.1 (m,2H); 5.20-5.30 (q, 2H); 5.65.75 (m,lH); 8.60 (s,2H)
GLC Retention Time: 9.53 minutes (lxxi) 4-( methoxymethyl )-2,3,5,6-tetrafluorobenzyl (RS)-2[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3,3trifluoropropionate using method 4 (compound No 213) 1H NMR (CDC13): 1.40 (s,9H); 3.40 (s,3H); 4.30 <q,lH);
4.60 (s,2H); 5.35 (s,2H); 8.75 (s,2H)
GLC Retention Time: 7.86 minutes (lxxii) (RS)-1-(6-phenoxypyrid-2-yl)-2,2,2-r r ifluoroethyl » (RS)-2-(2-(1,1-dimethylethyl)pyrimidin-5-y1)-3,325 dimethylbutanoate, using method 5 (compound No
32)
APO 0 0 0 5 7
118 1H NMR (CDC13): 0.95 (s); 1.00 (s); 1.40 (bs); 3.55 (2s);
5.05 (m); 6.8-7.0 (m); 7.05-7.25 (m); 7.35-7.45 (m); 7.60-7.65 (m); 7.70-7.80 (m); 8.70 (s); 8.75 (s)
Integration consistent with 3:2 mixture of diastereiosomers
GLC Retention Time: 10.73 minutes, 11.07 minutes (lxxiii) 4-(methoxymethyl)-2,3,5,6-tetrafluorobenzyl (RS)-2[2-(l,l-dimethylethyl)pyrimidin-5-yl]-3,3dimethylpent-4-enoate using method 3 (compound No 211) 1H NMR (CDC13): 1.05 (2s,6H); 1.4 (s,9H); 3.40 (s,3H);
3.45 (S,1H); 4.60 (bs,2H); 4.85 (d,lH);
5.05 (d,lH); 5.1-5.3 (dd,2H); 5.85-5.95 (dd,lH); 8.70 (s,2H)
GLC Retention Time: 10.0 minutes (lxxiv) 4-( hydroxymethyl)-2,3,5,6-tetrafluorobenzyl (RS)-2[2-(1,1-dimethylethyl)pyrimidin-5-y11-3,3dimethylbutanoate using method 3 (compound No 164). The preparation of 4-halomethyl-2,3,5,6tetrafluorobenzenemethanols is described in UK Patent No 2153819 1H NMR (CDCl-j): 1.00 (s,9H); 1.40 (s,9H); 2.16 (bs,lH);
3.40 (S,1H); 4.84 (bs,2H); 5.12-5.30 (bq,2H); 8.72 (s,2H)
GLC Retention Time: 10.04 minutes (lxxv) 2,3,5-tri fluoro-6-ethoxy-4-(ethoxymethyl) benzyl
119 (RS)-2-(2-(1,1-dimethylethyl)pyrimidin-5-y1)-3,3dimethylbutanoate, using method 3 (compound No 188)
250 MHz 1H NMR (CDCl-j): 0.99 (9H,s); 1.22 (3H,t); 1.26 5 (3H,t); 1.40 (9H,s); 3.36 (lH,s);
3.58 (2H,t); 4.08 (2H,m); 4.58 (2H,t); 5.15 (lH,dd); 5.24 (lH,dd); 8.72 (2H,s) (lxxvi) 2,3,5-trifluoro-6-ethoxy-4-(phenoxymethyl) benzyl (RS)-2-(2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3dimethylbutanoate using method 3 (compound No 194)
250 MHz XH NMR (CDCI3): 1.00 (9H,s); 1.25 (3H,t); 1.42 (9H,s); 3.36 (lH,s); 4.10 (2H,m);
5.12 (2H,s); 5.15 (lH,d); 5.25 (lH,d); 7.0 (2H,m); 7.40 (3H,m); 8.70 (2H,s) (lxxvii) 2,3,6-tr i fluoro-5-methoxy-4-(methoxymethyl)benzyl (RS)-2-(2-(1,1-dimethylethyl)pyrimidin-520 yl]-3,3-dimethylbutanoate, using method 3 (compound 217)
250 MHz 1H NMR (CDCl-j): 0.93 (9H,s); 1.34 (9H,s);
3.33(3H+1H,s); 3.85 (3H,d); 4.45 (2H,d); 5.05 (lH,d); 5.20 (lH,d);
8.65 (2H,s) (lxxviii) 2,3,5-tri fluor0-6-methoxy-4-[(1» methyl)ethoxy]methylbenzyl (RS)-2-(2-(1,1dimethylethyl)pyrimidin-5-y1)-3,3dimethylbutanoate, using method 3 (compound No
AP000057
120
190)
250 MHz XH NMR (CDCl3): 1.00 (9H,s); 1.21 (6H,d); 1.40 (9H,s); 3.36 (lH,s); 3.71 (1H,septet); 3.86 (3H,d); 4.59 (3Hrt); 5.15 (lH,dd); 5.25 (lH,dd); 8.73 (2H,s) (lxxix) 2,3,5-tr ifluoro-6-methoxy-4-(phenoxymethyl)benzyl (RS)-2-(2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3dimethylbutanoate, using method 3 (compound No 193)
250 MHz NMR (CDCl-j): 0.82 (9H,s); 1.22 (9H,s); 3.18 (1H,S); 3.68 (3H,d); 4.94 (2H,t); 4.96 (lH,dd); 5.04 (lH,dd); 6.80 (3H,m); 7.1 (2H,m); 8.54 (2H,s) (lxxx) 2,3,5-t ri fluoro-6-ethoxy-4-(methoxymethyl) benzyl (RS)-2-(2-(1,1-dimethylethyl)pyrimidin-5-y1]-3,3dimethylbutanoate, using method 3 (compound No 185)
250 MHz 1H NMR (CDC13): 1.00 (9H,s); 1.26 (3H,t); 1.40 (9H,s); 3.35 (lH,s); 3.40 (3H,s); 4.08 (2H,m); 4.57 (2H,t); 5.15 (lH,dd); 5.25 (lH,dd); 8.72 (2H,s) (lxxxi) 2,3,5,6-tetrafluoro-4-(phenoxymethyl)benzyl (RS)— 2-(2-(1,1-dimethylethyl)pyrimidin-5-y1)-3,3dimethylbutanoate, using method 3 (compound No 192)
250 MHz XH NMR (CDC13):. 0.8 (9H,s); 1.22 (9H,s); 3.2
121 (lH,s); 4.97 5.10 (lH,d); (2H,m); 8.55 (2H,s); 5.00 (lH,d); 6.80 (3H,m); 7.10 (2H,s) (lxxxii) 2,3,5-tr ifluoro-6-methoxy-4-(ethoxymethyl) benzyl 5 (RS)-2-(2-(1,1-dimethylethyl)pyrimidin-5-yl]3,3-dimethylbutanoate, using method 3 (compound No 187)
250 MHz 1H NMR (CDC13): 1.00 (9H,s); 1.25 (3H,t); 1.43 (9H,s); 3.38 (lH,s); 3.58 (2H,q);
3.87 (3H,d); 4.60 (2H,t); 5.15 (lH,dd); 5.25 (lH,dd); 8.75 (2H,s) (lxxiii) 2,3,5,6-tetrafluoro-4-(ethoxymethyl)benzyl (RS)2-(2-(1,1-dimethylethyl)pyrimidin-5-yl)-3,315 dimethylbutanoate, using method 3 (compound No
186)
250 MHz 1H NMR (CDClg): 1.00 (9H,s); 1.25 (3H,t); 1.45 (9H,s); 3.40 (1H,S); 3.60 (2H,q); 4.65 (2H,s); 5.20 (lH,d); 5.30 (lH,d); 8.73 (2H,s)
IO
(lxxxiv) 2,3,5,6-tetrafluoro-4-[(lmethyl)ethoxy]methylbenzyl (RS) — 2 —[2- (1,1 dimethylethyl)-pyrimidin-5-yl)-3,3dimethylbutanoate using method 3 (compound No 189)
250 MHz 1H NMR (CDClj): 0.98 (9H,s); 1.22 (6H,d); 1.41 (9H,s); 3.38 (lH,s); 3.73 (1H, septet); 4.6 (2H,s); 5.16 (lH,d); •5.28 (lH,d); 8.70 (2H,s)
122 (lxxxv) 2,3,5,6-tetrafluoro-4-(methoxymethy1)benzyl (RS)2-(2-(1-methylcyclohexyl)pyrimidin-5-y1)-3,3dimethylbutanoate, using method 2 (compound No 207 )
270 MHz XH NMR (CDCl-j): 1.00 (9H,s); 1.25 (3H,s); 1.ΣΟΙ.60 (8H,m); 2.34 (2H,m); 3.40 (lH,s); 3.42 (3H,s); 4.58 (2H,s);
5.17 (lH,d); 5.30 (lH,d); and 9.73 (2H,d) (lxxxvi) 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl (RS)2-[2-( tri fluoromethyl)pyrimidin-5-yl]-3,3• dimethylbutanoate, using method 4 (compound No 41)
270 MHz 1H NMR (CDCl-j): 1.00 (9H,s); 3.40 (3H,s); 3.53 (lH,s); 4.58 (2H,s); 5.20 (lH,d);
5.30 (lH,d); 8.96 (2H,s) (lxxxvii) 2,3,5,6-tetrafluorbenzyl-4-(methoxymethyl) benzyl (RS)-2-(2-(2-chlorophenyl)pyrimidin-5yl]-3,3-dimethylbutanoate using method 3 (compound No 208)
250 MHz 1H NMR (CDCl-j): 1.05 (9H,s)f 3.40 (3H,s); 3.50 (lH,s); 4.60 (2H,s); 5.23 (lH,d); 5.33 (lH,d); 7.35 (2H,m); 7.50 (lH,m); 7.75 (lH,m); 8.93 (2H,s) (lxxxviii) 4-fluoro-3-phenoxybenzyl (RS)-2-(2-(2-chloropheny1)pyrimidin-5-y1)-3,3-aimethylbutanoate using method 3 (compound No 209)
250 MHz 1H NMR (CDCl3):> 1.00 (9H,s); 3.48 (lH,s); 4.47
123 (lH,d); 5.13 (lH,d); 6.90-7.40 (10H,m); 7.50 (lH,m); 7.75 (lH,m); 8.90 (2H,s) (lxxxix) 4-(prop-2-en-l-yl)-2,3,5,6-tetrafluorobenzyl (RS)-2-(2-phenylpyrimidin-5-yl)-3-methylbutanoate using method 4 (compound No 113)
250 MHz 1H NMR (CDCl-j): 0.80 (d,3H); 1.06 (d,3H); 2.40 (m,lH); 3.26 (d,lH); 3.46 (m,2H); 5.18 (m,4H); 5.88 (m,lH); 7.48 (m,3H); 8.44 (m,2H); 8.78 (s,2H);
GLC Retention Time: 12.24 minutes (xc) 4-fluoro-3-phenoxybenzyl (RS)—2—[2—(l— methylcyclopropyl)pyrimidin-5-yl]-3,3dimethylbutanoate using method 3 (compound No 204)
270 MHZ 1H NMR (CDClj): 0.93 (2H,m); 0.95 (9H,s); 1.35;
(2H,m); 1.56 (3H,s); 3.3 (lH,s); 4.95 (lH,d); 5.50 (lH,d); 6.8-7.4 (8H,m); 8.61 (2H,s)
GLC Retention Time: 12.65 Minutes
EXAMPLE 21
This Example illustrates the preparation of 2,3,5,6tetrafluor0-4-(acetyloxymethyl)benzyl (RS)-2-(2-(l,ldimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate (compound No 166) from 2,3,5,6-tetrafluoro-4» (hydroxymethyl)benzyl (RS)-2-[2-(1,12 5 dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate (prepared according to example 20 (lxxiv).
4-(hydroxymethyl)-2,3,5,6-tetrafluorobenzyl 2-(2-(1,1AP000057
124 dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate (0.066 g) was dissolved in dry dichloromethane (2 cm3) and cooled to 0°C. To the stirred solution was added triethylamine (dry, 0.03 cm3), followed by acetyl chloride (0.016 cm3).
The reaction was kept at 0°C for 1 hour, then diluted with dichloromethane and a small volume of water. The organic fraction was separated, dried and evaporated under reduced pressure to yield an oil which was fractionated by thick layer chromatography (silica gel, eluted with dichloromethane/ethyl acetate 20:1 by volume; extracted with ethyl acetate) to give the title compound as a colourles oil (0.06 g).
NMR (CDC13): 1.00 (s,9H); 1.40 (s,9H); 2.10 (s,3H);
3.40 (S,1H); 5.12-5.30 (m,4H); 8.72 (s,2H).
GLC Retention Time: 10.56 minutes
EXAMPLE 22
The following compounds were prepared according to the method described in Example 21.
(i) 4-[(2,2-dimethylpropionyl)oxymethyl]-2,3,5,620 tetrafluorobenzyl (RS)-2-[2-(l,ldimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate (compound No 172) •'•H NMR (CDC13): 1.00 (s,9H); 1.20 (s,9H); 1.40 (s,9H);
* 3.40 (S,1H); 5.12-5.30 (m,4H); 8.72 (s,2H)
GLC Retention Time: 11.12 minutes
125 (i i) 4-[(2-methylpropiony1)oxymethyl]-2,3,5,6tetrafluorobenzyl (RS)-2-(2-(1,1dimethylethyl)pyr imidin-5-yl]-3,3-dimethylbutanoate (compound No 173) XH NMR (CDCl-j); 1.00 (s,9H); 1.16 (d,6H); 1.40 (s,9H);
2.50-2.60 (m,lH); 3.40 (s,lH); 5.12-5.30 (bq, 2H); 5.20 (bs, 2H); 8.72 (s,2H)
GLC Retention Time: 11.04 minutes (iii) 4-chloromethyl-2,3,5,6-tetrafluorobenzyl (RS)—2—[210 (l,l-dimethylethyl)pyrimidin-5-yl]-3,3dimethylbutanoate (compound No 167) prepared using methanesulphonyl chloride.
NMR (CDC13): 1.00 (s,9H); 1.40 (s,9H); 3.40 (S,1H);
4.68 (bs,2H); 5.12-5.30 (bq,2H); 8.72 (S,2H)
GLC Retention Time: 9.91 minutes
AP OOO057
EXAMPLE 23
This Example illustrates the preparation of 4(methoxymethyl )-2,3,5,6-tetrafluorobenzyl (RS)-2-(2-(1,1dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanthioate (compound No 195) from 4-hydroxymethyl-2,3,5,6tetrafluorobenzyl (RS)-2-(2-(1,1-dimethylethyl)pyrimidin-5yl]-3,3-dimethylbutanth ioate.
, 4-hydroxymethyl-2,3,5,6-tetrafluorobenzyl 2-(2-(1,1dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanthioate (0.064 g) was dissolved.in dichloromethane (2 cm3) and mixed with an aqueous solution of sodium hydroxide (2 cm3,
126
50% w/v) and tetrabutylammonium hydrogen sulphate (0.002 g; phase transfer catalyst). To the rapidly stirred mixture at the ambient temperature was added methyl iodide (0.2 cm2). The reaction mixture was stirred for 24 hours, stored for a further 60 hours and then diluted with dichloromethane. The organic fraction was separated, washed with water and dried over anhydrous magnesium sulphate. The solvent was evaporated under reduced pressure to yield an oil (0.073 g) which was fractionated by eluting through a bed of silica gel with dichloromethane/ethyl acetate (20:1 by volume). The required product was obtained as an oil (0.053 g).
2H NMR (CDCIj): 1.00 (s,9H); 1.40 (S,9H); 3.40 (s,3H); 3.48 (S,1H); 4.12-4.30 (bq,2H); 4.52 (bs,2H);
8.72 (s,2H)
GLC Retention Time: 10.82 minutes
EXAMPLE 24
The following compounds were prepared according to the method described in Example 23.
(i) 4-[(1,1-dimethylethyl) oxyearbonyImethoxymethyl]2,3,5,6-tetrafluorobenzyl (RS)-2-(2-(1,1dimethylethyl]pyrimidin-5-yl]-3,3-dimethylbutanoate (compound No 165) using 1,1-dimethylethyl 2bromacetate 2H NMR (CDCIj): 1.00 (s,9H); 1.40 (s,9H); 1.50 (s,9H);
3.40 (S,1H); 4.02 (s,2H); 4.76 (bs,2H);
5.12-5.30 (bq,2H); 8.72 (s,2H)
127
GLC Retention Time: 12.32 minutes
EXAMPLE 25
This Example describes the stages in the preparation of (+)-4-(methoxymethyl)~2,3,5,6-tetrafluorobenzyl 2-(2(l,l-dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate (compound No 15-resolved form).
Stage 1: Resolution of (RS)-2-[2-(1,1-dimethylethyl)pyrimidin-5-y1)-3,3-dimethylbutanoic acid (+)-2-(2-(1,1-dimethylethyl)pyrimidin-5-yl)-3,3dimethylbutanoic acid (0.234 g) was mixed with (-)-<<10 methylbenzylamine (available from Sigma Chemical Company, 0.071 g) in ethanol (5 cm2), and the mixture warmed until all of the reagents had dissolved. The solution was stored at -15°C to -10°C for 5 days to produce a solid precipitate which was filtered from the chilled solution. The solid was washed with a small volume of cold ethanol and recrystallised once from ethanol to give strands of the (-, -c<- methylbenzylamine salt on filtration. The solid was suspended in toluene/2M hydrochloric acid and warmed with stirring for 3 hours. The aqueous layer was separated, extracted with dichloromethane and the toluene and dichloromethane fractions combined. Evaporation of the solvents under reduced pressure gave a colourless solid (0.042 g) . Analysis by HPLC cyclobond column eluted with acetonitrile/water/formic acid in ratio 40/60/0.1 by volume) indicated the product to have a > 85% enantiomeric excess of (-)-2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3dimethylbutanoic acid.
L SOOOOdV
Melting Point: 224-227.4°C
128
Optical Rotation: (<JD 1.0° + 0.1° (chloroform)
A similar procedure using ( + )-<£- methylbenzylamine gave (+)-2-(2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3dimethylbutanoic acid in >85% enantiomeric excess.
Melting Point: 222.3-223.7 °C
Optical Rotation: [^]D θ·9° + 0.1° (chloroform)
Either enantiomer may be re-converted to the racemic acid by heating at temperatures from 150-230°C in the presence of an acid catalyst such as para-toluenesulphonic acid or concentrated sulphuric acid, either with no solvent, or in solution in a high-boiling solvent such as 1,4-dichlorobenzene, typically for 0.5 to 20 hours. This process provides a method of racemisation and recycling of the (+)-enantiomer, which has been found to yield esters having reduced insecticidal and acaricidal activity, thereby allowing a greater overall yield of the (-) — enantiomer which on esterification, gives esters in the more active enantiomeric or diastereoisomeric form.
Stage 2: The resolved acids obtained in stage 1 were esterified using method 3 (described in Example 19) to produce the (+) and (-) isomers of 4(methoxymethyl)-2,3,5,6-tetrafluorobenzyl 2-(2(1,1-dimethylethyl)pyr imidi n-5-yl]-3,3dimethylbutanoate (compound No 15 - resolved forms ).
The (+)-isomer (shown to be present in greater than
95% enantiomeric excess) exhibited an optical rotation (( d'- Iq) of 39.6° in chloroform (25.3° in methanol).
The (-)-isomer (>85% enantiomeric excess) exhibited an optical rotation ([^k]D of -38.5° + 0.1° in chloroform
129 (-24.5° in methanol).
Biological screening has shown that the (-)-enantiomer exhibits substantially greater insecticidal and acaricidal activity than the (+)-enantiomer.
EXAMPLE 26
This Example illustrates the stages in the preparation of 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl (RS)-2-[2(1,1-dimethylethyl)pyrimidin-5-yl]-3-methylbut-3-enoate (compound No 202)
Stage 1: Preparation of ethyl 2-[2-(1,110 dimethylethyl)pyrimidin-5-yl]-3-methylbut-2enoate
A 2.5 molar solution of n-butyl lithium in hexanes (5.5 cm3) was added in portions to a suspension of isopropyltriphenylphosphonium iodide (6 g) in dry diethyl ether, whilst the temperature was maintained between -10 and -20°C. After stirring for 1 hour at this temperature, a solution of ethyl 2-[2-(1,1-dimethylethyl)pyrimidin-5yl]-2-oxo-acetate (3 g) in dry diethyl ether (15 cm3) was added in portions. The stirred reaction mixture was allowed to warm to the ambient temperature, and allowed to stir for 16 hours. The reaction mixture was poured into water and extracted into ethyl acetate. The combined organic extracts were washed, dried over anhyrous magnesium sulphate, and concentrated by removal of the solvent under reduced pressure to give a dark brown oil, which was subjected to chromotography on silica gel, using hexane containing 10% ethyl acetate (by volume), as eluent to give ethyl 2-(2-(1,1-dimethylethyl)pyrimidin-5-yl]-3-methy1but2-enoate (0.4 g) as a clear oil.
130
270 MHz 1H NMR (CDClj): 1.23 (3H,t); 1.43 (9H,s); 1.75 (3H,s); 2.25 (3H,s); 4.15 (2H,q);
8.50 (2H,s)
Stage 2: Preparation of 2-[2-(1,1-dimethylethyl)pyrimidin5-ylJ-3-methylbut-2-enoic acid.
A solution of sodium hydroxide 0.24 g) and ethyl 2—[2 — (1,1-dimethylethyl)pyrimidin-5-yl]-3-methylbut-2-enoate (0.4 g) in isopropanol (10 cm2) and water (2 cm2) was heated to the reflux temperature for a period of 3 hours. After cooling to the ambient temperature the crude reaction mixture was concentrated by evaporation of the solvent under reduced pressure, and the residue was dissolved in water, and extracted with ethyl acetate. The aqueous portion was acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The combined organic extracts were washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent under reduced pressure to give 2-(2-(1,1dimethylethyl)-pyrimidin-5-yl]-3-methylbut-2-enoic acid , containing a small amount of 2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3-methylbut-3-enoic acid. The crude product was used without further purification.
270 MHz 1H NMR (CDCl-j): 1.42 (9H,s); 1.80 (3H,s); 2.33 (3H,s); 8.55 (2H,s)
Stage 3: Preparation of 2,3,5,6-tetrafluoro-4(methoxymethyl) benzyl 2-(2-(1,1-dimethylethyl)pyrimidin-5-yl]-3-methylbut-2-enoate
2-(2-(1,1-dimethylethyl)pyrimidin-5-yl]-3-methylbut2-enoic acid (0.25 g) was reacted with 2,3,5,6-tetrafluoro4-(methoxymethyl)benzyl alcohol (0.24 g) in the presence of
131
1-ethyl-3-(3-dimethylami nopropyl)ca rbodi imide, according to the procedure given in method 2 of Example 19.
The crude product was subjected to chromatography on silica gel using dichloromethane containing 20% by volume ethyl acetate as eluent, to give 2,3,5,6-tetrafluoro-4(methoxymethyl) benzyl 2-(2-(1,1-dimethylethyl)pyrimidin-5yl]-3-methylbut-2-enoate (0.18 g).
270 MHz XH NMR (CDCl3): 1.40 (9H,s); 1.75 (3H,s); 2.25 (3H,s); 3.39 (3H,s); 4.55 (2H,s);
5.25 (2H,s); 8.45 (2H,s)
The product was shown by NMR to contain 30% of
2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl 2-(2-(1,1dimethylethyl)pyrimidin-5-yl]-3-methy1but-3-enoate.
Stage 4: Preparation of 2,3,5,6-tetrafluoro-415 (methoxymethyl)benzyl (RS)-2-[2-(1,1dimethylethyl)pyrimidin-5-yl]-3-methylbut-3enoate (compound No 202).
A 1 molar solution of lithium hexamethyldisilazide (0.125 cm3) in dry tetrahydrofuran was added to a stirred solution of 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl 2[2-(l,l-dimethylethyl)pyrimidin-5-yl]-3-methylbut-2-enoate (0.05 g) in dry tetrahydrofuran (1 cm3) whilst the reaction temperature was maintained at -78°C. After 30 minutes, acetic acid (0.01 g) was added in one portion, and the stirred reaction mixture was allowed to warm to the ambient temperature, and quenched with water. Extraction into ethyl acetate, and concentration by removal of the solvent under reduced pressure gave 2,3,5,6-tetrafluoro-4{methoxymethyl)benzyl (RS)-2— (2 — {1,1— dimethylethyl)pyrimidin-5-yl)-3-methylbut-3-enoate (0.05
g) ·
APO 00/)5 7
132
270 MHz iH NMR (CDC13): 1.38 (9H,s); 1.60 (3H broad s);
3.40 (3H,s); 4.25 (lH,s); 4.56 (2H,s); 4.90 (lH,s); 5.05 (lH,s); 5.27 (lH,d); 5.33 <lH,d); 8.63 (2H,s)
The product was shown by NMR spectroscopic analysis to contain 20% of 2,3,5,6-tetrafluoro-4-( methoxymethyl) benzyl (RS)-2-(2-(1,1-dimethylethyl)pyrimidin-5-yl)-3-methylbut-2enoate .
EXAMPLE 27
This Example illustrates the stages in the preparation of Z-4 - (3-chloroprop-2-en-l-yl)-2,3,5,6-tetrafluorobenzyl alcohol.
(i) Preparation of Z-l-chloro-3-iodoprop-l-ene.
A solution of Z-l,3-dichloropropene (4.05g) and potassium iodide (6.0g) in dry acetone (75 cm3) was heated to the reflux temperature for a period of two hours. After cooling to the ambient temperature (ca. 25°C), the reaction mixture was poured into aqueous sodium thiosulphate solution, and then extracted with diethyl ether. The organic layer was washed with water, and brine, dried, and the solvent evaporated under reduced pressure to give Z-lchloro-3-iodoprop-l-ene as an orange oil (2.4g).
Tcis material was immediately carried through to the next stage.
GLC retention time : 1.04 minutes
133 (ii) Preparation of 2-[Z-4-(3-chloroprop-2-en-l-yl) 2.3.5.6- tetrafluorobenzyloxy]tetrahydropyran .
n-Butyl lithium (2.5M in hexane, 3 cm3) was added portionwise to a solution of 2-[4-bromo-2,3,5,65 tetrafluorobenzyloxy]-tetrahydropyran (1.7g) in dry tetrahydrofuran (10 cm3) under an atmosphere of dry nitrogen, whilst the reaction temperature was maintained at -70°C. After 30 minutes, copper (I) bromide - dimethyl sulphide complex (1.54g) was added in one portion and the reaction temperature allowed to warm to 0°C, for a period of 15 minutes. After cooling to -70°C, a solution of Z-l-chloro-3iodoprop-l-ene (2.03g) in dry tetrahydrofuran (3 cm3) was added portionwise, and the reaction mixture stirred for a further hour at -70°C. After warming to the ambient temperature, (ca. 25°C), aqueous ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. After drying, the solvent was evaporated under reduced pressure to give an orange oil. The residue was then subjected to medium pressure column chromatography on a silica gel column using a Gilson apparatus, eluting with petroleum ether (boiling range 40-60°C) containing diethyl ether (5% by volume) to give 2-[4-(3-chloroprop-2-en-l-yl) 2.3.5.6- tetrafluorobenzyloxy]-tetrahydropyran, as a mixture consisting predominantly of the Z isomer.
NMR (CDC13): 1.5-1.8 (m,6H); 3.5 (m,lH); 3.65 > (d,2H); 3.90 (m,lH); 4.60 (d,lH);
4.8 (m,2H); 5.8 (q,lH); 6.15 (m,lH)
GLC retention time : 5.98 minutes
134 (iii) Preparation of Z-4-(3-chloroprop-2-en-l-yl)-2,3,5, 6tetrafluorobenzyl alcohol.
The tetrahydropyranyl ether prepared in stage (ii) was dissolved in methanol (30 cm3), and to the stirred solution was added a catalytic amount of concentrated hydrochloric acid. After stirring tor two hours, the reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed and dried, and the solvent evaporated under reduced pressure to give Z—4-(3chloroprop-2-en-l-yl)-2,3,5,6-tetrafluorobenzyl alcohol (0.6g) as a colourless oil, which solidified on standing.
iH NMR (CDC13): 3.65 (d,2H); 4.8 (s,2H); 5.85 (q,lH); 6.2 (m,lH)
Infra red (liquid film): 3640, 1490, 1300, 1250 and 1040 cm'1
GLC retention time : 3.08 minutes.
EXAMPLE 28
This Example illustrates the stages in the preparation of 4-trimethylsilyl-2,3,5,6-tetrafluorobenzyl alcohol.
(i) Preparation of 2-[4-trimethylsilyl-2,3,5,6tetrafluorobenzyloxy]-tetrahydropyran.
A solution of n-butyl lithium (1.5M in hexane, 2.9 cm3) was added portionwise to a solution of 4-bromo2,3,5,6-tetrafluorobenzyloxy]-tetrahydropyran (1.5g)
135 in dry tetrahydrofuran (43 cm1) under an atmosphere of dry nitrogen, whilst the reaction temperature was maintained at -70°C. As the last portion of base was added, an intense purple colour developed.
Chlorotrimethylsilane (1.6 cm1, dried over alumina) was added portionwise, leading immediately to a dissipation of the purple colouration. The reaction mixture was then poured into water, and extracted into ethyl acetate. The organic layer was washed with water and brine, dried, and the solvent evaporated under reduced pressure to give 2—[4— trimethylsilyl-2,3,5,6-tetrafluorobenzyloxy]tetrahydropyran. This crude material (94% pure by Gas Chromatography) was carried immediately to the next stage, without further purification.
MHz ΣΗ NMR (CDC13): 0.5 (s,9H); 1.4-2.1 (m,6H); 3.4-4.4 (m,2H); 4.5-5.2 (m,3H)
GLC retention time : 5.07 minutes.
(ii) Preparation of 4-trimethylsilyl-2,3,5,620 tetrafluorobenzyl alcohol.
The crude tetrahydropyranyl ether prepared in Stage (i) was dissolved in methanol (20 cmJ), and to the stirred solution was added concentrated hydrochloric acid (3 drops). After stirring for 16 hours at the ambient temperature (ca. 25°C), the reacrion mixture was poured into ethyl acetate, washed with water and brine, and dried. Evaporation of the solvent under reduced pressure gave a yellow oil which was subjected to column chromatography on silica gel using petroleum ether (boiling range 40-60°C)
AP000057
136 containing diethyl ether (10% gradually increased to
40% by volume) as eluent to give 4-trimethylsilyl2,3,5,6-tetrafluorobenzyl alcohol (0.79g) .
MHz ΧΗ NMR (CDClj): 0.4 (s,9H); 1.9 (t,lH); 4.8 (m,2H)
GLC Retention Time: 2.24 minutes
EXAMPLE 29
This Example illustrates the stages in the preparation of 3,5-difluoro-4-methyl-2-methylthiobenzyl alcohol.
Stage 1: Preparation of methyl 2,3,5-trifluoro-6methylthio-4-(methoxymethyl) benzoate.
A solution of methanethiol (0.7 g) in methanol (10 cm2) was added to a stirred solution of sodium methoxide [by dissolving sodium metal (0.23 g) in methanol 10 cm2], at the ambient temperature over 15 minutes.
The above solution was added dropwise to a stirred solution of methyl 4-(methoxymethyl)-2,3,5,6tetrafluorobenzoate and stirring continued for a further 2 hours at the ambient temperature and stood overnight.
The reaction mixture was poured into water and was extracted into diethyl ether. The organic extracts were washed with water and brine, and dried over MgSO^. Removal of the solvent by evaporation under reduced pressure yielded an oil (2.0 g) which was purified by HPi^C (Gilson), eluting with hexane/diethyl ether (9:1 by volume). The first product eluted was identified as methyl 4(methoxymethyl)-2-methylthio-3,5,6-trifluorobenzoate (1.5
g) ·
137 1H NMR (CDC13): 4.48 (t,2H); 3.90 (s,3H); 3.32 (s,3H);
2.36 (s,3H)
Stage 2; Preparation of 3,5-dif luoro-4-methyl-2methylthiobenzyl alcohol.
Methyl 4-(methoxymethyl)-2-methylthio-3,5,6trifluorobenzoate (0.48 g) was dissolved in dry tetrahydrofuran (2 cm3) under a nitrogen atmosphere at room temperature. To the stirred solution was added dropwise a solution of lithium aluminium hydride (1.0 cm3 of a 1.0 molar solution in THF). The mixture was stirred for 0.5 hour then stored for 18 hours. The solution was treated with 2 molar hydrochloric acid and extracted with dichloromethane (twice), dried (anhydrous magnesium sulphate), and evaporated under reduced pressure to give a pale yellow liquid (0.37 g). The liquid was fractionated by eluting through a bed of silica gel with dichloromethane/ethyl acetate (50:1 by volume) to yield the
AP 0 0 0 0 5 7
title product (0.04 g) .
GLC Retention Time: 2.78 minutes
20 Molecular Ion: 204
EXAMPLE 30
This Example illustrates the preparation of 4-((1,1dimethylethyl)thiomethyl)-2,3,5,6-tetrafluorobenzyl alcohol
2-Methyl-2-propanethiol (0.207 cm3) was slowly added to a stirred mixture of sodium hydride (0.091 g, 56-60% dispersion in oil) in dry N,N-dimethylformamide (2 cm3) under a nitrogen atmosphere at room temperature. After 1
138 hour the solution was added slowly to a stirred solution of 4-bromomethyl-2,3,5,6-tetrafluorobenzyl alcohol (0.496 g, preparation described in UK Patent Application No 2153819) in dry N,N-dimethylformamide (2 cm3) under a nitrogen atmosphere at room temperature. On complete addition the reaction mixture was heated to 60°C for 2 hours. After cooling, the reaction mixture was treated with water (10 cm3) and extracted with diethyl ether (2 x 15 cm3).
The combined organic fractions were dried with anhydrous magnesium sulphate and evaporated under reduced pressure to give an orange oil. The oil was fractionated by eluting through a bed of silica gel (Merck 7729) with dichloromethane/ethyl acetate (100:2 by volume) to give the title product as a yellow gum (0.233 g).
GLC Retention Time: 4.57 minutes
Infra Red (liquid film): 3366, 2964, 1657, 1488, 1366,
1288, 1168, 1092, 1019, 942, 848, 670 cm-1
EXAMPLE 31
4-[(1-Methylethyl)thiomethyl )-2,3,5,620 tetrafluorobenzyl alcohol was prepared according to the method described in Example 30, using 2-propanethiol.
GLC Retention Time: 4.19 minutes . Infra Red (paraffin mull): 3417, 2921, 1462, 1376, 1290, 1016, 943 cm-1
139
EXAMPLE 32
This Example illustrates the preparation of 4methylthio-2,3,5,6-tetrafluorobenzyl alcohol.
4-Bromomethyl-2,3,5,6-tetrafluorobenzyl alcohol [10.0 g prepared according to the method described in UK Patent
Application No 2153819] was dissolved in toluene (dry, 250cm·3) and treated with thiourea (2.8 g). The reaction mixture was stirred and heated at the reflux temperature for 2 hours, further thiourea (1.5 g) was added and the mixture was heated for a further 1 hour. The reaction mixture was allowed to cool to the ambient temperature and stored for 18 hours. The solid (ca 15 g) which had precipitated from solution was filtered, and washed with toluene and diethyl ether.
This solid material was added to industrial methylated spirits (100 cm3) containing sodium hydroxide (4.5 g) and water (50 cm3). The mixture was stirred and heated at the reflux temperature for 3 hours, then cooled and the solvent evaporated under reduced pressure. The residue was diluted with water and extracted with dichloromethane (2 x 100 cm3). The basic, aqueous fraction was acidified with concentrated hydrochloric acid to pH 1 and the oil which separated was extracted with dichloromethane (2 x 120 cm3). The organic fraction was washed with water and dried over anhydrous magnesium sulphate. The solvent was evaporated under reduced pressure to yield an oil (6.3 g) which solidified on standing.
, Infra Red (Paraffin Mull): 3363, 2924, 2853, 1484, 1392, 1293, 1250, 1189, 1094, 1015, 935, 894, 663 cm-1
GLC Retention Time: 2.80 minutes
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140
EXAMPLE 33
This Example illustrates the preparation of 4(methyl thiomethyl )-2,3,5,6-tetrafluorobenzyl alcohol.
4-Thiomethyl-2,3,5,6-tetrafluorobenzyl alcohol (0.25 g prepared according to the method described in Example 32) was mixed with potassium carbonate (0.306 g) and acetone (5 cm2) and heated to the reflux temperature. Methyl iodide (0.083 cm2) was added rapidly to the refluxing mixture. After approximately 10 minutes the mixture was filtered, the filter cake was washed with acetone (5 cm2) and the filtrates evaporated under reduced pressure to give an offwhite solid. The solid was dissolved in dichloromethane (5 cm2) and the insoluble material was filtered off. The filtrates were evaporated under reduced pressure to give the title product as an off-white solid (0.122g).
GLC Retention Time: 3.50 minutes 2H NMR (CDCIj): 1.965 (t,lH); 2.10 (s,3H); 3.75 (s,2H); 4.82 (d,2H)
EXAMPLE 34
4-((Prop-2-yn-l-yl)thiomethyl]-2,3,5,6tetrafluorobenzyl alcohol was prepared according to the method described in Example 32 using prop-2-yn-l-thiol.
• GLC Retention Time: 4.62 minutes
Infra Red (liquid film): 3300, 2955, 1703, 1657, 1484, 1426, 1288, 1229, 1112, 1031,
945, 932, 670, 642 cm'1
141
EXAMPLE 35
4-[{Piperdin-l-yl)methy1)-2,3,5,6-tetrafluorobenzyl alcohol was prepared by a method analogous to that described in European Patent Application No 54360 for the 4-(N,N-diethylaminomethyl)-2,3,5,6-tetrafluorobenzyl alcohol.
Infra Red (liquid film
3379, 2974, 1483, 1383, 1281, 1199, 1042, 915, 869, 782, 748, 637 cm“l
GLC Retention Time: 3.71 minutes
EXAMPLE 36
This Example illustrates the preparation of ethyl 4( iodomethyl )-2,3,5,6-tetrafluorobenzoate.
Stage 1; 4-(Methoxymethyl)-2,3,5,6-tetrafluorobenzoic acid [5.0 g prepared by a process similar to that described in European Patent Application No
54360) was dissolved in thionyl chloride (50 cm2) and heated to the reflux temperature with stirring for 3 hours. The excess thionyl chloride was evaporated under reduced pressure to yield 4-(methoxymethyl)-2,3,5,620 tetrafluorobenzoyl chloride (ca 5 g) as a pale yellow liquid.
Infra Red (liquid film): 2938, 1770, 1654, 1487, 1388,
- 1301, 1193, 1091, 1049, 937, 846,
782, 731, 687 cm-1
142
Stage 2: The acid chloride from stage 1 (1.00 g) was dissolved in dry ethanol (5 cm3) and, when the initial exothermic reaction had subsided, the solution was stirred for a further 3 hours at the ambient temperature. The excess ethanol was evaporated under reduced pressure to yield ethyl 4-( methoxymethyl )-2,3,5,6-tetrafluorobenzoate (0.90 g) as a yellow oil.
GLC Retention Time: 2.82 minutes
The-ester from stage 2 (0.9 g) was dissolved in dry acetonitrile (5 cm3) and treated with sodium iodide (1.208 g) under a dry nitrogen atmosphere to give a yellow solution. To the stirred solution was added dropwise trimethylsilyl chloride (0.86 cm3) and the mixture, which had become red-brown, was warmed to 35-40°C, then allowed to slowly cool to the ambient temperature, and stirred for a further 18 hours. A sample was withdrawn and GLC analysis showed the reaction was ca 40% complete.
Further sodium iodide (1.02 g) and trimethylsilyl chloride (0.8 cm3) was added and the reaction heated to reflux for 3 hours. The mixture was allowed to cool to the ambient temperature, and stored for 60 hours. The solution was poured into mixture of ethyl acetate and water, the organic fraction separated and washed with (i) aqueous sodium meta-bisulpnite solution and (ii) saturated aqueous sodium chloride solution. The organic fraction was dried (anhydrous magnesium sulphate) and evaporated under reduced pressure to yield ethyl 4» ( iodomethyl )-2,3,5,6-tetrafluoro-benzoate (1.07 g) as an orange-red oil.
Infra Red (liquid film): 2986, 1734, 1653, 1484, 1391, 1367, 1314, 1229, 1164, 1115,
143
1068, 1014, 974, 942, 866, 746 cm-1
GLC Retention Time: 4.05 minutes
EXAMPLE 37
2-Methylethyl 4-( iodomethyl )-2,3,5,65 tetrafluorobenzoate was prepared by a process analogous to that described in Example 36.
Infra Red (liquid film): 2985, 1734, 1489, 1311, 1234,
1165, 1103, 1068, 975, 934, 828 cm-1
GLC Retention Time: 4.31 minutes (GLC Retention Time of intermediate 1-methylethyl 4(methoxymethyl)-2,3,5,6-tetrafluorobenzoate: 3.10 minutes)
EXAMPLE 38
This Example illustrates the preparation of 2,3,5,6tetrafluoro-4-[(l-methylethoxy)methyl]-benzyl alcohol.
Sodium (1.0 g) was added to dry isopropanol (200 cm·*), maintained at 40°C under an atmosphere of dry nitrogen. After dissolution was complete, 4-(bromomethyl)-2,3,5,6tetrafluorobenzyl alcohol (10.9 g) was added and the reaction was stirred for 16 hours, at the ambient temperature. The reaction mixture was poured into water, » acidified with dilute aqueous hydrochloric acid, and extracted into ethyl acetate. The combined organic extracts were washed with water, dried over anhydrous
AP 0 0 0 0 5 7
144 magnesium sulphate, and concentrated by evaporation of the solvent under reduced pressure. The residue was combined with the product of a similar reaction and distilled under reduced pressure to give 2,3,5,6-tetrafluoro-4-[(1-methyl5 ethoxy)methyl]-benzyl alcohol (0.8 g).
Boiling Point: 150-170°C/0.2 mm Hg
MHz XH NMR (CDCl-j): 1.20 (6H,d); 2.80 (lH,s); 3.70 (1H,septet); 4.55 (2H,s); 5.72 (2H,S)
EXAMPLE 39
This Example illustrates the preparation of 2,3,5trifluor0-4-( ethoxymethyl)-6-methoxybenzyl alcohol.
A solution of sodium methoxide (generated from 0.13 g sodium) in dry methanol (20 cm3) was added to a solution of 4-(ethoxymethyl)-2,3,5,6-tetrafluorobenzyl alcohol (1.2 g) in dry diglyme. The stirred reaction mixture was heated at 90°C for a period of 4 hours, under an atmosphere of dry nitrogen, after which time a further portion of sodium methoxide (0.1 g) was added, and heating continued for a further 8 hours. After cooling to the ambient temperature the reaction mixture was poured into water, acidified with dilute aqueous hydrochloric acid, and extracted into ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulphate, and concentrated by evaporation of the solvent under reduced pressure. The w brown residue was subjected to column chromatography on silica gel using hexane containing increasing amounts of diethyl ether (from 0% to 100%) by volume as eluent. The crude product thus obtained was again subjected to chromatography on silica gel in a similar manner to give
145
2,3,5-trifluoro-4-(ethoxymethyl)-6-methoxybenzyl alcohol (0.3 g) as a pale yellow oil.
250 MHz ΧΗ NMR (CDCl-j) : 1.24 (3H,t); 2.10 (1H,broad s);
3.57 (2H,d); 4.00 (3H,d); 4.60 (2H,t); 4.75 (2H,d)
EXAMPLE 40
The following alcohols were prepared using the procedure illustrated in Example 39.
(i) 6-methoxy-4-([1-methylethoxy)methyl]-2,3,5trifluorobenzyl alcohol.
60 MHz XH NMR (CDC13): 1.15 (6H,d); 2.50 (1H, broad s);
3.60 (1H,septet); 3.85 (3H,s); 4.5 (2H,s); 4.6 (2H,m) (i i) 6-methoxy-4-(phenoxymethyl)-2,3,5-tr ifluorobenzyl alcohol.
250 MHz 1H NMR (CDCl-j): 2.20 (lH,bs); 4.00 (3H,d); 4.78 (2H,d); 5.12 (2H,t); 7.0 (3H,m); 7.30 (2H,m) (iii) 6-ethoxy-4-(methoxymethyl )-2,3,5-tr ifluorobenzyl alcohol.
MHz XH NMR (CDC13): 1.40 (3H,t); 2.20 (1H, broad s);
3.40 (3H,s); 4.25 (2H,q); 4.58 (2H,t); 4.80 (2H,d) *
(iv) 6-ethoxy-4-(phenoxymethyl)-2,3,5-trifluorobenzyl alcohol
APO00057
146
250 MHz 1H NMR (CDClj): 2.10 (1H, broad s); 4.00 (3H,d);
4.75 (2H,d); 5.15 (2H,t); 7.00 (3H,m); 7.30 (2H,m) (v) 2-ethoxy-4-( ethoxymethyl )-3,4,5-tr ifluorobenzyl alcohol
MHz 1H NMR (CDCl3): 1.20 (3H,t); 1.40 (3H,t); 2.40 (1H,broad s); 3.55 (2H,q); 4.20 (2H,qd); 4.60 (2H,t); 4.75 (2H,d)
EXAMPLE 41
4-( methoxymethyl)-3-methoxy-2,5,6-trifluorobenzyl 10 alcohol was isolated by HPLC as a by-product in the reaction between 4-(methoxymethyl)-2,3,5,6tetrafluorobenzyl alcohol and sodium methoxide in methanol solution.
1H NMR (CDC13): 2.10 (1H, broad s); 3.39 (3H,d); 3.95 (3H,d); 4.53 (2H,d); 4.80 (2H,t)
EXAMPLE 42
This Example illustrates the stages in the preparation of 4-((2,2-dichlorocyclopropy1)methyl]-2,3,5,6tetrafluorobenzyl alcohol.
Stage 1:
4-[prop-2-en-l-yl]-2,3,5,6-tetrafluorobenzyl 20 tetrahydropyran-2-yl ether
4-[prop-2-en-l-yl]-2,3,5,6-tetrafluorobenzyl alcohol
147 (6.15 g prepared according to the method described in European Patent Application No 31199) was treated at the ambient temperature with 3,4-dihydro-2H-pyran (2.813 g) and para-toluenesulphonic acid (0.005 g) as catalyst.
The solution was stirred for 4 hours and residual dihydropyran removed by evaporation under reduced pressure. The'tetrahydropyranyl ether was obtained as a colourless liquid residue, and was used without further purification.
Infra red (liquid film): 2945, 1639, 1486, 1350, 1275,
1202, 1184, 1120, 1028, 975, 906,
869, 817 cm
GLC Retention Time: 4.94 minutes
Stage 2: 4-[(2,2-dichlorocyclopropyl) methyl]-2,3,5,6tetrafluorobenzyl tetrahydropyran-2-yl ether
APO 0 0 0 5 7
4-[prop-2-en-l-yl]-2,3,5,6-tetrafluorobenzyl tetrahydropyran-2-yl ether (1.0 g) was treated with aqueous sodium hydroxide (10 cm2; 40% w/v) and benzyltriethyl ammonium chloride (0.050 g; phase transfer catalyst).
To the rapidly stirred mixture was added chloroform (5 cm2, ethanol free) and the reaction heated at the reflux temperature for 6 hours. The reaction mixture was cooled to the ambient temperature, diluted with dichloromethane (100 cm2) and water (100 cm2). The organic fraction was separated, washed with water (50 cm2) and dried (anhydrous magnesium sulphate). The solvent was evaporated under reduced pressure to yield a brown oil which was » fractionated by chromatography on silica gel eluted with nhexane/ethyl acetate (25:1 by volume). The title product (0.44 g) was obtained as a colourless oil.
1H NMR (CDC13): 1.2-1.35 (t,lH); 1.45-2.00 (m;8H); 2.70148
2.85 (m;lH); 3.15-3.30 (m;lH); 3.45-3.65 (m,1H) 3.85-4.0 (m,lH); 4.50-4.60 (m,lH); 4.70-4.90 (m,2H);
GLC Retention Time: 7.90 minutes
Stage 3: 4-[(2,2-dichlorocyclopropylJmethyl]-2,3,5,6tetrafluorobenzyl alcohol.
4-[(2,2-dichlorocyclopropyl) methy1] — 2,3,5,6tetrafluorobenzyl tetrahydropyran-2-yl ether (0.240g) was heated at the reflux temperature for 3 hours in a mixture of methanol (5 cm3) and 2 M hydrochloric acid (1 cm3). The solvent was evaporated under reduced pressure and water removed azeotropically from the sample by heating with toluene (2x10cm·3). The title product (0.15 g) was obtained as an orange oil.
Infra Red (liquid film): 3364, 2977, 1658, 1485, 1382,
1277, 1221, 1100, 1017, 929, 903, 842, 759 cm-1
GLC Retention Time: 4.94 minutes
EXAMPLE 43
This Example illustrates the stages in the preparation of 4-(cyclopropylmethyl)-2,3,5,6-tetrafluorobenzyl alcohol.
*
Stage 1: 4-( cyclopropylmethyl)-2,3,5,6-tetrafluorobenzyltetrahydropyran-2-yl ether.
4-((2,2-dichlorocyclopropyl) methyl)-2,3,5,6149 tetrafluorobenzyl tetrahydropyran-2-yl ether (0.43 g prepared according to stage 2 of Example 42) was treated with tri-£-butyltin hydride (2 cm2) and aza-isobutyronitrile (AIBN) (0.005 g, catalyst) under a nitrogen atmosphere. The stirred solution was heated to 110°C for 5 hours, and further tr i-_n-butyltin hydride (1 cm2) and catalyst (0.005 g) were added. The mixture was heated at 110°C for a further 5 hours and more tri-n-butyitin hydride (1 cm2) and catalyst (0.0005 g) added. Heating was then continued for a further 10 hours.
The reaction was cooled and the crude product isolated by pouring the solution onto a short column of silica gel and eluting with firstly n-hexane to remove the organotin residues and, secondly, n-hexane/ethyl acetate(25:l by volume) to give two products, identified as 4—[(2— chlorocyclopropyl) methyl]-2,3,5,6tetrafluorobenzyl tetrahydropyran-2-yl ether (Molecular ion 251, GLC Retention Times: 6.41 and 6.85 minutes, consistent with a mixture of isomers) and the required 420 (cyclopropylmethyl)-2,3,5,6-tetrafluorobenzyl tetrahydropyran-2-yl ether, obtained as a colourless liquid :
Infra Red (Liquid film): 2944, 1485, 1276, 1120, 1028 cm-1·
GLC Retention Time: 5.36 minutes
Stage 2: 4-cyclopropylmethyl-2,3,5,6-tetrafluorobenzyl alcohol.
Prepared from 4-(cyclopropylmethyl)-2,3,5,6* tetrafluorobenzyl tetrahydropyran-2-yl ether by the method described in Stage 3 of Example 42.
APO''*** 7
GLC Retention Time: 2.60 minutes
150
Infra Red (liquid film): 3352, 1484, 1307, 1276, 1138, 1020, 922, 860 cm1
EXAMPLE 44
This Example illustrates the preparation of 4[(prop-2-ylidene) aminooxymethyl]-2,3,5,6-tetra-fluorobenzyl alcohol.
4-Bromomethyl-2,3,5,6-tetrafluorobenzyl alcohol (1.002 g, preparation described in UK Patent Application 2153819 A), acetone oxime (0.311 g), potassium t_-butoxide (0.424 g) and dry dimethoxyethane (3 cm3) were heated at the reflux temperature for 2 hours. The reaction was diluted with dichloromethane and water, the organic layer separated and the aqueous layer was extracted with further dichloromethane. The combined organic extracts were washed with water, dried over anhydrous magnesium sulphate and the solvent evaporated under reduced pressure to give the title product as an orange oil ( 0.835 g) .
GLC Retention Time: 3.62 minutes
Infra Red (thin film): 3376, 2957, 1734, 1487, 1369, 1286, 1032, 892, 828 cm1
EXAMPLE 45
This Example illustrates the preparation of 4-[3(triethylsily)propan-3-ylj-2,3,5,6-tetrafluorobenzyl » alcohol.
Reference: Organometallics, Vol 2, No 6, p 769-771 (1983)
151
4-[prop-2-en-l-yl]-2,3,5,6-tetrafluorobenzyl tetrahydropyran-2-yl ether prepared according to Stage 1 of Example 42) (1.04 g) was treated with triethylsilane (0.52 cm3) containing 5% platinum on carbon (catalyst, 0.05 g).
The mixture was placed in an ultrasound bath and sonicated for 3 hours. Further triethylsilane (0.1 cm3) was added and the mixture was sonicated for a further 2 hours. The mixture was diluted with dichloromethane and the catalyst was filtered from the solution. The solvent was evaporated under reduced pressure to yield the silylated tetrahydropyranyl ether as an oil.
GLC Retention Time: 9.31 minutes
The oil was dissolved in methanol (5 cm3) and dilute aqueous hydrochloric acid (1 cm3, 2 molar) was added. The solution was kept at the ambient temperature for 18 hours, the organic solvents evaporated under reduced pressure and water removed azeotropically by heating with propan-2-ol (twice) to give the title product as an oil (1.01 g).
Infra Red (liquid film): 3335, 2953, 2876, 1486, 1416,
1298, 1274, 1090, 1017, 890, 731 cm'}-
GLC Retention Time: 6.56 minutes
EXAMPLE 46
This Example illustrates the stages in the preparation of 1-methyicyclopropanecarbonitrile.
* (i) Preparation of 1-methylcyclopropanecarboxylic acid chloride.
ΑΡ0 no 05 7
152
Oxalyl chloride (59.7g) was added in portions to a stirred solution of 1-methylcyclopropanecarboxylic acid (40g commercially available from Aldrich Chemical Company Ltd) in chloroform (300 cm-1). The reaction mixture was then heated at the reflux temperature for 3 hours. After this time, the volatile components were removed by distillation at atmospheric pressure to leave a pale yellow liquid (49g) which was shown by gas liquid chromatography to contain a small amount of unreacted oxalyl chloride. The product was used without further purification.
Infra red (liquid film): 2980, 1850, 1780, 1430, 1300, 1285, 1055, 1080, 930 cm-1.
(ii) Preparation of 1-methylcyclopropanecarboxamide.
A solution of 1-methylcyclopropanecarboxylic acid chloride (49g) in chloroform (300 cm1) was added gradually to a concentrated aqueous solution of ammonia (300 cm1), previously cooled to 0°C by external cooling.
The reaction mixture warmed spontaneously to 20°C and a white solid precipitate was formed; the precipitate was redissolved by further addition of chloroform. The organic layer was separated, dried over anhydrous magnesium sulphate and the solvent evaporated under reduced pressure. The residual solid was recrystallised from a mixture of chloroform and n-hexane to give 1methylcyclopropanecarboxamide (17.6g) as colourless crystal.
Melting point : 148°C.
Infra red (paraffin mull): 3390, 3200, 1660, 1615, 1405, 1245, 1110, 880 cm’1.
153 (iii) Preparation of 1-methylcyclopropanecarbonitrile.
A mixture of 1-methylcyclopropanecarboxamide (7.0g) and excess phosphorus pentoxide was heated at 200°C. 1Methylcyclopropanecarbonitrile was continuously distilled from the reaction flask during heating and was collected by condensation (2.3g).
Boiling point : 126°C.
Infra Red (liquid film): 2980, 2950, 2250, 1465, 1430, 1035, 955, 895 cm'1.
1H NMR (CDC13): 0.76 (m, 2H); 1.24 (m, 2H); 1.40 (s, 3H).
EXAMPLE 47
1-Methylcyclohexylcarbonitrile was prepared according to the method given in Example 46 from 1methylcyclohexylcarboxylic acid.
(i) 1-methylcyclohexylcarboxylic acid chloride from 115 methylcyclohexylcarboxylic acid and oxalyl chloride.
Infra Red (thin film): 2937, 2958, 1789, 1450, 1378, 1278, 1142, 1047, 984, 932, 912, 951,
838, 764 and 642 cm-1 (ii) 1-methylcyclohexylcarboxamide from 1-methyl20 cyclohexylcarboxylic acid chloride and concentrated aqueous ammonia solution.
270 MHz 1H NMR (CDCl3)i 1.17 (3H,s); 1.30-1.60 (8H,m); 1.90 (2H,m); 5.70 (1H, broad s); 5.90
154 (1H, broad s).
Infra Red (thin film); 3400, 3353, 2923, 1642, 1620, 1458 and 1398 cm-1 (iii) 1-methylcyclohexylcarbonitrile from 15 methylcyclohexylcarboxamide and phosphorous pentoxide.
MHz LH NMR (CDCl-j): 1.35 (3H,s); 1.2-2.0 (10H,m)
Infra Red (liquid film): 2933, 2859, 2231 and 1451 cm'}
EXAMPLE 48
This Example illustrates an emulsifiable concentrate 10 composition which is readily convertible by dilution with water into a liquid preparation suitable for spraying purposes. The concentrate has the following composition:
% Weight
Compound No 1 25.0
SYNPERONIC NP13 (nonylphenol-ethyleneoxide 2.5 15 condensate; Synperonic is a registered trade mark)
Calcium dodecylbenzenesulphonate 2.5
AROMASOL H (alkylbenzene solvent; 70
Aromasol is a registered trade mark)
155
EXAMPLE 49
This Example illustrates an emulsifiable concentrate composition which is readily convertible by dilution with water into a liquid preparation suitable for spraying purposes. The concentrate has the following composition:
% Weight
Compound No 4 50.0
SYNPERONIC NP13 (nonylphenol-ethyleneoxide 6.0 condensate; Synperonic is a registered trade mark)
Calcium dodecylbenzenesulphonate 4.0
AROMASOL H (alkylbenzene solvent; 40.0
Aromasol is a registered trade mark)
EXAMPLE 50
This Example illustrates an emulsifiable concentrate composition which is readily convertible by dilution with water into a liquid preparation suitable for spraying purposes. The concentrate has the following composition:
% Weight
Compound No 15 1.0
SYNPERONIC OP10 (octylphenol-ethyleneoxide 3.0 condensate; Synperonic is a registered trade mark)
APO 00 0 5 7
156
Calcium dodecyibenzenesulphonate 2.0
AROMASOL H (alkylbenzene solvent; Aromasol is a registered trade mark) 94.0
EXAMPLE 51
This Example illustrates a wettable which is readily convertible by dilution powder composition with water into a
liquid preparation suitable for spraying purposes. The wettable powder has the following composition:
% Weight
Compound No 16 Silica 25.0 25.0
Sodium lignosulphonate Sodium lauryl sulphate Kaolinite 5.0 2.0 43.0
EXAMPLE 52
This Example illustrates a wettable composition which is readily convertible powder by dilution with
water into a liquid preparation suitable for spraying purposes. The wettable powder has the following
composition: % Weight
Compound No 5 Sodium lignosulphonate Sodium lauryl sulphate Kaolinite 1.0 5.0 2.0 92.0
157
EXAMPLE 53
This Example illustrates a wettable powder composition which is readily convertible by dilution with water into a liquid preparation suitable for spraying purposes. The wettable powder has the following composition:
% Weight
Compound No 11 Silica
Calcium lignosulphonate Sodium lauryl sulphate Kaolini te
40.0
40.0
5.0
2.0
13.0
EXAMPLE 54
This Example illustrates a dusting powder which may be applied directly to plants or other surfaces and comprises 1% by weight of Compound 25 and 99% by weight of talc.
L SO 0 0 OdV
EXAMPLE 55
This Example illustrates a concentrated liquid formulation suitable for application by ultra low volume techniques after mixing with paraffinic diluents.
Compound No 164 % Weight
90.0
SOLVESSO 200 (inert diluent; Solvesso is a registered trade mark)
10.0
158
EXAMPLE 56
This Example illustrates a concentrated liquid formulation suitable for application by ultra low volume techniques after mixing with paraffinic diluents.
% Weight
Compound No 187 25.0
SOLVESSO 200 (inert diluent; Solvesso 75.0 is a registered trade mark)
EXAMPLE 57
This Example illustrates a concentrated liquid formulation suitable for application by ultra low volume techniques after mixing with paraffinic diluents.
% Weight
Compound No 92 10.0
SOLVESSO 200 (inert diluent; Solvesso 90.0 is a registered trade mark)
EXAMPLE 58 *
This Example illustrates a capsule suspension »
concentrate which is readily convertible by dilution with 15 water to form a preparation suitable for application as an aqueous spray.
159 % Weight
Compound No 114
Alkylbenzene solvent (e.g. AROMASOL H) Toluene di-isocyanate Ethylenediamine
Polyvinyl alcohol Bentonite
Polysaccharide (e.g. KELTROL; Keltrol is a registered trade mark)
Water
10.0
5.0
3.0
2.0
2.0
1.5
0.1
76.4
EXAMPLE 59
This Example illustrates a capsule suspension concentrate which is readily convertible by dilution with water to form a preparation suitable for application as an aqueous spray.
% Weight
APO 0 0 0 5 7
Compound No 125
Alkylbenzene solvent (e.g. AROMASOL H) Toluene di-isocyanate
Ethylenediamine Polyvinyl alcohol
Bentonite
Polysaccharide (e.g. KELTROL; Keltrol is a registered trade mark)
Water
1.0
10.0
3.0
2.0
2.0
1.5
0.1
80.4
EXAMPLE 60
A ready for use granular formulation:
160 % Weight
Compound No 120 0.5 SOLVESSO 200 0,2 nonylphenol ethoxylate (eg Synperonic NP8) C.l Calcium carbonate granules 99.2 (0.3-0.7 mm)
EXAMPLE 61
An aqueous suspension concentrate:
% Weight
Compound No 179
Kaolinite
Sodium 1ignosulphonate nonylphenolethoxylate (eg Synperonic NP 8) propylene glycol
Bentonite
Polysaccharide (eg Keltrol)
Bactericide (eg Proxel; Proxel is a registered Trade Mark)
Water
5.0
15.0
3.0
1.5
10.0
2.0
0.1
0.1
63.3
EXAMPLE 62
A ready for use dust (D.P.) made from a concentrate
Concentrate :
% Weight
Compound No 205
161
Silica
Magnesium Carbonate
Dust Example containing 1% active ingredient:
Above concentrate Talc
EXAMPLE 63
This Example illustrates the insecticidal properties of the Products of this invention.
The activity of the Product was determined using a variety of insect pests. The Product was used in the form of'liquid preparations containing 500, 250 or 100 parts per million (ppm) by weight of the Product. The preparations were made by dissolving the Product in acetone and diluting the solutions with water containing 0.01% by weight of a wetting agent sold under the trade name
LISSAPOL NX until the liquid preparations contained the required concentration of the Product. Lissapol is a Registered Trade Mark.
The test procedure adopted with regard to each pest was basically the same and comprised supporting a number of the pests on a medium which was usually a host plant or a foodstuff on which the pests feed, and treating either or both the pests and the medium with the preparations.
The mortality of the pests was then assessed at periods usually varying from one to three days after the treatment.
APO00057
In the case of the species Musca domest ica (housefly), additional tests to determine the knockdown effect of the compounds were performed. Details are given in Table II.
162
The results of the tests are given in Table III for each of the Products, at the rate in parts per million given in the second column as a grading of mortality designated as A, B or C wherein A indicates 80-100% mortality or knockdown, B indicates 50-79% mortality or knockdown and C indicates less than 50% mortality or knockdown .
In Table III the pest organism used is designated by a letter code and the pests species, the support medium or food, and the type and duration of test is given in Table II.
163
TABLE II
DURATION x-s Λ <13 -ο \-ζ CO CO m CM
Ch ρ P XJ XJ P
o <J υ υ υ U
<0 CO CO <0 CO
ω Η ρ XJ u XJ P
cl. CO C C C C C
>· U3 o o o o o
Η o o o o υ
J. , II ua
Ω c c CO
ο ¢0 <0 Φ XJ P
ο D Φ a c c
Ch X XI <0 CO
H Φ Φ *a a
αύ £ X J= co 00 CL CL
o υ υ Φ (0
cu X c Ma c Ma c X Φ Φ
cu ο Φ <0 φ <0 • P x> υ υ
x> CxJ ρ Φ p Φ X ¢0 • P • P
CO £ U- a Ch ^a o o cd oc
co
P CL
Φ 1
Φ 3 Φ Φ P υ
<0 Ό co > co Φ • P P
υ CO a O c CL P Φ
•p ♦ P Φ CL υ CL
P 1 XJ t ac o c CL
ρ P Φ 3 X • P o
3 co 3 co co Φ x
cn Φ Φ υ p
ω m P CO P »a CO c X Ma
►—» 3 •P 3 • a CO P CO • P <0
CJ X e J= 0 P <0 .-a P Φ
ω υ υ Φ z“\ > CL P i-a
X >> P ϊο P CL CO P Φ x-\
ω c Φ c 1) Ό ¢0 C P C CO
<0 -o co Ό co • P CL 3 O Φ X
Η P • P P » ri 3 x CO O x Φ Ok.
CO P o. P CL N CL —a P a. P 0
ω Φ co Φ CO CO • P X φ ao
Η H s-z H v-Z xl Z z ’«a c
ω ζ-X
cd >
ω ►Ρ
Η
Η Φ <0 Φ
ω a X Ω Pl, a <-)
χ X H H £ z z
<0
CxJ Η
Ω
ο
CJ>
APO00057
O
0
σ
• -J cn
co 03 0 X ft)
2 o o CD < cr c-
3 ►“· cn
o 73 ft H
-3
rH cn
< x
cn
z-v 03 03 z~\ σ z-s ix
X ft — ft rr ft H
X c o 0) o (ft 0 (ft O 1—· cn
o co ft rr o rr 0 σ* 3* r-· cn
c ft 7? rr K rr rr (ft O H
co 0) H ft T ft c 0 O rr cn
Φ o o »—* 0 rr ft 3
ex (ft »—* (ft r·· O r·» T)
o ft ft) ft ft) 3 O CO cn
H· 3 3* 3- ft) cr 0
Φ ft DO tw c < M
CO co 3 ft 3 ft (ft σ* ex H· cn
rr 3 rl (ft c *T cn
I »->· 9 3 3 <: 0 ft
ft Ό (ft TJ ft) (ft rr M (0
ft) ft) cr □ 3* 3 ft ft 3 n
ex ω K· n H· x-z ft) ft
c ft ·»-✓ O rr I 3
ft) ft) ft) CO
rr μ-*
CO ft)
\«x 2 ft)
ft
s»Z
(ft Π T5 T3 3 ΤΙ 0 X w
c 0 (ft r-· 0 m G
<w rr (ft ft) H· >—· rt σ X
ft) rr co co N rr rr h-i 3
o rr rr ft ft 0 G 0
□ r*« r*· T □ X
ft ft CO H
c ft TO I—< nrj
0 TO TO ft ft) ft 0
o O O ex TO ft) 0
r—· rr rr ft rr» σ
·«»,.
o O 70 50 50 H ,
o o ft ft ft cn «:
□ □ co cn co cn X
rr rt t—« H· r·· H m
(ft ft) Cl ex (X
n ft c c C 0
rr rr 0) ο (ft x
►—
σ
G
ex χ
N5 K) N) ft) >
H
co M
s—✓ 0
z
TABLE II CONTINUED
- V9T -
Η· □ ο
Cl ο . Ο
r-« σ σ
η ΓΤ m
to to W 2 to
ΓΤ ο Π3 σ cr r
Φ ΓΤ »—·
ΙΛ - φ Η
σ -3
rr ΓΤ γη £T
& φ < JO
to Μ s-x <Ζ>
ΓΤ ΓΤ
σ □
φ CL W x-x s Η
Γ*· ►—· Ό σ' c σι
3 η Φ O o to CZ3
Φ to to CL c n Η
CL ΓΤ to o co to
Γ·» φ Φ X5 Φ (Λ
C rr r-t) CL Π3
Β Φ K— O m
ΓΤ to ri Γ*· 3 ο
C σ' a to Φ Φ ΓΗ
0) to 3 to to m
Μ rr 'C Φ rr ω
X 1 r-·
ΓΤ σ' € H· n
π ο O w to to
φ ΓΤ ri c CL
to σ' 3 to C
ΓΤ r—·
Φ *σ 1 ΓΤ
CL φ to
ω t—1
σ' ΓΤ to
φ to rt
Ι-Γι <
ο to to
σ Φ
φ CL s_z
3
3 Φ
ΓΤ) CL o co o 3 w
φ r*» o c o W C
00 C rr oo rr σ M3
ΓΤ 3 rr to rr ΓΗ Τ3
to O ri O ¢3 ο
γτ € 3 3 73
Γ·· Φ Η
Ο »-ι »— ε
3 φ Φ o ο
to o ο
C ΓΤ m H— σ
Γ-· π
ΓΤ φ
σ' to
ΓΤ Φ
σ' Ω- 50 75 Η Η
φ Φ 3 m -5
to to O on *0
XJ 3 r-« n Η σι
φ CL O-
00 C CL ο
ΓΤ 2 to 0 'Π
to Π 1— ε
• Φ 3
to
Γ*’
CL
C
to σ
1—· z—·. <3
2 CL 73
tsi 4> to >
Η
3* ω ΓΗ
O Ο
C ζ
<-l
to
S9I
TABLE II CONTINUED
166
TABLE III
Compound Number Rate (ppm) TUa TUe MP NL NC MD/KD MD BG/R BG/C HV SP DB
1 500 A A A A A C C A C C
2 500 A C A - A C A - C A A A
3 500 A A C - A C C - C B A C
* * * *
4 500 A C A — A A A B — A A A
5 500 A C A - B B C - C B A C
6 500 A - C - C C C - C c C B
9 500 A A A - A A A - B A A B
11 ' 500 A A A - A A A - C A A A
★ * * *
12 500 A A A — A A A A — A A A
14 500 A C A - A B A - C A C C
* ** * * *
15 500 A A A — A A A B — A A A
16 500 C A A - - A A** B - * A A* ★ c
17 500 B C C - C C C C - c C A
18 500 A C A - A A C - c A A A
25 500 A A A - A A C - c A A B
26 500 A A B - A A A - c C A A
30 500 A C A - A A A - c A A A
32 500 A B A - A A A - c A A A
41 500 A C A - A A A - A A A C
57 500 A C A - A A A - C A A C
61 500 A C A - A A A - C C A C
68 500 A c A - A C C - C A B c
74 500 A c B - A C B - c A A c
76 500 A c A - A A B - B A A c
78' 500 A B A - A A C - B A A A
82 1000 A C A - A A C - c A A c
* ** * * *
87 500 A A A • B A A A B A A
167
TABLE III CONTINUED
Compound Number Rate (ppm) TUa TUe MP NL NC MD/KD MD BG/R BG/C HV SP DB
90 500 A C A A* A A** A ★ A * A A*
91 500 A A A - A A A - A A A A
. * ** * * ★
92 500 A C A — A A A C — A A c
* it *
113 500 C C B c — A A C — c c c
114 500 A A A - A* A A A - * A * A ★ A
115 500 - A A A c - C A** A - A* it A it c
116 500 A A A A - A *★ A A - Ar A A A * A
117 500 A A A A - A A** A - A* A* g*
118 500 B C A C - - ** A C - * B A B c*
★ ** * Ar ★
119 500 A C A — A A A A c A A
120 500 A C A - A A A C - A A c
121 500 A C A c - B A** C - Ar A it A * A
** it Ar
122 500 A c A c - A A C - A A B
** * * it
123 500 A A A A - A A B - A A c
* ** A ★ *
125 500 A C A — A B B C — A A A
131 500 A A A - A A c - C C A A
135 500 A A A - A A A - c C A A
139 500 A C A - A A A - A A A C
161 500 A A A - A A A - B C A B
163 500 A C C - C C C - C C B C
164 500 A C B - C A C - C B A C
165 500 C c C - B C C - C C c c
166 500 A A A - B C C - c c A A
167 500 A A A - - c c - c A A A
168 500 A A A - A c c - c B B C
169 500 A A A - A A A - c C A C
170 500 A C C — B B c — c C A c
L SO 00 OdV
168
TABLE III CONTINUED
Compound Number Rate (ppm) TUa TUe MP NL NC MD/KD MD BG/R BG/C HV SP DB
171 500 A C C C C C C c C C
172 500 A c B - C C C - C c C C
173 500 A c A - A C C - C A A C
174 500 A c A - B c C - C C c c
175 500 A c C - C c C - C C c c
176 500 A c A - A A A - C A A c
177 500 A c A - A A C - C C A c
178 500 A c A - A C C - c C C c
179 500 A c A - A C C - c C c c
180 500 A c A - A A A - c A A c
181 500 A c A - A A A - c A A A
182 500 A c B - A C C - c C C c
183 500 A c C - A A A - c A A c
185 500 A c A - A A B - c A A c
186 500 A c A - A A C - c A A c
187 500 A c A - A A B - c B A c
188 500 A c A - B C C - c B A c
189 500 A c A - A B C - c C A c
190 500 A c A - A A c - c A A c
192 500 A c B - C C c - c C A c
193 500 A c A - B C c - c C A c
194 500 A c C - C C c - c c A c
195 '500 A A A - A c c - c A A A
196» 500 C c C - C c c - c c A c
197 500 A A A - A A c - c A A A
198 500 A c A — A A c — A A A A
169
TABLE III CONTINUED
Compound Number Rate (ppm) TUa TUe MP NL NC MD/KD MD BG/R BG/C HV SP DB
199 500 A A A A A A A A A B
200 500 A C A - A A C - C A A C
201 500 A B A - A A A - B A A A
202 500 A C A - A A C - C B A C
203 500 A B A - A A A - B A A C
204 500 A C A - A A A - B A A c
205 500 A C A - A C C - C A A c
206 500 A C A - A A A - B A A A
207 500 A C A - A A C - C C C C
208 500 A c A - A C C - C C C c
209 500 A c B - C C c - C A B c
210 100 A A C - - - - - C C C c
211 500 A A A - A A c - C c A c
212 500 A C A - A A c - C c B c
213 500 A c B - C A c - B c C c
214 500 ★ * it *
A c A — A A B A — c A c
216 500 A c C - B C C - c c B c
217 500 A c A - A A A - c A A c
218 500 A c A - A C C - c C C c
220 500 A c A — A A A — c C B B
Note:

Claims (20)

1. A compound of formula (I):
(i) and stereoisomers thereof, wherein:
r! is selected from alkyl containing 1 to 6 carbon ' atoms; alkenyl containing 2 to 8 carbon atoms;
5 alkynyl containing 2 to 6 carbon atoms; haloalkyl containing 1 to 4 carbon atoms; haloalkenyl containing 2 to 8 carbon atoms; and cycloalkyl containing 3 to 6 carbon atoms optionally substituted by one or more substituents selected from alkyl containing 1 to 4
10 carbon atoms and halogen;
R2 is selected from alkyl containing 1 to 8 carbon atoms; haloalkyl containing 1 to 4 carbon atoms; alkoxy containing 1 to 6 carbon atoms; alkylamino containing 1 to 4 carbon atoms; dialkylamino
15 containing a total of 2 to 8 carbon atoms; halogen;
cycloalkyl containing 3 to 6 carbon atoms optionally substituted by one or more substituents selected from halogen and alkyl containing 1 to 4 carbon atoms; and 'phenyl optionally substituted with one or more
20 » substituents selected from alkyl containing 1 to 4 carbon atoms, haloalkyl containing 1 to 4 carbon atoms, halogen and alkoxy containing 1 to 4 carbon
171
R3 is selected from hydrogen and halogen;
R4 is the residue of an alcohol of formula R^-OH which forms an insecticidal ester when combined with chrysanthemic acid, permethrin acid or cyhalothrin
5 acid; and
X is selected from oxygen and sulphur;
provided that R2 may not represent an alpha-branched alkyl group or a cycloalkyl group when R1 represents 1-methylethyl.
10 2. A compound of formula (I) as claimed in claim 1 wherein R1-, R2, R3 and X have any of the meanings given in claim 1, and R^ is selected from:
(i) a group of formula:
Rc
AP 0 0 0 0 5 7 wherein Y represents nitrogen, or carbon substituted 15 with either of a hydrogen atom or a methyl group, Ra represents hydrogen, halogen or methyl, R& represents phenyl, phenoxy, halophenoxy, benzyl or halogen, and * Rc represents hydrogen, methyl, trifluoromethyl, cyano or ethynyl;
172 (ii) a group of formula:
wherein :
Rd is selected from halogen; alkyl containing 1 to 8 carbon atoms; alkenyl containing 1 to 8 carbon atoms; alkynyl containing 1 to 8 carbon atoms; haloalkyl containing 1 to 6 carbon atoms; haloalkenyl containing 1 to 6 carbon atoms; a group of formula -SiR3; a group of formula -CO2R; a group of formula -OR; a group of formula -SR; a group of formula -(CH2)3-R^ where R^ represents chlorine, hydroxy, cyano, a group of formula -BR2, or a group of formula -SiR3; and a group of formula -CH2RL where R1 represents hydroxy, halogen, a group of formula -OR, a group of formula SR, alkenyloxy containing 2 to 4 carbon atoms, alkenylthio containing 2 to 4 carbon atoms, alkynyloxy containing 2 to 4 carbon atoms, alkynylthio containing 2 to 4 carbon atoms, phenyl optionally substituted with one or more halogen substituents, phenoxy optionally substituted with one or more halogen substituents, phenylthio optionally substituted with one or more halogen substituents, benzyloxy optionally substituted with one or. more halogen substituents, a group of formula -OCOR, a group of formula -OCOOR, a group of formula -O-N=CR2, a group of formula -NR2, piperidin-l-yl, pyrollidin-1yl, N-morpholino, or cyclopropyl optionally substituted with one or more halogen substituents,
25 ’
173 wherein R represents alkyl containing 1 to 4 carbon atoms;
Re, R^, r9 and R11 are independently selected from hydrogen, fluorine, chlorine, bromine, piperidin-l-yl, pyrollidin-l-yl, alkyl containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms, alkylthio containing 1 to 4 carbon atoms and a group of formula -NR2 wherein R represents alkyl containing 1 to 4 carbon atoms;
APO 7 and (iv) a group of formula:
wherein Z is selected from oxygen and sulphur, R3 is selected from hydrogen, alkyl containing 1 to 6 carbon atoms, alkenyl containing 1 to 6 carbon atoms, alkynyl
L containing 1 to 6 carbon atoms, and benzyl, and R is selected from alkyl containing 1 to 6 carbon atoms, alkenyl containing 1 to 6 carbon atoms, alkynyl
174 containing 1 to 6 carbon atoms, and benzyl.
3. A compound as claimed in claim 1 or claim 2 wherein R2, R3, R4 and X have any of the meanings given therein, and R^ is selected from ethyl, 1-methylethyl,
1,1-dimethylethyl, 1,1-dimethylpropyl, 1,1dimethylprop-2-en-l-yl, trifluoromethyl, cyclopropyl, 1-methylcyclopropyl, 2-methylprop-2-en-l-y1, 2-fluoro1,1-dimethylethyl, 2,2-difluoro-l,1-dimethylethyl, prop-l-en-2-yl and prop-2-en-l-y1.
4. A compound as claimed in claim 1 or claim 2 wherein r1, R3, R4 and X have any of the meanings given therein, and R2 is selected from methyl, ethyl, 1methylethyl, 1,1-dimethylethyl, 1,1-dimethylpropyl, trifluoromethyl, 2-fluoro-l,1-dimethylethyl, 2,2difluoro-1,1-dimethylethyl, trichloromethyl, cyclopropyl, 1-methylcyclopropyl, cyclohexyl, 1methylcyclohexy1, phenyl, 2-chlorophenyl, dimethylamino and chloro.
5. A compound as claimed in claim 1 or claim 2 wherein R1, R2, R4 and X have any of the meanings given therein, and R3 is selected from hydrogen, chlorine and fluorine.
6. A compound as claimed in claim 1 or claim 2 wherein R1, R2, R3 and X have any of the meanings given therein, and R4 is selected from (i) a group of formula:
175
Rc wherein Ra is selected from hydrogen and fluorine; R^ is selected from benzyl, phenoxy, 4-chlorophenoxy, 4bromophenoxy and 4-fluorophenoxy; Rc is selected from hydrogen, methyl, trifluoromethyl, ethynyl and cyano;
5 and Y represents nitrogen or carbon substituted with either of a hydrogen atom or a methyl group; and (ii) the group of formula:
AP 0 0 0 0 5 7 wherein Rd has any of the meanings given hereinbefore; Re is selected from fluorine, chlorine, bromine,
10 methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio and dimethylamino; R^ is selected from hydrogen and fluorine; and r9 and R11 are independently selected from fluorine, chlorine, bromine, methoxy, ethoxy, methyl and ethyl.
*
15 7. A compound of as claimed in claim 1 or claim 2 which is an ester of an alcohol or thioalcohol of formula
176
R^-x-H, wherein X is selected from oxygen and sulphur, and an acid selected from the group of acids consisting of :
2-(2-(1,1-dimethylethyl)pyrimidin-5-yl)-3,35 dimethylbutanoic acid and stereoisomers thereof,
2-(2-(1-methylethyl)pyrimidin-5-yl]-3,3dimethylbutanoic acid and stereoisomers thereof,
2-(2-(1-methylcyclopropyl)pyrimidin-5-y1)-3,3dimethylbutanoic acid and stereoisomers thereof,
10 2-(2-(1,1-dimethylpropyl)pyrimidin-5-yl)-3,3dimethylbutanoic acid and stereoisomers thereof,
2-[2-(tr i fluoromethyl)pyr imidin-5-yl)-3,3dimethylbutanoic acid and stereoisomers thereof,
2-(2-(1,1-dimethylethyl)pyrimidin-5-yl)-3,315 dimethylpent-4-enoic acid and stereoisomers thereof,
2-(2-(1,1-dimethylethyl)pyrimidin-5-yl)butanoic acid and stereoisomers thereof,
2-[2-(dimethylamino)pyrimidin-5-yl]-3,3dimethylbutanoic acid and stereoisomers thereof,
2 0 2-( 2-(cyclopropyl)pyrimidin-5-y1)-3,3-dimethylbutanoic acid and stereoisomers thereof,
2-(2-phenylpyrimidin-5-y1)-3,3-dimethylbutanoic acid ‘ and stereoisomers thereof,
2-(2-(4-methoxyphenyl)pyrimidin-5-yl)-3,3177 dimethylbutanoic acid and stereoisomers thereof,
2-(2-(1,1-dimethylethyl)pyrimidin-5-yl]-3-methylbut-3enoic acid and stereoisomers thereof,
2-[2-methylpyr imidin-5-yl]-3,3-dimethylbutanoic acid 5 and stereoisomers thereof,
2-[2-(1-methylcyclohexyl)pyrimidin-5-yl]-3,3dimethylbutanoic acid and stereoisomers thereof,
2-(2-(2-chlorophenyl)pyr imidin-5-yl]-3,3dimethylbutanoic acid and stereoisomers thereof,
10 2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3dimethylpentanoic acid and stereoisomers thereof,
2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]pent-4-enoic acid and stereoisomers thereof,
2-(2-(1,1-dimethylethyl)pyrimidin-5-yl1-3,3,315 trifluoropropanoic acid and stereoisomers thereof,
2-(2-(1,1-dimethylethyl)pyrimidin-5-yl]-2cyclopropylacetic acid and stereoisomers thereof,
2-(2-phenylpyrimidin-5-yl]-3-methylbutanoic acid and stereoisomers thereof,
2 0 2-(2-(trifluoromethyl)pyrimidin-5-yl]-3-methylbutanoic acid and stereoisomers thereof,
2-(2-(dimethylamino)pyr imidin-5-yl]-3-methylbutanoic acid and stereoisomers thereof,
178
2-(2-( trichloromethyl)pyrimidin-5-yl(-3-methylbutanoic acid and stereoisomers thereof,
2-[2-chloropyrimidin-5-yl]-3-methylbutanoic acid and stereoisomers thereof,
5 2-[2-methylpyrimidin-5-yl]-3-methylbutanoic acid and stereoisomers thereof,
2-(2-( trifluoromethyl)pyrimidin-5-yl]-2-(1methylcyclopropyl)acetic acid and stereoisomers thereof ,
10 2-(2-(1,1-dimethylethyl)pyrimidin-5-y1(-2-(1methylcyclopropyl)acetic acid and stereoisomers thereof,
2-(2-(trifluoromethyl)pyrimidin-5-yl(-3,3dimethylpentanoic acid and stereoisomers thereof,
15 2-(2-( trichloromethyl)pyrimidin-5-yl(-3,3dimethylbutanoic acid and stereoisomers thereof,
2-[2-chloropyrimidin-5-yl(-3,3-dimethylbutanoic acid and stereoisomers thereof, and
2- (2-(1,1-dimethylethyl)pyrimidin-5-y1(-3,320 dimethylbutanethioic acid and stereoisomers thereof.
8. A compound as claimed in claim 1 or claim 2 wherein
R1, R2 and R3 have any of the meanings given therein, and the group -X-R^ is selected from:
*
3- phenoxybenzyl,
25 l-cyano-l-(3-phenoxyphenyl(methyl,
179
2-methyl-3-phenylbenzyl,
4-methyl-2,3,5,6-tetrafluorobenzyl,
4- (prop-2-en-l-yl)-2,3,5,6-tetrafluorobenzyl,
N-3,4,5,6-tetrahydrophthalimidomethyl,
5 1-ethynyl-l-(3-phenoxyphenyl) methyl,
5- benzylfur-3-ylmethyl,
6- phenoxypyrid-2-ylmethyl,
1-cyano-l-(6-phenoxypyr id-2-yl) methyl,
1- (6-phenoxypyrid-2-yl)ethyl,
10 4-(prop-2-yn-l-yl)-2,3,5,6-tetrafluorobenzyl,
4-(but-2-yn-l-yl)-2,3,5,6-tetrafluorobenzyl,
4-(3-chloroprop-2-en-l-yl)-2,3,5,6-tetraf luorobenzyl, 4-( methoxymethyl )-2,3,5,6-tetrafluorobenzyl,
2- methoxy-4-(methoxymethyl )-3,5,6-trifluorobenzyl,
15 4-benzyl-2,3,5,6-tetrafluorobenzyl, • 3-benzyl-4-fTuorobenzyl,
4-[3-(trimethylsilyl)prop-2-yn-l-yl]-2,3,5,6tetrafluorobenzyl ,
4-(2-methylprop-2-en-l-yl)-2,3,5,6-tetrafluorobenzyl,
20 4-ethoxy-2,3,5,6-tetrafluorobenzyl,
4-trimethylsilyl-2,3,5,6-tetrafluorobenzyl,
4-(but-2-en-l-y1)-2,3,5,6-tetrafluorobenzyl,
4-(2-chloroprop-2-en-l-yl)-2,3,5,6-tetrafluorobenzyl, 4-fluoro-3-phenoxybenzyl,
25 2-chloro-6-fluorobenzyl,
1-cyano-l-(3-benzyl-4-fluorophenyl)methyl,
3- phenylami nobenzyl,
4- (2,3-dichloroprop-2-en-l-y1)-2,3,5,6tetrafluorobenzyl ,
30 pentafluorobenzyl,
1-cyano-l-(4-fluoro-3-phenoxyphenyl) methyl, ' 2,2,2-trifluoro-l-(6-phenoxypyrid-2-yl)ethyl, » 2,3,5,6-tetrafluoro-4-(4-chlorobenzyloxy)methyl(benzyl,
2,3,5,6-tetrafluoro-4-{hydroxymethyl) benzyl,
35 2,3,5,6-tetrafluoro-4-[((1,1AP 0 0 0 0 5 1
180 dimethylethyl)oxycarbonyl) methoxymethyl (benzyl,
2.3.5.6- tetrafluoro-4-(acetyloxymethyl) benzyl,
2.3.5.6- tetrafluor0-4-(chloromethyl)benzyl,
2.3.5.6- tetrafluoro-4- (ri-propyl) benzyl,
2.3.5.6- tetrafluoro-4-(methythiomethyl) benzyl,
2.3.5.6- tetrafluorO-4-(ethoxycarbonyl)ben2yl,
2.3.5.6- tetrafluor0-4-((1-methylethyl)oxycarbonyl]benzyl, '2,3,5,6-tetrafluoro-4-[(2,2-dimethylpropanoyl) oxymethyl(benzyl,
2.3.5.6- tetrafluoro-4-((2-methylpropanoyl)oxymethyl ] benzyl,
2.3.5.6- tetrafluoro-4-((1-methylethyl) thiomethyl] benzyl,
2.3.5.6- tetrafluor0-4-((1,1-dimethylethyl)thiomethyl] benzyl,
2.3.5.6- tetrafluoro-4-(Ν,Ν-diethylaminomethyl)benzyl,
2.3.5.6- tetrafluoro-4-[(piperidin-l-yl)methyl]benzyl,
2.3.5.6- tetrafluoro-4-[(N-prop-2-ylideneamino) oxymethyl(benzyl,
2.3.5.6- tetrafluoro-4-(cyclopropylmethyl)benzyl,
3-(4-chlorophenoxy)benzyl,
1- (3-(4-chlorophenoxy)pyrid-2-yl(ethyl,
3,5-difluoro-4-methyl-2-(methylthio)benzyl ,
2.3.5.6- tetrafluoro-4-(methylthio)benzyl,
2.3.5.6- tetrafluoro-4-(ethylthio)benzyl,
2- ethoxy-4-(methoxymethyl )-3,5,6-trifluorobenzyl,
2.3.5.6- tetrafluor0-4-(ethoxymethyl)benzyl,
2-methoxy-4-( ethoxymethyl)-3,5,6-trifluorobenzyl,
2-ethoxy-4-(ethoxymethyl )-3,5,6-tr ifluorobenzyl,
2.3.5.6- tetrafluoro-4-[(1-methylethyl) oxymethyl(benzyl,
2-methoxy-4-((1-methylethyl)oxymethyl]-3,5,6trifluorobenzyl,
2-ethoxy-4-[(1-methylethyl)oxymethyl(-3,5,6181 trifluorobenzyl, . 2,3,5,6-tetrafluoro-4-(phenoxymethyl) benzyl, 2-methoxy-4-(phenoxymethyl)-3,5,6-trifluorobenzyl, 2-ethoxy-4-(phenoxymethyl)-3,5,6-trifluorobenzyl,
5 2,3,5,6-tetrafluoro-4-[(2,2-dichlorocyclopropyl) methyl]benzyl,
2.5.6- trifluoro-3-methoxy-4-(methoxymethyl) benzyl,
2.3.5.6- tetrafluoro-4-[3-(triethylsilyl)prop-lyl]benzyl,
10 2-methyl-3,4,5,6-tetrafluorobenzyl,
2.3.5.6- tetrafluoro-4-[(prop-2-yn-l-yl) thiomethyl] benzyl,
9. A compound as claimed in claim 1 having the formula:
wherein R3, R2, R2 and X have any of the meanings 15 given in claim 1.
AP 0 0 0 0 5I
10. A compound of formula (II):
II c - Q wherein R3·, R2, and R3 have any of the meanings given in claim 1 and Q represents hydroxy, halogen or a lower alkoxy group containing from 1 to 6 carbon (II)
182 atoms .
11. A compound of formula (VI):
OHC — C — CH — C02R
II
CHR5 (VI) wherein R1· has any of the meanings given in claim 1, R represents lower alkyl containing from 1 to 6 carbon atoms, and R5 represents alkoxy containing from 1 to 6 carbon atoms, dialkylamino wherein each alkyl group contains from 1 to 4 carbon atoms, piperidin-l-yl or pyrollidin-l-yl.
12. A compound of formula (VII):
(VII) wherein R2 has any of the meanings given in claim 1.
183
13. A compound of formula (VIII):
CF
R‘ ii
C =CC12 (VIII) wherein R2 has any of the meanings given in claim 1.
14. A compound of formula (IX):
(IX) wherein R2, R3 and R4 have any of the meanings given 5 in claim 1.
15. A process for the preparation of a compound as claimed in claim 1, wherein R1, R2, R3, R4 and X have any of the meanings given therein, wherein:
(a) an acid of formula (II):
184 wherein Q represents the hydroxy group, is reacted directly with an alcohol of formula R4-OH or a thioalcohol of formula R4-SH, the reaction taking place in the presence of an acid catalyst or a dehydrating agent; or (b) an acid halide of formula (II) wherein Q represents a halogen atom, is reacted with an alcohol of formula R4-OH or a thioalcohol of formula R4-SH, the reaction taking place in the presence of a base; or (c) an acid of formula (II) wherein Q represents the hydroxy group, or an alkali metal salt thereof is reacted with either (i) a halide of formula Q'-R4, wherein Q' represents a halogen atom, or with a quaternary ammonium salt derived by reaction of such a halide with a tertiary amine, or (ii) with a compound of formula Q'-R4 wherein Q' represents the mesylate group or the tosylate group; or (d) a lower alkyl ester of formula (II) wherein Q represents a lower alkoxy group containing up to 6 carbon atoms is heated with an alcohol of formula R4OH to effect a transesterification reaction.
16. A process for the preparation of a compound of formula (II) wherein Q represents a lower alkoxy group of formula -OR containing up to 6 carbon atoms, R and RJ have any of the meanings given in claim i and R1represents a primary or secondary alkyl group, which comprises alkylation of a compound of formula (V):
185 ch2co2r (V)
17.
using a primary or secondary alkyl halide of formula R^-Hal, wherein Hal represents a halogen atom, in the presence of a base.
A process for the preparation of a compound of formula:
which comprises reaction of compound of formula (VI):
R1
I
0HC-C-CH-C02R
II 5
CHR3
AP 0 0 0 0 5 7 (VI) wherein R1· has any of the meanings given in claim 1, R represents lower alkyl containing from 1 to 6 carbon atoms, and R5 represents alkoxy containing from 1 to 6 carbon atoms, dialkylamino wherein each alkyl group
186
contains from 1 to 4 carbon atoms, piperidin-l-yl or pyrollidin-l-yl, with a compound of formula: NH 2 X Rz--- C NH2
wherein R2 has any of the meanings given in claim 1, or a salt thereof, optionally in the presence of a
5 base.
18. A process for the preparation of a compound of formula (VI) :
‘ R1 ohc-c-ch-co2R ii 5
CHR3 (VI ) wherein R1 has any of the meanings given in claim 1, R represents lower alkyl containing from 1 to 6 carbon
10 atoms, and R5 represents alkoxy containing from 1 to 6 carbon atoms, dialkylamino wherein each alkyl group contains from 1 to 4 carbon atoms, piperidin-l-yl or pyrollidin-l-yl, whch comprises reaction of an acetal of formula (R'0)2CH-CH2-CH(R1)-C02R, wherein R'
15 represents lower alkyl containing from 1 to 6 carbon atoms, with phosphorus oxychloride in the presence of • a formamide selected from an N,N-dialkylformamide, Nformylpiperidine and N-formylpyrollidine.
187
19. A process for the preparation of an acetal of formula (R'0)2CH-CH2-CH(R1)-CO2R> wherein R1 represents a tertiary alkyl substituent and both R and R' represent a lower alkyl group containing from 1 to 4 carbon atoms, which comprises the step of (i) reaction of a compound of formula R1-CH2CO2R with an allyl halide in the presence of a base to give a compound of formula CH2=CH-CH2-CH(R1· )-CO2R, followed by the step of (ii) ozonolysis of the compound of formula CH2=CH-CH2CH(R1)-CO2R to give an aldehyde of formula OHC-CH2CH(R1)-CO2R, followed by the step of t
(iii) reaction of the aldehyde of formula OHC-CH2CH(R1)-CO2R with a trialkyl orthoformate of formula HC(OR')3 to give the acetal of formula (R'O)2CH-CH2CHiR1)-CO2R.
20. A process for the preparation of a compound of formula:
APO 00 09 7
R2 -(f A- CH - C02R
N-ZZ/ wherein R2 has any of the meanings given in claim 1 and R represents a lower alkyl group containing from 1 to 4 carbon atoms, which comprises the step of reaction of a compound of formula (VIII):
188 with a lower alkanol containing from 1 to 4 carbon atoms in the presence of a base, followed oy the step of mild acidic hydrolysis.
21. An insecticidal or acaricidal composition comprising an insecticidally or acaricidally effective amount of a compound according to claim 1 in association with an insecticidally and acaricidally inert diluent or carrier.
I
22. A method of combating insect or acarine pests at a locus which comprises applying to the locus an insecticidally or acaricidally effective amount of a composition according to claim 21.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0162538A2 (en) * 1984-03-26 1985-11-27 Imperial Chemical Industries Plc Cyclopropane derivates
EP0227415A2 (en) * 1985-12-23 1987-07-01 Imperial Chemical Industries Plc Pyrimidine derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0162538A2 (en) * 1984-03-26 1985-11-27 Imperial Chemical Industries Plc Cyclopropane derivates
EP0227415A2 (en) * 1985-12-23 1987-07-01 Imperial Chemical Industries Plc Pyrimidine derivatives

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DK334888D0 (en) 1988-06-17
HUT47384A (en) 1989-03-28
CS421088A2 (en) 1991-02-12
ZA883862B (en) 1988-12-19
KR890000437A (en) 1989-03-14
NZ224836A (en) 1991-03-26
AU610184B2 (en) 1991-05-16
AP8800092A0 (en) 1988-05-01
GB2209525B (en) 1991-04-03
GB2209525A (en) 1989-05-17
PT87743A (en) 1988-07-01
EP0295839A2 (en) 1988-12-21
IL86560A0 (en) 1988-11-15
EP0295839A3 (en) 1991-07-31
HU203644B (en) 1991-09-30
RU1801108C (en) 1993-03-07
DK334888A (en) 1988-12-18
PT87743B (en) 1992-10-30
GB8813780D0 (en) 1988-07-13
GB8714233D0 (en) 1987-07-22
BR8802952A (en) 1989-01-10
CN1030412A (en) 1989-01-18
JPS6416769A (en) 1989-01-20
CN1019574B (en) 1992-12-23
OA08742A (en) 1989-03-31
AU1738988A (en) 1988-12-22
HU908470D0 (en) 1991-07-29
GB8812344D0 (en) 1988-06-29

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