CA1247107A - Synthesis of 2-substituted-5-methyl-pyridines and intermediates therefor - Google Patents

Abstract

Abstract A process for the synthesis of compounds which are known intermediates for the pyridyloxyphenoxy herbicides as well as intermediates used in the process.
Propionaldehyde and an acrylic compound, two readily available starting materials, are reacted to form a 2-formylpentanoic compound which is cyclized to a dihydro pyridone which is then oxidized to the 2-hydroxy pyridine.
The hydroxypyridine may be halogenated to a 2-halopyridine.

Description

IC-L-~m 1593~A

1;~4'~

This application ~s a division of Seri.al No.
437,645 filed September ~7, 1983.

Various 4-(5-halomethyl-2-pyridyloxy)phenoxy compounds are known to be useful as herbicides as di~closed in European Published Pat~nt Appllcation No.
4B3, United Kingdom Patent Specifications 1,5g9,121 and 1~5~9,126 and U.S. Patents 4,1~4,041 and 4,317~913. For example, butyl 2-[4-(5-trifluoromethyl-2-pyridyloxy) 10 phenoxylpropionatP which is also known as 1uazifop-butyl is an effective grass herbic~de which can be used in fields where broad-leaved crops such as cotton and soybeans ~re cultivated. Importan~ starting materials for ~uch pyridyloxy-phenoxy compounds are the 2-halo-5-tri-chloromethylpyridines such as 2-chloro-5 trichloromethyl-pyridine described in U.S. Patent 4,3179913. Such 2-halo-5-trichloromethylpyridines, in turn, may be prepared by chlorinating, under ultraviolet light irradiation, a 2-halo-5-methylpyridine as described in U.S. Patent 4,152,328.
An object of the present invention is an effioient, economical and reliable synthesis of 2-halo-5-methylpyridines as well as intermediates used in the synthesis.
A further object of the present invention is a method for preparing 2-halo-5-methylpyridines without utilizing pyridine/ and in particular 3-picoline~ star~ing materials to thus avoid the problems ~f byproduct formation in the halogenation reaction to yield ~I) wherein X is halogenO

~Z~7~ 7

2-U~D~ ol ~he Invention .__ The present invention comprises a method for the ~ynthesis of a 5-methylpyridine of the formula (I):

¦ l ~I) wherein X is a halogen or hydroxy, by condensing the acyclic aliphatic staxting materials propionaldehyde and an acrylic ester, amide or nitrile to form a gamma-methyl gamma-aldehydo ester amide or nitrile which ester may then be aminated ~ith a nitrogen source ~uch as an amine or 10 ammonium compound to form a dihydro 5-methyl-2-pyridone, which amide may be thermally cyclized and which nitrile may be converted to ~he pyridone Yia acid catalysi~. The pyridone may then be oxidized to the compound of formula (I) wherein X is hydrvxy which may be halogenated to the compound of formula (I) wherein X 1s halo. Also part of the present invention are the individual process steps and novel interme~iates formed in the ~ynthesis.

Detailed Description of the Inven~ion In the firs~ step a3 of the process of the pre~ent invention, propionaldehyde of the following formula (II) is reacted in a Michael type addition with an acrylic compound of ~he following formula (111~:

Y

(II) ~IIIS

3'7 wherein Y is a moie~y of the formula -COOR, -CONH2 or -CN
and R is an organic moiety, to produce 8 pentanoic aldehyde of the following fo~mula (IV):

(IV) ~,~0 `f R, in particular, ~ay be a substituted or unsubstituted alkyl or aryl group although a wide range of moieties may be used since the -OR function is removed in the following 6tep. Thus, R may be any grouping which is ~table to the Michael addition conditions used and which is removable as the -OR moiety upon nucleophilic attack by a nitrogen on the COOR group. Particul~r examples of R are alkyl of about 1 to 6 carbons, e.g., methyl or ethyl, aryl of about 6 to 10 carbons or arylalkyl of about 1 to 8 carbons ln the alkyl portion and about 6 to 10 carbo~s in the aryl portion, which aryl or ~ryl portion may be substituted by groups such as lower alkyl or halogen. The Michael addition may be conducted as known in the art such as a~ a tempe~ature of about 0~ to 100C, neat or in the presence of ~n inert solvent and optionally in the presence of a reaction catalyst such as strong baseO The compound of formula (I~) may be recovered by extraction, chromato~raphy or distillation.
Preferably, the irst step of the process is conducted in three stages by the use of protec~ion and depro~ection reackions which serve to activate ~he propionaldehye for the Michael addition, eo minimize side reactions and to avoid the use of strong reagents and catalysts. The three ~tages of the first step ~nvolYe i) reac~ing propionaldehye with a ~econdary amine of the fo~mNla HNRlR2, wherein Rl and R2 are independently organic moieties which may be sttached to each o~her to '7:~'7

-4 -form a ring, to form, directly or ~hrough an intermedia~e aminal the ensmine of ~he following formula (VII):

~ ~ ~ (VII) In particular, values of Rl and R2 include individual ~ubstituted and ~msub~tituted alkyl of about 1 to 6 carbons such as ethyl and butyl ~nd, when Rl and R2 are connected, substituted and unsubstituted heterocyclic rings such as 5- or fi-membered heterocyclic rings, e.g., to define the secondary amines pyrrolidine, piperldine and morpholine. The first stage i) may be conduc~ed at about -10 to 35C preferably in the presence of an alkali or alkaline earth metal carbonate, sulfate, halide or oxide, e.g., calcium sulfate, magnesium sulfate, ealcium chloride, ~odium sulfate, magnesium oxide, potassium carbonate, calcium oxide or even molecular sieves, as diselosed by D. Roelofsen et al. ln Recueil, Vol. 91, pages 605-610 ~1972~, with at least two moles of H~lR~
per mole of propionaldehyde. The 6econdary amine is used in excess in view of the intermediate formation of an aminal of the formula CH3CH2CH(NRlR~)~ which is then heated ~o form the enamine of formula (VII) and distil off the excess HNRlR2 which is released with formation of the double bond. Thus, the aminal ~ay be heated to about 75 to 100C at a vacuum ~f about 40 to 100 mm of Hg.
According to this aspect of the present invention, the enamine of formula (VII) and the secondary amine ~NRlR2 are coformed from the aminal and preferably, the ~NRlR2 will be separated from the enamine at thi~ point by fractional di~tillation. If the secondary a~ine has a bo~ling point close to the ensmine, e.g., if the secondary amine is morpholine, the distillation should be monitored 4'7 to avoid codi6tillation of the two products and/or an incomplete reaction of the aminal. If the aminal is obtained in wh~le or in part a~ this point, such may be taken on to the cyclobutane of formNla (VIII) a8 described below. This monitoring can be carried out by gas liquid chromatography and X nitrogen by elemental snalysis.
Disclosures of such enamine forMa~ions include C. Mannich and H. Davidsen in Ber., vol. 69, pages 2106-2112 (1936);
&. Opi~z et al. in Ann., Vol. 623, pages 112-117 (1959~;
P. de~enneville et al. in J. American Chemical Society, Vol. 72, pages 3073-3075 (1950); R. Dulou et al. in Bull.
Chem. Soc. France, pages 967-971 (1960); G. Kalaus in Ber., Vol. 114, pages 1476-1483 (lg81); and U.S. Paten~
3,074,940 to E. Benz~ng.
In the second stage li) of the first step of the invention, the enamine of formula (VII) is reac~ed with the acrylic compound of for~ula (III) to yield the compound of the following form~la (VIII):
\t~
l l (VIII) R'~ ~ ~ Y
whereln Y, Rl and R2 are as ~efined above for formulae (III) and CVII). The compound of formula ~II) may exist to a limited exten~ in the form of the open chain enamine of the s$ructure SRlR2~)HC=CHGH3~CH~)2Y. The syn~hesi~ of cyclobutanes OI' the formula ~VIII) cype is described in 25 detail by I. Fleming et al. in the Journals of the Chemical Society, pages 2165-2174 (1964) and in U.S.
Patents 3,0519 622; 3 ,133,924; 3,369,024; 3,481,936; and 3,481,939. The reaction may be carried out neat or in the presenc2 of ~ nitrile, ether, ester, halogenated slkane or 30 ketone solvent , e . g ., acetonitrile , although a neat reaction is preferred in view o:f simplicity. The reaction '7~3 may be carried out at room temperature up to the boiling point of the acrylic compound of formula (III), e.g., up to about 170C, with the higher temperatures of this range being advantageously used to complete the reaction. The

5 enamine of formula (VII) may be cooled to about -5 to 20C
with dropwise addition of the acrylic compound of formula (III~ followed by warming to the range of room temperature to about the boiling point of the acrylic compound.
The third stage iii) of the first step of the invention process is the hydrolysis of the compound of formula (VITI) to the aldehyde of formula ~IV) with recovery of one mole of the secondary amine HNRlR2. The reaction may be conducted in an aqueous acidic medium such as in the presence of an aqueous organic or mineral acid, such as acetic, sulfuric, hydrochloric, phosphoric or toluene sulfonic acids, optionally with a solvent such as those listed for the second stage ii) of the first step, at a temperature of about 25D to 105~C at a pH of about 1.5 to 4.5. The solvent or this reaction may advantageously be that used in stage ii) whereby the product of s~age ii) need not be purified but rather may be sinply carried forward in it~ crude sta~e with sol~7ent.
However, B solvent other ~han the aqueous acidic reaction ~edium need not be present. The aldehyde of formula (IV) may be recovered by extraction of the aqueous acid solution containing HNR1R2 with a neutral organic solvent such as ethyl acetate or methylene chloride.
Al~ernatively, the third stage hydrolysis iii) may be conducted under basic conditions and in the event of saponifica~ion of the ester, the acid is formed, i.e., the compound of formula ~IV) wherein Y is -COOR and R is hydrogen, and such may be cyclized to the dihydropyridone of formula (~) as explained below. A disclosure of reactions leading to ~IV) wherein Y is -COOCH3 was made by W. Pirkle et al. in the Journal of Organic Chemistry, Vol.

40, pages 1617-1620 (1975) with similar reactions being described by G. Stork in the Journal of the American Chemical Society, Vol. 85, pages ~07-221 (1963). The reaction of aerylonitrile~ i.e., eompound (III) where Y=CN, with the pyrrolidine enamine of n-hPptaldehyde is deseribed by Ross C. Terrell, Ph.D. The~is Columbia University (1955) as ylelding ~-cyanoethyl-n-hep~aldehyde and compound (IY) where Y=CN may be produced in a similar manner.
In the second step b) of the process of the invention when Y-COOR, the aldehyde of formula (IV) is reac~ed with an amine or ammonium salt to form the dihydropyridone of the following formula (V3:

~u~ lo or) The cyclization in ~tep b) may be carried out with a nitrogen source ~uch as an amine or ammonium salt, with specific examples being ammonium carbamate, ammonium carbonate, ammonium hydroxide, ammonia, ammonium bicarbonate, ammonium acetate or ammonium orthophosphate.
In general, an ammonium salt of a weak acid such as phosphoric, carbonic or acetic acid is pre~erred. The reaction may be carried out neat or in a solventg e.g., a high boiling solvent, for one or bo~h reactants such as a carboxylic acid, e.g., acetic acid, an alkanol which use is less preferred~ e.g., ethanol, an aromatic hydrocarbon compound, e.g., benzene or toluene, a halogen~ted aromatic hydrocarbon, e.g., a mono-, di- or tri-chlorobenæene, or a ketone, e.g.l methyl ethyl ketone, methyl isobutyl ketone and disobutyl ketone. The temperature of ~he cyclization reaction will vary depending on the partioular ni~rogen source used and the ~olvent but is, in general~ from about room temper~ture up to the boiling point of ~ny solvent or reactant utilized, e.~., from about 25 to 150C.
In the ~econd step b) of the process of the invention when Y'CONH2 the aldehyde of Formula (IV) is thermally cyclized ~t a temperature of about 100 to 200C
neat or in a high boiling sol~ent such as aromatic hydrocarbon compound, e.g., benzene, xylene or.acrylamide, or a halogenated aromatic hydrocarbon, e.g., a mono-, di-or tri-chlorobenzene and the pyridone of formula (V) may be recovered by standard techniques ~uch as distillation vr extraction.
In the second step b~ when Y=CN, the aldehyde (IV) is converted to the pyridone (V) by acid catalysis~
e.g., with hydrogen halide such as ~Cl, ~ulfuric acid, phosphoric acid or a sulfonic acid at a temperature of room temperature to about 100C neat or in a solvent such as a halogenated hydrocarbon. Such reactiQn conditions are described by N. P. Susherina et al. in Chemical ~bstracts, Yol. 55 7410e, by A. I. Mey~rs in J. Organic Chemistry, Vol. 29, pageS 1435-1438 ~1964) ~nd in German Offenlegundschrift 2,245,0g7 (March 21, 1974).
In one aspect of the invention, the cyclization step b) may be conducted in two stages by iv) dimeTiz~ng the aldehyde of formula (IV) where Y-CQOR by reaction with excess ammonia or other nitrogen ~ource to yield the pyridone adduct of the following formula (X):

O ~ ~ X N ~

followed by v) pyrolyzing the compound of formula ~X~ with loss of NH3 at a temperature of about 200 to 300C to yield ~he dihydro-pyrldine of the formula ~V).

'7~

9.

In the third step c~ of the proce~s of the present inYention, the d~hydropyrldone of formula (V) is oxidized to the pyridone of the following fo~mula (VI):

(VI) 0~

In one aspect of the present invention, the oxidation step c) may be carried out by a fir~t stage vi) co~prising dihalo-genating the compound of formula (V) with a halogénating ~gent such as chlorine, bromine, sulfuryl bromide or sulfuryl chloride ~n an equimolar to slight molar excess at about 25 to 40C in a solvent such as a halogenated hydrocarbon, e.g., chloroform or chlorobenzene, to produce the dihalo compound of the following formula tIX~:

wherein Xl is a halogen atom, such as chloro or bromo. In a further ~tage ~ 9 the dihalo eompound of formula (IX) may then be dehydrohalogenated to produce the pyridine of formula ~YI) by heating to a temperature of about 100 to 170C neat or in the presence of a high boiling solvent 20 such as chlorobenzene. In general, the product of the de'nydrohalogenation stage vii3 is the hydrohalide salt of the pyridine of formula ~VI~ which may be carried on directly to the ~-methylpyridine of formula (I) wherein X
is a halogen, or may be firs~ converted to the ree base by neutrali2ation in an aq~eous base such as sodium hydroxide or sodium carbonate followed by vaeuum evaporation and extraction with an organic solvent such as J~I~

hot acetone or ethanol. The halogenation o various dihydro pyridones i8 described by N. P. Shusherina et al.
in Chemical Abstracts, Vsl. 55 7410f ~1961), Vol. 60 4101 ~1964), vol. 58 9011d and 12507h ~1963) and by D. Diller et al. in Berichte Vol. 110, pages 2956-2957 (1g77).
In the dihalogenation stage vi) used to produce the dihalo compound of for~ul~ ~IX), several products have been observed ~hich may be readily converted to pyridone of formula (VI) together with or separate from the dlhalo compound (IX). In particular, the reaction conditions described above for ~tage vi) have yielded both the hydroxy halo compound of the following formula (XI) when water is present:
%
~O ~ N ~ O (XI) wherein ~2 is a halo~en such as bromo or chloro, and the dimeric compound of the followin~ formula (XII):

X ~ ~ ~XIO

wherein X3 is a halogen such as bromo or chloro. In general, use of lower temperaturcs for the dihalogenation 20 stage vi~ will produce compound (IX) while higher temperatures9 e.g., about 40 to 80C will yield the by-products (XI) and/or ~XII). Thus, at a reaction temperature of 40 to 80C for 2 hours in toluene with a 50Z molar excess of ~ulfuryl chloride, compound ~V) ~ay be vacuum ev~porated and extracted with toluene to leave insoluble whioh ~nclude the compound of for~ula (XI~
wherein X ~ chloro, m.p. 135D ~o 142C. If ~he same ~ 7 reaction ls conducted in chloroform at 30 to 60C, the crystaline product contains the dimer of formula ~
wherein X3 is chloro, m.p. 157 to 159C. The hydroxy halo compound (XI) and dimeric compound (XII) m~y be 5 converted to the pyridine (VI) by heatin~ ~o about 175 to 250C neat or in the presence o ~ high boiling solvent.
An advantage of the invention p~ocess that the by~products of this step can be converted to the next stage product in ~he same manner as the desired product, i.e. 9 (XI~ ~nd (XII~ are converted to (VI) in the same manner as (IX) would be.
The oxida~ion s~ep c) may also be carried out by reacting the dihydropyridone of formula SV) with a halogenating agent such as N-chloro- or N-bromo-succini~ide or 1,3-dichloro- or 1,3-dibromo-5,5-dimethylhydantoin which adds halogen at an allylic position or the posi~ion alpha to the carbonyl, i.e., the 3- or 4-halo-~-pyridone to yield the compound of the following formula ~XIII):
X~

~ (XIII~

wherein X4 is halogen ~uch as bromo or chloro. The compound of formula ~XIII) may then be converted to the pyridine of formula ~VI) by thermal elimination of HX4.
In ~he final s~ep d~ of ~he overall ~rocess of the in~ention9 the pyridone (VI) is halogenated with a ~5 halogenating agent 6uch ~s a sulfur halide, e.g., thlonyl chloride, sulfuryl chloride, a caTboxylic acid halide, e.g., phosgene, or a phosphorus halide such as phenyl-phosphonic d chloride, phosphorus oxychloride or phosphorus pentachloride, in a high boiling solvent such as a aromatlc hydrocarbon sol~ent~ e.g., toluene or ~'7~tJ'~f xylene, or a halogenated aromatic hydrocarbon, e.g., chlorobenzene, at ~ temper~ture of about 90 to 120C to yield the compound of formula (I) wherein X is a halogen, e.g., chloro bromo or iodo. The molar ratio of halogenating agent:compound of formula (VI) may vary, e.g., a ratio of POC13:(VI) of about 1.5:1 to 4.5:1 or of PC15:(VI) of about 0.3:1 to 0.5:1 ~ay be used. In addition, a combination of phospho~us halides may be used~
e.g., a mixture of POC13 and PC15 in a molar ratio of 1:0.1 or 1.6:0.45. Thus, the molar ratio of halide atoms in the phosphorous halide:compound of for~ula (VI) should be about 6:1. The reaction of 2-hydroxy-5-methylpyridine to yield 2-chloro-5-methylpyridine is also described by W.
Herz et al. in the Journal of Organic Chemistry, Vol. 22 9 pages 122-125 (1961).
Par~icular aspects of the process of the present invention which are advantageous are high yields obtained, the novel skeletal formation of a B-picoline while simultaneously functionalizing the 2-position with a group which is readily transformed to chlorine and the in situ generation of the ammonium compound such as ammonium acetate in the conversion of the compound of formula (IV) to ~V).
Also part of the present invention are novel in~ermediat~s as described herein.
In ~he following Examples and throughout the specification, the following abbreviations are used: C
(degrees Centigrade); ml (milliliters); g ~grams); m (moles); mm (millimeters); GLC (gas liquid chromatography); GC/MS (gas chromatograph-mass spectrometry~; IR (infrared); ~ (nuclear magnetic resonance); mp ~melting point); bp (boiling point);
dS-DMSO (deuterated dimethyl sulfoxide); and the conventional symbols for the chemical elements.

~'7~

Example 1 Step a), stage i) to yield morpholinoplopene of formula (VII) (NRlR2=morpholine) A 500 ml 4-neck flask was equipped wit~ a stirrer, thermome~er, addition funnel and condenser. To the flask was charged 191.7 g ~2.2 m) o morpholine and 138.2 g ~1 m~ of potassium carbonate (anhydrous) and the mixture was stirred and cooled to -5C with an ice-salt bath. To the flask was added 58 g (1 m) of propionaldehyde over a period of 55 minu~es at a pot temperature of -5~C. The temperature was then allowed to rise to 25~ to 27C and the reaction was contînued for 2 hours at 25C. The product was filtered and ~he filter cake washed with four 15 ml washes of toluene. The fitrate w~s heated under vacuum while morpholine was stripped using a 1 foot Vigreux eolumn. This treatment was carried out at an oil bath temperature of 85 to 112C, a pot temperature of 70 to 90C, a vapor temperature of 41 to 58C and at a pressure of approximately 35 to 40 mm of Hg. The vacuum stripping was carried out until 133 . 3 g of product was obtained as a residue. &LC and ~C/MS e3tablished that the pred~minant product was 4-(2-propenyl)morpholine.
13C 2~IR in d6-I)MSO (in ~ units):l5.2 ~CH3); 95.1 (CH3-C~)=; 140.8 (-CH--CH-~; 49.4 (-N(-CH2-)2~; and 66.1 (O(-GH2-)2).

To a thin slurry of 191.7 g ~2.2 m) of morpholine and 84.0 g ~1.5 m~ of calcium oxide was added dropwi~e 58 ~ (1 m) of propionaldehyde over a 30 minute period a~ 15~C. The reaction was mildly exothenmic and some cooling was applied. The slurry was filtered after 30 minutes reaction ti~e at 25C and the filter cske was washed with two 40 ml washes of morpholine. The filtrate was gradually heated to 75 to 85C und~r vacuum and then held at 85C pot temperature and a pressure of 40 mm of Hg ~acuum over 2 hours while distilling morpholine in a Vigreux column. The product pot residue weighed 116.6 g.

Example 3 Step a), stage ii) to yield acrylic compound of formula (VIII) ~Y=500R; R=CH3; ~RlR~=morpholine) A solution of 40 g of crude morpholinopropene produced in Exampl~ 1 in 175 ml of acetonitrile is cooled ~o ~2DC in an ice-salt bath and treated with a solution o~
30.5 g (0.35 m) of methylacrylate in 70 ml of acetoni~rile dropwise over a period of 20 minutes at -2 to 0C. The temperature of the solution is then gradually raised and held at 66 to 76C for 17 hours. At that point, a predominate product peak can be detected by G~C together with a smaller unidentified peak while at the same time, the morpholinopropene peak has almost completely disappeared. The methyl 3-methyl-2-(4-morpholinyl)cyolo-butane carboxylate was ch~racterized by GC/MS and NMR.
3C NMR in d6-DMSO (in ~ units):66.3 (0(-CH2-)2); 50.2 (-N(-CH2-)2); 70.8 (N-CH); 31.0 (CH3-CH); 26.2 (cyclo-butane-CH2-~; 39.1 (CH-COOCH3~; 174.1 (-COOCH3);
51.4 (-COOCH3); and 20.6 (CH-CH3).

To 63.5 g of ~he crude morpholinopropene product of Example 2 wa~ gradually added 45.7 ml ~0.51 m) of methyl acrylate at room temperature. The react;on mixture '7 was then heated to 80C until the reaction w~s complete in 7 hours as determined by GLC. The yield of product ~as 106.4 g with no loss during vacuum ~tripping to remove unreacted acrylate at 1 hour at 55C under a pressure of 50 mm of Hg.

Example 5 Step a), stage iii) to yield methyl 4-formyl-pentanoate of formula (IV) (Y=COOR; R=CH3) A solution of 18 g (0.3 m) of acetic acid in 120 ml of water is added to ~he crude morpholino cyclobutane carboxylate ester product of Example 3 and the reaction mix~ure is heated at 70 to 79C for 5 hours. The product solution is ~ooled to room temperature, diluted with 150 ml of water and extracted 3 times with ethyl acetate, 100 ml each wash. The extracts were washed 2 times with dilute sodium chloride brine solution and methyl 4-formylpPntanoate is obtained after vacuum s~ripping at 60 to 70C and a moderate vacuum of 100 mm to 28 mm of Hg in a yield of 29.2 g.
The crude methyl 4-formylpen~anoate obtained above was purified by distillation at 83~ to SSC ~t 6 mm to 8 mm of Hg ~i~h 90% recovery. Purity by GLC after distillation was determined ~o be 95.3~ and ~he product was characterized by IR, NMR and GC/MS.
13C NMR in d6-DMSO (in ~ units~:51.4 (-COOCH3); 173.2 (-COOCH3); 31.0 (-CH2-COOCH3); 25.4 ~-CH~-CH2-COOCH3);
45.1 (CH-CH3~; 13.0 (CH-CH3); and 204.7 ~-CHO).

Example 6 To a sample o:E 53.2 g (û.l9 m~ of undistilled 30 morpholino cyslobutane ester prepared as in Example 4 was '7~( added with stirring at 26C 46.3 ml (0.19 equivalents) of 4.1 Normal H2S04. The temperature rose to 42C and the reaction mixture was then heated to 98C and held under reflux for 3.5 hours to produce a two-phase reaction product. The upper layer was separated, diluted with 25 ml of methylene chloride and extracted twice with water, 25 ml each. Vacuum evaporation of the methylene chlori~e yielded 25.6 g of methyl 4-for~yl pentanoa~e which was 87.5% pure by GLC.

Example 7 To a sample of 103.6 g (0.41 m) of morpholino cyclobutane carboxylate ester prepared as in Example 4 was slowly added with stirring an aqueous HCl solution made up of 41 ml of concentra~ed HCl mixed with 48 ml of water to result in 0.49 m of HCl. During the addition over 0.75 hours, the temperature rose to 70C and the reaction mixture was then heated at 106C under reflux for 3~ hours to yield a two phase reaction product. The upper layer was separated in a separatory funnel and the lower aqueous layer was extracted three times with methylene chloride, 70 ml each. The combined extracts were ~ashed once wi~h 80 ml of water, vacuum evaporated and combined with the upper product layer yielding 49.1 g of methyl 4-formylpentanoate which was 97% pure by GLC.

~5 Example 8 Step b) to yield 5-methyl-3,4-dihydro-2(1H)-pyridone of formula (V) To 1.44 g (O.Ol m) of methyl 4-formylpentanoate dissolved in lO ml of acetic acid was added 1.54 g (0.02 m) of ammonium acetate and the mixture was heated at 80 -17~

to 125C for 16 hours. GLC showed about 11% unreacted starting material, 89Z of the desired title product and no by-products. The product was vacuum stripped, dissolved in 10 ml of ethyl acetate and washed 4 times with water, 2.5 ml each wash. The product was distilled after vacuum stripping of ethyl acetate to yield 0.5 g of 5-methyl-3,4-dihydro-2(1H)pyridone, bp 103C at 0.5 mn of Hg. The produc~ was recrystallized from ethyl acetate, mp, 76 to 78C.
Elemental Analysis: ~ 12.13% ~Calculated 12.8%~.
13C NMR in d6-DMSO (in ~ units~:l9.0 (CH3); 169.0 (C=O);
30.1 (CH2 to C=O); 25.5 ~CH2 ~ to C=O); 112.0 (C(CH3)=CH); and 120.3 (CH directly attached to NH) Example 9 The procedure of Example 8 was repeated utilizing 33.7 g (0.234 m) of methyl 4-formylpentanoate, 36 g (0.467 m) of ammonium acetate and 200 ml of acetic acid at 105C with a reaction time of 22 hours. The product was vacuum stripped at 65 ~o 95C bath temperature at 10 mm of Hg and 200 ml of distillate were collected. The residue was dissolved in 200 ml of toluene ~nd washed four ~imes with 50 ml of water each ~ime. The aqueous extracts were washed two times with 70 ml of toluene each time and the combined toluene extracts were ~acuum stripped at 40 to 50C at 80 to 100 mm of Hg, The '7~

yield of 5-methyl-3,4-dihydro-2(1H)-pyridone which ~olidified at room temperature was 13.6 g (52~ yield~.

Example 10 A neat reaction was eonducted to yield 5-methyl-3,4-dihydro-2(1H)pyridone by mixing 10 g (0.0693 m) of 4-formyl-pentanoate and 10.7 g (0.139 m~ of ammonium acetate at room temperature followed by stirrin~ and heating to 100~ to 110C for 1.5 hours. A fairly vigorous reaction occurred a~ 95~ with bubbling and release of some NH3.
After four washings vf the residue with 10 to 15 ml of chlorobenzene, the product was shown in the chlorobenzene to have a yield of 73% by GLC.

Example 11 A sample of 5 g (0.0347 m) of 4-formylpentanoate was stirred with 3.57 g (0.045 m) of ammonium bicarbonate and heated to 40G. To th~ mixture was gradually added 3 g (0.05 m) of acetic acid at 41 to 45~C over 35 minutes while the ini~ial foaming disappeared. The clear solution was heated at 92 to 97~C for 2 hours to yield 9.28 g which was distilled at a ba~h ~emperature of 100 to 122C
at about 1 mm of Hg vacuum to yi~ld 2.14 g of the compound of formula ~V~ which was 98.5% pure by GLC analysis.

Example 12 To 5.4 g of 4-formylpentanoate was added 5.6 g (a 95Z excess~ of ~mmonium acetate and 50 ml of ethanol.
The reaction was carried out at 30~C for 5 hours an~ the ethanol was then vacuum stripped after 16 hours a~ room t~mperature. The product was partitioned in 30 ml toluene and 13 ml of water, the water layer was discarded and the toluene layer was refluxed at 82 to 88~C for 3 hours.
The product was obtained by vacuum evaporation of the toluene and the purity of the 5-methyl-3,4-dihydro-2(1H) pyridone was 81~ by GLC.
During this reaction, a reaction intermediate, probably the methyl 4-iminopentanoate, was detected by GLC
when the reaction was carried out for only 10 minutes to 1 hour.

Example 13 To 6.0 g (0.0416 m) of me~hyl ~-formylpentanoate in 15 ml of absolute ethanol is added 10.5 g of a NH4OH
solution (prepared from 33.3 g of a 30% NX40H solution and 100 ml of water3. The reaction was carried out at room temperature for 20 hours followed by vacuum stripping at 30~ to 55C under a moderste vacuum of about 200 to 40 mm of Hg. Distillation of the product under forcing conditions of a pot temperature of 125 to 130C at a pressure of l mm of Hg gave a fraction distilling at 100 to 110C which was identified as 5-methyl-3,4-dihydro-2-(lH)pyridone~ The product ~as 95.3% pure by GLC.

Example 14 A solution of 5 g of methyl 4-formylpentanoate in 15 ml of chlorobenzene was slowly added to a solution of 3.0 g of ammonium acetate in 15 ml of chlorobenzene which is then held at 90 to 100C. The volatiles were allowed to distill during the reaction so that the temperature could be maintained at 98C for 1.5 hours after the addition. Gradually, clearing took place during the l. 5 hours and GLC of the product showed ORly 5-me~hyl-3,4-dihydro-2(1H)pyridone and a small amount of s~ar~ing '7 material, Distillation yielded the desired products as a white crystaline ~olld in 90~ yield.
The above reaction was repeated using 3.1 ~ of ammonium bicarbonate and 2.6 g of acetlc acid in the place of the ammonium acetate.

Example 15 To a reaction vessel was charged 380 ml of chloro~benzene followed by 67 g (1.11 m) of glacial ~cetic acid. To ~he ves6el was then added 63.5 g (1.12 m) of ammonium hydroxide in the form of a concentrated aqueous solution over 5 minutes at 25~ to 37C while stirring and eooling with an ice bath. The temperature was then r ised to 90C at which point the addition of a solution of 127 g (0.88 m) of methyl 4-formylpentanoate in 254 ml of chlorobenzene was started. The methyl 4-formylpentanoate was added over 40 minutes while the temperature ~as held at 90~ to 96C. The reaction mixture was two-phased and was continuously heated at 90 to 95C while volatiles were allowed to distill offO One hour after complete 20 addition, GLC analysis showed little unreacted pentanoate and after two hours, only about 2% was unreac~ed. The product was isola~ed by vacu~m stripping of chlorobenzene at a pot temperature of 60 to 85C with a final vacuum of 20 mm of Hg. The product of formula (V) was then distiiled at a pot temperature of 100~ to 150C, a vapor temperature of 93 to 113C at about 1 mm of Hg. The yield of formula ~V) as a yellow solid was 83.6 g ~0.75 m) which was 99% pure by GLC (85~ yield).

-21~

Example ]6 Steps a) and b) to yie].d 5-methyl-3 ~4-dihydro-2(1H)-pyridone of formula ~V) via acrylamide of formula ( III ~ (Y~CONH2 ) A sample of 25 g of morpholinopropene of the formula (VII) was di~solved in 80 ml of aeetonitrile at room temperature and treated with a warm solution of 39.1 g of acrylamide in 100 ml of acetonitrile dropwise at a reaction temperature of 25DC. The temperature was then raised to 80 ~o 85QC and held there for abou~ 40 hours.
The produc~ was fil~ered hot to remove a small amount of insoluble mat~er and was then treated with a solution of 12 g of glacial acetic acid in 80 ml of water at 75 to 80C for 6.5 hours. The product was vacuum-stripped at b8C un~er moderate vacuum to remove acetonitrile and the residue was washed with toluene and ethyl acetate. GLC of the aqueous solution showed a composition of about 2:1 acrylamide: aldehyde of formula ( IV) (Y0CONH2~. The aqueous solution was vacuum~~tripped at 50 to 60~C under 40 mm of Hg pressure to leave the prsduct as a light amber viscous residue. This was ~reated with 100 ml of ethanol, crystallized and filtered to remove part of the aerylamide. Final vacuum-stripping gave 5~.9 g of residue consisting of acrylamide and 4-formylpentanamide. The produc~ of formula (V) was generated therDally from this product by treatement a~ 100 to 140C under high vacuum.
During this treatment, 12.5 g of distillate was produced compr;sing the compound of formula ~V) and acrylamide.
Remaining was 35 g comprising compound (V) and morpholinoprop7on-amide. ~LC analysis showed that the distillate contained about 40% by weight (V) while the residue eontained 20% (Y). Addition of ace~onitrile to the distillate and hot ethyl acetate to the residue gave '710~7 acrylamide as a crystalllne solid, mp 76 to 80C from the distillate and morpholinopropionamide, mp 94 to 100C as a crystalline solid from the residue. The compound o formula (V) was found in the solutions after crystallizations to the extent of about 60~.

Example 17 Step b), ~tages iv) and v) to yield the pyridone adduct of formula (X) as an intermediate and 5 methyl-3,4-dihydro-2(1H)pyridone of formula (V) as a final product.

To 2 . O g of methyl 4~formylpentanoate was added with stirring 9 ml of concentrated ammonium hydroxide solution gradually and an exothermic reaction took place with a temperature rise from 25 to 55C. After ~ hour, GLC showed ~9% product and the temperature was then held at 88 to 96C for 1 additional hour and the product was then vacuum stripped at 80C under a pressure of 5 to 20 mm of Hg for ~ hour. Although the GLC analysis showed product with a very high purity, the N~R analysis determined that no 5-methyl-3,4-dihydro-2(1H)pyridone was present. The conclusion reached is that an intermediate was prepared which converted to the desired product under GLC injection conditions~ Isolation of the intermediate was carried out by crystallization with 3 ml of ethyl acetate. The yield of several fraetions was 25% as a crystaline white solid, mp, 158 to 166C. The compound was insoluble in ethanol, acetone and toluene bu~ soluble in methylene chloride. The product was dissolved in a hot mixture of 7 parts by volume of methanol and 9 parts by ~Jolume of ethyl acetate and recrystallized to give an mp of 182 to 18~C.

Elemental Analysis: N, 17.0% (Calculated for the c~mpound of formula (X) as C12H21N30~, N, 17.55~).
3C NMR in CDC13 (shift of ~ 77.0 ppm using CDC13 as the standard) (in ~ ~mits):174,6, 173.4 (C=O); 31.3, 30.6 ~CH2-C=O); 26.3, 23.3 (CH2-CH2-C-0); 35.8, 33.3 (CH-CH3~;
75.3, 71.0 ~NH-CH-NH): and 17.9, 17.7 (CH3) Exa~ le 18 The high-melting inter~ediate prepared in Example 17 was prepared under milder conditions by treat~ng 2 g (0.014 m) of 4-formylpentanoa~e in 5 ml of absolute ethanol with 3.5 g (0.02 m) of dilute NH40H
solution (prepared from 33.3 g of a 30% NH40H solution and 100 ml of water) at room temperature. GLC samples taken during the reaction showed a mixture of s~arting material, the desired product peak due ~o the inter~ediate of formula (X) and methyl 4-iminom~thylpentanonate. After 24 hours at room temperature, the maJor peak was the product.
The reaction mixture was vacuum evaporated at 60C under l to 6 mm of Hg to give 1.5 g of product which was recrystallized from 3.5 ml of ethyl acetate, mp 171 to 174~C.
The product of formula (X) was recrys~allized from excess acetone/methanol to yield crystals, mp 178 to 182~C.
Elemen~al Analysis: C, 59.85% (Calculated 60.2Z~i H, 8.63%
(Calculated 8.85~3; N, 17.58% (Calculated 17.55%).

Example 19 Step c), stages ~i) and vii) to yield the dihalo compound (IX) (X1DC1) as an intermediate and pyridone (VI) as a final product.

A solution of 1.5 g (0.0135 m3 of 5-methyl-3,4-dihydro-2tlH)pyridone of formNla ~V) in 9 ml of chloroform was treated with sulfuryl chloricle dropwise at 25 to 33G. After 1 hour at 30C, a GLC in ethanol solution ~with potassium hydroxide) showed conversion of the starting material to the chloro ethoxy adduct indicating reaction of chlorine across the double bond with no starting material. After 2 hours at 33C, the product was vacuum stripped at 15 to 45C over a period of 3 hours gradually reducing the pressure from 200 to 15 to 30 mm of Hg. The yield was 2.63 g of a colorless amorphous product of the formula (IX) wh~rein Xl is chloro. A sample of 2.32 g of this product was stirred with magnet for 1.5 hours at a bath temperature of 132 to 138C under 12 to 35 mm of Hg. The yield was 1.57 g of product of the formula (VI) as the hydrochloride and free base.
The free base of the compound of formula (VI) was generated by adding 4 ml of water followed by 0.4 g of sodium carbonate to the product produced in the above paragraph to result in a pH of 9 and vacuu~ stripping followed with recovery of the pyridone of formula (VI) by washing the residue with warm acetone to yield 0.53 g of the compound of formula (VI) in the acetone, mp, 150D to 172DC. Preferably, the extraction with warm acetone is replaced by an ethanol extraction.
In a similar example, th,e product was recrystallized from methanol to yield a product with a melting point of 178 to 180C.

Exam~le 20 The procedure of Example 19 was ~epeated utilizing 5 g of the starting material of formula (V).
The free base was generated with 15 ml of water and 1.7 g of sodium carbonate at a pH of 8.5 and the mixture was then vacuum stripped to remove water. The residue was washed with hot ethanol and the ethanol was then vacuum stripped to yield the product of formula (VI)~ mp 119 to 147C.

Exam~le 21 The procedure of Example l9 was repeated with the substitution of chlorobenzene, also known as monochlorobenzene, for chloroform as follows. The reaction was carried out using 4 g of ~he product of formula ~V), 8 ml of chlorobenzene and 4.4 ml of sulfuryl chloride of the formula SO2CL2 (a 50% excess). The dropwise addition of sulfuryl chloride was carried out at 23 to 38C with slight cooling followed after one hour by application of a vacuum o 75 to 150 mm of Hg at 27 to 38C for l hour. The temperature is then raised to 123C
in the pot and 141 to 143DC in the oil bath at a pressure not less than 220 mm of Hg for 3 hours. The product precipitates out as a fairly fluid lower layer during thP
reacticn, is quite viscous on cooling and consists of the compound of fo~mula (VI), partly in the form of the hydro-chloride salt.

Examp le 22 Into a solution of 7.0 g of the compound of ormula (V) in 35 ml of chlorobenzene at 20DC was introduced 7 g of chlorine gas over a period of 30 minutes. This solution was added gradually over 1 hour to 15 ml of shlorobenzene at 130~C while nitrogen was bubbled through the solution. After addition, the reaction was continued for 4 hours as the product precipitated. To the product was added 18 ml of water and the produc~ mixture was neutralized to a pH o 8 . 5 in the aqueous phase with 5 ml of 5 Normal NaOH. After vacuum stripping, the product was dissolved with ethanol and diluted to a volume of 100 ml. This solution was analyzed by GLC and found to contain 5.4 g of th~ compound of formula (VI) (78.6 yield), Example 23 Steps c) and d) to yield compound (I) (X~Cl) without isolation of pyridine (VI) A sample of 4 g of crystallized 5-methyl-3,4-dihydro-2(1H~pyridone of formula (V) ~as dissolved in 8 ml 10 of chloroben~ene and was treated with 4.4 ml of sulfuryl chloride as described in Example 20. After dehydrohalo-genation at 129C, the product consisted of a lower dark product phase which was very viscous at 40C. To the slurry of both phases was added 10.4 ml of POC13 ~t 40D
over ~ hour followed by 3.4 g of phosphorous pentachloride.
The mole ratio o the product of formula (VI):POC13:PC15 was 1:3:0.45. The reaction mixture became homogenous and was heated at 116 to 118C for 4 hours. To the product was then added to 50 g of crushed ice, 50 ml of chloro~
benzene and 162 ml of a 13~ aqueous sodium hydroxide solution. Phase separation was made in a separatory funnel and the lower aqeuous lay r was extracted 3 times with 20 ~1 of chlorobenzene each. The product layer and chlorobenz ne extracts were combined and analyzed by GLC.
The thus-produced chlorobenzene solution contained 1.5 g of the product of formula (I) wher~in X is chloro.

Example 24 Into a solution of 7.0 g of the compound of formula (V) in 35 ml of chlorobenzene was introduced 8.0 g of chlorine gas at 20 over a period of 1.25 hours. This .0'7 solution was added gradually to 15 ml of stirred chloro-ben2ene held at 130C over a period of 1 hour. The reaction was continued at 130C for ~.S hours and the product slurry was cooled to 60C. To this was then add~d 14.5 g of POC13 dropwise over 15 minutes followed by 2.62 g of PC15 also at 60C. The reaction mixture was heated to 115C for 4.5 hours. For the purposes of analysis, the -product was added to 40 ml of methanol, vacuum stripped at 50C at 130 mm of Hg and the addi~ion of methanol and vacuum stripping was repeated. The product was then neutralized to a pH of 6 with 45 ml of alcholic KOH
solution, prepared from 16 g of KOH in 100 ml of methansl, and diluted to 100 ml with methanol. The product solution was analyzed by GLC and was found to contain 4.85 g of the compound of formula (I) wherein X is chloro.

Example 25 Step d) to yield compound (I) (X=Cl) To 4~2 g of the compound of formula ~VI ) was added 15 ml of POC13 at 25 to 34 followed by 3 g of PC15. The reaction mixture was stirred and heated at 110C for 4 hours and gradual solution took place. The produc~ was added to 100 g ~f cru~hed ice and neutralized to pH 8 with 80 ml of 15% sodium hydroxide while cooling.
The aqueous solution was extracted 5 times ~ith 24 ml of ~5 methylene chloride each. The extracts were analyzed by GLC and evaporated at 40C at 4 mm of Hg to a constan~
wei~ht. The yield was 3.9 g of the compound of formula (I) wherein X is chloro.
Elemental Analysis. Cl, 26.55% (Calculated, 27.3%); N, 10.75% (Calculated, 10.98%~.
The GLC retention times and NMR of the pr~duct were identical to those of authentic samples of the compound of formula (I) ~herein X is chloro.

Ex_mple 26 In the above Example 25, separations of the product phase from the aqueous phase may be difficult and inco~plete if the product phase is too concentrated. A
more dilute syste~ is believed to be more practica~ as described below.
The procedure of ~xample 25 was repeated with a 1:1 Sw:w) dilution (weight:weigh~ of the compound of fonmula (VI) with chlorobenzene. A sample of 3.0 g of compound (VI) was mixed with 3 g of chlorobenzene and 4 ml of POC13 were added gradually at 25D to 32C, followed by 2.6 g of PC15 at 27 to 32C. The s~urry was heated to reflux and held at 117 to 119C for about 4 hours. The product was cooled to room temperature and added to 50 g of ice~ diluted with 17 ~1 of chlorobenzene and neutralized ~o a pH of 8.0 wi~h a 15Z NaOH aqueous solution. rrhe chlorobenzene solution was separated in a separatory funnel as the lower layer. The upper layer was diluted with 30 ml of water and estracted t~o times with 10 ml of chloroben2ene each. The combined chlorobenzene solutions were analyzed by GLC to indicate 2.9 g of compound (I a wherein X is chloro.

Example 27 To 50 ml o toluene at 8C was added 10 g of phosgene under a nitrogen blanket. The solution was heated to 45C and a warm solution of 4 g of the compound of formula ~VI) in 10 ml of dimethylformamide was added dropwise over 18 minutes with foaming and precipitation.
The reaction mixture was stirred and heated to 56C over 2 hours. The product ~ixture was then covled and mixed with 4 ml of water and neutralized with 20 ml of dilu~e NH40H
(produced from 80 ml of concentrated NH40H diluted wi~h '7 water to lO0 ml) and 2 g sodium carbonate to a p~ of 8.
Phase separation was made in a separatory funnel and the upper phase was vacuum ætripped ~t 45C and a pressure of 65 mm of Hg ~o yield 1.9 g of the compound of fonmula ~I) where X is Cl.

Example 28 Step c) to yield ~XI) (X =Cl).

A solution of 0.5 g of the compound of formula (V) in 3 ml of toluene was treated gradually over 20 minutes at 25 to 40C with 0.55 ml of S02Cl2 while stirring. The solution was then heated at 62 to 75C for 2 hours. Th2 product was vacuum stripped over l.75 hours at a bath te~perature of 60C down to a pressure of 12 mm of Hg . The yield was 0 . 86 g of product . The product was extracted with 4 ml of warm toluene leaving 0.26 g of toluene-insoluble product. Of the insoluble product, 0.2 g was dissolved in a hot solvent mixture of l ml of acetone and 0.5 ml of cyclohexane which crystallized at room temperature. The yield of compound of formula (XI ) was 0.11 g, mp 13~D to 142C. Characteri7.ation was made by MS and Elemental Analysis.

Examp le 29 Step c) to yield (XII) (X3=Cl).

A solution of 0 . 5 g of the compound of formula (V) in 3 ml of chloroform was stirred and treated at ?8 to 36DC gradually with 0.55 ml of S02Cl2. The solution was heated to S2 to 65C and precipitation of product occurred at that temperature. The solution was cooled to room temperature and filtered. The product was washed two '7 tlmes with 2 ml chloroform each. The yield was 0.26 g of product, mp 157 to 159C. The chloroform washes where vacuum stripped to obtain 0.53 g of additional product.
The product obtained was the hydrochloride Ralt of the compound of formula (XII) wherein X3 is chloro as shown by MS, NMR and Elemental Analysis. Af~er washing with hot acetone, the purified product had an mp of 160 to 162C~

Claims (3)

1. A 2,3-dihalo-3-methyl-6-piperidone compound of the following formula wherein X1 is a halogen.

2. The compound of Claim 1, wherein X1 is chlorine or bromine.

3. The compound of Claim 2, wherein X1 is chlorine.