Synthesis of 2-substituted-5-methyl-pyridines

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.

BACKGROUND OF THE INVENTION 
Various 4-(5-halomethyl-2-pyridyloxy)phenoxy compounds are known to be 
useful as herbicides as disclosed in European Published patent application 
No. 483, United Kingdom patent specification Nos. 1,599,121 and 1,599,126 
and U.S. Pat. Nos. 4,184,041 and 4,317,913. For example, butyl 
2-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]propionate which is also 
known as fluazifopbutyl is an effective grass herbicide which can be used 
in fields where broad-leaved crops such as cotton and soybeans are 
cultivated. Important starting materials for such pyridyloxy phenoxy 
compounds are the 2-halo-5-trichloromethylpyridines such as 
2-chloro-5-trichloromethylpyridine described in U.S. Pat. No. 4,317,913. 
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. Pat. No. 4,152,328. 
An object of the present invention is an efficient, 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, starting materials to thus avoid the problems of byproduct 
formation in the halogenation reaction to yield (I) wherein X is halogen. 
SUMMARY OF THE INVENTION 
The present invention comprises a method for the synthesis of a 
5-methylpyridine of the formula (I): 
##STR1## 
wherein X is a halogen or hydroxy, by condensing the acyclic aliphatic 
starting 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 with a nitrogen source such as an amine or ammonium 
compound to form a dihydro-5-methyl-2-pyridone, which amide may be 
thermally cyclized and which nitrile may be converted to the pyridone via 
acid catalysis. The pyridone may then be oxidized to the compound of 
formula (I) wherein X is hydroxy which may be halogenated to the compound 
of formula (I) wherein X is halo. Also part of the present invention are 
the individual process steps and novel intermediates formed in the 
synthesis. 
DETAILED DESCRIPTION OF THE INVENTION 
In the first step (a) of the process of the present invention, 
propionaldehyde of the following formula (II) is reacted in a Michael type 
addition with an acrylic compound of the following formula (III): 
##STR2## 
wherein Y is a moiety of the formula --COOR, --CONH.sub.2 or --CN and R is 
an organic moiety, to produce a pentanoic aldehyde of the following 
formula (IV): 
##STR3## 
R, in particular, may 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 step. Thus, R may be any grouping 
which is stable to the Michael addition conditions used and which is 
removable as the --OR moiety upon nucleophilic attack by a nitrogen on the 
--COOR group. Particular 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 in the alkyl portion and about 6 to 10 carbons in the aryl 
portion, which aryl or aryl 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 at a temperature of about 0.degree. to 100.degree. C., 
neat or in the presence of an inert solvent and optionally in the presence 
of a reaction catalyst such as strong base. The compound of formula (IV) 
may be recovered by extraction, chromatography or distillation. 
Preferably, the first step of the process is conducted in three stages by 
the use of protection and deprotection reactions which serve to activate 
the propionaldehye for the Michael addition, to minimize side reactions 
and to avoid the use of strong reagents and catalysts. The three stages of 
the first step involve (i) reacting propionaldehye with a secondary amine 
of the formula HNR.sup.1 R.sup.2, wherein R.sup.1 and R.sup.2 are 
independently organic moieties which may be attached to each other to form 
a ring, to form, directly or through an intermediate aminal the enamine of 
the following formula (VII): 
##STR4## 
In particular, values of R.sup.1 and R.sup.2 include individual 
substituted and unsubstituted alkyl of about 1 to 6 carbons such as ethyl 
and butyl and, when R.sup.1 and R.sup.2 are connected, substituted and 
unsubstituted heterocyclic rings such as 5- or 6-membered heterocyclic 
rings, e.g., to define the secondary amines pyrrolidine, piperidine and 
morpholine. The first stage (i) may be conducted at about -10.degree. to 
35.degree. C. preferably in the presence of an alkali or alkaline earth 
metal carbonate, sulfate, halide or oxide, e.g., calcium sulfate, 
magnesium sulfate, calcium chloride, sodium sulfate, magnesium oxide, 
potassium carbonate, calcium oxide or even molecular sieves, as disclosed 
by D. Roelofsen et al. in Recueil, Vol. 91, pages 605-610 (1972), with at 
least two moles of HNR.sup.1 R.sup.2 per mole of propionaldehyde. The 
secondary amine is used in excess in view of the intermediate formation of 
an aminal of the formula CH.sub.3 CH.sub.2 CH(NR.sup.1 R.sup.2).sub.2 
which is then heated to form the enamine of formula (VII) and distil off 
the excess HNR.sup.1 R.sup.2 which is released with formation of the 
double bond. Thus, the aminal may be heated to about 75.degree. to 
100.degree. C. at a vacuum of about 40 to 100 mm of Hg. According to this 
aspect of the present invention, the enamine of formula (VII) and the 
secondary amine HNR.sup.1 R.sup.2 are coformed from the aminal and 
preferably, the HNR.sup.1 R.sup.2 will be separated from the enamine at 
this point by fractional distillation. If the secondary amine has a 
boiling point close to the enamine, e.g., if the secondary amine is 
morpholine, the distillation should be monitored to avoid codistillation 
of the two products and/or an incomplete reaction of the aminal. If the 
aminal is obtained in whole or in part at this point, such may be taken on 
to the cyclobutane of formula (VIII) as described below. This monitoring 
can be carried out by gas liquid chromatography and % nitrogen by 
elemental analysis. Disclosures of such enamine formations include C. 
Mannich and H. Davidsen in Ber., vol. 69, pages 2106-2112 (1936); G. Opitz 
et al. in Ann., Vol. 623, pages 112-117 (1959); P. deBenneville 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 (1981); and E. Benzing U.S. Pat. No. 3,074,940. 
In the second stage (ii) of the first step of the invention, the enamine of 
formula (VII) is reacted with the acrylic compound of formula (III) to 
yield the compound of the following formula (VIII): 
##STR5## 
wherein Y, R.sup.1 and R.sup.2 are as defined above for formulae (III) and 
(VII). The compound of formula (VIII) may exist to a limited extent in the 
form of the open chain enamine of the structure (R.sup.1 R.sup.2 
N)HC.dbd.CHCH.sub.3 (CH.sub.2).sub.2 Y. The synthesis of cyclobutanes of 
the formula (VIII) type is described in detail by I. Fleming et al. in the 
Journals of the Chemical Society, pages 2165-2174 (1964) and in U.S. Pat. 
Nos. 3,051,622; 3,133,924; 3,369,024; 3,481,936; and 3,481,939. The 
reaction may be carried out neat or in the presence of a nitrile, ether, 
ester, halogenated alkane or ketone solvent, e.g., acetonitrile, although 
a neat reaction is preferred in view of simplicity. The reaction may be 
carried out at room temperature up to the boiling point of the acrylic 
compound of formula (III), e.g., up to about 170.degree. C., with the 
higher temperatures of this range being advantageously used to complete 
the reaction. The enamine of formula (VII) may be cooled to about 
-5.degree. to 20.degree. C. 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 (VIII) to the aldehyde of formula 
(IV) with recovery of one mole of the secondary amine HNR.sup.1 R.sup.2. 
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 25.degree. to 105.degree. C. at a pH of about 
1.5 to 4.5. The solvent for this reaction may advantageously be that used 
in stage (ii) whereby the product of stage (ii) need not be purified but 
rather may be simply carried forward in its crude state with solvent. 
However, a solvent other than the aqueous acidic reaction medium need not 
be present. The aldehyde of formula (IV) may be recovered by extraction of 
the aqueous acid solution containing HNR.sup.1 R.sup.2 with a neutral 
organic solvent such as ethyl acetate or methylene chloride. 
Alternatively, the third stage hydrolysis (iii) may be conducted under 
basic conditions and in the event of saponification 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 (V) 
as explained below. A disclosure of reactions leading to (IV) wherein Y is 
--COOCH.sub.3 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 207-221 (1963). The reaction of acrylonitrile, i.e., 
compound (III) where Y.dbd.CN, with the pyrrolidine enamine of 
n-heptaldehyde is described by Ross C. Terrell, Ph.D. Thesis Columbia 
University (1955 ) as yielding .alpha.-cyanoethyl-n-heptaldehyde and 
compound (IV) where Y.dbd.CN may be produced in a similar manner. 
In the second step (b) of the process of the invention when Y.dbd.COOR, the 
aldehyde of formula (IV) is reacted with an amine or ammonium salt to form 
the dihydropyridone of the following formula (V): 
##STR6## 
The cyclization in step (b) may be carried out with a nitrogen source such 
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 preferred. The reaction may be carried out neat or in a solvent, e.g., 
a high boiling solvent, for one or both 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 
halogenated aromatic hydrocarbon, e.g., a mono-, di- or tri-chlorobenzene, 
or a ketone, e.g., methyl ethyl ketone, methyl isobutyl ketone and 
disobutyl ketone. The temperature of the cyclization reaction will vary 
depending on the particular nitrogen source used and the solvent but is, 
in general, from about room temperature up to the boiling point of any 
solvent or reactant utilized, e.g., from about 25.degree. to 150.degree. 
C. 
In the second step (b) of the process of the invention when 
Y.dbd.CONH.sub.2 the aldehyde of Formula (IV) is thermally cyclized at a 
temperature of about 100.degree. to 200.degree. C. neat or in a high 
boiling solvent 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 such as distillation or extraction. 
In the second step (b) when Y.dbd.CN, the aldehyde (IV) is converted to the 
pyridone (V) by acid catalysis, e.g., with hydrogen halide such as HCl, 
sulfuric acid, phosphoric acid or a sulfonic acid at a temperature of room 
temperature to about 100.degree. C. neat or in a solvent such as a 
halogenated hydrocarbon. Such reaction conditions are described by N. P. 
Susherina et al. in Chemical Abstracts, Vol. 55 7410e, by A. I. Meyers in 
J. Organic Chemistry, Vol. 29, pages 1435-1438 (1964) and in German 
Offenlegundschrift No. 2,245,097 (Mar. 21, 1974). 
In one aspect of the invention, the cyclization step (b) may be conducted 
in two stages by (iv) dimerizing the aldehyde of formula (IV) where 
Y.dbd.COOR by reaction with excess ammonia or other nitrogen source to 
yield the pyridone adduct of the following formula (X): 
##STR7## 
followed by (v) pyrolyzing the compound of formula (X) with loss of 
NH.sub.3 at a temperature of about 200.degree. to 300.degree. C. to yield 
the dihydropyridine of the formula (V). 
In the third step (c) of the process of the present invention, the 
dihydropyridone of formula (V) is oxidized to the pyridone of the 
following formula (VI): 
##STR8## 
In one aspect of the present invention, the oxidation step (c) may be 
carried out by a first stage (vi) comprising dihalogenating the compound 
of formula (V) with a halogenating agent such as chlorine, bromine, 
sulfuryl bromide or sulfuryl chloride in an equimolar to slight molar 
excess at about 25.degree. to 40.degree. C. in a solvent such as a 
halogenated hydrocarbon, e.g., chloroform or chlorobenzene, to produce the 
dihalo compound of the following formula (IX): 
##STR9## 
wherein X.sup.1 is a halogen atom, such as chloro or bromo. In a further 
stage (vii), the dihalo compound of formula (IX) may then be 
dehydrohalogenated to produce the pyridine of formula (VI) by heating to a 
temperature of about 100.degree. to 170.degree. C. neat or in the presence 
of a high boiling solvent such as chlorobenzene. In general, the product 
of the dehydrohalogenation stage (vii) is the hydrohalide salt of the 
pyridine of formula (VI) which may be carried on directly to the 
5-methylpyridine of formula (I) wherein X is a halogen, or may be first 
converted to the free base by neutralization in an aqueous base such as 
sodium hydroxide or sodium carbonate followed by vacuum evaporation and 
extraction with an organic solvent such as hot acetone or ethanol. The 
halogenation of various dihydro pyridones is described by N. P. Shusherina 
et al. in Chemical Abstracts, Vol. 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 (1977). 
In the dihalogenation stage (vi) used to produce the dihalo compound of 
formula (IX), several products have been observed which may be readily 
converted to pyridone of formula (VI) together with or separate from the 
dihalo compound (IX). In particular, the reaction conditions described 
above for stage (vi) have yielded both the hydroxy halo compound of the 
following formula (XI) when water is present: 
##STR10## 
wherein X.sup.2 is a halogen such as bromo or chloro, and the dimeric 
compound of the following formula (XII): 
##STR11## 
wherein X.sup.3 is a halogen such as bromo or chloro. In general, use of 
lower temperatures for the dihalogenation stage (vi) will produce compound 
(IX) while higher temperatures, e.g., about 40.degree. to 80.degree. C. 
will yield the by-products (XI) and/or (XII). Thus, at a reaction 
temperature of 40.degree. to 80.degree. C. for 2 hours in toluene with a 
50% molar excess of sulfuryl chloride, compound (V) may be vacuum 
evaporated and extracted with toluene to leave insolubles which include 
the compound of formula (XI) wherein X.sup.2 is chloro, m.p. 135.degree. 
to 142.degree. C. If the same reaction is conducted in chloroform at 
30.degree. to 60.degree. C., the crystaline product contains the dimer of 
formula (XII) wherein X.sup.3 is chloro, m.p. 157.degree. to 159.degree. 
C. The hydroxy halo compound (XI) and dimeric compound (XII) may be 
converted to the pyridine (VI) by heating to about 175.degree. to 
250.degree. C. neat or in the presence of a high boiling solvent. An 
advantage of the invention process that the by-products of this step can 
be converted to the next stage product in the same manner as the desired 
product, i.e., (XI) and (XII) are converted to (VI) in the same manner as 
(IX) would be. 
The oxidation step (c) may also be carried out by reacting the 
dihydropyridone of formula (V) with a halogenating agent such as N-chloro- 
or N-bromo-succinimide or 1,3-dichloro- or 
1,3-dibromo-5,5-dimethylhydantoin which adds halogen at an allylic 
position or the position alpha to the carbonyl, i.e., the 3- or 
4-halo-2-pyridone to yield the compound of the following formula (XIII): 
##STR12## 
wherein X.sup.4 is halogen such as bromo or chloro. The compound of 
formula (XIII) may then be converted to the pyridine of formula (VI) by 
thermal elimination of HX.sup.4. 
In the final step (d) of the overall process of the invention, the pyridone 
(VI) is halogenated with a halogenating agent such as a sulfur halide, 
e.g., thionyl chloride, sulfuryl chloride, a carboxylic acid halide, e.g., 
phosgene, or a phosphorus halide such as phenylphosphonic dichloride, 
phosphorus oxychloride or phosphorus pentachloride, in a high boiling 
solvent such as a aromatic hydrocarbon solvent, e.g., toluene or xylene, 
or a halogenated aromatic hydrocarbon, e.g., chlorobenzene, at a 
temperature of about 90.degree. to 120.degree. C. 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 POCl.sub.3 : (VI) of about 1.5:1 to 4.5:1 or of PCl.sub.5 : (VI) 
of about 0.3:1 to 0.5:1 may be used. In addition, a combination of 
phosphorus halides may be used, e.g., a mixture of POCl.sub.3 and 
PCl.sub.5 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 formula (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, pages 122-125 (1961). 
Particular aspects of the process of the present invention which are 
advantageous are high yields obtained, the novel skeletal formation of a 
.beta.-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 intermediates as described 
herein. 
In the following Examples and throughout the specification, the following 
abbreviations are used: .degree.C. (degrees Centigrade); ml (milliliters); 
g (grams); m (moles); mm (millimeters); GLC (gas liquid chromatography); 
GC/MS (gas chromatograph-mass spectrometry); IR (infrared); NMR (nuclear 
magnetic resonance); mp (melting point); bp (boiling point); d.sub.6 -DMSO 
(deuterated dimethyl sulfoxide); and the conventional symbols for the 
chemical elements.

EXAMPLE 1 
Step (a), stage (i) to yield morpholinopropene of formula (VII) (NR.sup.1 
R.sup.2 .dbd.morpholine) 
A 500 ml 4-neck flask was equipped with a stirrer, thermometer, addition 
funnel and condenser. To the flask was charged 191.7 g (2.2 m) of 
morpholine and 138.2 g (1 m) of potassium carbonate (anhydrous) and the 
mixture was stirred and cooled to -5.degree. C. with an ice-salt bath. To 
the flask was added 58 g (1 m) of propionaldehyde over a period of 55 
minutes at a pot temperature of -5.degree. C. The temperature was then 
allowed to rise to 25.degree. to 27.degree. C. and the reaction was 
continued for 2 hours at 25.degree. C. The product was filtered and the 
filter cake washed with four 15 ml washes of toluene. The fitrate was 
heated under vacuum while morpholine was stripped using a 1 foot Vigreux 
column. This treatment was carried out at an oil bath temperature of 
85.degree. to 112.degree. C., a pot temperature of 70.degree. to 
90.degree. C., a vapor temperature of 41.degree. to 58.degree. C. 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. GLC and 
GC/MS established that the predominant product was 
4-(2-propenyl)morpholine. 
.sup.13 C NMR in d.sub.6 --DMSO (in .delta. units):15.2 (CH.sub.3) 95.1 
(CH.sub.3 --CH).dbd.; 140.8 (--CH.dbd.CH--); 49.4 (--N(--CH.sub.2 
--).sub.2); and 66.1 (O(--CH.sub.2 --).sub.2). 
EXAMPLE 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 dropwise 58 g (1 m) of propionaldehyde over a 30 
minute period at 15.degree. C. The reaction was mildly exothermic and some 
cooling was applied. The slurry was filtered after 30 minutes reaction 
time at 25.degree. C. and the filter cake was washed with two 40 ml washes 
of morpholine. The filtrate was gradually heated to 75.degree. to 
85.degree. C. under vacuum and then held at 85.degree. C. pot temperature 
and a pressure of 40 mm of Hg vacuum 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.dbd.COOR; R.dbd.CH.sub.3 ; NR.sup.1 R.sup.2 .dbd.morpholine) 
A solution of 40 g of crude morpholinopropene produced in Example 1 in 175 
ml of acetonitrile is cooled to -2.degree. C. in an ice-salt bath and 
treated with a solution of 30.5 g (0.35 m) of methylacrylate in 70 ml of 
acetonitrile dropwise over a period of 20 minutes at -2.degree. to 
0.degree. C. The temperature of the solution is then gradually raised and 
held at 66.degree. to 76.degree. C. for 17 hours. At that point, a 
predominate product peak can be detected by GLC 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)cyclobutane carboxylate was characterized by 
GC/MS and NMR. 
.sup.13 C NMR in d.sub.6 --DMSO (in .delta. units):66.3 (O(--CH.sub.2 
--).sub.2); 50.2 (--N(--CH.sub.2 --); 70.8 (N--CH); 31.0 (CH.sub.3 --CH); 
26.2 (cyclobutane--CH.sub.2 --); 39.1 (CH--COOCH.sub.3) 174.1 
(--COOCH.sub.3); 51.4 (--COOCH.sub.3); and 20.6 (CH--CH.sub.3). 
EXAMPLE 4 
To 63.5 g of the crude morpholinopropene product of Example 2 was gradually 
added 45.7 ml (0.51 m) of methyl acrylate at room temperature. The 
reaction mixture was then heated to 80.degree. C. until the reaction was 
complete in 7 hours as determined by GLC. The yield of product was 106.4 g 
with no loss during vacuum stripping to remove unreacted acrylate at 1 
hour at 55.degree. C. under a pressure of 50 mm of Hg. 
EXAMPLE 5 
Step (a), stage (iii) to yield methyl 4-formylpentanoate of formula (IV) 
(Y.dbd.COOR; R.dbd.CH.sub.3) 
A solution of 18 g (0.3 m) of acetic acid in 120 ml of water is added to 
the crude morpholino cyclobutane carboxylate ester product of Example 3 
and the reaction mixture is heated at 70.degree. to 79.degree. C. for 5 
hours. The product solution is cooled 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-formylpentanoate is obtained after vacuum stripping 
at 60.degree. to 70.degree. C. and a moderate vacuum of 100 mm to 28 mm of 
Hg in a yield of 29.2 g. 
The crude methyl 4-formylpentanoate obtained above was purified by 
distillation at 83.degree. to 85.degree. C. at 6 mm to 8 mm of Hg with 90% 
recovery. Purity by GLC after distillation was determined to be 95.3% and 
the product was characterized by IR, NMR and GC/MS. 
.sup.13 C NMR in d.sub.6 --DMSO (in .delta. units):51.4 (--COOCH.sub.3); 
173.2 (--COOCH.sub.3); 31.0 (--CH.sub.2 --COOCH.sub.3); 25.4 (--CH.sub.2 
--CH.sub.2 --COOCH.sub.3); 45.1 (CH--CH.sub.3); 13.0 (CH--CH.sub.3); and 
204.7 (--CHO). 
EXAMPLE 6 
To a sample of 53.2 g (0.19 m) of undistilled morpholino cyclobutane ester 
prepared as in Example 4 was added with stirring at 26.degree. C. 46.3 ml 
(0.19 equivalents) of 4.1 Normal H.sub.2 SO.sub.4. The temperature rose to 
42.degree. C. and the reaction mixture was then heated to 98.degree. C. 
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 chloride yielded 25.6 g of methyl 4-formyl pentanoate 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 concentrated 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 70.degree. C. and the reaction mixture was then heated 
at 106.degree. C. under reflux for 31/2 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 washed once with 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. 
EXAMPLE 8 
Step (b) to yield 5-methyl-3,4-dihydro-2(1H)pyridone of formula (V) 
To 1.44 g (0.01 m) of methyl 4-formylpentanoate dissolved in 10 ml of 
acetic acid was added 1.54 g (0.02 m) of ammonium acetate and the mixture 
was heated at 80.degree. to 125.degree. C. for 16 hours. GLC showed about 
11% unreacted starting material, 89% 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 103.degree. C. at 0.5 mm of Hg. The 
product was recrystallized from ethyl acetate, mp, 76.degree. to 
78.degree. C. 
Elemental Analysis: N, 12.13% (Calculated 12.8%). 
.sup.13 C NMR in d.sub.6 --DMSO (in .delta. units):19.0 (CH.sub.3); 169.0 
(C.dbd.O); 30.1 (CH.sub.2 .alpha. to C.dbd.O); 25.5 (CH.sub.2 .beta. to 
C.dbd.O); 112.0 (C(CH.sub.3).dbd.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 105.degree. C. with a reaction time of 22 hours. The 
product was vacuum stripped at 65.degree. to 95.degree. C. bath 
temperature at 10 mm of Hg and 200 ml of distillate were collected. The 
residue was dissolved in 200 ml of toluene and washed four times with 50 
ml of water each time. The aqueous extracts were washed two times with 70 
ml of toluene each time and the combined toluene extracts were vacuum 
stripped at 40.degree. to 50.degree. C. at 80 to 100 mm of Hg. The yield 
of 5-methyl-3,4-dihydro-2(1H)-pyridone which solidified at room 
temperature was 13.6 g (52% yield). 
EXAMPLE 10 
A neat reaction was conducted to yield 5-methyl-3,4-dihydro-2(1H)pyridone 
by mixing 10 g (0.0693 m) of 4-formylpentanoate and 10.7 g (0.139 m) of 
ammonium acetate at room temperature followed by stirring and heating to 
100.degree. to 110.degree. C. for 1.5 hours. A fairly vigorous reaction 
occurred at 95.degree. C. with bubbling and release of some NH.sub.3. 
After four washings of 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 40.degree. C. To the 
mixture was gradually added 3 g (0.05 m) of acetic acid at 41.degree. to 
45.degree. C. over 35 minutes while the initial foaming disappeared. The 
clear solution was heated at 92.degree. to 97.degree. C. for 2 hours to 
yield 9.28 g which was distilled at a bath temperature of 100.degree. to 
122.degree. C. at about 1 mm of Hg vacuum to yield 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 95% excess) of ammonium 
acetate and 50 ml of ethanol. The reaction was carried out at 30.degree. 
C. for 5 hours and the ethanol was then vacuum stripped after 16 hours at 
room temperature. The product was partitioned in 30 ml toluene and 10 ml 
of water, the water layer was discarded and the toluene layer was refluxed 
at 82.degree. to 88.degree. 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 methyl 4-formylpentanoate in 15 ml of absolute 
ethanol is added 10.5 g of a NH.sub.4 OH solution (prepared from 33.3 g of 
a 30% NH.sub.4 OH solution and 100 ml of water). The reaction was carried 
out at room temperature for 20 hours followed by vacuum stripping at 
30.degree. to 55.degree. C. under a moderate vacuum of about 200 to 40 mm 
of Hg. Distillation of the product under forcing conditions of a pot 
temperature of 125.degree. to 130.degree. C. at a pressure of 1 mm of Hg 
gave a fraction distilling at 100.degree. to 110.degree. C. which was 
identified as 5-methyl-3,4-dihydro-2(1H)pyridone. The product was 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.degree. to 100.degree. C. The 
volatiles were allowed to distill during the reaction so that the 
temperature could be maintained at 98.degree. C. for 1.5 hours after the 
addition. Gradually, clearing took place during the 1.5 hours and GLC of 
the product showed only 5-methyl-3,4-dihydro-2(1H)pyridone and a small 
amount of starting material. Distillation yielded the desired products as 
a white crystaline solid in 90% yield. 
The above reaction was repeated using 3.1 g of ammonium bicarbonate and 2.6 
g of acetic acid in the place of the ammonium acetate. 
EXAMPLE 15 
To a reaction vessel was charged 380 ml of chlorobenzene followed by 67 g 
(1.11 m) of glacial acetic acid. To the vessel 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.degree. to 37.degree. C. while stirring and cooling 
with an ice bath. The temperature was then raised to 90.degree. C. 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 was 
held at 90.degree. to 96.degree. C. The reaction mixture was two-phased 
and was continuously heated at 90.degree. to 95.degree. C. while volatiles 
were allowed to distill off. One hour after complete addition, GLC 
analysis showed little unreacted pentanoate and after two hours, only 
about 2% was unreacted. The product was isolated by vacuum stripping of 
chlorobenzene at a pot temperature of 60.degree. to 85.degree. C. with a 
final vacuum of 20 mm of Hg. The product of formula (V) was then distilled 
at a pot temperature of 100.degree. to 150.degree. C., a vapor temperature 
of 93.degree. to 113.degree. C. 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). 
EXAMPLE 16 
Steps (a) and (b) to yield 5-methyl-3,4-dihydro-2(1H)-pyridone of formula 
(V) via acrylamide of formula (III) (Y.dbd.CONH.sub.2) 
A sample of 25 g of morpholinopropene of the formula (VII) was dissolved in 
80 ml of acetonitrile 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 25.degree. C. The temperature was then raised to 80.degree. 
to 85.degree. C. and held there for about 40 hours. The product was 
filtered hot to remove a small amount of insoluble matter and was then 
treated with a solution of 12 g of glacial acetic acid in 80 ml of water 
at 75.degree. to 80.degree. C. for 6.5 hours. The product was 
vacuum-stripped at 48.degree. C. under 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) (Y.dbd.CONH.sub.2). The aqueous 
solution was vacuum-stripped at 50.degree. to 60.degree. C. under 40 mm of 
Hg pressure to leave the product as a light amber viscous residue. This 
was treated with 100 ml of ethanol, crystallized and filtered to remove 
part of the acrylamide. Final vacuum-stripping gave 58.9 g of residue 
consisting of acrylamide and 4-formylpentanamide. The product of formula 
(V) was generated thermally from this product by treatement at 100.degree. 
to 140.degree. C. under high vacuum. During this treatment, 12.5 g of 
distillate was produced comprising the compound of formula (V) and 
acrylamide. Remaining was 35 g comprising compound (V) and 
morpholinopropionamide. GLC analysis showed that the distillate contained 
about 40% by weight (V) while the residue contained 20% (V). Addition of 
acetonitrile to the distillate and hot ethyl acetate to the residue gave 
acrylamide as a crystalline solid, mp 76.degree. to 80.degree. C. from the 
distillate and morpholinopropionamide, mp 94.degree. to 100.degree. C. as 
a crystalline solid from the residue. The compound of formula (V) was 
found in the solutions after crystallizations to the extent of about 60%. 
EXAMPLE 17 
Step (b), stages (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 2.0 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.degree. to 55.degree. 
C. After 1/2 hour, GLC showed 99% product and the temperature was then 
held at 88.degree. to 96.degree. C. for 1 additional hour and the product 
was then vacuum stripped at 80.degree. C. under a pressure of 5 to 20 mm 
of Hg for 1/2 hour. Although the GLC analysis showed product with a very 
high purity, the NMR 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 
fractions was 25% as a crystaline white solid, mp, 158.degree. to 
166.degree. C. The compound was insoluble in ethanol, acetone and toluene 
but soluble in methylene chloride. The product was dissolved in a hot 
mixture of 7 parts by volume of methanol and 9 parts by volume of ethyl 
acetate and recrystallized to give an mp of 182.degree. to 184.degree. C. 
Elemental Analysis: N, 17.0% (Calculated for the compound of formula (X) as 
C.sub.12 H.sub.21 N.sub.3 O.sub.2, N, 17.55%). 
.sup.13 C NMR in CDCL.sub.3 (shift of +77.0 ppm using CDCL.sub.3 as the 
standard) (in .delta. units):174.6, 173.4 (C.dbd.O); 31.3, 30.6 (CH.sub.2 
--C.dbd.O); 26.3, 23.3 (CH.sub.2 --CH.sub.2 --C.dbd.O); 35.8, 33.3 
(CH--CH.sub.3); 75.3, 71.0 (NH--CH--NH): and 17.9, 17.7 (CH.sub.3). 
EXAMPLE 18 
The high-melting intermediate prepared in Example 17 was prepared under 
milder conditions by treating 2 g (0.014 m) of 4-formylpentanoate in 5 ml 
of absolute ethanol with 3.5 g (0.02 m) of dilute NH.sub.4 OH solution 
(prepared from 33.3 g of a 30% NH.sub.4 OH solution and 100 ml of water) 
at room temperature. GLC samples taken during the reaction showed a 
mixture of starting material, the desired product peak due to the 
intermediate of formula (X) and methyl 4-iminomethylpentanonate. After 24 
hours at room temperature, the major peak was the product. The reaction 
mixture was vacuum evaporated at 60.degree. C. under 1 to 6 mm of Hg to 
give 1.5 g of product which was recrystallized from 3.5 ml of ethyl 
acetate, mp 171.degree. to 174.degree. C. 
The product of formula (X) was recrystallized from excess acetone/methanol 
to yield crystals, mp 178.degree. to 182.degree. C. 
Elemental Analysis: C, 59.85% (Calculated 60.2%); H, 8.63% (Calculated 
8.85%): N, 17.58% (Calculated 17.55%). 
EXAMPLE 19 
Step (c), stages (vi) and (vii) to yield the dihalo compound (IX) (X.sup.1 
.dbd.Cl) as an intermediate and pyridone (VI) as a final product. 
A solution of 1.5 g (0.0135 m) of 5-methyl-3,4-dihydro-2(1H)pyridone of 
formula (V) in 9 ml of chloroform was treated with sulfuryl chloride 
dropwise at 25.degree. to 33.degree. C. After 1 hour at 30.degree. C., 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 33.degree. C., the product was vacuum stripped at 15.degree. to 
45.degree. C. 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) wherein X.sup.1 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.degree. to 138.degree. C. 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 vacuum 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, 150.degree. to 172.degree. C. Preferably, the extraction with 
warm acetone is replaced by an ethanol extraction. 
In a similar example, the product was recrystallized from methanol to yield 
a product with a melting point of 178.degree. to 180.degree. C. 
EXAMPLE 20 
The procedure of Example 19 was repeated 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.degree. to 147.degree. C. 
EXAMPLE 21 
The procedure of Example 19 was repeated with the substitution of 
chlorobenzene, also known as monochlorobenzene, for chloroform as follows. 
The reaction was carried out using 4 g of the product of formula (V), 8 ml 
of chlorobenzene and 4.4 ml of sulfuryl chloride of the formula SO.sub.2 
CL.sub.2 (a 50% excess). The dropwise addition of sulfuryl chloride was 
carried out at 23.degree. to 38.degree. C. with slight cooling followed 
after one hour by application of a vacuum of 75 to 150 mm of Hg at 
27.degree. to 38.degree. C. for 1 hour. The temperature is then raised to 
129.degree. C. in the pot and 141.degree. to 143.degree. C. 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 the reaction, is 
quite viscous on cooling and consists of the compound of formula (VI), 
partly in the form of the hydrochloride salt. 
EXAMPLE 22 
Into a solution of 7.0 g of the compound of formula (V) in 35 ml of 
chlorobenzene at 20.degree. C. 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 chlorobenzene at 130.degree. 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 
product mixture was neutralized to a pH of 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 the compound of formula (VI) (78.6% 
yield). 
EXAMPLE 23 
Steps (c) and (d) to yield compound (I) (X.dbd.Cl) without isolation of 
pyridine (VI) 
A sample of 4 g of crystallized 5-methyl-3,4-dihydro-2(1H)pyridone of 
formula (V) was dissolved in 8 ml of chlorobenzene and was treated with 
4.4 ml of sulfuryl chloride as described in Example 20. After 
dehydrohalogenation at 129.degree. C., the product consisted of a lower 
dark product phase which was very viscous at 40.degree. C. To the slurry 
of both phases was added 10.4 ml of POCl.sub.3 at 40.degree. over 1/2 hour 
followed by 3.4 g of phosphorous pentachloride. The mole ratio of the 
product of formula (VI):POCl.sub.3 :PCl.sub.5 was 1:3:0.45. The reaction 
mixture became homogenous and was heated at 116.degree. to 118.degree. C. 
for 4 hours. To the product was then added to 50 g of crushed ice, 50 ml 
of chlorobenzene and 162 ml of a 13% aqueous sodium hydroxide solution. 
Phase separation was made in a separatory funnel and the lower aqeuous 
layer was extracted 3 times with 20 ml of chlorobenzene each. The product 
layer and chlorobenzene extracts were combined and analyzed by GLC. The 
thus-produced chlorobenzene solution contained 1.5 g of the product of 
formula (I) wherein 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.degree. over a 
period of 1.25 hours. This solution was added gradually to 15 ml of 
stirred chlorobenzene held at 130.degree. C. over a period of 1 hour. The 
reaction was continued at 130.degree. C. for 4.5 hours and the product 
slurry was cooled to 60.degree. C. To this was then added 14.5 g of 
POCl.sub.3 dropwise over 15 minutes followed by 2.62 g of PCl.sub.5 also 
at 60.degree. C. The reaction mixture was heated to 115.degree. C. for 4.5 
hours. For the purposes of analysis, the product was added to 40 ml of 
methanol, vacuum stripped at 50.degree. C. at 130 mm of Hg and the 
addition 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 methanol, 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.dbd.Cl) 
To 4.2 g of the compound of formula (VI) was added 15 ml of POCl.sub.3 at 
25.degree. to 34.degree. followed by 3 g of PCl.sub.5. The reaction 
mixture was stirred and heated at 110.degree. C. for 4 hours and gradual 
solution took place. The product was added to 100 g of crushed ice and 
neutralized to pH 8 with 80 ml of 15% sodium hydroxide while cooling. The 
aqueous solution was extracted 5 times with 24 ml of methylene chloride 
each. The extracts were analyzed by GLC and evaporated at 40.degree. C. at 
4 mm of Hg to a constant weight. The yield was 3.9 g of the compound of 
formula (I) wherein X is chloro. 
Elemental Analysis: Cl, 26.55% (Calculated, 27.8%); N, 10.75% (Calculated, 
10.98%). 
The GLC retention times and NMR of the product were identical to those of 
authentic samples of the compound of formula (I) wherein X is chloro. 
EXAMPLE 26 
In the above Example 25, separations of the product phase from the aqueous 
phase may be difficult and incomplete if the product phase is too 
concentrated. A more dilute system is believed to be more practical as 
described below. 
The procedure of Example 25 was repeated with a 1:1 (w:w) dilution 
(weight:weight of the compound of formula (VI) with chlorobenzene. A 
sample of 3.0 g of compound (VI) was mixed with 3 g of chlorobenzene and 4 
ml of POCl.sub.3 were added gradually at 25.degree. to 32.degree. C., 
followed by 2.6 g of PCl.sub.5 at 27.degree. to 32.degree. C. The slurry 
was heated to reflux and held at 117.degree. to 119.degree. C. for about 4 
hours. The product was cooled to room temperature and added to 50 g of 
ice, diluted with 17 ml of chlorobenzene and neutralized to a pH of 8.0 
with a 15% NaOH aqueous solution. The chlorobenzene solution was separated 
in a separatory funnel as the lower layer. The upper layer was diluted 
with 30 ml of water and extracted two times with 10 ml of chlorobenzene 
each. The combined chlorobenzene solutions were analyzed by GLC to 
indicate 2.9 g of compound (I) wherein X is chloro. 
EXAMPLE 27 
To 50 ml of toluene at 8.degree. C. was added 10 g of phosgene under a 
nitrogen blanket. The solution was heated to 45.degree. C. 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 56.degree. 
C. over 2 hours. The product mixture was then cooled and mixed with 4 ml 
of water and neutralized with 20 ml of dilute NH.sub.4 OH (produced from 
80 ml of concentrated NH.sub.4 OH diluted with water to 100 ml) and 2 g 
sodium carbonate to a pH of 8. Phase separation was made in a separatory 
funnel and the upper phase was vacuum stripped at 45.degree. C. and a 
pressure of 65 mm of Hg to yield 1.9 g of the compound of formula (I) 
where X is Cl. 
EXAMPLE 28 
Step (c) to yield (XI) (X.sup.2 .dbd.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.degree. to 40.degree. C. with 0.55 
ml of SO.sub.2 Cl.sub.2 while stirring. The solution was then heated at 
62.degree. to 75.degree. C. for 2 hours. The product was vacuum stripped 
over 1.75 hours at a bath temperature of 60.degree. C. 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 1 
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 
135.degree. to 142.degree. C. Characterization was made by MS and 
Elemental Analysis. 
EXAMPLE 29 
Step (c) to yield (XII) (X.sup.3 .dbd.Cl). 
A solution of 0.5 g of the compound of formula (V) in 3 ml of chloroform 
was stirred and treated at 28.degree. to 36.degree. C. gradually with 0.55 
ml of SO.sub.2 Cl.sub.2. The solution was heated to 62.degree. to 
65.degree. C. and precipitation of product occurred at that temperature. 
The solution was cooled to room temperature and filtered. The product was 
washed two times with 2 ml chloroform each. The yield was 0.26 g of 
product, mp 157.degree. to 159.degree. C. The chloroform washes where 
vacuum stripped to obtain 0.53 g of additional product. The product 
obtained was the hydrochloride salt of the compound of formula (XII) 
wherein X.sup.3 is chloro as shown by MS, NMR and Elemental Analysis. 
After washing with hot acetone, the purified product had an mp of 
160.degree. to 162.degree. C.