Table Of Content11
CHAPTER
Introduction
R. Murugan1, Eric F.V. Scriven2
1VertellusSpecialtiesInc,1500SouthTibbsAvenue,Indianapolis,IN46241,USA.,2UniversityofFlorida,Gainesville,FL32611,USA
1. INTRODUCTION
Pyridines were first described by Anderson in the 1840s.1 He obtained 2-methylpyridine (beta-
picoline)fromboneoildistillation,andsubsequentlypyridineandsomedimethylpyridines(lutidines).2
Later (1877), Sir William Ramsey was the first to report a synthesis of pyridine that involved passing
a mixture of acetylene and hydrogen cyanide through a hot tube.3 The now well-known Hantzsch
synthesis appeared in 1882 (Scheme 1.1),4 and a vapour phase synthesis by Chichibabin in 1906.5
Me
Me
H O Me H
EtO2C CO2Et NH EtO2C CO2Et [Ox] EtO2C CO2Et
3
Me Me Me N Me Me N Me
OO H
Scheme 1.1 Hantzschpyridinesynthesis.
In the first half of the last century, most pyridines used industrially came from the basic fraction
obtainedfromcoaltardistillation.Thenthegrowthindemandfor pyridine-basedchemicalsbeganto
outstripthesupplyfromnaturalsources.Thedemandwasdrivenbytheneedfor3-pyridinecarboxylic
acid(niacin),itsamide(niacinamide), andtheantituberculosisdrug Isoniazid.The discoverythatthe
addition of 2-vinylpyridine to butadieneestyrene latex binder gave a large increase in adhesion of
rubber to tirecord drove a dramatic increase in demand for 2-methylpyridine, the precursor of
2-vinylpyridine.Thedemandcreatedbythesefactorsandothersledtothedevelopmentofasynthetic
pyridineprocessbasedonChichibabin’searlyvapourphasework.Thisprocesswasfirstdevelopedand
operatedonalargecommercialscale,influidisedbedreactors,byReillyTar&ChemicalCorporation
in the early 1950s.6 Most processes operated today by the three major producers (Vertellus, USA;
Jubilant, India; and Red Sun, China) to manufacture pyridine and methylpyridines are based on this
process. Twovariations are practised that involve high-temperaturevapour phase processes that both
yield coproducts which depend on the nature of the feed, catalyst, and conditions. A feed of acet-
aldehyde and ammonia gives a mixture of 2- and 4-methylpyridines (Eqn (1.1)); a feed of acetalde-
hyde, formaldehyde, and ammonia gives a mixture of pyridine and 3-methylpyridine (Eqn (1.2)).
Onlyrecently,byastudyusinglabelledcarbons,hasthepositionofeachofthecarbonsintheproducts
been attributed precisely to the carbon in the aldehyde from which it came.7
Pyridines:fromlabtoproduction (cid:1)2013ElsevierLtd.
ISBN978-0-12-385235-9,http://dx.doi.org/10.1016/B978-0-12-385235-9.00001-1 Allrightsreserved. 1
2 R.Murugan,EricF.V.Scriven
Me
Vap. phase (1.1)
CH3CHO + NH3 +
Cat. 400-500oC N Me N
Me
Vap. phase
CH3CHO + HCHO + NH3 + (1.2)
Cat. 400-500oC N N
The pyridine/3-picoline process is operated at greater volume driven largely by the demand for
pyridine that is converted to the herbicide paraquat (demand 26,000 MTY) and the insecticide
chlorpyrifos (35,000 MTY) obtained from 3-picoline in a multistep process, these volumes refer to
sales in 2008. Worldwide,over 100 to 1000 tons of pyridine andproducts containing apyridinering
areproducedannually.Thecoproductratiosintheseprocessescanbevariedtosomeextentbychanges
in feeds, operating conditions, and use of different catalysts to promote formation of one coproduct
over theother.However,coproductmixturesarealwaysformed.Commercialsuccess,therefore,also
dependsonresponsetodemandforeachofthecoproductsandtheirdownstreamderivativesbylow-
cost synthetic routes based on best technology. Pyridine value-added chains based on the two major
vapour phase coproduct reactions are illustrated (Figure 1.1).
OneimportantliquidphasereactionisoperatedcommerciallybyLonzaandprovidesasignificant
source of niacin (Scheme 1.2).8
2. VALUE CHAINS
The reactions below have formed the basis for production of high-volume pyridine derivatives
availablecommerciallyfromthemajor pyridineproducersor viaothercompaniesthatbuypyridines,
the methyl- and cyano-pyridines from the major pyridine producers. These reactions are:
1. Ammoxidationevapour phaseconversionof amethylgroupstonitriles(Eqn(1.3)).Themain
useofpyridine3-carbonitrileisfor productionofniacinamideinalargescalecommercialprocess
that involves a controlled hydrolysis.
Me CN
NH / Air / 450oC
3
(1.3)
N V O cat. N
2 5
Gas phase
2. Reductionofnitrilestocarbinols,aldehydes,andhydrolysistoamides,carboxylicacids(Scheme
1.3). Reduction of nitriles under various conditions offers a large range of products.
3. Oxidation of methyl groups to carbinols, aldehydes, and carboxylic acids (Scheme 1.4). Pyri-
dine3-carboxylicacidisnotonlyanimportantproduct(niacin)inthevitaminbusinessbutitcan
alsobeconvertedto2-chloropyridine-3-carboxylicacidanimportantintermediateforproduction
of a number of pharmaceutical and agricultural products (Scheme 1.5).
Introduction 3
NMe
2
Cl Cl
CN
N Cl N Cl
OH DMAP
Cl Cl
Ph PH N S O
COOH P
Cl N O
O
N Cl N CCl3 Chlorpyrifos
H
Azacyclonol N Nitrapyrin (P)
Me
Polymers
Latex
PVNO N N N Me N
Me Me Me
+
N NH2 N N N NH2 H2N N
Me
N CN
+
2Cl- N
N COOH
H
+
N CONH2 N NH
Me NO2
N N
Paraquat + N Cl
N
O_ H
N Cl N
Me Me
NH Imidacloprid
2 O HN O
N
N
N
N
Cl
Br
Chlorantraniliprole
Figure1.1 Pyridineandpicolinevalue-addedchains.
4 R.Murugan,EricF.V.Scriven
CH3CHO+ NH3 HOAc (cat.) Me HNO3 COOH -CO2 COOH
Me N HOOC N N
Scheme 1.2 Liquidphasepyridinesynthesis.
O O
OH NH2
N N
OH CN NH2
N N N
O RNH2
H
R N
N H
NH
N N
N
Scheme 1.3 Catalyticreductionofpyridinenitriles.
CH CH OH CHO COOH
3 2
N N N N
2-methylpyridine (2-picoline) Pyridine-2-carboxylic acid (Picolinic acid)
3-methylpyridine (3-picoline) Pyridine-3-carboxylic acid (Nicotinic acid)
4-methylpyridine (4-picoline) Pyridine-4-carboxylic acid (Isonicotinic acid)
Scheme 1.4 Oxidationofmethylpyridines.
Introduction 5
OMe
CONMe N
2
HN
HN N
N S O OMe
O
O
Nicosulfuron
O
COOH H O COOH COOH OH
2 2 POCl
3
+
N NH
N N N Cl
_
O
CF
3
F F
O
Niflumic acid
N
H
N O O
NH Me
CF3 N N
N
Diflufenican
BI-RG-587
Scheme 1.5 Somemedicinalandagriculturalproductsbasedon2-chloropyridine-3-carboxylicacid.
4. Reduction of the pyridine ring to piperidines (Eqn (1.4)) or partially reduced pyridines.
H
2
Cat. (1.4)
N N
H
5. Ringaminationsatthe2-positionbytreatmentofvariouspyridineswithsodamide(Eqn(1.5)),
or at positions 3- and 4- by Hofmann reaction on the respective amide (Eqn (1.6)).
NaNH2 NaNH2
(1.5)
N N NH H N N NH
2 2 2
CN CONH NH
NaOH, H2O 2 NaOCl 2
(1.6)
N N NaOH N
Diazonium salts, formed from pyridinamines, provide an important way to functionalise pyridine ring
positions, comparable with benzene chemistry. This is exemplified by a step in the synthesis of
6 R.Murugan,EricF.V.Scriven
CONH2 NaOCl NH2 Cl2 NH2 NaNO2 Cl
N NaOH N N Cl HCl N Cl
Cl
Me
N O
NH NH
N O Me
Cl
N
Rynaxypyr
Br
Scheme 1.6 SynthesisofRynaxypyr.
Rynaxypyr (Scheme 1.6) (and also in a route to Imidacloprid, Section 1.3) that also includes
a Hofmann rearrangement step.9
Now other options are available for synthesis of pyridines especially those based on cross-coupling
reactions. These starting materials for these reactions usually depend on the availability of chloro- or
bromo-pyridines (see Chapter 3). Several dichloropyridines are available as by-products from the
chlorpyrifos process (Scheme 1.7).10
Cl2 Cl Cl NaOH Cl Cl Cl Cl
N Vap. Phase Cl N Cl Cl N OH Cl N O
O P
Me O
S
Me
Chlorpyrifos
Scheme 1.7 SynthesisofChlorpyrifos.
2.1. Routes to 3,5-Dimethyl-4-Methoxy-2-Pyridylcarbinol
Thepyridinederivative,3,5-dimethyl-4-methoxy-2-pyridylcarbinol,isanintermediateusedtomake
Omeprazole,aprotonpumpacidinhibitor.Twoapproachesareshown(Scheme1.8)onefrom2,3,5-
collidineandtheotherfrom3,5-lutidine.Thefirstthreestepsofeachinvolve;N-oxidation,nitration,
and replacement of the 4-nitro substituent by methoxide. In one case, the2-hydroxymethyl group is
installed by the reaction of 2,3,5-trimethyl-4-methoxypyridine N-oxide with acetic anhydride11 to
form the 3,5-dimethyl-4-methoxy-2-acetoxymethylpyridine, which on hydrolysis gives the final
Introduction 7
NO
2
Me Me 1. N-oxidation Me Me
+
2. Nitration
N Me N Me
O-
NaOMe
OMe OMe
Me Me Me Me
Ac O
2
+
N Me N
O- OAc
Hyd.
OMe
Me Me
OMe
N OMe Me Me
H Minisci Rxn.
N S Me Me
O +
N
N
N OMe
OH
MeO MeOSO3-
Omeprazole
Me SO
2 4
OMe
Me Me
Me Me
1. N-Oxidation
+
N 2. Nitration N
O-
3. NaOMe
Scheme 1.8 SyntheticroutestoOmeprazole.
2-pyridylcarbinol product. In the other route, the intermediate 3,5-dimethyl-4-methoxypyridine
N-oxideonmethylationwithdimethylsulphategavetheN-methoxypyridiniumsaltwhichundergoes
theMiniscireaction12(radicalsubstitution)tointroducetheCH OHgroupatthe2-positonwiththe
2
eliminationoftheN-methoxygroup.Thesecondapproachhasprovedmoreeconomicalthanthefirst
approach.13
It should be noted that of these two approaches, treatment of N-oxide with Ac O or Minisci
2
reaction sometimes do not work as well for less substituted pyridine N-oxides, owing to lack of
regiospecificityor low yields.
8 R.Murugan,EricF.V.Scriven
3. STRATEGIC CONSIDERATIONS e RING SYNTHESIS VS SUBSTITUENT
MANIPULATION
When considering approaches to a target pyridine, it is important to identify a high-yield synthetic
route based on the lowest cost readily available starting material which usually appears earliest in the
value-added chains (Figure 1.1). Examples given of commercial routes (1 to 5 above) offer a further
indication of availability of starting materials and technology involved. Then a comparison should
be made of the pyridine-based route with costs of routes based on pyridine-ring synthesis from the
cheapest building blocks available. It is interesting to make the above comparison for a specific case.
A large volume insecticide Imidacloprid was developed by Bayer AG in the 1990s. Several synthetic
routestothekeyintermediate2-chloro-5-methylpyridine,or thesubsequentintermediate2-chloro-
5-chloromethylpyridine were developed (Scheme 1.9). Three of these routes have been operated
commercially.
Two routes are based on 3-picoline, a first-generation pyridine, the lowest cost starting material.
Initial work focused on chlorination of the N-oxide which always gave a mixture of 2- and 6-chlo-
rination, and no way was found to change this to exclusively 6-chlorination.14 The Chichibabin
amination of 3-picoline, similarly, favoured 2 over 6-substitution by 9:1. However, further work on
thisreactionprovedmorefruitful.Itwas observedthatbyrunningtheaminationunderahighinitial
NH CH
3
NNO
N 2
N
NaNH
2
Cl N Cat. H2O2
Imidacloprid CH
CH 3
3
+
N
H2N N -
O
NaNO /HCl
2
POCl
3
CCl
3 H2 Cl Cl2 CH3
Cl N Cat. Cl N
Cl N
DMF/POCl
Cl 3
2
CH
CH 3
3
H O N
N O
C H
6 5
Scheme 1.9 SyntheticroutestoImidacloprid.
Introduction 9
ammonia pressure, the product ratio was switched in the desired direction to >4:1.15 Therefore,
2-amino-5-methylpyridine became the intermediate of choice for development of a manufacturing
process. Conversion to 2-chloro-5-methylpyridine was achieved by a high-yield non-aqueous
diazotisation followed by chlorination with gaseous HCl. A further high-yield chlorination at the
5-methyl group, using chlorine and sodium bicarbonate, afforded 2-chloro-5-chloromethylpyridine
again in high yield.16 These two chlorinations would seem to have promise of extension for chlori-
nation of related pyridines and other heterocycles.
Two ring synthesis reactions have proved to be competitive with the above 3-picoline-based
process. One involves a Vilsmeier cyclisation (Scheme 1.10)17 similar to some developed by Meth-
Cohn.18 This process utilises benzylamine and the coproduct benzyl chloride is available for recycle
(by conversion to benzylamine) or reuse in other ways.
Me Me
Me
O H H Me Me Vilsmeier N Cl
+ NaOH N Ac2O N O Reaction +
H N
2 DMF/POCl
3 Cl
Scheme 1.10 Formationof2-chloro-5-methylpyridinebyaVilsmeierringclosure.
Thethirdcommercialprocessisbasedonreactionof acroleinwithacrylonitrile;cyclopentadiene,
which can be recycled, acts as a protecting group (Scheme 1.11).19
Anotherringsynthesisbasedoncis-pentenonitrile(anylonby-product)hasbeenclaimedbutithas
never been operated commercially.20
O CN
Heat
+ O
H
H Base NC
O H
Heat
Cl
Cl HCl/PCl5 OHC Cl2
OHC CN +
Cl
Cl N
CN Recycled
Scheme 1.11 Formationof2-chloro-5-chloromethylpyridinefromacroleinandacrylonitrile.
10 R.Murugan,EricF.V.Scriven
R1
R2
R1
R2
CONEt (i) O B O Br
2
CONEt2 Na CO / Pd(PPh ) (cat.) CONEt2
N 2 3 34
N Toluene / reflux / 12 h N
R1 = H, OMe
(i) 1. B(OiPr) ; 2. LDA; 3. Pinacol or
3
diethanolamine; 4. concentrate R2= OMe, CN, H
Scheme 1.12 Onepotdirected-ortho-metallation,Suzuki-Miyauracoupling.
The comparative economics of the three commercial processes above is obviously very close and
competitivedifferentiation,asitoftendoes,dependsonaccesstolowcostrawmaterialsandrequired
manufacturing technology available to the competitors rather than on just synthetic chemistry
considerations. Patent protection of the lowest cost process can, of course, also be the key factor in
competitivedifferentiation.Itishopedtheconsiderationofvaluechainsinthesectionandtheabove
case study will prove helpful for those evaluating routes to pyridine intermediates.
The application of directed ortho metallation and cross-coupling reactions have had a great
influence on the best methods for synthesis of multiply substituted pyridines, particularly those of
medicinal importance. Snieckus has combined in a one-pot reaction a directed ortho-metal-
lationeboronation and a SuzukieMiyaura coupling of a pyridine derivative (Scheme 1.12).21
In another case, the same group combined a directed ortho metallation with a halogen dance.22
The2-,3-,and4-pyridylO-carbamatesbelowwereusedtointroduceelectrophilesinhighyieldsto
give trisubstituted pyridines (Scheme 1.13). The electrophiles used included methanol, TMS, and
iodine.
4. CHALLENGES AND NEEDS
Mostpyridinesproducedcommerciallyarerequiredfortheirbioactivity.Especially,thepharmaceutical
industryhasstringentspecificationsforproducts,andtherequirementthatlate-stageintermediatesand
finalproductsaremanufacturedbyFDAapprovedprocessesinFDAregulatedequipment.Allchemical
processesdevelopedtodayneedtobenotonlylowestcostbutalsosustainable.Thispresentsachallenge
particularly to process development chemists. Process development techniques have become very
specialised. They are not dealt with in this book as they have been well covered in a recent book.23
Some of the successful methods used to develop the best processes for a series of products, including
many pyridines continue to appear in Organic Process Research and Development. The above consider-
ationsamongothershaveledtothestudyespeciallyofcatalyticreactionswithagreatdealofintensity
and success.24 This has resulted in several new reactions in pyridine chemistry that involve specific
CeH activation and have the advantage of eliminating several steps, for example, halogenation and
