WO2012107831A1

WO2012107831A1 - Method of making a pyridone compound, 5-ethyl-1-phenyl-2-(1h)-pyridone, and intermediates thereof

Info

Publication number: WO2012107831A1
Application number: PCT/IB2012/000238
Authority: WO
Inventors: Pablo Miguel BERNAL-VAZQUEZ; José Miguel LAZCANO-SERES; Roberto Carlos MELGAR-FERNANDEZ; Cuauhtemoc CARRASCO-PACHECO; Armando ZAMBRANO-HUERTA; Alberto MARTINEZ-DIAZ; Maria de la Luz REYES-REYES
Original assignee: Signa SA de CV
Current assignee: Signa SA de CV
Priority date: 2011-02-11
Filing date: 2012-02-10
Publication date: 2012-08-16
Anticipated expiration: 2013-08-11

Abstract

There are provided methods for the preparation of 5-ethyl-1-phenyl-2(1H)-pyridone and intermediates thereof. Thus, there is provided a one-pot method from the production of 5-ethyl-2(1H)-pyridone from butyl aldehyde and a compound of the Formula 9. There is also provided a process for the preparation of 5-ethyl-1-phenyl-2(1H)- pyridone comprising reaction of 5-ethyl-2(1H)-pyridone with phenyl halide in the presence of Cu20 and a first base.

Description

METHOD OF MAKING A PYRIDONE COMPOUND, 5-ETHYL-1 -PHENYL-2- (1H)-PYRIDONE, AND INTERMEDIATES THEREOF

TECHNICAL FIELD

This invention relates to the field of chemical synthesis of organic compounds and in particular to synthesis of a pyridone compound, 5-Ethyl-1 - phenyl-2(1 /-/)-pyridone and intermediates thereof.

BACKGROUND

5-Ethyl-1-phenyl-2(1 H)-pyridone (1 ) belongs to a class of substituted pyridones known to be useful for the treatment of fibrosis and sepsis as disclosed in, for example, US 5,716,632 and WO20091 1 1785.

(1)

US 3,839,346 discloses novel analgesic compositions containing as the active ingredient the compound, 5-methyl-1 -phenyl-2-(1 H) pyridone. In addition, a general method for the synthesis of aromatic group N-substituted 2(1 H) pyridones is described wherein a 2-(1 H) pyridone, which may be substituted, is reacted with an appropriate halo-aromatic compound in the presence of an alkali metal carbonate and copper powder. The appropriate aromatic N-substituted pyridone is obtained in excellent yield.

US 4,473,696 discloses 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 for form a 2-formylpentanoic compound which is cyclized to a dihydropyridone which is then oxidized to the 2- hydroxypyridine. The hydroxypyridine may be halogenated to a 2-halopyridine. US 4,645,839 discloses a method for synthesizing the aromatic compound 5-methyl-2-pyridone from the corresponding 3,4-dihydro compound by dehydrogenation using sulphur. Particular advantages are achieved by reaction at about 180°C or less. The product is useful as an intermediate for the preparation of various pyridyloxyphenoxy herbicides.

WO 03/014087 discloses a process for the preparation of 5-methyl-1- phenyl-2(1H)-pyridinone of the general formula (2) useful as an original drug, which can dispense with special reagents and apparatuses and by which the objective compound can be obtained in decreased steps by easy operation. That is, a process for the preparation of 5-methyl-1-phenyl-2(1/-/)-pyridinone represented by the general formula (14), characterized by reacting 5-methyl- 2(1rV)-pyridinone represented by the general formula (13) with bromobenzene or chlorobenzene in the presence of both at least one copper catalyst selected from among cuprous catalysts and cupric catalysts and a base.

(14)

US2007/0049624 concerns a new process for preparation of 5-methyl-1- phenyl-1(/-/)-pyridone, which consists in three steps which provide greater performance from a high purity product. Pharmaceutical compositions of topical application and use thereof are also described.

WO2009/111785 discloses a pharmaceutical composition comprising 5- ethyl-1-phenyl-2-(1/-/)-pyridone (5-EPP) and its use for the treatment of sepsis, and methods for synthesizing 5-EPP. SUMMARY

The present invention is directed to methods of preparing a pyridone compound, 5-ethyl-1-phenyl-2(1/-/)-pyridone (1), and intermediates thereof.

In illustrative embodiments of the present invention, 5-ethyl-1-phenyl-2(1H)- pyridone and the intermediates thereof may be prepared by an exemplary process as set out in Scheme 1. Exemplary reagents and conditions for these reactions are disclosed herein.

Scheme 1

In illustrative embodiments of the present invention, there is provided a process for the preparation of 5-ethyl-1-phenyl-2(1H)-pyridone (1) comprising reaction of 5-ethyl-2(1/-/)-pyridone with phenyl halide in the presence of Cu₂O and a first base.

According to illustrative embodiments of the present invention, there is provided a process for the preparation of a compound of the Formula (2):

(2) wherein R⁴ is H or phenyl, comprising the following steps:

i) reaction of butyl aldehyde with an acrylic compound of the Formula 9:

0)

wherein R³ is alkyi, substituted alkyi, aryl, substituted aryl, arylalkyi or substituted arylalkyi, in the presence of a dehydrating agent and a secondary amine of the Formula HNR¹R² wherein

R¹and R² are either a) two independent groups or b) together form a single ring group with the N to which they are bonded;

R and R², when independent groups, are independently selected from the group consisting of: alkyi, substituted alkyi, aryl, substituted aryl, arylalkyi, and substituted arylalkyi;

R¹ and R², when together form a single ring group with the N to which they are bonded, are a heterocyclic ring or a substituted heterocyclic ring;

ii) hydrolysis of the product of step i) with an aqueous acid;

iii) cyclization of the product of step ii) with an amine of the Formula NH₂R⁴ or the corresponding ammonium salt, wherein R⁴ is H or phenyl;

iv) dehydrogenation of the product of step iii) by treatment with sulfur whereby the products of steps i), ii) and iii) are not isolated.

In illustrative embodiments of the present invention, there is provided a compound of the Formula 4:

(4)

wherein R⁴ is phenyl or hydrogen

In illustrative embodiments of the present invention, there is provided a compound of the Formula 4a:

H

(4a) Other aspects and features of the present invention will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments of the invention.

DETAILED DESCRIPTION

As used herein, the term "substituted" refers to the replacement of a hydrogen atom on a compound with a substituted group. A substituent may be a non-hydrogen atom or multiple atoms of which at least one is a non-hydrogen atom and one or more may or may not be hydrogen atoms. For example, without limitation, substituted compounds may comprise one or more substituent's selected from the group consisting of: R", OR", NR"R", SR", halogen, SiR"R'"R"", OC(O)R", C(O)R", CO₂R", CONR"R"\ NR'"C(O)₂R", S(O)R", S(O)₂R", CN, and NO₂.

As used herein, each R", R"\ and R"" may be selected, independently, from the group consisting of: hydrogen, halogen, oxygen, substituted or un substituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, and arylalkyl groups.

As used herein, the term "alkyl" by itself or as part of another substituent, means, unless otherwise stated, a saturated straight or branched chain, or cyclic hydrocarbon radical, or combination thereof having the number of carbon atoms designated (e.g. C-1 -C10 or 1- to 10-membered means one to ten carbons). When there is no indication of the number of carbon atoms in the alkyl, it is meant, unless otherwise indicated by context, that there are from 1 to 10 carbons. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec- butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

As used herein, the term "aryl" by itself or as part of another substituent, means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent which can be a single ring or multiple rings (often from 1 to 3 ring) which are fused together or linked covalently. "Aryl" includes, but is not limited to, "heteroaryl" groups. "Heteroaryl" refers to an aryl group that contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl and heteroaryl groups include: phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4- oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,

2- thiazolyl, 4-thiazolyl, 5-thazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridinyl,

3- pyridinyl, 4-pyridinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1- isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6- quinolyl. The term "aryl" when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term "arylalkyl" is meant to include those radicals in which an aryl group is attached to an alky group (e.g., benzyl, phenylethyl, pyridylmethyl, etc.) including those alkyl groups in which a carbon atom containing group (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, etc).

As used herein, a "heterocyclic ring" means, unless otherwise stated, a 5- or 6- membered saturated monocyclic ring, having at least one heteroatom selected from S, N and O.

According to illustrative embodiments of the present invention, there is provided a process for the preparation of 5-ethyl-1-phenyl-2(1/-/)-pyridone (1) comprising reaction of 5-ethyl-2(1/-/)-pyridone with phenyl halide in the presence of CU2O and a first base.

Unexpectedly, we have discovered that 5-ethyl-2(1H)-pyridone may be coupled with phenyl halide in the presence of cuprous oxide and a base, with no need for using an anhydrous base or performing additional steps of preactivating the copper such as preparing a copper-zinc catalyst. The first base may be an inorganic base. The first base may be selected from the group consisting of alkali metal carbonates and alkali metal phosphates. The first base may be potassium carbonate or potassium phosphate.

In the reaction of 5-ethyl-2(1/-/)-pyridone with phenyl halide in the presence of Cu₂0 and a first base, the reaction may be conducted neat, whereby the phenyl halide acts as both reactant and solvent.

The reaction of 5-ethyl-2(1H)-pyridone with phenyl halide in the presence of Cu₂0 and a first base may be performed at an elevated temperature, particularly above 100°C. The temperature will vary depending on the nature of the phenyl halide. The elevated temperature may be from about 100°C to the boiling point of any solvent or reactant used. If appropriate, water produced during the course of the reaction may be removed by the use of a Dean-Stark apparatus or another similar mechanism.

The product of the reaction of 5-ethyl-2(1H)-pyridone with phenyl halide in the presence of Cu₂0 and a first base may be crystallized by addition of a suitable co-solvent to the crude reaction product. The suitable co-solvent may be selected from the group consisting of alkyl ethers (e.g. tetrahydrofuran, dioxane, diethyl ether, methyl f-butyl ether, diisopropyl ether, butyl ether), alkyl esters (e.g. ethyl acetate, isopropyl acetate), and mixtures thereof.

(2)

wherein R⁴ is H or phenyl, comprising the following steps:

i) reaction of butyl aldehyde with an acrylic compound of the Formula 9:

wherein R³ is alkyi, substituted alkyi, aryl, substituted aryl, arylalkyi or substituted arylalkyi, in the presence of a dehydrating agent and a secondary amine of the Formula HNR R² wherein

R¹ and R², when independent groups, are independently selected from the group consisting of: alkyi, substituted alkyi, aryl, substituted aryl, arylalkyi, and substituted arylalkyi;

ii) hydrolysis of the product of step i) with an aqueous acid;

Unexpectedly, we have discovered that pyridones of the Formula 2 could be obtained by the aforementioned "one-pot" process which does not require isolation and purification of any intermediates.

Although the present invention is not limited to any particular intermediates, it is postulated that, in one embodiment, the aforementioned "one- pot" process proceeds via the pathway shown in Scheme 2.

Scheme 2

In some embodiments, the compound of the Formula 9 is a compound in which R³ is a C1-C3 alkyl group. In some embodiments, the compound of the Formula 9 is a compound in which R³ is methyl.

The dehydrating agent may be a suitable chemically inert agent and/or mechanism capable of removing water from the reaction mixture. The dehydrating agent may be selected from the group consisting of alkali or alkaline earth metal carbonate (e.g. sodium carbonate, potassium carbonate), alkali or alkaline earth metal sulfate (e.g. calcium sulfate, magnesium sulfate, sodium sulfate), alkali or alkaline earth metal halide (e.g. calcium chloride), alkali or alkaline earth metal oxide (calcium oxide, magnesium oxide) and molecular sieves.

In some embodiments, the compound of the Formula HNR R² is a compound in which R¹ and R² are both ethyl. In some embodiments, the compound of the Formula HNR¹R² is a compound in which R¹ and R² are both benzyl. In some embodiments, the compound of the Formula HNR R² is a heterocyclic ring or a substituted heterocyclic ring. In some embodiments, the compound of the Formula HNR¹R² is selected from the group consisting of piperidine, piperazine, N-methyl piperazine, pyrrolidine and morpholine.

Step i) of the process for preparation of a compound of the Formula 4 may be conducted neat or in the presence of a first organic solvent. The first organic solvent may be selected from the group consisting of alkyl ethers (e.g. tetrahydrofuran, dioxane, diethyl ether, methyl f-butyl ether, diisopropyl ether, butyl ether), aromatic and aliphatic hydrocarbons (e.g. toluene, xylenes, hexanes, and heptanes), nitriles (e.g. acetonitrile, propionitrile, butyronitrile, and benzonitrile) and mixtures thereof.

Step i) of the process for the preparation of a compound of the Formula 4 may be conducted at an elevated temperature, from about 50°C to about the boiling point of any solvent or reactant used.

The aqueous acid may be a suitable aqueous organic or aqueous mineral acid. The acid may be selected from the group consisting of alkanoic acids (e.g. acetic acid, propanoic acid), arylsulfonic acids (e.g. p-toluene sulfonic acid, benzene sulfonic acid) and mineral acids (e.g. hydrochloric acid, sulfuric acid, phosphoric acid).

The hydrolysis may be conducted at a temperature from about 25°C to about the boiling point of any reactant or solvent used.

Following hydrolysis, the organic phase containing product may be separated from the aqueous phase and carried forward to step iii).

In some embodiments, the amine of the Formula NH₂R⁴ or the corresponding ammonium salt is ammonia or ammonium acetate. In some embodiments, the amine of the Formula NH₂R⁴ or the corresponding ammonium salt is aniline or benzene ammonium acetate.

The cyclization may be conducted at a temperature from about 25°C to about the boiling point of any reactant or solvent used.

Following the cyclization, solvent and traces of water may be removed by distillation.

Sulfur may be charged in one portion or portionwise to control the formation of gaseous sulfur by-products (e.g. hydrogen sulfide, S0₂, SO3, H₂S0₄).

The dehydrogenation may be conducted at an elevated temperature up to about the boiling point of the solvent used.

Examples

The following examples are illustrative of some of the embodiments of the invention described herein. These examples should not be considered to limit the spirit or scope of the invention in any way.

Example 1 :

One-pot process for the preparation of 5-ethyl-2(1/-/)-pyridone

Butyl aldehyde (400 g, 1.0 mol) was added to a mixture of morpholine (970.4 mL 2.0 mol), methyl acrylate (1432.6 g, 3.0 mol) and potassium carbonate (153.3 g, 0.2 mol) in xylenes. The reaction was heated at 75-80°C for 4 hours, then morpholine (485.2 ml_, 1.0 mol) was added and the reaction was maintained for 8 hours. After consumption of the starting material, acetic acid (1111.4 imL, 3.5 mol) was added and the temperature was adjusted to 75-80°C for 4 h. The organic layer was separated, ammonium acetate (342.1 g, 0.8 mol) was charged and the reaction mixture was heated to reflux for 2 to 4 hours. After reaction was complete by TLC, the reaction mixture was concentrated until a KF of NMT 0.25% was obtained. Finally, sulphur (204.25 g, 2.3 mol) was added and the reaction mixture was heated at reflux at 130°C for 5 to 7 hours in normal atmosphere. Then, water (4.0 vol) and Celite^® (5%) were added, and the mixture was filtered through a Celite^® pad and washed with xylenes (1.0 vol). The phases were allowed to separate and the organic layer was washed with 5% hydrochloric acid solution (2.0 vol). The aqueous layer was separated and joined with the previously separated. Heptane (2x2.0 vol) was added and the aqueous layer was separated. The pH of the aqueous phase was adjusted to 8-9 with 25% sodium hydroxide solution followed by addition of n-butanol (2x2.0 vol). The organic layer was separated and concentrated, 3% charcoal was added and the mixture was filtered through a Celite^® pad, washed with n-butanol (1.0 vol) and concentrated to dryness to give 5-ethyl-2(1H)-pyridone in 30% yield. HPLC Purity 99.93%.

¹H NMR (CDCI₃) δ 13.61 (s, 1 H), 7.36-7.40 (dd, 1 H, J = 2.4, 9.0 Hz), 7.18 (brd, 1 H, J = 1.91 Hz), 6.54-6.57 (d, 1 H, J = 9.2 Hz), 2.42 (q, 2H, J = 7.5 Hz), 1.16 (t, 3H, J = 7.5).

Example 2:

Preparation of 5-ethyl-1-phenyl-2( H)-pyridone

As described in example 1 , butylaldehyde (200.0 g, 1.0 mol) was reacted with N- methylpiperazine (319.5 g, 1.15 mol), methyl acrylate (286.5 g, 1.2 mol), potassium carbonate (192 g, 0.5 mol), xylenes (1.0 vol), acetic acid (556 ml_, 3.5 mol), aniline (278 mL 1.1 mol), sulphur (27.2 g, 1.0 mol) to yield 30% of 5-ethyl-1- phenyl-2(1H)-pyridone. HPLC Purity 99.95%. ¹H NMR (CDCI₃) δ 7.49-7.47 (m, 2H), 7.45-7.35 (m,3H), 7.31 (dd, 1 H, J = 2.4, 9.3 Hz), 7.10 (brd, 1 H, J = 1.95 Hz), 6.62 (d, 1 H, J = 9.3 Hz) 2.41 (q, 2H, J = 7.5 Hz), 1.17 (t, 3H, J = 7.5).

Example 3:

Preparation of 5-ethyl-1-phenyl-2(1/-/)-pyridone

To a suspension of bromobenzene (51.1 g, 2.0 mol), potassium carbonate (22.5 g, 1.0 mol) and copper (I) oxide (1.2 g, 0.05 mol) was added 5-ethyl-2(1H)- pyridone (20.0 g, 1.0 mol) obtained following the general procedure outlined in example 1. The mixture reaction was heated to 140-145°C. Water was removed by using a Dean-Stark apparatus. After stirring for 4 h, water (4.0 vol) was added and temperature was adjusted to 40-45°C. The organic layer was separated and sodium hydroxide solution (26g, 2.0 mol), charcoal (3%) and Celite^® (3%) were added. The mixture was stirred for 1 hour. The solution was then filtered through a Celite^® pad and washed with xylenes. The organic layer was separated and concentrated. Methyl f-butyl ether was added and the reaction mixture was cooled to -10°C. Solids were filtered and washed with methyl f-butyl ether (2.0 vol) to give 5-ethyl-1-phenyl-2(1/-/)-pyridone in 90% yield.

Example 4:

Preparation and purification of 5-ethyl-1-phenyl-2(1H)-pyridone

The 5-ethyl-1-phenyl-2(1H)-pyridone (20 g, 1.0 mol) obtained following the method essentially described at example 3 was added to a solution of sodium hydroxide (20 g, 2.0 mol). The mixture was stirred for 1 h at room temperature, then, methyl t- butyl ether (2.0 vol) was added. The mixture was adjusted to 40-45°C and maintained for 1 h, then allowed to cool to room temperature. The phases were allowed to separate and the aqueous layer was extracted with methyl f-butyl ether (2.0 vol) at 40-45°C. The organic layer was separated and joined with the previously obtained layer. Silica gel (0.3%) and charcoal (3%) were added and the mixture was heated to 40-45°C. The mixture was filtered through a Celite^® pad, washed with methyl f-butyl ether and concentrated until appearance of solids. The mixture was cooled to - 0°C, filtered and washed with methyl f-butyl ether (2.0 vol) to yield 5-ethyl-1-phenyl-2(1/7)-pyridone in 90% yield.

Although various embodiments of the invention are disclosed herein, many adaptations and modifications may be made within the scope of the invention in accordance with the common general knowledge of those skilled in this art. Such modifications include the substitution of known equivalents for any aspect of the invention in order to achieve the same result in substantially the same way. Numeric ranges are inclusive of the numbers defining the range. The word "comprising" is used herein as an open-ended term, substantially equivalent to the phrase "including, but not limited to", and the word "comprises" has a corresponding meaning. As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a thing" includes more than one such thing. Citation of references herein is not an admission that such references are prior art to the present invention. The invention includes all embodiments and variations substantially as hereinbefore described.

Claims

is claimed is:

A process for the preparation of a com ound of the Formula (1)

(1)

comprising reaction of 5-ethyl-2(1H)-pyridone with phenyl halide in the presence of Cu₂0 and a first base.

2. The process of claim 1 wherein the phenyl halide is bromobenzene.

3. The process of claim 1 or 2 wherein the first base is selected from the group consisting of alkali metal carbonates and alkali metal phosphates.

4. The process of claim 1 or 2 wherein the first base is potassium carbonate.

5. The process of claim 1 or 4 wherein the first base is not anhydrous.

6. The process of claim 1 wherein the 5-ethyl-2(1/-/)-pyridone is prepared by a process comprising the following steps:

i) reaction of butyl aldehyde with an acrylic compound of the Formula

9:

wherein R³ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl, in the presence of a dehydrating agent and a secondary amine of the Formula HNR¹R² wherein

R¹ and R², when independent groups, are independently selected from the group consisting of: alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;

R¹ and R², when together form a single ring group with the N to which they are bonded, are a heterocyclic ring or a substituted heterocyclic ring; ii) hydrolysis of the product of step i) with an aqueous acid;

iii) cyclization of the product of step ii) with ammonia or an ammonium salt;

The process of claim 5 wherein the 5-ethyl-2(1/-/)-pyridone is prepared by a process comprising the following steps:

i) reaction of butyl aldehyde with an acrylic compound of the Formula

R and R², when together form a single ring group with the N to which they are bonded, are a heterocyclic ring or a substituted heterocyclic ring; ii) hydrolysis of the product of step i) with an aqueous acid;

iii) cyclization of the product of step ii) with ammonia or an ammonium salt;

The process of claim 7 wherein the compound of Formula 9 is a compound in which R³ is a C1-C3 alkyl group.

The process of claim 7 wherein the compound of Formula 9 is a compound in which R³ is methyl.

10. The process of claim 7 or 8 wherein the dehydrating agent is potassium carbonate.

11. The process of claim 10 wherein the secondary amine of the Formula HNR¹R² is selected from the group consisting of Ν,Ν-diethylamine, N,N- dibenzylamine, piperadine, piperazine, N-methyl piperazine, morpholine and pyrrolidine.

12. The process of claim 10 wherein the secondary amine of the Formula HNR¹R² is morpholine.

13. The process of claim 12 wherein the aqueous acid is acetic acid.

14. The process of claim 13 wherein the cyclization is performed with ammonium acetate.

15. A process for the preparation of a compound of the Formula (2):

wherein R⁴ is H or phenyl, comprising the following steps:

i) reaction of butyl aldehyde with an acrylic compound of the Formula

9:

(9)

R and R² are either a) two independent groups or b) together form a single ring group with the N to which they are bonded;

R¹ and R², when independent groups, are independently selected from the group consisting of. alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; R¹ and R², when together form a single ring group with the N to which they are bonded, are a heterocyclic ring or a substituted heterocyclic ring; ii) hydrolysis of the product of step i) with an aqueous acid;

iii) cyclization of the product of step ii) with an amine of the Formula NH₂R⁴ or the corresponding ammonium salt, wherein R⁴ is H or phenyl; iv) dehydrogenation of the product of step iii) by treatment with sulfur

16. The process of claim 15 wherein the compound of Formula 9 is a compound in which R³ is a C1-C3 alkyl group.

17. The process of claim 15 wherein the compound of Formula 9 is a compound in which R³ is methyl.

18. The process of claim 17 wherein the dehydrating agent is potassium carbonate.

19. The process of claim 15 or 17 wherein the secondary amine of the Formula HNR¹R² is selected from the group consisting of N,N- diethylamine, N,N-dibenzylamine, piperadine, piperazine, N-methyl piperazine, morpholine and pyrrolidine.

20. The process of claim 17 wherein the secondary amine of the Formula HNR¹R² is morpholine.

21. The process of claim 20 wherein the aqueous acid is acetic acid.

22. The process of claim 21 wherein the cyclization is performed with ammonium acetate.

23. A compound of the Formula

wherein R⁴ is phenyl or hydrogen.

A compound of the Formula 4a:

H

(4a)