WO1998015524A1

WO1998015524A1 - Improved process for the synthesis of beta-ketonitriles

Info

Publication number: WO1998015524A1
Application number: PCT/US1997/018159
Authority: WO
Inventors: Edward Mark Davis; James E. Ellis
Original assignee: Warner-Lambert Company
Priority date: 1996-10-10
Filing date: 1997-10-07
Publication date: 1998-04-16
Also published as: ZA979066B; CO5290252A1; AU4811697A

Abstract

An improved process for the preparation of β-ketonitrile is described where an α-β-enone hydrocyanated in the presence of a tetraalkylammonium hydroxide and acetone cyanohydrin to the desired product as well as the use of β-ketonitriles in the preparation of hydroxybutenolides.

Description

IMPROVED PROCESS FOR THE SYNTHESIS OF β-KETONITRILES

The present invention relates to a method for the synthesis of β-ketonitriles that have utility in the preparation of endothelin-A (ET_A) receptor antagonists. Doherty A.M., et al . J . Med . Chem . , 1995;38:1259-63, disclosed a novel series of hydroxybutenolide compounds with activity as endothelin antagonists. These compounds are nonpeptide antagonists which have ET_A selective activity at nanomolar concentrations. 3- (Benzo [1,3] dioxol-5-yl) -5-hydroxy-5- (4-methoxy- phenyl-4- (3 , 4 , 5-trimethoxybenzyl) -2- (5H) -furanone was reported by Doherty A.M., et al . , __J. Med . Chem . ,

1995;38:1259-63, to be an orally active highly selective ET_A receptor antagonist. 2- (Benzo [1 , 3] dioxo- 5-yl) -4- (4-methoxyphenyl) -4-oxobutyronitrile is a key intermediate in the preparation of 3- (benzo [1, 3] dioxol- 5-yl) -5-hydroxy-5- (4-methoxyphenyl-4- (3 , 4 , 5-trimethoxy- benzyl) -2- (5H) -furanone . A synthetic procedure for preparing this compound, as well as other β-ketonitrile intermediates, is disclosed in Doherty A.M., et al . , J . Med . Chem . , 1995;38:1259-63. Although this procedure provides the target compounds, it is difficult to conduct on a large scale.

Ishii, H., et al . , J . Chem . Soc . Perkin Trans . I .. 1987; Davey W. and Tivey D.J., J . Chem . Soc . , 1958:1230; and Lapworth A. and Wechsler E., J . Chem . Soc . , 1910; 97: 3 disclosed a procedure for preparing β-ketonitriles from α,β-enones using potassium cyanide and acetic acid. However, this procedure is undesirable from a scale-up perspective as a result of large amounts of hydrogen cyanide being generated in the process. Base catalyzed hydrocyanation of chalcones with active cyanohydrin was first described by Nazarov I.N. and Zav'zalov S.I. (J. fen. Chem.. USSR (Engl. Transl.) 1954;24:475 [CA. 1955 ;49 : 6139_f] ) . According to Nagata W. and Yoshioka M. (Organic

Reactions, Dauben W.O., ed. , John Wiley & Sons, Inc, 1977, Vol. 25, 255-476) the reactivity of the Nazarov method is low because of the low cyanide concentration in the reaction medium. The reactivity can be increased to some extent by using a large excess of acetone cyanohydrin without solvent and with saturated methanolic potassium hydroxide as the catalyst.

Betts B.E. and Davey W. ,τ fh m . finr. .. 1958:4193 following the Nazarov procedure used acetone cyanohydrin in the presence of sodium carbonate. They reported an optimum reaction stoichiometry of 2 moles of acetone cyanohydrin and 10 mole percent of base per mole of chalcone substrate. However, this procedure is not amenable to large scale synthesis and reaction rate decreased dramatically as the reaction scale was increased. This is pronounced when chalcones with several electron donating substituents were used. The electron donating substituents decrease the electrophilicity of the chalcone double bond resulting in a decreased rate of Michael addition by the cyanide anion.

Thus, we have surprisingly and unexpectedly found that the hydrocyanation of α-β-enones in the presence of a phase transfer base and acetone cyanohydrin afford large scale synthesis of β-ketonitriles.

The object of the present invention is an improved, efficient, and economical process for the hydrocyanation of chalcones. Thus, the present method minimizes the generation of undesirable and highly toxic by-products and is amenable to large scale synthesis . SUMMARY OF THE INVENTION

Accordingly, a first aspect of the present invention is an improved process for the preparation of a compound of Formula I

wherein R, R , and R may be the same or different and each is hydrogen, alkyl, alkoxy, amino, alkylamino, dialkylamino, aryl, halogen, C0₂alkyl, or cyano ; and

-_>

R is aryl or

which comprises : treating a compound of Formula II

-| Z) wherein R, R , R , and R^J are as defined above with acetone cyanohydrin and a tetraalkylammonium hydroxide in a solvent to afford a compound of Formula I. A second aspect of the present invention is an improved process for the preparation of the compound of Formula A

and the keto acid and pharmaceutically acceptable salts thereof, corresponding to the opened lactone ring of a compound of Formula A which comprises:

Step (a) treating the compound of Formula Ila

with acetone cyanohydrin and a tetraalkylammonium hydroxide in a solvent to afford the compound of Formula la

Step (b) treating the compound of Formula la with an acid in methanol to afford the compound of Formula B

Step (c) treating the compound of Formula B with 3 , 4 , 5-trimethoxybenzaldhyde in the presence of a base in a solvent followed by the addition of an acid to afford the compound of Formula A; Step (d) and if desired, converting the resulting compound of Formula A to the keto acid pharmaceutically acceptable salt corresponding to the opened lactone ring of Formula A by deprotonation with a base and if so desired, converting the keto acid salt form to the compound of Formula A by heating in an inert solvent with an acid.

DETAILED DESCRIPTION OF THE INVENTION

In the compounds of Formula I, the term "alkyl" means a straight or branched hydrocarbon radical having from 1 to 8 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, π-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, π-hexyl, π-heptyl, π-octyl, and the like.

"Alkoxy" and " thioalkoxy" are O-alkyl or S-alkyl of from 1 to 6 carbon atoms as defined above for "alkyl" . "Alkylamino" is N-alkyl of from 1 to 6 carbon atoms as defined above for "alkyl".

"Dialkylamino" is N-dialkyl of from 1 to 6 carbon atoms as defined above for "alkyl".

The term "aryl" means an aromatic radical which is a phenyl group, a phenyl group substituted by 1 to

4 substituents selected from alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, hydroxy, halogen, trifluoromethyl, amino, alkylamino as defined above for alkyl, dialkylamino as defined above

for alkyl, nitro, cyano, ca

as defined above for alkyl,

O II

, as defined above for alkyl, -C-N (alkyl) ₂ as defined above for alkyl, -(CH₂)_n2-NH₂ wherein n² is an integer of 1 to 5, - (CH₂) _n2-NH-alkyl as defined above for alkyl and n , - (CH₂) _n2-N (alkyl) ₂ as defined above

for alkyl and n 2 ,

as defined above

for alkyl, and n and as defined

above for alkyl and n^ , "Halogen" is fluorine, chlorine, bromine, or iodine .

"Chalcone" is 1 , 3-diphenyl-2-propen-l-one or a phenyl substituted derivative thereof.

"HPLC" is high performance liquid chromatography.

1 " H NMR" is proton nuclear magnetic resonance spectrometry .

Particularly preferred compounds of Formula I prepared by the improved process of the first aspect of the present invention are selected from the group consisting of:

2- (Benzo [1, 3] dioxo-5-yl) -4- (4-methoxyphenyl) - 4 -oxobutyronitrile ;

2- (4 -Cyanopheny1 ) -4-phenyl-4-oxobutyronitrile;

2- (4-Methoxycarbonylphenyl) -4 -phenyl-4- oxobutyronitrile;

2-Phenyl-4-phenyl-4-oxobutyronitrile; 2-Phenyl-4- (4 -fluorophenyl) -4-oxobutyronitrile;

2- (4 -Fluorophenyl) -4-phenyl-4-oxobutyronitrile;

2-Phenyl-4- (4-methoxyphenyl) -4-oxobutyronitrile;

2- (4-Methoxyphenyl) -4-phenyl-4-oxobutyronitrile; 2- (4-Methylphenyl) -4-phenyl-4-oxobutyronitrile;

2-Phenyl-4- (4-methylphenyl) -4-oxobutyronitrile;

2- (4- (Dimethylamino) phenyl) -4-phenyl-4- oxobutyronitrile; and

2- (3,4, 5-Trimethoxyphenyl) -4- (4-methoxyphenyl) -4- oxobutyronitrile .

The process of the present invention in its first aspect is a new, improved, economical and commercially feasible method for the synthesis of β-ketonitriles. The process of the present invention in its first aspect is outlined in Scheme I.

SCHEME I

A compound of Formula II wherein R, R , and R^ may be the same or different and each is hydrogen, alkyl, alkoxy, amino, alkylamino, dialkylamino, aryl, halogen,

-C0₂-alkyl or, cyano; and -_> R^J is aryl, or

may be prepared from a compound of Formula IV wherein

R, R 1 , and R "? are as defined above and a compound of Formula III wherein R is as defined above using the acid catalyzed Claisen-Schmidt reaction described by

Lyle R.E. and Parodis L.P., __L Amer . Chem. Son . ,

1955 ; 77 : 6667 which is amenable to chalcones containing electron withdrawing substitutions or using a modification of the base catalyzed Claisen-Schmidt reaction described by Kohler E.P. and Chadwell H.M., τg. Synth.. 1941 Coll Vol. I, 2nd Ed; 78 to afford a compound of Formula II.

A compound of Formula I is prepared by treating a compound of Formula II with acetone cyanohydrin in the presence of a phase transfer base, such as, for example, a tetraalkylammonium hydroxide base, for example, tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrabutylammonium hydroxide, and the like in a solvent such as, for example, methanol, ethanol, isopropanol, ethoxyethanol, acetone, methylethyl ketone, and the like using a slight excess of acetone cyanohydrin such as, for example, about 1.25 moles and about 5 mole percent of the tetraalkylammonium hydroxide per mole of a compound of Formula II, i.e., the chalcone to afford a compound of Formula I. Preferably, the reaction is carried out with tetramethylammonium hydroxide base in acetone using about 5 mole percent of base and about 1.25 moles of acetone cyanohydrin per mole of chalcone . Acetone is the preferred solvent because it gives least color formation during the reaction and is the easiest to handle as a waste product. Since acetone is a by-product of the reaction, no mixed solvents are obtained from the reaction workup. Also, the acetone is easily separated from the rest of the reaction mixture by atmospheric distillation. This allows easy destruction of the excess cyanide. When this distillation separation was used in large scale synthesis, the acetone distillate contained less than 10 parts per million (ppm) of HCN and the residual cyanide in the water was treated with sodium hypochloride without any problems .

The process of the present invention in its second aspect is a new, improved, economical and commercially feasible method for preparing a compound of Formula A. The process of the present invention in its second aspect is outlined in Scheme II.

SCHEME II

The compound of Formula la may be prepared from the compound of Formula Ila using the methodology previously described for preparing a compound of Formula I from a compound of Formula II. The compound of Formula B may be prepared by hydrolyzing the compound of Formula la in methanol in the presence of an acid such as, for example, hydrochloric acid, para toluene sulfonic acid and the like to afford the compound of Formula B. Preferably, the reaction is carried out in the presence of hydrochloric acid.

The compound of Formula A may be prepared from the compound of Formula B and 3 , 4 , 5-trimethoxybenzaldehyde in the presence of a base such as, for example, sodium methoxide and the like in a solvent such as, for example, methanol, ethanol, and the like followed by subsequent treatment with an acid such as, for example, acetic acid and the like to afford the compound of Formula A. Preferably, the reaction is carried out in the presence of sodium methoxide in ethanol and subsequently treated with acetic acid.

The ring-opened keto acid, sodium salt of Formula A-l may be prepared by deprotonation of the compound of Formula A with a base such as, for example, sodium methoxide, sodium hydroxide, sodium carbonate, and the like in a solvent such as, for example, methanol and the like to afford the compound of Formula A-l. Preferably, the compound of Formula A is treated with sodium carbonate in methanol . The ring closed lactone form of the compound of the invention may be regenerated by dissolution of the ring opened keto acid sodium salt form of the compound of the invention in a solvent such as, for example, methanol, ethanol, and the like, at about 0°C to about the boiling point of the solvent with strong acid catalysis such as, for example, concentrated hydrochloric acid, glacial acetic acid, and the like. Preferably, the lactone may be regenerated with glacial acetic in methanol .

The compound of the present invention may exist in solvated or unsolvated form and such forms are equivalent to the unsolvated form for the purposes of this invention.

The following examples are illustrated to show the present process, the preparation of starting materials, and the use of 2- (benzo [1, 3] dioxo-5-yl) -4- (4-methoxy- phenyl) -4 -oxobutyronitrile obtained by the first aspect of the present invention to prepare 2- (benzo [1, 3] - dioxol-5-yl) -4- (4-methoxyphenyl) -4-oxobutyric acid methyl ester which in turn is used to prepare 3-(benzo- [1, 3] dioxol-5-yl) -5-hydroxy-5- (4-methoxyphenyl-4-

(3 , 4 , 5-trimethoxybenzyl) -2- (5H) -furanone and the ring opened keto acid i.e., (Z) sodium 2- (Benzol [1, 3] dioxol- 5-yL) -4- (4-methoxyphenyl) 3- (3,4, 5-trimethoxybenzyl) -4- oxobut-2-enoate which are useful as an ET_A selective receptor antagonists.

EXAMPLE 1 nf.nf.ral hydrocyanation procedure

The chalcone (0.1 mole) was slurried into 50 mL acetone. Acetone cyanohydrin (5.32 g, 0.0625 mole) was added all at once followed by 25% aqueous solution of tetramethylammonium hydroxide (2.25 g, 0.00625 mole). The mixture was heated at reflux until the reaction was complete by HPLC. After cooling the mixture to room temperature, 25 mL water was added to induce crystallization. The slurry was cooled below 10°C and filtered to collect product. The product was washed with water and vacuum dried at 45°C. The products were recrystallized from ethanol, if necessary, for analytical testing. EXAMPLE 2 2 - .Benzo M , 1 dioxo-5-y1. -4- (4 -me hoxypheny1.4- nxohnt-.ymn. tri 1 e

3- (Benzo [1, 3] dioxo-5-yl) -1- (4-methoxyphenyl) -prop- 2-en-l-one (9.3 kg, 32.9 moles) was slurried into 32 L of acetone at room temperature. 3.5 kg (41.1 moles) of acetone cyanohydrin and 0.75 L (2.08 moles) 25% aqueous solution of tetramethylammonium hydroxide were added to the slurry. The reaction was heated at reflux for 10 hours. The mixture was cooled and 18 L of water added to crystallize the product. The resulting slurry was then cooled to 0 to 10°C for at least 3 hours. The product was collected by centrifugation and dried at 40 to 50°C. 8.6 kg (85% of theory) of product was obtained with a purity of 99% by HPLC; mp 93.9-94.9°C.

¹H NMR (200 MHz, dg-DMSO): 3.4 and 3.6 (both 1H, dd, CHCH₂CO) , 3.9 (3H, s, OMe) , 4.5 (1H, t, ArCHCH₂) , 5.95 (2H, s, OCH₂0) , 7.3 (1H, d, ArH) , 7.35 to 7.5 (4H, m, ArH) , 7.9 (2H, d, ArH) . In a process analogous to Example 1 using the appropriate starting materials, the corresponding compounds of Formula I are prepared as follows:

EXAMPLE 3 2- .4- yanopheny1. -4-pheny1 -4-oxobnryr ni tri 1 e

Reaction time 30 minutes; yield 56%, purity 90.9% by HPLC, mp 136.8-137.3°C;

^■'^■H NMR (200 MHZ, dg-DMSO): 3.8 and 4.1 (both 1H, dd, CHCH₂CO) , 4.8 (1H, dd, ArCHCH₂) , 7.1 to 8.1 (9H, m, ArH) .

EXAMPLE 4 2 - ( -Methoxy arbony1 phenyl . -4-phenyl -4 -oxobπtyroni tr 1 p Reaction time 45 minutes; yield 90%, purity 99.4% by HPLC, mp 113.9-114.5°C; ¹H NMR (200 MHz, CDCI3) : 3.5 and 3.7 (both 1H, dd, CHCH₂CO) , 3.9 (3H, s, OCH3) , 4.65 (1H, dd, ArCHCH₂) , 7.4 to 7.65 (5H, m, ArH), 7.9 (2H, d, ArH), 8.05 (2H, d, ArH) .

EXAMPLE 5 2 -Phenyl -4 -Phenyl -4 -oxobutyronitrile

Reaction time 1 hour; yield 93.2%, purity 99.7% by HPLC, mp 124.9-125.4°C (literature 127°C, Betts B.E. and Davey W. , .T. rh^m Snr . 1958:4193);

¹H NMR (200 MHz, dg-DMSO): 3.75 and 4.0 (both 1H, dd, CHCH₂C0) , 4.6 (1H, dd, ArCHCH₂) , 7.3 to 7.7 (8H, m, ArH) , 8.0 (2H, m, ArH) .

EXAMPLE 6

2. -Phenyl -4- (4-f1.inrophenyl . -4-oxobutyro trile

Reaction time 2 hours; yield 95%, purity 98.2% by

HPLC; mp 134.0-134.5°C;

¹H NMR (200 MHz, dg-DMSO): 3.75 and 4.0 (both 1H, dd, CHCH₂C0) , 4.6 (1H, t, ArCHCH₂) , 7.2-7.7 (7H, m, ArH),

8.15 (2H, d, ArH) .

EXAMPLE 7 2 - .4 -Fluorophenyl . -4-phenyl -4 -oxobutyronitrile Reaction time 1.5 hours; yield 94%, purity 93.6% by HPLC; mp 101.9-102 _5°C.

¹H NMR (200 MHz, dg-DMSO): 3.7 and 4.0 (both 1H, dd, CHCH₂CO) , 4.65 (1H, m, ArCHCH₂) , 7.3 (2H, t, ArCH) , 7.4-7.7 (5H, m, ArH), 8.0 (2H, d, ArH).

EXAMPLE 8 2-Phenyl -4- .4 -mehhoxyphenyl . -4-oxobutyronitrile

Reaction time 3 hours; yield 97%, purity 100% by HPLC; mp 56.3-58.1°C (literature 65°C Betts B.E. and Davey W. , ,T Che . Soc . _r 1958:4193); ¹H NMR (200 MHz, CDCI3) : 3.5 and 3.7 (both 1H, dd, CHCH₂CO) , 3.9 (3H, s, OCH3) , 4.6 (1H, t, ArCHCH₂) , 6.9 (2H, m, ArH), 7.4 (5H, m, ArH), 7.9 (2H, , ArH).

EXAMPLE 9

2 - .4-M thoxyphenyl . -4 -phenyl -4-oxobntyroni tri 1 e

Reaction time 2.75 hours; yield 97.7%, purity 100% by HPLC; mp 116.6-117.2°C (literature 119°C Betts B.E. and Davey W. , .T. Chem. Snr . , 1958:4193);

¹H NMR (200 MHz, dg-DMSO): 3.7 and 3.95 (both 1H, dd, CHCH₂CO) , 3.75 (3H, s, OCH3) , 4.1 (1H, m, ArCHCH₂) , 6.95 (2H, d, ArH), 7.5-7.7 (5H, m, ArH), 8.0 (2H, d, ArH) .

EXAMPLE 10

2 - (4 -Methyl henyl . -4 -pheny -4 -oxobntyroni tri 1 e

Reaction time 2.5 hours; yield 95.5%, purity 100% by HPLC; mp 135.1-135.7°C (literature 137°C, Betts B.E. and Davey W. , .T . Chem . fine .. 1958:4193);

¹H NMR (200 MHz, dg-DMSO): 2.3 (3H, s, CH3) , 3.7 and 4.0 (both 1H, dd, CHCH₂C0) , 4.6 (1H, t, ArCHCH₂) , 7.2 (2H, m, ArH), 7.5 (5H, m, ArH), 8.0 (2H, m, ArH).

EXAMPLE 11 3-Phenyl -4- (4 -methy phenyl . -4 -oxobutyroni tri 1

Reaction time 3.5 hours; yield 97%, purity 100% by HPLC; mp 75.4-77.5°C;

¹H NMR (200 MHz, dg-DMSO): 2.4 (3H, s, CH3) , 3.7 (1H, dd, -CH-), 3.95 (1H, dd, -CH-), 4.6 (1H, m, ArCHCH₂) , 7.3-7.6 (7H, m, ArH), 7.9 (2H, d, ArH).

EXAMPLE 12 2- (4 -Pi methylamino) phenyl . -4 -phenyl -4 -oxobutyroni tri le Reaction time 5 hours; yield 84.8%, purity 93% by HPLC; mp 102.5-103.6°C (literature 103°C Betts B.E. and Davey W. , ,τ rh_Pm . Soc . _f 1958:4193); ¹H NMR (200 MHz, dg-DMSO): 2.85 (6H, S, CH₃) , 3.65 and 3.9 (both 1H, dd, CHCH₂CO) , 4.5 (1H, dd, ArCHCH₂) , 6.7 (2H, d, ArH), 7.3 (2H, d, ArH), 7.4-7.8 (5H, m, ArH) , 8.1 (2H, dd, ArH) .

EXAMPLE 13 2 - .3.4, -Tri e oxyphenyl .4- .4 -methoxyphenyl . -4- oxobutyronitrile

Reaction time 9 hours; yield 87.2%, purity 98.1% by HPLC; mp 126.8-127.4°C;

¹H NMR (200 MHz, dg-DMSO): 3.6 (1H, dd, CHCH₂CO) , 3.7 (3H, s, OCH₃) , 3.83 (6H, s, OCH3) , 3.9 (3H, s, OCH3) , 4.0 (1H, dd, CHCH₂CO) , 4.5 (1H, m, ArCHCH₂) , 6.9 (2H, s, ArH), 7.1 (2H, d, ArH), 8.0 (2H, d, ArH).

EXAMPLE 14 ( 7Λ Sodium 2- (benzol f1 , 31 dioxol -5-yl . -4- .4-methoxy- phenyl.3- (3 _f 4, 5-trimethoxybenzyl . -4-oxobut- 2-enoate

Step (a) Preparation of:

2 - .Benzo M _f 31 di oxol -5-yl . -4- (4 -methoxyphenyl . -4- oxob..tyri.c acid methyl es er

2- (Benzo [1, 3] dioxol-5-yl) -4- (4 -methoxyphenyl) -4- oxobutyronitrile (Example 2) (763.4 g, 2.5 moles) was slurred in methanol (4 L) along with 37% hydrochloric acid (533 mL, 6.4 moles) . The mixture was heated at reflux until the reaction was complete by HPLC and then cooled to 0°C for at least 3 hours. The slurry was filtered and washed with methanol. The product was dried under vacuum to give 2- (benzo [1, 3] dioxol-5-yl) -4- ( -methoxyphenyl) -4 -oxobutyric acid methyl ester (816 g, 97% theory) HPLC 96.3% by area;

¹H NMR (200 MHz, CDCI3) : δ 3.2 and 4.2 (both 1H, dd, CHCH₂C0) , 3.7 (3H, s, OCH3) , 3.75 (1H, t, ArCHCH₂) , 3.8 (3H, s, OCH3) , 6.0 (2H, s, 0CH₂0) , 6.7-7.0 (5H, m, ArH) , 7.95 (2H, d, ArH) . Step (b) Preparation of:

2 - (Benzo [1. 1 di oxol -5-yl . -5-hydroxy-5- (4 -methoyy- phenyl . -4- (3.4.5-tri methoxybenzyl . -2 (5H) -furanone

Sodium methylate (115 g, 2.13 moles) was added to ethanol (1.0 L) , stirred until dissolved and then cooled to 40°C using an ice bath. To a separate flask was added 2- (benzo [1, 3] dioxol-5-yl) -4- (4-methoxy- phenyl) -4-oxobutyric acid methyl ester (435 g, 1.27 moles), 3 , 4 , 5-trimethoxybenzaldehyde (250 g, 1.27 mole) and the sodium methylate-ethanol solution.

The reaction was held at 27 to 35°C for 3 hours. After 3 hours glacial acetic acid (200 mL, 3.18 moles) was added and the reaction heated to 70 °C. After 10.5 hours at 70°C, the reaction was cooled 0°C. The resulting slurry was filtered and washed twice with cold ethanol (300 mL each) and 4 times with water (500 mL each) . The isolated product was immediately slurried in water (1.5 L) at 20°C, filtered and washed twice with water (500 mL each) and once with cold ethanol (300 mL) . The product was dried under vacuum to give the desired product (499.4 g, 77.4% theory), HPLC 96.8% by area;

^-H NMR (400 MHz, d₅-pyridine) : δ 3.6 (6H, s, OCH₂) , 3.7 (3H, s, OCH₃) , 3.8 (3H, s, OCH3) , 4.1 (2H, d, ArCH₂) , 6.0 (2H, s, OCH₂0) , 6.3 (2H, s, ArH), 7.0 (3H, m, ArH), 7.0 (1H, m, ArH), 7.1 (2H, , ArH), 7.9 (2H, m, ArH), 10.5 (1H, s broad, OH).

Step (c) Preparation of: (Z. Sodinm 2 - (benzo \ Λ _r 1 i oxol - 5-yl . -4 - (4 -methoyy- phenyl . -3- (3,4.5-tri ethoxybenzyl . -4 -oxobut-2-enoate

3- (Benzo [1, 3] dioxol) -5-hydroxy-5- (4-methoxy- phenyl) -4- [ (3,4, 5-trimethoxyphenyl) methyl] -2 (5H) - furanone (20 g, 0.04 mole), and sodium carbonate powder (4.75 g, 0.045 mole) was added to methanol (55 mL) .

This slurry was stirred for 44 hours then filtered to give a colorless solution which is stirred vigorously and diluted with isopropyl alcohol (IPA) (330 mL) . The product precipitated rapidly. After 18 hours the slurry was filtered and washed twice with IPA. The wet cake was dried under vacuum to give of (Z) sodium 2- (benzo [1,3] dioxol-5-yl) -4- (4 -methoxyphenyl) -3- (3,4,5- trimethoxybenzyl) -4-oxobut-2-enoate (19.6 g, 94.0% theory), sodium content Calculated: 4.35% Found: 4.78%; HPLC 99.45% wt/wt;

¹H NMR (200 MHz, dg-DMSO): δ 3.4 (2H, d, ArCH₂) , 3.5 (3H, s, OCH₃) , 3.6 (6H, s, OCH3) , 3.8 (3H, s, OCH3) , 6.0 (2H, s, OCH₂0) , 6.2 (2H, s, ArH), 6.7-7.0 (5H, m, ArH), 7.75 (2H, d, ArH).

Claims

A process for the preparation of a compound of Formula I

wherein R, R 1-¹-, and R2 may be the same or different and each is hydrogen, alkyl, alkoxy, amino, alkylamino, dialkylamino, aryl, halogen,

C0₂alkyl, or cyano; and

R is aryl or

which comprises : treating a compound of Formula II

wherein R, R 1 , R2 , and R°3 are as defined above with acetone cyanohydrin and a tetraalkylammonium hydroxide in a solvent to afford a compound of Formula I .

2. A process according to Claim 1 wherein the tetraalkylammonium hydroxide is selected from the group consisting of: tetramethylammonium hydroxide; tetraethylammonium hydroxide; and tetrabutylammonium hydroxide .

3. A process according to Claim 2 wherein the tetraalkylammonium hydroxide is tetramethylammonium hydroxide.

4. A process according to Claim 1 wherein the solvent is selected from the group consisting of: acetone; and methyl ethyl ketone .

5. A process according to Claim 4 wherein the solvent is acetone.

6. A process according to Claim 1 wherein the tetraalkylammonium hydroxide is 5 mole percent per mole of a compound of Formula II.

7. A process according to Claim 1 wherein 1.25 mole of acetone cyanohydrin is used per mole of a compound of Formula II.

8. A process according to Claim 1 for the preparation of a compound of Formula I selected from the group consisting of:

2- (Benzo [1, 3] dioxo-5-yl) -4- (4 -methoxyphenyl) - 4 -oxobutyronitrile;

2- (4-Cyanophenyl) -4 -phenyl-4 -oxobutyronitrile; 2- (4-Methoxycarbonylphenyl) -4-phenyl-4- oxobutyronitrile ; 2 -Phenyl-4 -phenyl-4 -oxobutyronitrile; 2-Phenyl-4- (4 -fluorophenyl) -4 -oxobutyronitrile; 2- (4 -Fluorophenyl) -4 -phenyl-4 -oxobutyronitrile; 2-Phenyl-4- (4 -methoxyphenyl) -4 -oxobutyronitrile; 2- (4 -Methoxyphenyl) -4 -phenyl-4 -oxobutyronitrile; 2- (4-Methylphenyl) -4 -phenyl-4 -oxobutyronitrile ; 2 -Phenyl-4- (4-methylphenyl) -4 -oxobutyronitrile; 2- (4- (Dimethylamino) phenyl) -4-phenyl-4- oxobutyronitrile; and 2- (3,4, 5-Trimethoxyphenyl) -4- (4 -methoxyphenyl) -4- oxobutyronitrile .

9. A process according to Claim 1 for the preparation of 2 -benzo [1,3] dioxo-5-yl) -4- (4 -methoxyphenyl) -4- oxobutyronitrile .

10. A process for the preparation of the compound of Formula A

Step (a) treating the compound of Formula Ila

11. A process according to Claim 10 wherein in

Step (a) the tetraalkylammonium hydroxide is selected from the group consisting of: tetramethyammonium hydroxide; and tetraethyl- ammonium hydroxide; and tetrabutylammonium hydroxide .

12. A process according to Claim 11 wherein the tetraalkylammonium hydroxide is tetramethylammonium hydroxide .

13. A process according to Claim 10 wherein in Step (a) the solvent is selected from the group consisting of: acetone; and methyl ethyl ketone.

14. A process according to Claim 13 wherein the solvent is acetone.

15. A process according to Claim 10 wherein in Step (a) the tetraalkylammonium hydroxide is 5 mole percent per mole of the compound of Formula Ila.

16. A process according to Claim 10 wherein in

Step (a) 1.25 moles of acetone cyanohydrin is used per mole of the compound of Formula Ila.

17. A process according to Claim 10 wherein in Step (b) the acid is selected from the group consisting of: hydrochloric acid; and para toluene sulfonic acid.

18. A process according to Claim 17 wherein the acid is hydrochloric acid.

19. A process according to Claim 10 wherein in Step (c) the base is sodium methoxide.

20. A process according to Claim 10 wherein in Step (c) the solvent is selected from the group consisting of: methanol; and ethanol.

21. A process according to Claim 20 wherein the solvent is ethanol.

22. A process according to Claim 10 wherein in Step (c) the acid is acetic acid.

23. A process according to Claim 10 wherein in Step (d) the base is selected from the group consisting of : sodium methoxide; sodium hydroxide; and sodium carbonate.

24. A process according to Claim 23 wherein the base is sodium carbonate.

25. A process according to Claim 10 wherein in Step (d) the solvent is selected from the group consisting of: methanol; and ethanol.

26. A process according to Claim 25 wherein the solivent is methanol.