KR20050024424A - Process and intermediates for making non-nucleoside HIV-1 reverse transcriptase inhibitors - Google Patents

Abstract

The present invention relates to methods and novel intermediates for preparing HIV reverse transcriptase inhibitors.

Description

Process and intermediates for making non-nucleoside HIV-1 reverse transcriptase inhibitors

The synthetic process of the invention starts with the starting compound of formula II.

In Chemical Formula II,

R ² , R ⁴ , R ⁵ and R ¹¹ are as defined for the compound of Formula I,

X is chlorine, iodine or bromine or is a fluorosulfonate residue selected from the group consisting of -OSO ₂ F and -OS0 ₂ (CF ₂ ) _n CF ₃ , where n is an integer from 0 to 10.

Methods for preparing starting compounds of formula II, wherein X is bromine, are described in US Pat. No. 6,420,359. Compounds wherein X is other than bromine may be prepared by similar methods apparent to those skilled in the art.

Preference is given to using compounds of the formula (II) wherein X is bromine.

The starting compound of formula (II) is first subjected to a palladium-catalyzed coupling reaction to arylate the malonate or malonate substitution of formula (III).

In Chemical Formula III,

R ¹² is a cyano group or a group of the formula -COOR ¹⁴ wherein R ¹⁴ is a C _1-4 -alkyl group, C _1-4 -alkyloxy-C _1-4 -alkyl group, phenyl, naphthyl, thiophenyl , Furyl, pyridyl, imidazole or benzyl),

R ¹³ is a cyano group, a group of the formula -COOR ¹⁵ wherein R ¹⁵ is a C _1-4 -alkyl group, C _1-4 -alkyloxy-C _1-4 -alkyl group, phenyl, naphthyl, thiophenyl , Furyl, pyridyl, imidazole or benzyl), a group of formula -SO ₂ R ¹⁶ , wherein R ¹⁶ is a C _1-4 -alkyl group, phenyl, furyl, pyridyl or benzyl, formula -P ( O) (OR ¹⁷ ) ₂ , wherein R ¹⁷ is phenyl, furyl or pyridyl, or a group of the formula -SOR ¹⁸ , wherein R ¹⁸ is a C _1-4 -alkyl group, C _1-4 -alkyl Oxy-C _1-4 -alkyl group, phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl).

Preference is given to using malonate substitutes of the formula III.

Formula III

In Chemical Formula III,

R ¹² is a cyano group or a group of the formula -COOR ¹⁴ wherein R ¹⁴ is a C _1-4 -alkyl group, C _1-4 -alkyloxy-C _1-4 -alkyl group, phenyl, naphthyl, thiophenyl , Furyl, pyridyl, imidazole or benzyl),

R ¹³ is a cyano group, a group of formula -SO ₂ R ¹⁶ , wherein R ¹⁶ is a C _1-4 -alkyl group, phenyl, furyl, pyridyl or benzyl, formula -P (O) (OR ¹⁷ ) ₂ (wherein R ¹⁷ is phenyl, furyl or pyridyl) or a group of the formula -SOR ¹⁸ , wherein R ¹⁸ is a C _1-4 -alkyl group, C _1-4 -alkyloxy-C _1-4 -alkyl Group, phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl).

The reaction of the compound of formula II with the compound of formula III is carried out in an organic solvent in the presence of a palladium catalyst, a suitable ligand and a strong base. Suitable solvents are, by way of non-limiting example, toluene, ethylbenzene, xylene, DMF, DMA, NMP, dioxane and THF, with toluene being preferred. Virtually any palladium catalyst can be used, for example Pd (OAc) ₂ , PdCl ₂ , Pd ₂ dba ₃ and Pd on carbon, with Pd (OAc) ₂ being preferred. Suitable bases are, for example, metal hydrides such as NaH; metal alkoxides such as t-BuOK, t-BuONa and Na-tert-amylate; Metal carbonates such as Na ₂ CO ₃ , K ₂ CO ₃ and Cs ₂ CO ₃ and metal phosphates such as K ₃ PO ₄ , with NaH being preferred. When the reactant of formula III is malonate (a compound in which both R ¹² and R ^{13 are} carboxylic ester groups), suitable ligands are t-Bu ₃ P, one of the ligands described and claimed in US Pat. No. 6,307,087 or US Pat. And the ferrocenyl phosphine described in 6,057,456 and US Pat. No. 6,072,073. If the reactant of formula III is not malonate, but is a malonate substitute (a compound in which both R ¹² and R ¹³ are not carboxylic ester groups), the ligands described above may be used and further non-limiting examples include triarylphosphine, For example, PPh ₃ , o-Tol ₃ P, p-Tol ₃ P and o-Fur ₃ P may also be used. In this case, the preferred ligand is PPh ₃ .

The reaction is preferably carried out at elevated temperature, more preferably in the range of about 50 to 150 ° C.

The above-described reaction of coupling the compound of formula II and the compound of formula III affords the intermediate of formula IV.

In Formula IV,

R ² , R ⁴ , R ⁵ , R ¹¹ , R ¹² and R ¹³ are as defined above.

Separation of the intermediate of formula IV is optional before proceeding to the next process step. 1-port synthesis without separating intermediate (IV) has been found to be very easy. If the remaining base is a metal hydride, for example NaH, without separating intermediate (IV), it is advantageous to quench the base with a preparation such as isopropyl alcohol before proceeding to the next step.

If the intermediate of formula IV contains sulfur or phosphorus (since R ¹³ in the reactants of formula III is a group of formula -SO ₂ R ¹⁵ or -P (O) (OR ¹⁶ ) ₂ ), the next process step is sulfur or Reductive decomposition of phosphorus-containing groups. Methods of carrying out such reductive decomposition are well known to those skilled in the art. For example, this can be done using a Raney nickel or molten metal reaction.

Subsequent reductive decomposition is carried out, or if the intermediate of formula IV does not contain sulfur or phosphorus, the intermediate of formula IV is hydrolyzed to obtain further intermediate of formula V.

In Formula V,

R ² , R ⁴ , R ⁵ and R ¹¹ are as defined above,

R ¹⁹ may be -COOH or when the reactant of formula III is malonate and mild hydrolysis conditions are used, R ¹⁹ may further be a group of formula -COOR ¹⁴ , wherein R ¹⁴ is as described above.

Hydrolysis is easy and can be carried out in a way that is obvious to those skilled in the art. For example, an aqueous base such as NaOH can be used, preferably at room temperature or higher.

Intermediates of formulas IV and V are believed to be novel and form part of the present invention.

Separation of the intermediate (V) is preferably carried out before proceeding to the next step.

The carboxylic acid or ester intermediate of formula (V) is then reduced to yield the alcohol of formula (VI).

In Formula VI,

R ² , R ⁴ , R ⁵ and R ¹¹ are as defined above.

Reduction is carried out in an easy way which is obvious to those skilled in the art. Regardless of whether the intermediate of formula V is an acid or an ester, the reduction may be carried out using borane, boron hydride or other metal hydride or dissolved metal reducing agent, borane is preferred for the acid, boron hydride for the ester Is preferred. If borane is used, it is preferred to make in situ from boron hydride such as sodium borohydride and an electrophilic reagent such as HCl.

Finally, the alcohol of formula VI Condensation reaction with a reaction product of This condensation can be performed by the method described in US Pat. No. 6,420,359.

The nature and scope of the invention may be better appreciated through the following examples.

Example 1:

Arylation of Malononitrile: Formation of Compounds of Formula IV wherein R ² = R ⁴ = H, R ⁵ = Me, R ¹¹ = ethyl and R ¹² = R ¹³ = CN

The flask was charged with 10.0 g of tricyclic bromide (compound of formula II wherein R ² = R ⁴ = H, R ⁵ = Me, R ¹¹ = ethyl and X = Br; 30 mmol, 1 equiv), 0.95 g (3.6 eq) triphenylphosphine mmol, 0.12 equiv), 0.55 g (0.6 mmol, 0.04 equiv) of Pd ₂ dba ₃ and 40 mL of 1,4-dioxane. Then, 2.16 g (90 mmol, 3 equivalents) of sodium hydride was added dropwise to the mixture for 15 minutes, and the dropwise addition was terminated using 40 ml of 1,4-dioxane. Then a solution of 2.57 g (39 mmol, 1.3 equiv) of malononitrile in 5 ml of 1,4-dioxane is added and the mixture is heated to 90 ° C. After 18 hours, the mixture is cooled to room temperature and carefully quenched with 100 ml of saturated ammonium chloride solution. The pH is then adjusted to 6 with 1N HCl and the mixture is extracted with dichloromethane. The organic solution is dried (magnesium sulfate) and the solvent is removed in vacuo to yield 7.03 g (73%) of product as a brown oil. NMR and MS represent the desired product (compound of formula IV wherein R ² = R ⁴ = H, R ⁵ = Me, R ¹¹ = ethyl and R ¹² = R ¹³ = CN).

Example 2:

Arylation of Diethylmalonate: Formation of Compound of Formula IV wherein R ² = R ⁴ = H, R ⁵ = Me, R ¹¹ = ethyl and R ¹² = R ¹³ = CO ₂ Et

A 500 mL two-neck round bottom flask equipped with a mechanical stirrer, reflux condenser and thermocouple was purged with argon for 20 minutes, 404 mg (1.80 mmol, 0.03 equiv) of Pd (OAc) ₂ , 2- (di-t-butylphosphino 2.08 g (3.60 mmol, 0.06 equiv) and tricyclic bromide (compound of formula II wherein R ² = R ⁴ = H, R ⁵ = Me, R ¹¹ = ethyl and X = Br) 20.0 g (60.0 mmol) , 1 equivalent). To this mixture in an inactivated flask is then added 25.5 g (120 mmol, 2 equiv) of K ₃ P0 ₄ , 100 mL of PhMe and 13.8 mL (90.0 mmol, 1.5 equiv) of diethylmalonate. The stirred suspension is placed in an oil bath and measured by HPLC and heated under reflux for 24 hours under nitrogen until the bromide is consumed. The reaction mixture is cooled to room temperature, diluted with water (150 mL) and toluene (50 mL) is added. The mixture is stirred at room temperature for 1 hour until all solids are dissolved. The two-phase solution is then transferred to a separatory funnel and the layers are separated. The aqueous layer is extracted with toluene (50 mL). The combined organic layers are filtered through a pad of Celite and concentrated in vacuo to give a viscous oil and evaporated to dryness to give an orange solid. Silica gel chromatography (1: 1 EtOAc: Hex) to give pure malonate additive (R ² = R ⁴ = H, R ⁵ = Me, R ¹¹ = ethyl and R ¹² = R ¹³ = C0 ₂ Et) 20.5 g) (83%) are obtained as a colorless solid with a melting point of 122 to 123 ° C.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.38 (d, J = 2.5 Hz, 1H), 8.19 (dd, J = 1.5, 4.6 Hz, 1H), 8.16 (d, J = 2.4 Hz, 1H), 7.47 (dd, J = 1.5, 8.0Hz, 1H), 7.09 (dd, J = 4.7, 8.0Hz, 1H), 4.56 (s, 1H), 4.20 (m, 6H), 3.49 (s, 3H), 1.25 ( t, J = 7.1 Hz, 9H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ: 167.30 (s), 167.23 (s), 159.31 (s), 154.50 (s), 151.18 (d), 144.34 (d), 141.93 (d), 131.63 (s) , 130.74 (d), 123.52 (s), 120.57 (s), 119.78 (d), 62.17 (t), 54.80 (d), 41.24 (t), 37.30 (q), 13.96 (q), 13.58 (q) .

Elemental analysis for C ₂₁ H ₂₄ N ₄ 0 ₅ :

Calc .: C, 61.15; H, 5.87; N, 13.58.

Found: C, 61.14; H, 5. 66; N, 13.51.

Example 3: Arylation of Isopropylcyanoacetate and Formation of Compound of Formula V wherein R ² = R ⁴ = H, R ⁵ = Me, R ¹¹ = ethyl, and R ¹⁹ = CO ₂ H

The 800 liter deactivated reactor was charged with 12.0 kg (300 mol, 2.5 equiv) of 60% NaH / oil, 0.27 kg (1.2 mol, 0.01 equiv) of Pd (OAc) _2, 1.26 kg (4.8 mol, 0.04 equiv) and PPh ₃ Fill with 40 kg of click bromide (compound of formula II wherein R ² = R ⁴ = H, R ⁵ = Me, R ¹¹ = ethyl and X = Br; 120 mol, 1 equiv). The reactor is deactivated again, then 70 kg of PhMe is charged and the mixture is heated to 60 ° C. This mixture is then added to a solution of 17.4 liters (138 mol, 1.15 equiv) of cyanoisopropylacetate in 20 liters of PhMe for 2 hours at a fixed rate via a metering pump (Note: H ₂ gas evolution). The reaction contents are then heated to 100 ° C. and maintained for 1.5 hours. Partial preparative HPLC was performed to show that arylation was terminated with a compound of formula IV wherein R ² = R ⁴ = H, R ⁵ = Me, R ¹¹ = ethyl, R ¹² = CN, and R ¹³ = CO ₂ iPr. The mixture is then cooled to 35 ° C. and quenched by addition of 19 kg (308 mol, 2.6 equivalents) of isopropanol for 20 minutes (Note: H ₂ gas evolution). Then 438 kg (417 mol, 3.5 equiv) of 1 M NaOH solution is added and the mixture is heated to 80 ° C. and maintained for 8 hours. Partial aliquots were performed by HPLC to indicate that hydrolysis was terminated with the desired carboxylic acid. The mixture is cooled to 25 ° C. and the phases are separated. The upper phase is treated with waste and the lower aqueous phase is returned to the reactor. Then 218 kg EtOAc is charged and the mixture is stirred for 15 minutes and the phases are separated. Return the lower aqueous phase to the reactor and cool to 10 ° C. This mixture is then slowly added with 6N H ₂ SO ₄ to a final pH of 3.3 with continuous monitoring of pH: this requires 133 kg of H ₂ SO ₄ solution. The slurry obtained is then warmed up to 25 ° C. and maintained for 1 hour. Centrifuge the batch and wash twice with 40 kg H ₂ O. The solid is dried under full vacuum at 40 ° C. until the LOD is less than 1%, yielding 36.0 kg of carboxylic acid (R ² = R ⁴ = H, R ⁵ = Me, R ¹¹ = ethyl and R ¹⁹ = CO ₂ H). Compound; 96%) as an off-white solid. Melting point 226 to 228 ° C; ¹ H NMR (500 MHz, DMSO) δ: 12.47 (s, 1H), 8.32 (d, J = 2.0 Hz, 1H), 8.20 (dd, J = 4.6, 1.5 Hz, 1H), 7.96 (d, J = 2.3 Hz, 1H), 7.81 (dd, J = 8.0, 1.6 Hz, 1H), 7.24 (m, J = 4.6, 8.0 Hz, 1H), 4.08 (q, J = 7.0 Hz, 2H), 3.63 (s, 3H ), 3.43 (s, 3H), 1.17 (t, J = 7.0 Hz, 3H).

¹³ C NMR (125 MHz, DMSO) δ: 172.22 (s), 166.26 (s), 157.47 (s), 153.96 (s), 151.32 (d), 144.06 (d), 141.59 (d), 131.72 (d), 131.14 (s), 126.01 (s), 120.28 (d), 120.12 (s), 40.45 (t), 36.74 (q), 36.34 (t), 13.42 (q).

Elemental Analysis for C ₁₆ H ₁₆ N ₄ 0 ₃ :

Calc .: C, 61.53; H, 5. 16; N, 17.94.

Found: C, 61.28; H, 4.94; N, 17.56.

Example 4:

Arylation of Methylphenylsulfonyl Acetate: Formation of Compounds of Formula IV wherein R ² = R ⁴ = H, R ⁵ = Me, R ¹¹ = ethyl, R ¹² = CO ₂ Me and R ¹³ = SO ₂ Ph

The flask is filled with 165 mg (0.18 mmol, 0.02 equiv) of Pd ₂ dba ₃ , 577 mg (2.2 mmol, 0.12 equiv) of triphenylphosphine and 45 mL of 1,4-dioxane. After stirring for 15 minutes in an inert atmosphere, 647 mg (27 mmol, 3 equiv) of NaH are added dropwise. To this mixture is then added 3.00 g of tricyclic bromide (compound of formula II wherein R ² = R ⁴ = H, R ⁵ = Me, R ¹¹ = ethyl and X = Br; 9.00 mmol, 1 equiv) and methylphenylsul 2.50 g (11.7 mmol, 1.3 equiv) of polyvinyl acetate are added. The mixture is then heated at 60 ° C. for 18 hours, cooled to room temperature and quenched by addition of 0.5 ml of H ₂ O. Dioxane is removed under vacuum to yield 3.5 g (about 90%) of the crude product as a gray solid. NMR and MS represent the desired arylation product (compound of formula IV wherein R ² = R ⁴ = H, R ⁵ = Me, R ¹¹ = ethyl, R ¹² = CO ₂ Me and R ¹³ = SO ₂ Ph).

Example 5 Arylation of Diethylphosphonyl Acetonitrile: Formula wherein R ² = R ⁴ = H, R ⁵ = Me, R ¹¹ = ethyl, R ¹² = CN and R ¹³ = P (O) (OEt) ₂ Formation of Compounds of IV

The flask was charged with 1.00 g of tricyclic bromide (compound of formula II wherein R ² = R ⁴ = H, R ⁵ = Me, R ¹¹ = ethyl and X = Br; 3.00 mmol, 1 equiv), 55 mg (0.06) of Pd ₂ dba ₃ mmol, 0.02 equiv), 95 mg (0.36 mmol, 0.12 equiv) of triphenylphosphine and 0.69 g (3.90 mmol, 1.3 equiv) of diethylphosphonyl acetonitrile. 15 mL of 1,4-dioxane is then added to this mixture, followed by addition of 216 mg (9.00 mmol, 3 equivalents) of NaH. The resulting mixture is then heated at 70 ° C. for 3 hours. The mixture is cooled to room temperature, quenched carefully by dropwise addition of 25 mL of H ₂ O and 20 mL of dichloromethane are added. The pH is then adjusted to 2.5 with aqueous HCl and diluted with additional H ₂ 0 (25 mL) and dichloromethane (25 mL). The phases are then separated and the organic phase is concentrated to a brown oil. The oil is then triturated with 10 ml of t-butylmethyl ether to precipitate the product and filtered to give 0.95 g of the product as off white solid. NMR and MS are the desired arylation products (compounds of formula IV wherein R ² = R ⁴ = H, R ⁵ = Me, R ¹¹ = ethyl, R ¹² = CN and R ¹³ = P (O) (OEt) ₂ ) Indicates.

Technical field of invention

The present invention relates to novel preparations and novel intermediates for the synthesis of specific nonnucleoside reverse transcriptase inhibitors.

Background of the Invention

Diseases known as acquired immunodeficiency syndrome (AIDS) are caused by strains known as human immunodeficiency virus (HIV), in particular HIV-1. In order for HIV to be replicated by the host cell, information from the viral genome must be integrated into the host cell's DNA. However, HIV is a retrovirus, meaning that its genetic information is in the form of RNA. Thus, the HIV replication cycle requires a step of transcription of the viral genome (RNA) into DNA. Transcription of viral RNA to DNA is performed by enzymes that are suitably replicated reverse transcriptase (RT). HIV virions include a copy of RT along with viral RNA.

Reverse transcriptases have three known enzymatic actions. It acts as RNA-dependent DNA polymerase, ribonuclease and DNA-dependent DNA polymerase. Acting as an RNA-dependent DNA polymerase, RT transcribes single-stranded DNA copies of viral RNA. Acting as a ribonuclease, RT destroys the original viral RNA and releases the DNA just produced from the original RNA. Finally, acting as a DNA-dependent DNA polymerase, RT uses the first DNA strand as a template to produce a second supplemental DNA strand. The two strands form double-stranded DNA, which is integrated into the genome of the host cell by another enzyme called integrase.

Compounds that inhibit the enzymatic action of HIV-1 reverse transcriptase can inhibit the replication of HIV-1 in infected cells. Such compounds are useful for the prevention or treatment of human HIV-1 infection, for example, 3'-aziode-3'-deoxythymidine (AZT), 2 ', 3'-dideoxyinosine (ddI) , Exemplified by known RT inhibitors such as 2 ', 3'-dideoxycytidine (ddC), d4T, 3TC, nevirapine, delavirdine, epavirenz and abakavir, whereby the RT inhibitor is HIV infected Approved as a medicament for use in the treatment of

As in antiviral therapy, the use of RT inhibitors in the treatment of HIV infection ultimately leads to viruses that are less sensitive to certain drugs. Resistance to these drugs (reduced sensitivity) is the result of mutations that occur in the reverse transcriptase segment of the pol gene. Several mutant strains of HIV have been characterized and resistance to known therapeutic agents is due to mutations in the RT gene. Some of the most commonly found mutants are Y181C mutants where tyrosine Y is mutated to a cystine C residue at codon 181 and K103N where lysine K is substituted by asparagine N at position 103. Other mutants with increased expression frequency during treatment with known antiviral agents include the single mutants V106A, G190A, Y188C and P236L and the double mutants K103N / Y181C, K013N / P225H, K103N / V108I and K103N / L100I.

Continued treatment of HIV infection with antiviral agents is expected to increase the incidence of new resistant strains. Thus, there is a need for new RT inhibitors with the effect of different patterns on various mutants.

Of particular relevance to the present invention are HIV-RT inhibitors described in US Pat. No. 6,420,359. All dipyrido [3,2-b: 2 ', 3'-e] containing 2- (quinolinyl) oxyethyl or 2- (1-oxido-quinolinyl) oxyethyl groups in the 8-position These compounds, which are [1,4] diazepine-6-ones, show increased activity against mutant strains of certain clinically important HIV-1. It is an object of the present invention to provide a process for the selective preparation of compounds described in US Pat. No. 6,420,359.

Summary of the Invention

The present invention provides an improved process for the preparation of compounds of formula (I) as well as pharmaceutically acceptable salts thereof.

In Formula I,

R ² is selected from the group consisting of H, F, Cl, C _1-4 alkyl, C _3-4 cycloalkyl and CF ₃ ,

R ⁴ is H or Me,

R ⁵ is H, Me or Et, and if both R ⁴ and R ⁵ are not Me, and R ⁴ is Me, then R ⁵ cannot be Et,

R ¹¹ is Me, Et, cyclopropyl, propyl, isopropyl or cyclobutyl,

Q is

It is selected from the group consisting of.

Claims (8)

(a) reacting the starting compound of formula II with a malonate or malonate substitute of formula III in the presence of a palladium catalyst, a suitable ligand and a strong base in an organic solvent to obtain an intermediate of formula IV, (b) if the intermediate of formula IV contains sulfur or phosphorus-containing groups, reducing the sulfur or phosphorus-containing groups to decompose, (c) hydrolyzing the intermediate of Formula IV to obtain further intermediate of Formula V, (d) reducing the carboxylic acid or ester intermediate of formula V to yield an alcohol of formula VI and (e) the alcohol of formula VI Condensing with a reactant to yield the final product of formula (I). Formula I Formula II Formula III Formula IV Formula V Formula VI In Chemical Formulas I, II, III, IV, V and VI, R ² is selected from the group consisting of H, F, Cl, C _1-4 alkyl, C _3-4 cycloalkyl and CF ₃ , R ⁴ is H or Me, R ⁵ is H, Me or Et, and if both R ⁴ and R ⁵ are not Me, and R ⁴ is Me, then R ⁵ cannot be Et, R ¹¹ is Me, Et, cyclopropyl, propyl, isopropyl or cyclobutyl, Q is Is selected from the group consisting of X is chlorine, iodine or bromine or is a fluorosulfonate residue selected from the group consisting of -OSO ₂ F and -OS0 ₂ (CF ₂ ) _n CF ₃ , where n is an integer from 0 to 10, and R ¹² is a cyano group or a group of the formula -COOR ¹⁴ wherein R ¹⁴ is a C _1-4 -alkyl group, C _1-4 -alkyloxy-C _1-4 -alkyl group, phenyl, naphthyl, thiophenyl , Furyl, pyridyl, imidazole or benzyl), R ¹³ is a cyano group, a group of the formula -COOR ¹⁵ wherein R ¹⁵ is a C _1-4 -alkyl group, C _1-4 -alkyloxy-C _1-4 -alkyl group, phenyl, naphthyl, thiophenyl , Furyl, pyridyl, imidazole or benzyl), a group of formula -SO ₂ R ¹⁶ , wherein R ¹⁶ is a C _1-4 -alkyl group, phenyl, furyl, pyridyl or benzyl, formula -P ( O) (OR ¹⁷ ) ₂ , wherein R ¹⁷ is phenyl, furyl or pyridyl, or a group of the formula -SOR ¹⁸ , wherein R ¹⁸ is a C _1-4 -alkyl group, C _1-4 -alkyl Oxy-Ci_ ₄ -alkyl group, phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl), R ¹⁹ may be -COOH or when the reactant of formula III is malonate and mild hydrolysis conditions are used, R ¹⁹ may further be a group of formula -COOR ¹⁴ , wherein R ¹⁴ is as described above. (a) reacting a starting compound of formula (II) with a malonate or malonate substitute of formula (III) in an organic solvent in the presence of a palladium catalyst, a suitable ligand and a strong base to give a compound of formula (IV) Manufacturing method. Formula IV Formula II Formula III In Chemical Formulas II, III, and IV, R ² is selected from the group consisting of H, F, Cl, C _1-4 alkyl, C _3-4 cycloalkyl and CF ₃ , R ⁴ is H or Me, R ⁵ is H, Me or Et, and if both R ⁴ and R ⁵ are not Me, and R ⁴ is Me, then R ⁵ cannot be Et, R ¹¹ is Me, Et, cyclopropyl, propyl, isopropyl or cyclobutyl, R ¹² is a cyano group or a group of the formula -COOR ¹⁴ wherein R ¹⁴ is a C _1-4 -alkyl group, C _1-4 -alkyloxy-C _1-4 -alkyl group, phenyl, naphthyl, thiophenyl , Furyl, pyridyl, imidazole or benzyl), R ¹³ is a cyano group, a group of the formula -COOR ¹⁵ wherein R ¹⁵ is a C _1-4 -alkyl group, C _1-4 -alkyloxy-C _1-4 -alkyl group, phenyl, naphthyl, thiophenyl , Furyl, pyridyl, imidazole or benzyl), a group of formula -SO ₂ R ¹⁶ , wherein R ¹⁶ is a C _1-4 -alkyl group, phenyl, furyl, pyridyl or benzyl, formula -P ( O) (OR ¹⁷ ) ₂ , wherein R ¹⁷ is phenyl, furyl or pyridyl, or a group of the formula -SOR ¹⁸ , wherein R ¹⁸ is a C _1-4 -alkyl group, C _1-4 -alkyl Oxy-Ci_ ₄ -alkyl group, phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl), X is chlorine, iodine or bromine or is a fluorosulfonate residue selected from the group consisting of -OSO ₂ F and -OS0 ₂ (CF ₂ ) _n CF ₃ , where n is an integer from 0 to 10. (a) reacting the starting compound of formula II with a malonate or malonate substitute of formula III in the presence of a palladium catalyst, a suitable ligand and a strong base in an organic solvent to obtain an intermediate of formula IV, (b) when the intermediate of formula IV contains a sulfur or phosphorus-containing group (since R ¹³ in the reactants of formula III is a group of formula -SO ₂ R ¹⁵ or -P (O) (OR ¹⁶ ) ₂ ), Reducing the sulfur or phosphorus-containing group to decompose and (c) hydrolyzing the intermediate of formula (IV) to obtain a compound of formula (V). Formula V Formula II Formula III Formula IV In Chemical Formulas II, III, IV, and V, R ² is selected from the group consisting of H, F, Cl, C _1-4 alkyl, C _3-4 cycloalkyl and CF ₃ , R ⁴ is H or Me, R ⁵ is H, Me or Et, and if both R ⁴ and R ⁵ are not Me, and R ⁴ is Me, then R ⁵ cannot be Et, R ¹¹ is Me, Et, cyclopropyl, propyl, isopropyl or cyclobutyl, R ¹⁹ is —COOH or a group of formula —COOR ¹⁴ wherein R ¹⁴ is a C _1-4 -alkyl group, C _1-4 -alkyloxy-C _1-4 -alkyl group, phenyl, naphthyl, thiophenyl, Furyl, pyridyl, imidazole or benzyl), X is chlorine, iodine or bromine or is a fluorosulfonate residue selected from the group consisting of -OSO ₂ F and -OS0 ₂ (CF ₂ ) _n CF ₃ , where n is an integer from 0 to 10, and R ¹² is a cyano group or a group of the formula -COOR ¹⁴ wherein R ¹⁴ is a C _1-4 -alkyl group, C _1-4 -alkyloxy-C _1-4 -alkyl group, phenyl, naphthyl, thiophenyl , Furyl, pyridyl, imidazole or benzyl), R ¹³ is a cyano group, a group of the formula -COOR ¹⁵ wherein R ¹⁵ is a C _1-4 -alkyl group, C _1-4 -alkyloxy-C _1-4 -alkyl group, phenyl, naphthyl, thiophenyl , Furyl, pyridyl, imidazole or benzyl), a group of formula -SO ₂ R ¹⁶ , wherein R ¹⁶ is a C _1-4 -alkyl group, phenyl, furyl, pyridyl or benzyl, formula -P ( O) (OR ¹⁷ ) ₂ , wherein R ¹⁷ is phenyl, furyl or pyridyl, or a group of the formula -SOR ¹⁸ , wherein R ¹⁸ is a C _1-4 -alkyl group, C _1-4 -alkyl Oxy-C _1-4 -alkyl group, phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl). The method of claim 3, wherein the reactant of formula III is malonate and the ligand used is t-Bu ₃ P or ferrocenyl phosphine or one of the ligands described and claimed in US Pat. No. 6,307,087. 4. The process of claim 3 wherein the reactant of formula III is a malonate substitute and the ligand used is t-Bu ₃ P, ferrocenyl phosphine or triarylphosphine. The method of claim 5, wherein the ligand is PPh ₃ , o-Tol ₃ P, p-Tol ₃ P or o-Fur ₃ P. Compound of formula IV. Formula IV In Formula IV, R ² is selected from the group consisting of H, F, Cl, C _1-4 alkyl, C _3-4 cycloalkyl and CF ₃ , R ⁴ is H or Me, R ⁵ is H, Me or Et, and if both R ⁴ and R ⁵ are not Me, and R ⁴ is Me, then R ⁵ cannot be Et, R ¹¹ is Me, Et, cyclopropyl, propyl, isopropyl or cyclobutyl, R ¹² is a cyano group or a group of the formula -COOR ¹⁴ wherein R ¹⁴ is a C _1-4 -alkyl group, C _1-4 -alkyloxy-C _1-4 -alkyl group, phenyl, naphthyl, thiophenyl , Furyl, pyridyl, imidazole or benzyl), R ¹³ is a cyano group, a group of the formula -COOR ¹⁵ wherein R ¹⁵ is a C _1-4 -alkyl group, C _1-4 -alkyloxy-C _1-4 -alkyl group, phenyl, naphthyl, thiophenyl , Furyl, pyridyl, imidazole or benzyl), a group of formula -SO ₂ R ¹⁶ , wherein R ¹⁶ is a C _1-4 -alkyl group, phenyl, furyl, pyridyl or benzyl, formula -P ( O) (OR ¹⁷ ) ₂ , wherein R ¹⁷ is phenyl, furyl or pyridyl, or a group of the formula -SOR ¹⁸ , wherein R ¹⁸ is a C _1-4 -alkyl group, C _1-4 -alkyl Oxy-C _1-4 -alkyl group, phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl). Compound of Formula V. Formula V In Formula V, R ² is selected from the group consisting of H, F, Cl, C _1-4 alkyl, C _3-4 cycloalkyl and CF ₃ , R ⁴ is H or Me, R ⁵ is H, Me or Et, and if both R ⁴ and R ⁵ are not Me, and R ⁴ is Me, then R ⁵ cannot be Et, R ¹¹ is Me, Et, cyclopropyl, propyl, isopropyl or cyclobutyl, R ¹⁹ is a -COOH group or a group of formula -COOR ¹⁴ wherein R ¹⁴ is a C _1-4 -alkyl group, C _1-4 -alkyloxy-C _1-4 -alkyl group, phenyl, naphthyl, thiophenyl , Furyl, pyridyl, imidazole or benzyl).