Background of The Invention U. S. Patent No. 5,367,093 describes a method for the preparation of the miticidal phenylhydrazine derivative, isopropyl-2- (4-methoxy- [1, 1'-biphenyl]-3- yl) hydrazine carboxylate (bifenazate), using a six-step procedure which comprises the undesirable steps of preparation and reduction of a diazonium salt.

Certain phenylhydrazine derivatives can be prepared using the methods described in U. S. Patent No.

4, 864, 032 (amination of Grignard); in Mitchell, J. Org.

Chem. 59 : 682 (1994) (amination of electron-rich arenes); and in Lenarsic, J. Org. Chem. 64: 2558 (1999) (by electrophilic azodicarboxylates).

It is the purpose of this invention to provide new intermediates useful in the preparation of bifenazate.

It is also a purpose of this invention to provide a new method for the preparation of bifenazate.

Summary of the Invention The present invention relates to compounds of the formula:

(I) wherein R is hydrogen (IA) or isopropyl ester (COACH (CH3)2) (IB).

The compounds of formulas IA and IB are useful as intermediates in the preparation of bifenazate.

The present invention also relates to a method for preparing the compound of IA which comprises hydrolyzing

the compound of IB in the presence of an effective amount of a base in a suitable organic solvent.

The present invention further relates to a method for preparing bifenazate comprising methylating Compound IA in the presence of an effective amount of a methylating agent and a base, in a suitable solvent.

Detailed Description of the Invention The compounds of this invention can be prepared as described below in SCHEME 1.

1. Amination OH OH tz O OHOHO Lewi s Ac i d NN O'\ d tNAol IN 0 1 p O H Solvant N N'O'\ ( ! B) 4-Hydroxybiphenyl is reacted with di-isopropyl azodicarboxylate in the presence of an effective amount of Lewis acid in a suitable solvent, to produce Compound IB. Useful Lewis acids include, e. g., boron trifluoride etherate and aluminum chloride. The concentration of the Lewis acid to the 4-hydroxybiphenyl in the reaction mixture can be between about 1: 0.2 to about 1: 1.1 (mol/mol), preferably about 1: 1.1 (mol/mol). Suitable organic solvents are those organic solvents which are not

deleterious to the amination reaction and include, e. g., ethyl acetate, dichloromethane, toluene, and glyme. The temperature of the reaction mixture should be from about 0°C to about 60°C, preferably at room temperature.

2. Selective Hydrolysis O O OH 0 0 0 OH H 0 Basa wN/y O H O H Solvent (IB) (IA) Compound IB is treated with an effective amount of a base in a suitable organic solvent to produce Compound IA. Useful base compounds are those base compounds which can hydrolyze the ester functionality and include, e. g., sodium hydroxide and potassium hydroxide. The concentration of the base to Compound IB can be between about 7: 1 to about 10: 1 (mol/mol), preferably about 9: 1 (mol/mol). Suitable organic solvents are those organic solvents which are not deleterious to the hydrolysis reaction and include, e. g, toluene, dimethyl sulfoxide, and glyme. Preferably, the temperature of the organic solvent should be above room temperature and below 110°C.

Compound IA is then methylated in the presence of an effective amount of a methylating agent and a base, in a suitable organic solvent. For the purpose of this

invention, a"methylating agent"is any compound which is capable of substituting a methyl group for the hydrogen atom in the 4-hydroxy group in Compound IA. Useful methylating agents include, e. g., dimethylsulfate and methyl iodide. The concentration of methylating agent to Compound IA can be between about 1: 1 to about 1: 1.2 (mol/mol), preferably about 1: 1 (mol/mol). Useful base compounds are those base compounds which can depronate phenols and include, e. g., sodium carbonate and potassium carbonate. The concentration of base to Compound IA can be between about 1: 1 to about 3: 1 (mol/mol), preferably about 2: 1 (mol/mol). Suitable organic solvents are those organic solvents which are not deleterious to the methylation reaction and include, e. g., toluene and acetone. The methylation reaction can be conducted at about room temperature. The methylation process is exemplified below in Scheme 2.

SCHEME 2 OH H 0 CH30 H 0 I I XNuNJt O H O H Methylating Agent ou (ira) Bifenazate The following examples are provided to illustrate the present invention.

Example 1 Preparation of 1, 2-Hydrazinedicarboxyli. c acid, 1- (4- hydroxv-fl 1'-biphenyll-3-vl)-bis (1-methylethyl) ester (Compound IB) To a solution of 4-hydroxybiphenyl (5.50 g) in ethyl acetate (60 mL) at room temperature was added boron trifluoride etherate (4.1 mL). The resultant mixture was cooled to-5°C, added dropwise di-isopropyl azodicarboxylate (6.3 mL), and stirred at that temperature for 30 min. and then stirred at room temperature for two hours. The mixture was then quenched with water (100 mL) and extracted with ethyl acetate (50 mL). The organic phase was separated, dried over magnesium sulfate, and concentrated under vacuum to leave an oil which was chromatographed on silica gel using 20- 30% ethyl acetate/hexane to produce Compound IB as beige- colored solid (10.65 g, 88% yield). lH-NMR (ppm, in CDC1- 3): m (12) 1.30; m (2) 5.04; m (2) 7.10; m (1) 7.32; dd (2) 7.43; m (3) 7.51-7.55; br s (1) 8.53.

Example 2 Preparation of hydrazinecarboxylic acid, 2- (4-hydroxy- fl, l'-biphenyl]-3-yl)- 1-methylethyl ester (Compound IA) Potassium hydroxide (5.0 g) was added to a stirred suspension of Compound IB produced above in Example 1 (5.15 g) in toluene (50 mL). The resultant purple mixture was bubbled with nitrogen for 20 min, and then heated at 45°C for 4 days. The mixture was then cooled to 0°C and then 6M HCl was added to the mixture until the pH of the mixture was about 1. The mixture was then extracted with ethyl acetate. The organic phase was separated, washed with brine, dried over magnesium sulfate, and concentrated to a brown solid.

Recrystallization from toluene produced Compound IA as

beige-colored powder (3.35 g, 85% yield). 1H-NMR (ppm, in CDC13) : d (6) 1.81; septet (1) 5.04; br d (1) 5.91; br s (1) 6.61; d (1) 6.74; dd (1) 7.01; d (1) 7.14; dd (1) 7.32; dd (2) 7.42; dd (2) 7.61.

Example 3 Preparation of hydrazinecarboxylic acid, 2- (4-methoxy- fl, 1-biphenyll-3-yl)-1-methylethyl ester (bifenazate) A suspension of Compound IA prepared above in Example 2 (2.63 g) and potassium carbonate (2.50 g) in acetone (40 mL) was bubbled with nitrogen for 20 minutes.

Dimethyl sulfate (0.96 mL) at room temperature was then added to the suspension. After 2 hours, the resultant reaction mixture was cooled in ice bath. 2M HC1 was then cautiously added (ca. 30 mL) to the reaction mixture until the pH of the reaction mixture was about 1. The reaction mixture was then concentrated to remove most acetone. The solid formed from the concentrated reaction mixture was filtered, washed with water, hexane, and dried under air with suction to produce bifenazate (2.60 g). 1H-NMR spectral data is consistent with the H-NMR reported for bifenazate in U. S. Patent No. 5,367,093.