Claims:We Claim:
1. An improved process for the preparation of 1-(4-chlorphenyl)-2-cyclopropyl-1-acetone having the Formula (I)
Formula (I)

or its salts, which comprises :

(a). reacting a compound of Formula (III)
Formula (III)
with trialkylorthoformate using a catalyst in a solvent to obtain a compound of Formula (IV),
Formula (IV)
(b). reacting compound of Formula (IV) with a phosphate reagent using AlCl3 as Lewis acid in a solvent to obtain a compound of Formula (V),
Formula (V)

(c). reacting compound of Formula (V) with cyclopropylmethyl ketone in a solvent and a base to obtain compound of Formula (VI),
Formula (VI)

(d). treating the compound of Formula (VI) with an acid in a solvent to obtain compound of Formula (I).

2. The process as claimed in claim 1, wherein the process relates to preparation of 1-(4-chlorphenyl)-2-cyclopropyl-1-acetone having the Formula (I) Formula (I) or its salts, which comprises
(a). reacting a compound of Formula (III)
Formula (III)
with trialkylorthoformate using p-toluene sulfonic acid in toluene to obtain a compound of Formula (IV),
Formula (IV)
(b). reacting compound of Formula (IV) with trimethylphosphate using AlCl3 as Lewis acid in chloroform toluene to obtain a compound of Formula (V),
Formula (V)
(c). reacting compound of Formula (V) with cyclopropylmethyl ketone in toluene and sodamide to obtain compound of Formula (VI),
Formula (VI)

(d). treating the compound of Formula (VI) with aqueous hydrochloric acid in methanol to obtain compound of Formula (I).
4. The process as claimed in claim 1, wherein the base is alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; Lithium diisopropylamide (LDA), Sodium amide (NaNH2), Sodium hydride (NaH).
5. The process as claimed in claims 1 and 3, wherein the base is Sodium amide.
6. The process as claimed in claim 1, wherein the solvent is methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, acetone, N,N-dimethylformamide and the like or mixtures thereof, aromatic hydrocarbon solvents selected from toluene, xylene, phenol, styrene, diethylbenzene, ethylbenzene, halogenated solvent selected from dichloromethane, dichoroethane, chloroform.
7. The process as claimed in claims 1 and 6, wherein the solvent is methanol, toluene, chloroform and dichloromethane.
8. The process as claimed in claim 1, wherein the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoro acetic acid, formic acid or mixture thereof.
9. The process as claimed in claim 1, wherein the phosphate reagent is trimethyl phosphate, dialkyl phosphate, phosphorus oxychloride in methanol.
10. The process for preparing Cyproconazole comprising the process for preparing compound of Formula (I) as claimed in any of claims 1-9 wherein the process comprises:

(a). reacting a compound of Formula (III)
Formula (III)
with trialkylorthoformate using a catalyst in a solvent to obtain a compound of Formula (IV),
Formula (IV)

(b). reacting compound of Formula (IV) with a phosphate reagent using AlCl3 as Lewis acid in a solvent to obtain a compound of Formula (V),
Formula (V)

(c). reacting compound of Formula (V) with cyclopropylmethyl ketone in a solvent a and base to obtain compound of Formula (VI),
Formula (VI)

(d). treating the compound of Formula (VI) with an acid in a solvent to obtain compound of Formula (I),
(e). converting compound of Formula (I) to Cyproconazole of Formula (II).

Dated this Twelfth (12th) day of January, 2021

__________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883
, Description:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

AN IMPROVED PROCESS FOR THE PREPARATION OF A COMPOUND USEFUL IN THE PREPARATION OF FUNGICIDE

We, COROMANDEL INTERNATIONAL LIMITED,
an Indian company incorporated under Companies Act of 1956, having its principal place of business at Coromandel House, Sardar Patel Road, Secunderabad – 500 003, Telangana, India.

The following specification particularly describes the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of a compound useful in the preparation of a fungicide.

The present invention specifically relates to an improved process for the preparation of Cyproconazole intermediate or its salts.

The present invention specifically relates to an improved process for the preparation of 1-(4-chlorphenyl)-2-cyclopropyl-1-acetone having the Formula (I)
Formula (I)

or its salts.

The present invention also relates to a process for the preparation of Cyproconazole having the Formula (II)
Formula (II)

or its salts using compound of Formula (I).

BACKGROUND OF THE INVENTION

Cyproconazole is an azole fungicide used to control a wide range of fungi on cereal crops, coffee, sugar beet, fruit trees, grapes, including rust on cereal crops, powdery mildew on cereal crops, fruit tree and grapes, and scab on apple. It is both a prevention and treatment fungicide and having molecular structure of:

Formula (II)

IN 206569 (79/MUM/2003) discloses a process for the preparation of Cyproconazole intermediate, which is shown in the scheme given below :

US 9227900B2 discloses a process for the preparation of Cyproconazole intermediate of Formula (I), which is shown in the scheme given below :

CN 101857576 A discloses a process for the preparation of Cyproconazole intermediate of Formula (I) which is shown in the scheme given below :

The process described in the prior-art involves usage of involves additional purifications which leads to less yield and hence are not suitable on industrial scale.

Accordingly, there is a need to industrially acceptable /scalable process which does not need any further purifications to obtain Cyproconazole intermediate of Formula (I) in high yields compared to prior-art processes.

The inventors of the present invention have surprisingly found a simple, cost effective and industrially viable process. The process was designed with consideration like environmental, economical aspects and the optimal duration times of the individual stages were determined. Further, the process of the present invention involves non-polar solvent for which recovery is high and hence industrially and economically feasible process and has safe operations.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide an improved process for the preparation of a compound useful in the preparation of fungicide.

Another objective of the present invention is to provide an improved process for the preparation of Cyproconazole intermediate or its salts.

Yet another objective of the present invention is to provide an improved process for the preparation of 1-(4-chlorphenyl)-2-cyclopropyl-1-acetone having the Formula (I)
Formula (I)

which is commercially feasible / industrially scalable which involves use of simple and commercially available starting materials.

Still another objective of the present invention is to provide process for the preparation of Cyproconazole having the Formula (II)
Formula (II)

or its salts using compound of Formula (II).

SUMMARY OF THE INVENTION

Accordingly, the present invention relates to an improved process for the preparation of a compound useful in the preparation of a fungicide.

The present invention specifically relates to an improved process for the preparation of Cyproconazole intermediate or its salts.

The present invention relates to an improved process for the preparation of 1-(4-chlorphenyl)-2-cyclopropyl-1-acetone having the Formula (I)
Formula (I)

or its salts, which comprises :

(a). reacting a compound of Formula (III)
Formula (III)
with trialkylorthoformate using a catalyst in a solvent to obtain a compound of Formula (IV),
Formula (IV)

(b). reacting compound of Formula (IV) with a phosphate reagent using AlCl3 as Lewis acid in a solvent to obtain a compound of Formula (V),
Formula (V)

(c). reacting compound of formula (V) with cyclopropylmethyl ketone in a solvent and a base to obtain compound of Formula (VI),
Formula (VI)

(d). treating the compound of Formula (VI) with an acid in a solvent to obtain compound of Formula (I).

The present invention specifically relates to an improved process for the preparation of 1-(4-chlorphenyl)-2-cyclopropyl-1-acetone having the Formula (I)
Formula (I)

or its salts, which comprises
(a). reacting a compound of Formula (III)
Formula (III)
with trialkylorthoformate using p-toluene sulfonic acid in toluene to obtain a compound of Formula (IV),
Formula (IV)

(b). reacting compound of Formula (IV) with trimethylphosphate using AlCl3 as Lewis acid in toluene to obtain a compound of Formula (V),
Formula (V)

(c). reacting compound of Formula (V) with cyclopropylmethyl ketone in toluene and sodamide to obtain compound of Formula (VI),
Formula (VI)

(d). treating the compound of Formula (VI) with aqueous hydrochloric acid in methanol to obtain compound of Formula (I).

In still another aspect, the present invention relates to a process for the preparation of Cyproconazole having the Formula (II)
Formula (II)

or its salts which comprises

(a). reacting a compound of Formula (III)
Formula (III)
with trialkylorthoformate using a catalyst in a solvent to obtain a compound of Formula (IV),
Formula (IV)

(b). reacting compound of Formula (IV) with a phosphate reagent using AlCl3 as Lewis acid in a solvent to obtain a compound of Formula (V),
Formula (V)

(c). reacting compound of Formula (V) with cyclopropylmethyl ketone in a solvent a and base to obtain compound of Formula (VI),
Formula (VI)

(d). treating the compound of Formula (VI) with an acid in a solvent to obtain compound of Formula (I),

(e). converting compound of Formula (I) to Cyproconazole of Formula (II).

DETAILED DESCRIPTION OF THE INVENTION

The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.

The base used in this reaction include but not limited to a strong base selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; Lithium diisopropylamide (LDA), Sodium amide (NaNH2), Sodium hydride (NaH) and the like. Preferably Sodium amide.

The solvent system used in the reaction medium is one or more selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, acetone, N,N-dimethylformamide and the like or mixtures thereof, aromatic hydrocarbon solvents selected from toluene, xylene, phenol, styrene, diethylbenzene, ethylbenzene, halogenated solvent selected from dichloromethane, dichoroethane, chloroform etc. Preferably, methanol, toluene, chloroform and dichloromethane.

The acid as used in the reaction medium is one or more selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoro acetic acid, formic acid or mixture thereof.

The phosphate reagent as used in the reaction medium is one or more selected from trimethyl phosphate, dialkyl phosphate, phosphorus oxychloride in methanol etc.

The catalyst as used in the reaction medium is one or more selected from p-toluene sulfonic acid, methane sulfonic acid etc.

In yet another embodiment the present invention provides an improved process for the preparation of compound of Formula (IV) which comprises reacting the compound of Formula (III) with trialkylorthoformate using a catalyst in a solvent. The reaction is carried out at a temperature in the ranging from room temperature to reflux temperature of the solvent. Duration of the reaction varies from 1 to 5 hours. The progress of the reaction is monitored by HPLC, thereafter the solvent is removed azeotropically.

In yet another embodiment the present invention provides an improved process for the preparation of compound of Formula (V) which comprises reacting compound of Formula (IV) with a phosphonating agent using AlCl3 in a solvent. The reaction is carried out at a temperature in the ranging from -10°C to ambient temperature of the solvent. Duration of the reaction varies from 30 minutes to 5 hours. The progress of the reaction is monitored by HPLC, thereafter the reaction mass is quenched with chilled water and solvent is removed by distillation.

In yet another embodiment the present invention provides an improved process for the preparation of compound of Formula (VI) which comprises reacting compound of Formula (V) with cyclopropylmethyl ketone using a base in a solvent. The reaction is carried out at a temperature in the ranging from 0°C to ambient temperature of the solvent. Duration of the reaction varies from 1 to 5 hours. The progress of the reaction is monitored by HPLC, thereafter the reaction mass is quenched with chilled water and solvent is removed by distillation.

In yet another embodiment the present invention provides an improved process for the preparation of compound of Formula (I) which comprises treating compound of Formula (VI) with an acid in a solvent. The reaction is carried out at a temperature in the ranging from 0°C to ambient temperature of the solvent. Duration of the reaction varies from 1 to 5 hours. The progress of the reaction is monitored by GC, thereafter the reaction mass is dilute with toluene, extract the organic layer with water and solvent is removed by distillation.

The intermediates formed in the present invention may be isolated or not. Any of the above reactions may be carried out in-situ reactions to obtain compound of Formula (I) or its derivative. The above compounds may be isolated as salts or free bases, if the above compounds are isolated as salts they are converted to their free bases first and used for further reactions.

The advantages of the present invention is use of AlCl3 reagent in step 2 as Lewis acid which is simple, easily available compared to Lewis acid disclosed for similar reactions in prior-art. This process involves use non-polar solvent (toluene) for which recovery is high and the process does not include further purifications. The use of AlCl3 and as the process does not involve any additional purification has resulted in better yields (around 95%) obtained for all the steps

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES
Example-1: Preparation of Ketal (IV) from 4-Chlorobenzaldehyde:

4-Chlorobenzaldehyde (91.0 gm; 0.647 mole) was taken in a four neck 5.0 liter RBF equipped with condenser with chilled water circulation, overhead stirrer, and addition funnel and thermometer pocket. To this toluene (455 ml, 5.0 vol) and trimethyl ortho formate (75.5 gm; 0.711 mole; 1.1 eqv.) was added, stir the mass for 30 minutes at 25-30°C. p-toluene sulphonic (PTSA; 2.0 gm, 0.02 eqv, catalytic) was added to the reaction mass, which was refluxed slowly for 2-3 hrs. The reaction was monitored by HPLC for 4-Chlorobenzaldehyde Content (Benzaldehyde content NMT 1.0 %; by Area percent) (Note: Remove 1.0 vol of azeotropic mixture to reach temperature to 110°C).

The reaction contents were cooled to room temperature, and washed the organic layer twice with water (2x 100 ml) and allowed the layers to settle down for 30 minutes. The toluene layer was separated and toluene distilled out at 110°C to obtain light brown liquid compound. (Contains Ketal product).

(w/w): 117.0 g (97%, yield) and Purity by HPLC: ~96%

Example-2: Preparation of Phosphonate (V) :

Ketal (117.0 gm; 0.626 mole) was taken in a four necked 5.0 liter RBF equipped with condenser with chilled water circulation, overhead stirrer, and addition funnel and thermometer pocket and toluene (350 mL, 3.0 vol) was added at 25?C. The contents were cooled to -5?C, and TMP (124.0 gm; 1.0 mole; 1.6 eqv) was slowly add for 10 -15 min and maintain the reaction for 20 min at -10?C. Thereafter, AlCl3 (150.0 g, 1.125 mole, 1.8 eq) was added portion wise into the reaction mass at (~ -5?C) for a period 60 minutes and stir the reaction mass at the same temperature -5?C for 30min and stir for additional 60 min. The progress of the reaction was monitored by HPLC for ketal content (Ketal content: NMT: 1.0% by area). After completion of reaction, the above contents were slowly quenched with ice cold water. (2.0 vol, 2x100 mL) maintaining temperature to -5?C for 30min. After quenching, warm the above reaction contents to 25-30?C and allowed to settle for 30 min, the organic layer was separated, washed with water (2x100ml) and distilled the organic layer at 110°C to obtain pale yellow liquid compound. (Contains phosphonate).

Weight: ~155.6 gm (Purity: 96% by HPLC). Yield: ~ 94.1%.

Example-3: Preparation of Phosphonate (V) :

Ketal (117.0 gm; 0.626 mole) was taken in a four necked 5.0 liter RBF equipped with condenser with chilled water circulation, overhead stirrer, and addition funnel and thermometer pocket and chloroform (350 mL, 3.0 vol) was added at 25?C. The contents were cooled to -5?C, and TMP (124.0 gm; 1.0 mole; 1.6 eqv) was slowly add for 10 -15 min and maintain the reaction for 20 min at -10?C. Thereafter, AlCl3 (150.0 g, 1.125 mole, 1.8 eq) was added portion wise into the reaction mass at (~ -5?C) for a period 60 minutes and stir the reaction mass at the same temperature -5?C for 30min and stir for additional 60 min. The progress of the reaction was monitored by HPLC for ketal content (Ketal content: NMT: 1.0% by area). After completion of reaction, the above contents were slowly quenched with ice cold water. (2.0 vol, 2x100 mL) maintaining temperature to -5?C for 30min. After quenching, warm the above reaction contents to 25-30?C and allowed to settle for 30 min, the organic layer was separated, washed with water (2x100ml) and distilled the organic layer at 59-60°C to obtain pale yellow liquid compound. (Contains phosphonate)

Weight: ~157.0 gm (Purity: 96% by HPLC). Yield: ~ 95%.

Example 4: Preparation of Cyclopropyl-isomer :

Phosphonate (157.0 gm; 0.593 mole) was taken in a four neck 5.0-liter RBF equipped with condenser with chilled water circulation, overhead stirrer, and addition funnel and thermometer pocket. To this toluene (785.0 mL) add CPMK (50.0 g, 0.59 moles,1.0 eq) was added and stirred the contents at room temperature and cooled the reaction contents to -5?C. Soda amide (57.8 gm; 1.48 mole, 2.5 eq,) was charged portion wise into the reaction mass at (~ -5?C) for 30min- 1hr and stirred the reaction mass at 5-10?C for 2 hrs. The reaction was monitored by GC for phosphonate content. (Limit: phosphonate content: less than:1.0% by area). The reaction mass was slowly quenched with chilled water (200ml) and stirred for 30 minutes and allowed the layers to settle down for 30 minutes (Note: While quenching with water temperature raised to 15-20?C). The organic layer was separated and extracted with additional amount of toluene (100 ml). Combine the total organic layer and washed with water (2X100 mL), stir for 10 min to separate the organic layer. Collect the organic layer and distill out to at 50-55?C under reduced pressure to afford Step-3 product. (Cyclopropyl isomers)

Weight: ~118.0 gm (Purity; 95-96% by HPLC). Yield: ~ 96%.

Example 5: Preparation of 1-(4-chlorphenyl)-2-cyclopropyl-1-acetone:

Charge 6N HCl (590.0 ml, 5.0 vol), cool the contents to 10?C, and Methanol (118.0 mL, 1 vol) was added slowly. To this step-3 product (Cyclopropyl isomers) (118.0 g) was added and the contents stirred at room temperature (24-26?C) for 15hrs. The reaction was monitored by GC for isomers content (Limit: isomers content: less than: 1.0% by area). The reaction mass was diluted with toluene (4 vol, 472.0 ml) and stirred for 30 minutes and the layers were allowed to settle down for 30 minutes. The organic layer was separated and extracted with additional amount of toluene (100 ml). The total organic layer was combined and wash with water (2x100 mL), stirred for 10 min to separate the organic layer. The organic layer was collected and distill out at 50-55?C under reduced pressure to afford CP-Ketone.

Weight: ~105.0 gm (Purity; ~95-96% by HPLC). Yield: ~ 95%.

Overall yield: 83.17%