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Title:
A PROCESS FOR PRODUCING ACETYLNORBORNENE, AN INTERMEDIATE IN THE SYNTHESIS OF BIPERIDEN
Document Type and Number:
WIPO Patent Application WO/2008/065672
Kind Code:
A2
Abstract:
The present invention relates to a novel process for the production of acetylnorbornene, efficiently and industrially useful manner. The process is applicable for the large scale production of acetylnorbornene and consists of preparation of 5-cyanonorbornene and its reaction with appropriate Grignard reagents. The product contains higher proportion of the exo form than the endo form, which is important for the synthesis of biperiden.

Inventors:
GOTTUMUKKALA, Venkata, Subbaraju (Lakshmisurya, A-16 Nalanda Nagar,Tirupati 2, Andhra Pradesh, 517 50, IN)
MAMILLAPALLI, Rambhadra, Sarma (Plot No.12, Rami Reddy NagarNear IDPL Colony,Hyderabad 7, Andhra Pradesh, 500 03, IN)
TERLI, Chiranjeevi (102 Doyen Chambers, Behind Saradhi StudiosAmeerpet,Hyderabad 3, Andhra Pradesh, 500 07, IN)
Application Number:
IN2006/000470
Publication Date:
June 05, 2008
Filing Date:
November 27, 2006
Export Citation:
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Assignee:
SAIRAM ORGANICS PVT.LTD. (102 Doyen Chambers, Behind Saradhi StudiosAmeerpet,Hyderabad 3, Andhra Pradesh, 500 07, IN)
GOTTUMUKKALA, Venkata, Subbaraju (Lakshmisurya, A-16 Nalanda Nagar,Tirupati 2, Andhra Pradesh, 517 50, IN)
MAMILLAPALLI, Rambhadra, Sarma (Plot No.12, Rami Reddy NagarNear IDPL Colony,Hyderabad 7, Andhra Pradesh, 500 03, IN)
TERLI, Chiranjeevi (102 Doyen Chambers, Behind Saradhi StudiosAmeerpet,Hyderabad 3, Andhra Pradesh, 500 07, IN)
International Classes:
C07C45/44
Foreign References:
US3554886A1971-01-12
US3715342A1973-02-06
Other References:
BLOCH ET AL.: 'Stereoselective Aldol Condensations Induced by a Thermolabile Group.' TETRAHEDRON LETTERS vol. 27, no. 30, 1986, pages 3511 - 3514, XP008111176
BLOCH ET AL.: 'Aldolisation Stereocontrolee Par Un Groupe Thermolable.' TETRAHEDRON LETTERS vol. 44, no. 9, 1988, pages 2523 - 2539, XP008111241
See also references of EP 2102140A2
Attorney, Agent or Firm:
NAIR, R., R. et al. (DePenning & DePenning, 31 South Bank RoadChennai 8, Tamil Nadu, 600 02, IN)
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Claims:

Claims

1. A method for producing 5-Acetylnorbornene comprising the steps of a) reacting cyclopentadiene with acrylonitrile to obtain 5-Cyanonorbornene and b) reacting the 5-Cyanonorbornene with methyl magnesium chloride to obtain 5-Acetylnorbornene.

2. The method as claimed in claim 1, wherein cyclopentadiene and acrylonitrile are used in a molar ratio of θ.5.1 to 2:1, preferably 1 :1.

3. The method as claimed in claim 1, wherein the reaction of cyclopentadiene and acrylonitrile is carried out at a temperature of -10° to 80° C, preferably 40 to 50° C.

4. The method as claimed in claim 1, wherein 5-Cyanonorbornene and methyl magnesium chloride are used in the molar ratio of 0.2 :1 to 1 :1.

5. The method as claimed in claim 1, wherein the reaction of 5- Cyanonorbornene and methyl magnesium chloride is carried out at a temperature of -10° to 50° C.

6. The method as claimed in claim 1, wherein the methyl magnesium chloride is used as a solution in a organic solvent.

7. The method as claimed in claim 6, wherein the organic solvent is selected from ether, tetrahydrofuran, 1,4-dioxan or toluene.

•8. • The method as claimed in claim 1, wherein the ratio of exo/endo forms of 5-Acetylnorbornene is from 1 to 10, particularly 1.5 to 4.0.

Description:

A PROCESS FOR PRODUCING ACETYLNORBORNENE, AN INTERMEDIATE IN THE SYNTHESIS OF BIPERIDEN

The present invention relates to a novel process for the production of acetylnorbornene, which is an intermediate in the synthesis of biperiden. In particular, the present invention relates to a process for producing acetylnorbornene containing higher proportion of the exo form than the endo form, which is essential for the synthesis of biperiden. The process can be applied in large scale production of acetylnorbornene and consists of preparation of 5- cyanonorbornene and its reaction with appropriate Grignard reagents

Background of the invention

Exo form of 5 -Acetylnorbornene is a key intermediate for the synthesis of biperiden (I),

I which is an antiparkinsonian agent of the anticholinergic type. In conventional method 5 -Acetylnorbornene is synthesized through Diels-Alder reaction between cyclopentadiene and methyl vinyl ketone (Scheme 1).

Scheme - 1

The product obtained in the conventional method contains very high endo isomer. Further, the product has to be subjected to additional step of equilibration in the presence of a base to generate desired exo/endo ratio. In addition, methyl vinyl ketone, which is used as the starting material in the prior art process, has the disadvantage of being less stable and polymerizes on standing. Further, methyl vinyl ketone is expensive and difficult to handle because of its high toxic nature.

The conventional method is not fully satisfactory for the industrial working since the reaction between cyclopentadiene and methyl vinyl ketone is highly exothermic and limits the scope for the scaling up.

Therefore, the need for a method which produces acetylnorbornene with a higher proportion of the exo form than the endo form and which overcomes the disadvantages stated above, has been in demand.

Accordingly, one of the objects of the present invention is to provide provide a practical method for the production of 5-acetymorbornene in a large scale, economically and efficiently.

Another objects of the present invention is to provide to a method for producing 5-acetylnorbornene in predominantly exo form.

Accordingly applicants have developed a method for producing 5- Acetylnorbornene comprising the steps of a) reacting cyclopentadiene with acrylonitrile to form 5-Cyanonorbornene and b) reacting of 5-Cyanonorbornene with methyl magnesium chloride.

Disclosure of the invention

The reaction of cyclopentadiene with acrylonitrile provides 5-Cyanonorbornene (II) which on treatment with methyl magnesium chloride results 5- Acetylnorbornene (III) and the details are shown in Scheme 2.

Scheme - 2

Hereinafter the invention is explained more specifically referring to the working examples, it being understood that the Examples incur no restricting effect on the invention.

Example 1 :

Preparation of 5-Cyanonorbornene:

To a solution of acrylonitrile (249.4 g, 4.7 mol) in methanol (260 mL) at 40° C was added cyclopentadiene monomer (311.0 g, 4.7 mol) slowly over a period of 45

min. The temperature of the reaction was maintained between 40 and 50 C for one hour. The solvent was removed under vacuum to obtain a residue (487.3 g), which on distillation under high vacuum produced 5-cyanonorbornene (453.3 g, 80.8% yield).

Example 2:

Preparation of 5-Acetylnorborneiie:

1 ,4-dioxan was added slowly over a period of one hour, at room temperature to a solution of methyl magnesium chloride (263.6 mL, 3.0 M solution in THF, 0.53 mol). 5-Cyanonorbornene (30 g, 0.25 mol) was then added slowly at room temperature over a period of one hour and then the reaction mixture was refluxed for 90 min. After completion of the reaction the reaction mixture was cooled and poured into ice-cold water (200 mL). On usual work-up followed by distillation under vacuum produced Acetylnorbornene (25.5 g, 75% yield). The ratio of exo to endo isomers is 1.8 [Gas Chromatograph analysis ( area %) : exo/endo =

41.80/23.16 = 1.8].