Tricyclic compounds and process for preparation thereof

Patent metadata

Field	Value
Publication number	US-9950983-B2
Application number	US-201515328425-A
Country	US
Kind code	B2
Filing date	Jul 23, 2015
Priority date	Jul 23, 2014
Publication date	Apr 24, 2018
Grant date	Apr 24, 2018

Abstract

The present invention discloses tricyclic compounds of formula (I) or salt thereof and their process for synthesis. Further, the present invention relates to the use of these novel tricyclic compounds of formula (I) or salt thereof as insect repellents.

First claim

We claim:

1. A compound of formula (I)

wherein
R 1 , R 3 , and R 4 are selected from the group consisting of hydrogen, alkyl (C 1 to C 2 ), COOH, COR, CONRR, CH 2 OR, and NRR;
R 2 , R 6 , R 7 and R 8 are selected from group consisting of hydrogen, alkyl (C 1 to C 4 ), COOH, COR, CONRR, CH 2 OR, NRR;
R 5 is selected from group consisting of hydrogen, COOH, CONRR, CH 2 OR, and NRR;
wherein any two of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 may form a 3 to 8 membered carbocyclic ring which may optionally be substituted or may contain a heteroatom selected from O or N;
X is selected from C═O; C═S or C—R—R;
R is hydrogen;
‘ ’ represents a single or double bond;
either of the rings in formula (I) may additionally contain at least one carbonyl group or salt thereof.

2. The compound as claimed in claim 1 , wherein the compounds of formula (I) are selected from the group consisting of:
i. (1aR,1bR,2R,6aS)-1,1,1b,2-Tetramethyl-1,1a,1b,2,3,6a-hexahydro-cyclopropa[a]indene-4,6-dione (1a),
ii. Ethyl(1R,1aS,1bR,2R,6aR)-1b,2-dimethyl-4,6-dioxo-1,1a,1b,2,3,4,6,6a-octahydrocyclopropa[a]indene-1-carboxylate (1b),
iii. (1aR,6aR)-1,1-Dimethyl-1a,1b,2,3,6,6a-hexahydrocyclopropa[a]-inden-4(1H)-one (1c),
iv. (1aR,6aR)-1,1,5-trimethyl-1a,1b,2,3,6,6a hexahydrocyclopropa[a]inden-4(1H)-one (1d),
v. (1aR,1bS,6aR)-1,1,2-Trimethyl-1a,1b,2,3,6,6a-hexahydrocyclo propa[a]inden-4(1H)-one (1e),
vi. (1aR,1bS,6aR)-2-Ethyl-1,1-dimethyl-1a,1b,2,3,6,6a-hexahydrocyclopropa[a]inden-4(1H)-one (1f),
vii. (1aR,1bS,6aR)-1,1-Dimethyl-2-propyl-1a,1b,2,3,6,6a-hexahydrocyclopropa[a]inden-4(1H)-one (1g),
viii. (1aR,1bR,6aR)-1,1,2,2-Tetramethyl-1a,1b,2,3,6,6a-hexahydrocyclopropa[a]inden-4(1H)-one (1h).

3. A process for the preparation of compounds of formula (I) as claimed in claim 1 , wherein said process comprising the steps of:
a) adding boron trifluoride diethyl etherate (BF 3 .OEt 2 ) to a solution of diene compounds of formula 4

and (E)-2-methylbut-2-enal of formula 3

in Dichloromethane (CH 2 Cl 2 ) followed by stirring the reaction for the period ranging from 10 to 12 h at temperature in the range of −78° C. to 30° C. to afford compound of formula 6

or
b) adding Grubbs second-generation catalyst to a solution of compound of formula 6 of step (a) followed by stirring the mixture for 22 to 24 h temperature in the range of 25 to 30° C. to afford compound of formula 7

c) adding Manganese triacetate dehydrate [Mn(OAC) 3 .2H 2 O] and tert-butyl hydroperoxide (t-BuOOH) to a solution of compound of formula 7 of step (b) in ethyl acetate (EtOAc) followed by stirring the reaction mixture for 22 to 24 h at temperature 25 to 30° C. to give compound of formula 8a

d) adding 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) to a suspension of (ethoxycarbonylmethyl)-dimethylsulfonium bromide in chloroform (CHCl 3 ) to obtain a mixture followed by addition of solution of compound of formula 8a of step (c) in CHCl 3 and stirring the reaction mixture to afford compound of formula 1b

e) adding zinc dust to a stirred solution of dienedione of formula 8a of step (c) in acetic acid followed by stirring for 20 to 30 min at temperature in the range of 25 to 30° C. to afford enone compound of formula 9

f) adding ethylene glycol and p-Toluenesulfonic acid (PTSA) to a solution of compound of formula 9 of step (e) in benzene followed by refluxing for 50 to 60 minutes at temperature in the range of 80 to 85° C. to afford compound of formula 10

g) adding the solution of t -BuLi in pentane and isopropyldiphenylsulfonium tetrafluoroborate in THF to a solution of compound of formula 10 of step (f) followed by cooling the reaction mixture to (−)15 to (−)20° C. for 50 to 60 minutes quenching the reaction mixture to give compound of formula 11

h) adding 2-iodoxybenzoic acid (IBX) and trifluoroacetic acid (TFA) to a solution of ketone of formula 11 of step (f) in dimethyl sulfoxide (DMSO) followed by stirring the reaction mixture at 70 to 80° C. for 20 to 24 h to afford compound of formula (I).

4. The process for the preparation of compounds of formula (I) as claimed in claim 3 , wherein the step (c) is carried out under nitrogen atmosphere.

5. The process for the preparation of compounds of formula (I) as claimed in claim 3 , wherein the process further comprises adding a solution of tert-Butyllithium ( t -BuLi) in pentane and isopropyldiphenylsulfonium tetrafluoroborate in THF to a solution of compound of formula 8a

of step (c) followed by cooling the mixture to −30° C. for 1 h to afford Nardoaristolone B

6. A process for the preparation of compounds of formula (I) as claimed in claim 1 , wherein said process comprises adding potassium tert-butoxide (KOtBu) and ketone compound to a stirred solution of compound of formula 14 ((1R,5S)-6,6-dimethylbicyclo[3.1.0]hexan-3-one)

and sodium sulfate (Na 2 SO 4 ) in tertiary butanol followed by stirring the reaction mixture for the period ranging from 0.5 h-6 h at temperature 25° C.-60° C. to afford compounds of formula (I).

7. The process for the preparation of compounds of formula (I) as claimed in claim 6 , wherein ketone compounds is selected from methyl vinyl ketone, pent-1-en-3-one, (E)-pent-3-en-2-one, (E)-hex-3-en-2-one, (E)-hept-3-en-2-one, 4-methylpent-3-en-2-one.

8. The compound as claimed in claim 1 , wherein the compounds are used as insect repellents.

9. The compound as claimed in claim 1 , wherein protection period of the compounds of formula (I) against mosquito bites is in the range of 1.23 h to 6.46 h at the concentration in the range of 0.25 to 0.50 mg/cm 2 .

Assignees

• Council Scient Ind Res

Inventors

• Reddy Dumbala Srinivasa
• Handore Kishor Laxman

Classifications

• C07C49/643 Primary

  having three rings · CPC title

• C07C2603/08

  containing three- or four-membered rings · CPC title

• C07C2603/12

  only one five-membered ring · CPC title

• C07C2603/10

  containing five-membered rings · CPC title

• A01N35/06

  containing keto or thioketo groups as part of a ring, e.g. cyclohexanone, quinone; Derivatives thereof, e.g. ketals · CPC title