Method for the preparation of derivatives of spiro (4,5)-decane and derivatives thus obtained

• US 4,028,351 A
• Filed: 02/11/1975
• Issued: 06/07/1977
• Est. Priority Date: 09/07/1971
• Status: Expired due to Term

• Current Assignee: Istituto Chemioterapico Di Lodi SPA
• Original Assignee: Buskine SA
• Inventors: Taccone, Ida
• Primary Examiner(s): Todd, G. Thomas
• Application Number:
  US05/549,061
• Time in Patent Office: 847 Days
• Field of Search: 260/240 K, 260/293.58, 260/293.66
• US Class Current: 546/19
• CPC Class Codes: C07C 201/12 by reactions not involving the formation of nitro groups
• CPC Class Codes: C07C 205/09 of an unsaturated carbon skeleton
• CPC Class Codes: C07C 209/365 by reduction with preservation of halogen-atoms in compounds containing nitro groups and halogen atoms bound to the same carbon skeleton
• CPC Class Codes: C07C 211/29 the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
• CPC Class Codes: C07C 227/18 by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
• CPC Class Codes: C07C 229/24 having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
• CPC Class Codes: C07D 498/10 Spiro-condensed systems
• CPC Class Codes: C07F 3/003 without C-Metal linkages

Abstract

Derivatives of spiro-(4,5)-decane, are prepared from an N-substituted-4-piperidone according to a modification of the Reformatsky reaction. The N-substituted-4-piperidone is reacted in an appropriate solvent or solvent mixture with an alpha halogen ester in the presence of activated zinc. The obtained beta-hydroxy ester is reacted with an excess of hydrazine, the resultant compound being a beta hydroxy hydrazide. The latter is subjected to a Curtius transposition with nitrous acid in excess.

Claims

1. A method for the preparation of a spiro-[ 4,5]- decane derivative having the formula:

##STR44## in which R is selected from the group consisting of beta-phenylethyl, 3'"'"',4'"'"'-methylenedioxy (beta-phenyl-ethyl)-, beta-(p-fluoro)-phenyl-ethyl;

beta-phenoxy-ethyl, cinnamyl, diphenyl-methyl, and beta-(3'"'"'-trifluoromethyl)-phenyl- ethyl, and R'"'"' is hydrogen or phenyl, which comprises the steps of;

6. The method of claim 1, wherein the mole ratio of N-substituted piperidone to alpha-halogen alkyl acetate to activated elemental zinc in

7. step (1) is 1 :

2.5 ;

5. 3. The method of claim 1, wherein the reaction of step (2) is carried out until, on analyzing the reaction mixture, the absence of the N-substituted 4-piperidone is checked.

8. The method of claim 1, wherein the decomposition of the final adduct in step (4) takes place by hydrolysis carried out with a mixture of acetic acid and water in the volume ratio of 1:

1.

9. The method of claim 1, wherein the reaction medium of step (1) is an anhydrous mixture of benzene and ethyl ether in the volume ratio of 1 :

1.

10. The method of claim 1, wherein the ratio of the betahydroxy ester product to hydrzine in step (6) is 1 to 10, and the ratio of hydrazide to nitrous acid in step (7) is 1 :

1.6.

11. The method of claim 1, wherein step (7) is carried out under a blanket of petroleum ethers having a boiling point between 60°

C and 90°

C.

2. reacting, at a temperature of between 50°

and 60°

C, an alpha-halogen alkyl acetate, having the formula ##STR45## wherein R'"'"' is as defined above and X is Cl, Br or I, in the presence of activated elemental zinc to form a primary adduct having the formula ##STR46## wherein R'"'"' and X have the above defined meanings, in an anhydrous solvent mixture of benzene and ethyl ether, until the alpha-halogen alkyl ester is wholly absent from the reaction mixture;

2.

3. adding at least one mole of an N-substituted-4-piperidone of the formula ##STR47## where R is as defined above per mole of primary adduct in the reaction mixture from step (1) at a temperature between 0°

and 20°

C. to form a final adduct, having the formula ##STR48##

4. completely precipitating the final adduct at a temperature of 0°

C by stepwise addition of anhydrous ethyl ether, and separating the final organo-metallic adduct by filtering and drying;

4. decomposing the solid final adduct with water to form an oily beta-hydroxy ester product of the formula ##STR49##

5. wherein R and R'"'"' are as defined above;

5. neutralizing the reaction mixture from step (4 ) to pH 7;

extracting the beta-hydroxy ester product with an organic solvent and isolating the beta-hydroxy ester;

6. reacting said beta-hydroxy ester product with excess hydrazine for 8 to 30 hours at a temperature of 40°

-60°

C, in the molar ratio of ester to hydrazine of 1;

1.5 to 1;

100, to form the corresponding beta-hydroxy-hydrazide, having the formula ##STR50## and (7) rearranging said beta-hydroxy hydrazide, according to the Curtius transportion reaction, by reacting it with excess nitrous acid, in the presence of a diluted mineral acid at a temperature from room temperature to 60°

C, to form the spiro [4,5]-decane derivative of formula (I).

12. 1-oxo-2-oxa-3,8-diaza-8-phenoxyethyl-spiro-decane.

13. 1-oxa-2-oxo-3,8-diaza-8-cinnamyl-spiro decane.

14. 1-oxa-2-oxo-3,8-diaza-8-diphenylmethyl-spiro-decane.