Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-06-13
1998-03-31
Bond, Robert T.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546208, 548550, 540350, 540480, 540602, 570181, 570186, C07D20996
Patent
active
057340617
DESCRIPTION:
BRIEF SUMMARY
This case is a 371 of PCT/US 94/14083, filed 7 Dec. 1994 which claims priority of British Application 9325854.9, filed 17 Dec. 1993.
The present invention relays to an improved process for the preparation of spirocyclic lactams which utilizes .alpha.,.omega.-diiodides in the spiro alkylation of lactams N-substituted with a tertiary amine group. The resultant spirocyclic lactams are useful in the production of various substituted azaspiranes. Such compounds are described in U.S. Pat. No. 4,963,557 as being useful as immunomodulatory agents.
BACKGROUND OF THE INVENTION
Processes for the preparation of spirocyclic lactams have previously been described. In particular radical cyclizations are reported in (a) Nagushima, H. et al., J.C.S. Chem. Commun., 1985, 518, (b) Jolly, R. S. et al., J. Am. Chem. Soc., 1988, 110, 7536 and (c) Cossy, J. et al., Tetrahedron Lett., 1989, 4531. None of the above references, however, describe the preparation of spirocyclic lactams N-substituted with a tertiary amine substituent.
Additionally, U.S. Pat. No. 4,963,557 describes the formation of cyclic-1-carboxy-1-acetic acid anhydrides via the dehydration of cyclic-1-carboxy-1-acetic acid compounds. As used therein subsequent amidation of the anhydride followed by reduction of the spiroimides thus obtained yields pharmaceutically active azaspiranes N-substituted with a tertiary amine substituent.
The above disclosures require numerous reaction steps and difficult isolation procedures resulting in low overall yields. Thus, there is a need in the art for a safe, economical and reliable method to prepare spirocyclic lactams N-substituted with a tertiary amine substituent.
This invention relates to the novel use of .alpha.,.omega.-diiodides as difunctional electrophiles in the spiroalkylation of lactams N-substituted with a tertiary amine group. The invented process is advantageous in that it shortens the number of overall steps, utilizes a convergent synthetic scheme, eliminates the need for chromatography and increases overall yield.
This discovery is particularly surprising in view of corresponding research which concluded that chlorides, bromides, tosylates and mesylates fail when substituted for iodine in the invented process.
SUMMARY OF THE INVENTION
This invention relates to an improved process for the preparation of spirocyclic lactams which utilizes .alpha.,.omega.-diiodides in the spiroalkylation of lactams N-substituted with a tertiary amine group.
This invention relates to an improved process for the preparation of
This invention specifically relates to an improved process for the preparation of
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term compound of Formula I where n is 3, R.sup.3 and R.sup.4 are each methyl and R.sup.1 and R.sup.2 are each propyl.
As used herein, the term N,N-diethyl-8,8-dipropyl-2-azaspiro R.sup.3 and R.sup.4 are --CH.sub.2 --CH.sub.3 and R.sup.1 and R.sup.2 are each propyl.
As used herein, the term 2-(3-piperidinopropyl)-8,8-dipropyl-2-azaspiro R.sup.4 are joined together to form a cyclic alkyl group containing 5 carbon atoms and R.sup.1 and R.sup.2 are each propyl.
By the term "appropriate solvent" as used herein is meant a solvent such as tetrahydrofuran, hexane, or diethyl ether.
By the term "organic solvent" as used herein is meant a solvent such as methylene chloride, ethylene chloride, chloroform, ethylene glycol, carbon tetrachloride, tetrahydrofuran (THF), ethyl ether, toluene, ethyl acetate, hexane, dimethylsulfoxide (DMSO), N,N'-dimethyl-N,N'-propylene urea, N-methyl-2-pyrrolidinone, methanol, isopropyl alcohol, dimethylformamide (DMF), pyridine, quinoline or ethanol.
By the term "reduced temperature" as used herein is meant below 25.degree. C., preferably at 0.degree. C. when a salt of hexamethyldisilane (as described herein) is used, preferably at -78.degree. C. when an alkyllithium reagent (as described herein) is used.
By the term "appropriate reducing agent" as used herein is meant a compound capable of reductively removing an oxo substituent, such as lithium
REFERENCES:
patent: 4963557 (1990-10-01), Badger et al.
patent: 5049680 (1991-09-01), O'Lenick et al.
Bailey et al. "J. Org. Chem." vol. 49, pp. 2048-2107 (1948).
Tetrahydron Letters, vol. 23, No. 49, pp. 5123-5125 (1982).
Tetrahydron Letters, vol. 30, No. 34, pp. 4531-4534 (1989).
J. Chem. Soc., Chem. Commun, pp. 518-519 (1985).
Bond Robert T.
SmithKline Beecham Corporation
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