Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1991-01-08
1992-02-25
Shen, Cecilia
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
540596, 540598, 540602, 544145, 544147, 544150, 544153, 544154, 544155, 544157, 544162, 544359, 544380, 546195, 546196, 548517, 548525, 548527, 548528, 548950, 548952, 548953, C07D22314, C07C20968, C07C21142, C07C20928
Patent
active
050915266
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to a process for the chiral synthesis of enantiomeric intermediates for the biologically trans hexahydrobenzo[d]naphtho[2,1-b]azepines. These compounds have been disclosed as possessing anti-psychotic, anti-depressant and sedative activities in European Patent Application No. 230270. The synthesis described in European Patent Application No. 230270 produces a racemic mixture of the trans and cis amines. It has been found that the trans amine possesses higher biological activity in general than the cis amine. In addition, one enantiomer of the trans amine possesses considerably greater activity than the other. A chiral synthesis producing only a single enantiomer of the trans amine would therefore increase the yield of the biologically more active enantiomer by a factor of about two.
Stereospecific preparation of amines has been disclosed. For example, Tetrahedron Letters, 1981, 22(28), 2633, describes the asymmetric synthesis of the cis-2-substituted cyclohexamines of the general formula ##STR3## wherein the asterisks indicate chiral centers and the R and NH.sub.2 substituents are in the cis orientation. Also, Bulletin de la Societe Chimique de France, 1970, 12, 4439, describes a study of the reaction products of the asymmetric synthesis of alpha-substituted ethylamines having the general formula ##STR4## wherein the R group is, for example, ethyl or isopropyl. However, these articles do not disclose or suggest that such techniques would be applicable to compounds of the present invention.
SUMMARY OF THE INVENTION
The present invention relates to a process for producing compounds of the general formula 3 ##STR5## wherein: R* is ##STR6## Q is methylene, --O-- or --S--; m and n are independently variable and may each have a value of 0, 1 or 2, with the provisos that the sum of m and n is not greater than 3, that m may not equal zero when Q is --O-- or --S--, and that when Q is --CH.sub.2 --, m and n cannot both be zero; --N(R.sup.1).sub.2, --NHC(O)R.sup.1 or --OP(O)(OH)OR.sup.1 ; (provided that both are not hydrogen), alkyl, aralkyl, cycloalkyl, aryl, hydroxyalkyl, or alkoxyalkyl; may be --R.sup.4 NR.sup.5 R.sup.6 {wherein R.sup.4 is alkanediyl, R.sup.5 is hydrogen or alkyl and R.sup.6 is alkyl, or R.sup.5 and R.sup.6 together with the nitrogen atom to which they are attached form a 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 1-(4-alkylpiperazinyl), 4-morpholinyl or 1-(hexahydroazepinyl) group}; may form a 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-(4-alkylpiperazinyl), 1-(4-alkoxyalkylpiperazinyl), 1-(4-hydroxyalkylpiperazinyl), 1-(3-hydroxyazetidinyl), 1-(3-alkoxyazetidinyl), 1-(-hydroxypyrrolidinyl), 1-(3-alkoxypyrrolidinyl), 1-(3- or 4-hydroxypiperidinyl), 1-(3- or 4-alkoxypiperidinyl), 1-(4-oxopiperidinyl) or 1-(3-oxopyrrolidinyl) ring; --CHR.sup.7 CO.sub.2 R.sup.8, wherein R.sup.7 and R.sup.8 are the same or different and each is hydrogen, alkyl or aralkyl; cycloalkylalkyl, alkoxycarbonylalkyl, cycloalkyl, 1-adamantyl, cycloalkoxyalkyl, alkoxy, aralkyloxy, cycloalkoxy, aryloxy or --CHR.sup.7 NHR.sup.8 ; and R.sup.10 is hydrogen, alkyl or aryl}; ##STR7## in the presence of a reducing agent, H.sub.2 in the presence of catalyst, or a dissolving metal and acid;
A key feature of the present invention is the use of R* which must have a chiral center due to R.sup.11 and R.sup.12 not being identical. R.sup.11 and R.sup.12 are chosen based on the desired absolute stereochemistry of the final product.
In a preferred embodiment of the invention, said reducing agent is NaCNBH.sub.3, NaBH.sub.4, t-butyl amine borane (TBAB) or Zn dust. In one preferred embodiment of the invention, the cis amine of formula 3 is converted to the trans amine of formula 4 ##STR8## using a strong base.
Another preferred embodiment of the invention further comprises producing compound 2 from a compound of formula 1 ##STR9## by reacting compound 1 with an optically active amine of the formula H.sub.2 NR* wherein all the substituents are as previously defined.
REFERENCES:
patent: 4973586 (1990-11-01), Berger et al.
Tetrahedron Letters, vol. 22, No. 28, pp. 2633-2636 (1981).
March, J. Advanced Organic Chemistry 3rd Ed., Wiley & Sons, pp. 693-694 (1985).
The Merck Index 10th Ed., pp. 1233-1234 (1983).
Bulletin de la Societe Chimique de France, vol. 12, pp. 4439-4446 (1970).
Berney et al, CA 94-139592d (1981).
Carlsson et al, CA 98-178996r (1983).
Berger et al, CA 108-37669z (1988).
Berger et al, CA 113-145348f (1990).
Takai, CA 113-106396a (1990).
Berger Joel G.
Clader John W.
Lee, Jr. Warrick E.
Mazer Edward H.
Nowak Henry P.
Schering Corporation
Shen Cecilia
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