Process for the preparation of ste specific 1'-spiro-nucleosides
First Claim
Patent Images
1. A process for the preparation of a compound of the formula I ##STR110## in which A is the group ##STR111## or --CH═
- CH--;
R1 is hydrogen, halogen, hydroxyl, C1 -C4 alkoxy, C1 -C4 alkoxy-C1 -C4 alkoxy, tri-C1 -C6 alkylsilyloxy, benzyloxy or phenoxy which are unsubstituted or substituted by C1 -C4 alkyl, C1 -C4 haloalkyl, halogen, cyano or nitro, R10 --C(O)--O--, R3 (R4)N--, ##STR112## azido, cyano or L1 --O--, whereinL1 is a protective group;
R2 is hydrogen, halogen, hydroxyl, C1 -C4 alkoxy, C1 -C4 alkoxy-C1 -C4 alkoxy, tri-C1 -C6 alkylsilyloxy, benzyloxy or phenoxy which are unsubstituted or substituted by C1 -C4 alkyl, C1 -C4 haloalkyl, halogen, cyano or nitro, R10 --C(O)--O--, R3 (R4)N--, azido, cyano or L1 --O--,whereinL1 is a protective group, with the proviso that only one of the substituents R1 or R2 is azido;
orR1 together with R2 is --OSi(R11)R20 O-- or --OC(R12)R21 O--;
R3 is hydrogen, unsubstituted or substituted C1 -C10 alkyl, C3 -C10 alkenyl or C3 -C10 alkynyl, formyl, C1 -C10 alkylcarbonyl which is unsubstituted or substituted by halogen, hydroxyl, C1 -C4 alkoxy, C1 -C4 alkylamino, di-C1 -C4 alkylamino, cyano, C1 -C4 alkoxycarbonyl, carbamoyl, C1 -C4 alkylaminocarbonyl, di-C1 -C4 alkylaminocarbonyl or phenyl, C3 -C10 alkenylcarbonyl, C3 -C10 alkynylcarbonyl, C1 -C10 alkoxycarbonyl or phenoxycarbonyl or benzyloxycarbonyl which are unsubstituted or substituted by halogen, C1 -C4 alkyl, C1 -C4 haloalkyl, C1 -C4 alkoxy or C1 -C4 haloalkoxy;
R4 is hydrogen, unsubstituted or substituted C1 -C10 alkyl, C3 -C10 alkenyl or C3 -C10 alkynyl, formyl, C1 -C10 alkylcarbonyl which is unsubstituted or substituted by halogen, hydroxyl, C1 -C4 alkoxy, C1 -C4 alkylamino, di-C1 -C4 alkylamino, cyano, C1 -C4 alkoxycarbonyl, carbamoyl, C1 -C4 alkylaminocarbonyl, di-C1 -C4 alkylaminocarbonyl or phenyl, C3 -C10 alkenylcarbonyl, C3 -C10 alkynylcarbonyl, C1 -C10 -alkoxycarbonyl or phenoxycarbonyl or benzyloxycarbonyl which are unsubstituted or substituted by halogen, C1 -C4 alkyl, C1 -C4 haloalkyl, C1 -C4 alkoxy or C1 -C4 haloalkoxy, with the proviso that only one of the substituents R3 or R4 is formyl;
orR3 together with R4 is --(CH2)n --, --(CH2)o --O--(CH2)p --, --(CH2)o --S--(CH2)p -- or --(CH2)o --NH--(CH2)p --, which can be unsubstituted or substituted by C1 -C4 alkyl;
n is 4, 5 or 6;
o is 1,2, 3 or 4;
p is 1, 2, 3 or 4; and
the sum of o and p is 3, 4 or 5;
R10 is hydrogen, C1 -C4 alkyl or benzyl or phenyl which are unsubstituted or substituted by C1 -C4 alkyl, C1 -C4 alkoxy, C1 -C4 haloalkyl, halogen or cyano;
R11 is C1 -C4 alkyl or phenyl;
R20 is C1 -C4 alkyl;
orR11 together with R20 is --(CH2)n3 --;
R12 is hydrogen, C1 -C4 alkyl or phenyl;
R21 is hydrogen or C1 -C4 alkyl;
orR12 together with R21 is --(CH2)n3 --;
n3 is 4, 5 or 6;
R8 is unsubstituted or substituted C1 -C10 alkyl, C2 -C10 alkenyl, C2 -C10 alkynyl, C1 -C10 alkyl-C(Q)--, C2 -C10 alkenyl-C(Q)--, C2 -C10 alkynyl-C(Q)--, C2 -C10 alkenyloxycarbonyl, C2 -C10 alkynyloxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl, cyano, carboxyl, phenyl, nitro, C1 -C10 alkoxycarbonyl, R3 (R4)N--C(O)-- or L2 --NH--C1 -C10 alkyl,whereinL2 is a protective group;
R9 is hydrogen, unsubstituted or substituted C2 -C10 alkyl, C2 -C10 alkenyl, C2 -C10 alkynyl, C1 -C10 alkyl-C(Q)--, C2 -C10 alkenyl-C(Q)--, C2 -C10 alkynyl-C(Q)--, phenyl, benzyl, phenyl-C(Q)--, phenoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl-C1 -C10 alkyl or benzyloxycarbonyl-C1 -C10 alkyl, C1 -C4 alkoxycarbonyl, C1 -C4 alkoxy-C(O)----NH--SO2 --, NH2 --SO2 --, R18 (R19)N--C(Q)--, R3 (R4)N--C(O)--C1 -C10 alkyl, C1 -C4 alkoxy-NH--C(O)--, phenoxy-NH--C(O)-- or benzyloxy-NH--C(O)--;
orR8 and R9 together form a ring --X--Y--Z--,in whichX is the groups C1 -C3 alkylene ##STR113## wherein the alkylene chain can be unsubstituted or substituted by halogen, hydroxyl, C1 -C4 alkoxy, amino, C1 -C4 alkylamino, di-C1 -C4 alkylamino, cyano, carboxyl, C1 -C4 alkoxycarbonyl, C1 -C4 alkylcarbonyloxy, carbamoyl, C1 -C4 alkylaminocarbonyl, di-C1 -C4 alkylaminocarbonyl or phenyl;
Q is oxygen or sulfur;
Y is oxygen, C1 -- or C2 -alkylene which is unsubstituted or substituted by C1 -C4 alkyl or --NR5 --;
Z is the groups C1 -C3 alkylene, ##STR114## wherein the alkylene chain can be unsubstituted or substituted by halogen, hydroxyl, C1 -C4 alkoxy, amino, C1 -C4 alkylamino, di-C1 -C4 alkylamino, cyano, carboxyl, C1 -C4 alkoxycarbonyl, carbamoyl, C1 -C4 alkylaminocarbonyl, di-C1 -C4 alkylaminocarbonyl or phenyl, ##STR115## or Y and Z together are a group ##STR116## wherein bonding to the ring C atom takes place via the C atom;
R5 is hydrogen, unsubstituted or substituted C1 -C10 alkyl, C3 -C10 alkenyl, C3 -C10 alkynyl, C3 -C10 alkenylcarbonyl or C3 -C10 alkynylcarbonyl, formyl, C1 -C10 alkylcarbonyl which is unsubstituted or substituted by halogen, hydroxyl, C1 -C4 alkoxy, amino, C1 -C4 alkylamino, di-C1 -C4 alkylamino, cyano, C1 -C4 alkoxycarbonyl, carbamoyl, C1 -C4 alkylaminocarbonyl, di-C1 -C4 alkylaminocarbonyl or phenyl, C1 -C10 alkoxycarbonyl or phenoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl or phenyl which are unsubstituted or substituted by halogen, C1 -C4 alkyl, C1 -C4 haloalkyl, C1 -C4 alkoxy or C1 -C4 haloalkoxy;
R6 is unsubstituted or substituted C1 -C10 alkyl, carboxyl, C1 -C4 alkoxycarbonyl, carbamoyl, C1 -C4 alkylaminocarbonyl or di-C1 -C4 alkylaminocarbonyl;
R7 is hydrogen, C3 -C7 cycloalkyl or unsubstituted or substituted C1 -C10 alkyl, C2 -C10 alkenyl, C3 -C10 alkynyl or benzyl;
R13 is hydrogen or unsubstituted or substituted C1 -C10 alkyl, C1 -C10 alkylcarbonyl, phenyl or benzyl;
R16 is C1 -C5 alkyl, C3 -C5 alkenyl, phenyl or benzyl;
R18 is unsubstituted or substituted C1 -C10 alkyl, C1 -C10 alkoxycarbonyl, phenoxycarbonyl, benzyl, benzyloxycarbonyl, C1 -C6 alkylcarbonyl, C1 -C4 alkylaminocarbonyl, di-C1 -C4 alkylaminocarbonyl or L2 ; and
R19 is hydrogen, formyl, C1 -C10 alkylcarbonyl which is unsubstituted or substituted by halogen, hydroxyl, C1 -C4 alkoxy, amino, C1 -C4 alkylamino, di-C1 -C4 alkylamino, cyano, carboxyl, C1 -C4 alkoxycarbonyl, carbamoyl, C1 -C4 alkylaminocarbonyl, di-C1 -C4 alkylaminocarbonyl or phenyl, C3 -C10 alkenylcarbonyl, C3 -C10 alkynylcarbonyl, C1 -C10 alkoxycarbonyl, phenoxycarbonyl, benzyl, benzyloxycarbonyl, C1 -C4 alkylaminocarbonyl, di-C1 -C4 alkylaminocarbonyl or L2, or salts of these compounds, which comprisesa) cyclizing the compound of the formula XI ##STR117## in which A, R8 and R9 are as defined, but A is other than ##STR118## if R1 and R2 simultaneously are hydroxyl or H2 N-- and R17 is halogen, hydroxyl, C1 -C10 alkoxy, unsubstituted or substituted C1 -C10 alkyl--C(O)O--, benzyloxy or benzoyloxy, CF3 C(O)O--, C1 -C10 alkoxy-C(O)O--, C1 -C6 alkylsulfonyloxy, phenylsulfonyloxy, CF3 S(O)2 O-- or a group L1 --O--,whereinL1 is a protective group;
orR17 and R8 together form a group ##STR119## ═
N--OR7, --O--CH(R6)-- or --O--C(R12)R21 --O--CH2 --; and
the radicals R22 independently of one another are fluorine, chlorine, bromine, unsubstituted or substituted C1 -C10 alkyl, carboxyl, C1 -C4 alkoxycarbonyl, carbamoyl, C1 -C4 alkylaminocarbonyl or di-C1 -C4 alkylaminocarbonyl;
into the compound of the formula XII ##STR120## in which A, R8 and R9 are as defined, and subsequently b1) splitting the N--O bond in the compound of the formula XII by hydrogenolysis or with an organometallic compound to give 1'"'"',1'"'"'-disubstituted nucleosides of the formula I, or b2) first cyclizing the compound of the formula XII, in which R8 and R9 are as defined, with the exception of C1 -C10 alkyl, C2 -C10 alkenyl, C2 -C10 alkynyl, phenyl or benzyl, to give the compound of the formula XIII ##STR121## in which A, X, Y and Z are as defined, in a manner known per se, and subsequently splitting the N--O bond by hydrogenolysis or with an organometallic compound to give 1'"'"'-spiro-nucleosides of the formula I.
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Abstract
The invention relates to a novel process for stereocontrolled preparation of 1'"'"',1'"'"'-disubstituted and 1'"'"'-spiro-nucleosides of the formula I ##STR1## in which the substituents A, R8 and R9 are as defined in claim 1, and to novel intermediates and their use in this process and to processes for the preparation of the novel intermediates. The process is illustrated by the example of biologically active (+)-hydantocidin.
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Citations
38 Claims
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1. A process for the preparation of a compound of the formula I ##STR110## in which A is the group ##STR111## or --CH═
- CH--;
R1 is hydrogen, halogen, hydroxyl, C1 -C4 alkoxy, C1 -C4 alkoxy-C1 -C4 alkoxy, tri-C1 -C6 alkylsilyloxy, benzyloxy or phenoxy which are unsubstituted or substituted by C1 -C4 alkyl, C1 -C4 haloalkyl, halogen, cyano or nitro, R10 --C(O)--O--, R3 (R4)N--, ##STR112## azido, cyano or L1 --O--, whereinL1 is a protective group; R2 is hydrogen, halogen, hydroxyl, C1 -C4 alkoxy, C1 -C4 alkoxy-C1 -C4 alkoxy, tri-C1 -C6 alkylsilyloxy, benzyloxy or phenoxy which are unsubstituted or substituted by C1 -C4 alkyl, C1 -C4 haloalkyl, halogen, cyano or nitro, R10 --C(O)--O--, R3 (R4)N--, azido, cyano or L1 --O--, wherein L1 is a protective group, with the proviso that only one of the substituents R1 or R2 is azido;
orR1 together with R2 is --OSi(R11)R20 O-- or --OC(R12)R21 O--; R3 is hydrogen, unsubstituted or substituted C1 -C10 alkyl, C3 -C10 alkenyl or C3 -C10 alkynyl, formyl, C1 -C10 alkylcarbonyl which is unsubstituted or substituted by halogen, hydroxyl, C1 -C4 alkoxy, C1 -C4 alkylamino, di-C1 -C4 alkylamino, cyano, C1 -C4 alkoxycarbonyl, carbamoyl, C1 -C4 alkylaminocarbonyl, di-C1 -C4 alkylaminocarbonyl or phenyl, C3 -C10 alkenylcarbonyl, C3 -C10 alkynylcarbonyl, C1 -C10 alkoxycarbonyl or phenoxycarbonyl or benzyloxycarbonyl which are unsubstituted or substituted by halogen, C1 -C4 alkyl, C1 -C4 haloalkyl, C1 -C4 alkoxy or C1 -C4 haloalkoxy; R4 is hydrogen, unsubstituted or substituted C1 -C10 alkyl, C3 -C10 alkenyl or C3 -C10 alkynyl, formyl, C1 -C10 alkylcarbonyl which is unsubstituted or substituted by halogen, hydroxyl, C1 -C4 alkoxy, C1 -C4 alkylamino, di-C1 -C4 alkylamino, cyano, C1 -C4 alkoxycarbonyl, carbamoyl, C1 -C4 alkylaminocarbonyl, di-C1 -C4 alkylaminocarbonyl or phenyl, C3 -C10 alkenylcarbonyl, C3 -C10 alkynylcarbonyl, C1 -C10 -alkoxycarbonyl or phenoxycarbonyl or benzyloxycarbonyl which are unsubstituted or substituted by halogen, C1 -C4 alkyl, C1 -C4 haloalkyl, C1 -C4 alkoxy or C1 -C4 haloalkoxy, with the proviso that only one of the substituents R3 or R4 is formyl;
orR3 together with R4 is --(CH2)n --, --(CH2)o --O--(CH2)p --, --(CH2)o --S--(CH2)p -- or --(CH2)o --NH--(CH2)p --, which can be unsubstituted or substituted by C1 -C4 alkyl; n is 4, 5 or 6; o is 1,2, 3 or 4; p is 1, 2, 3 or 4; and
the sum of o and p is 3, 4 or 5;R10 is hydrogen, C1 -C4 alkyl or benzyl or phenyl which are unsubstituted or substituted by C1 -C4 alkyl, C1 -C4 alkoxy, C1 -C4 haloalkyl, halogen or cyano; R11 is C1 -C4 alkyl or phenyl; R20 is C1 -C4 alkyl;
orR11 together with R20 is --(CH2)n3 --; R12 is hydrogen, C1 -C4 alkyl or phenyl; R21 is hydrogen or C1 -C4 alkyl;
orR12 together with R21 is --(CH2)n3 --; n3 is 4, 5 or 6; R8 is unsubstituted or substituted C1 -C10 alkyl, C2 -C10 alkenyl, C2 -C10 alkynyl, C1 -C10 alkyl-C(Q)--, C2 -C10 alkenyl-C(Q)--, C2 -C10 alkynyl-C(Q)--, C2 -C10 alkenyloxycarbonyl, C2 -C10 alkynyloxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl, cyano, carboxyl, phenyl, nitro, C1 -C10 alkoxycarbonyl, R3 (R4)N--C(O)-- or L2 --NH--C1 -C10 alkyl, wherein L2 is a protective group; R9 is hydrogen, unsubstituted or substituted C2 -C10 alkyl, C2 -C10 alkenyl, C2 -C10 alkynyl, C1 -C10 alkyl-C(Q)--, C2 -C10 alkenyl-C(Q)--, C2 -C10 alkynyl-C(Q)--, phenyl, benzyl, phenyl-C(Q)--, phenoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl-C1 -C10 alkyl or benzyloxycarbonyl-C1 -C10 alkyl, C1 -C4 alkoxycarbonyl, C1 -C4 alkoxy-C(O)----NH--SO2 --, NH2 --SO2 --, R18 (R19)N--C(Q)--, R3 (R4)N--C(O)--C1 -C10 alkyl, C1 -C4 alkoxy-NH--C(O)--, phenoxy-NH--C(O)-- or benzyloxy-NH--C(O)--;
orR8 and R9 together form a ring --X--Y--Z--, in which X is the groups C1 -C3 alkylene ##STR113## wherein the alkylene chain can be unsubstituted or substituted by halogen, hydroxyl, C1 -C4 alkoxy, amino, C1 -C4 alkylamino, di-C1 -C4 alkylamino, cyano, carboxyl, C1 -C4 alkoxycarbonyl, C1 -C4 alkylcarbonyloxy, carbamoyl, C1 -C4 alkylaminocarbonyl, di-C1 -C4 alkylaminocarbonyl or phenyl; Q is oxygen or sulfur; Y is oxygen, C1 -- or C2 -alkylene which is unsubstituted or substituted by C1 -C4 alkyl or --NR5 --; Z is the groups C1 -C3 alkylene, ##STR114## wherein the alkylene chain can be unsubstituted or substituted by halogen, hydroxyl, C1 -C4 alkoxy, amino, C1 -C4 alkylamino, di-C1 -C4 alkylamino, cyano, carboxyl, C1 -C4 alkoxycarbonyl, carbamoyl, C1 -C4 alkylaminocarbonyl, di-C1 -C4 alkylaminocarbonyl or phenyl, ##STR115## or Y and Z together are a group ##STR116## wherein bonding to the ring C atom takes place via the C atom; R5 is hydrogen, unsubstituted or substituted C1 -C10 alkyl, C3 -C10 alkenyl, C3 -C10 alkynyl, C3 -C10 alkenylcarbonyl or C3 -C10 alkynylcarbonyl, formyl, C1 -C10 alkylcarbonyl which is unsubstituted or substituted by halogen, hydroxyl, C1 -C4 alkoxy, amino, C1 -C4 alkylamino, di-C1 -C4 alkylamino, cyano, C1 -C4 alkoxycarbonyl, carbamoyl, C1 -C4 alkylaminocarbonyl, di-C1 -C4 alkylaminocarbonyl or phenyl, C1 -C10 alkoxycarbonyl or phenoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl or phenyl which are unsubstituted or substituted by halogen, C1 -C4 alkyl, C1 -C4 haloalkyl, C1 -C4 alkoxy or C1 -C4 haloalkoxy; R6 is unsubstituted or substituted C1 -C10 alkyl, carboxyl, C1 -C4 alkoxycarbonyl, carbamoyl, C1 -C4 alkylaminocarbonyl or di-C1 -C4 alkylaminocarbonyl; R7 is hydrogen, C3 -C7 cycloalkyl or unsubstituted or substituted C1 -C10 alkyl, C2 -C10 alkenyl, C3 -C10 alkynyl or benzyl; R13 is hydrogen or unsubstituted or substituted C1 -C10 alkyl, C1 -C10 alkylcarbonyl, phenyl or benzyl; R16 is C1 -C5 alkyl, C3 -C5 alkenyl, phenyl or benzyl; R18 is unsubstituted or substituted C1 -C10 alkyl, C1 -C10 alkoxycarbonyl, phenoxycarbonyl, benzyl, benzyloxycarbonyl, C1 -C6 alkylcarbonyl, C1 -C4 alkylaminocarbonyl, di-C1 -C4 alkylaminocarbonyl or L2 ; and R19 is hydrogen, formyl, C1 -C10 alkylcarbonyl which is unsubstituted or substituted by halogen, hydroxyl, C1 -C4 alkoxy, amino, C1 -C4 alkylamino, di-C1 -C4 alkylamino, cyano, carboxyl, C1 -C4 alkoxycarbonyl, carbamoyl, C1 -C4 alkylaminocarbonyl, di-C1 -C4 alkylaminocarbonyl or phenyl, C3 -C10 alkenylcarbonyl, C3 -C10 alkynylcarbonyl, C1 -C10 alkoxycarbonyl, phenoxycarbonyl, benzyl, benzyloxycarbonyl, C1 -C4 alkylaminocarbonyl, di-C1 -C4 alkylaminocarbonyl or L2, or salts of these compounds, which comprises a) cyclizing the compound of the formula XI ##STR117## in which A, R8 and R9 are as defined, but A is other than ##STR118## if R1 and R2 simultaneously are hydroxyl or H2 N-- and R17 is halogen, hydroxyl, C1 -C10 alkoxy, unsubstituted or substituted C1 -C10 alkyl--C(O)O--, benzyloxy or benzoyloxy, CF3 C(O)O--, C1 -C10 alkoxy-C(O)O--, C1 -C6 alkylsulfonyloxy, phenylsulfonyloxy, CF3 S(O)2 O-- or a group L1 --O--, wherein L1 is a protective group;
orR17 and R8 together form a group ##STR119## ═
N--OR7, --O--CH(R6)-- or --O--C(R12)R21 --O--CH2 --; andthe radicals R22 independently of one another are fluorine, chlorine, bromine, unsubstituted or substituted C1 -C10 alkyl, carboxyl, C1 -C4 alkoxycarbonyl, carbamoyl, C1 -C4 alkylaminocarbonyl or di-C1 -C4 alkylaminocarbonyl; into the compound of the formula XII ##STR120## in which A, R8 and R9 are as defined, and subsequently b1) splitting the N--O bond in the compound of the formula XII by hydrogenolysis or with an organometallic compound to give 1'"'"',1'"'"'-disubstituted nucleosides of the formula I, or b2) first cyclizing the compound of the formula XII, in which R8 and R9 are as defined, with the exception of C1 -C10 alkyl, C2 -C10 alkenyl, C2 -C10 alkynyl, phenyl or benzyl, to give the compound of the formula XIII ##STR121## in which A, X, Y and Z are as defined, in a manner known per se, and subsequently splitting the N--O bond by hydrogenolysis or with an organometallic compound to give 1'"'"'-spiro-nucleosides of the formula I. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 14, 15, 16, 17, 18, 19, 20, 21, 36, 37, 38)
- CH--;
- 12. A process for the preparation of the compound of the formula Ia ##STR158## which comprises (1) reacting the compound of the formula IXa ##STR159## with an N-hydroxyimide and (2) hydrazine hydrate, (3) converting the compound of the formula Xa thus obtained ##STR160## with an isocyanate of the formula IV
- space="preserve" listing-type="equation">L.sub.2 N═
C═
O (IV),
in which L21 is hydrogen, benzyl, acetyl, tosyl, 2-nitrobenzyl, 3,4-dimethoxybenzyl or p-methoxybenzyl, into the compound of the formula XIa ##STR161## (4) subsequently cyclizing this with a catalytic amount of a Lewis or Bronsted acid in an aprotic organic solvent to give the compound of the formula XIIa ##STR162## (5) subjecting this compound to a further cyclization by reaction with an oxidizing agent and (6) in the tricyclic compound of the formula VIIIa thus obtained ##STR163## wherein in the compounds of the formulae XIa, XIIa and VIIIa the radical L21 is as defined, splitting off the radical L21 by oxidation or reduction and thus converting the compound into the compound of the formula XIIIa ##STR164## (7) in which the N--O bond is split with an organometallic compound or by hydrogenolysis to give the compound of the formula XIVa ##STR165## and (8) subsequently hydrolysing this compound to remove the isopropylidene protective group. - View Dependent Claims (22, 23, 24, 25, 26, 27, 28, 29)
- space="preserve" listing-type="equation">L.sub.2 N═
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13. A process for the preparation of the compound of the formula Ia ##STR166## which comprises (9) reacting the compound of the formula IIb ##STR167## in which TBDMS is the protective group ##STR168## with an acetylide and subsequently with acetic anhydride, and (10) removing the TBDMS protective group, in the compound of the formula IXb thus obtained ##STR169## (11) by means of N-hydroxyphthalimide (12) followed by hydrazinolysis, obtaining the alkoxylamine derivate of the formula XIb ##STR170## and (4) cyclizing this with a catalytic amount of Lewis or Bronsted acid in an aprotic
the compound of the Formula XIIb ##STR171## and (3) converting this with p-methoxybenzyl isocyanate into the compound of the formula XIIe ##STR172## and (13) subsequently reducing this to give the compound of the formula XIIf ##STR173## subjecting the latter compound, (14) after the ozonolysis and reaction with dimethyl sulfide, (15) to a further oxidation to give the compound of the formula VIIIa ##STR174## wherein in the compounds of the formulae XIIe, XIIf and VIIIa, the PMB radical is the p-methoxybenzyl group, (6) splitting off the radical PMB in the compound of the formula VIIIa with cerium ammonium nitrate and thus converting the compound into the compound of the formula XIIIa ##STR175## (7) in which the N--O bond is split with an organometallic compound or by hydrogenolysis to give the compound of the formula XIVa ##STR176## (8) and subsequently hydrolysing this compound to remove the isopropylidene protective group.
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Current AssigneeCiba-Geigy Corporation (Novartis Ag)
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Original AssigneeNovartis Corporation (Novartis Ag)
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InventorsChemla, Philippe
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Primary Examiner(s)Wilson, James O.
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Application NumberUS08/265,297Time in Patent Office1,320 DaysField of Search536/28.6, 536/28.7, 536/28.8, 536/27.22, 536/55.3, 544/1, 544/63, 544/65, 548/300.7, 548/301.4US Class Current536/55.3CPC Class CodesC07D 491/10 Spiro-condensed systemsC07F 9/6561 containing systems of two o...C07H 9/04 Cyclic acetals
