US2004249172A1PendingUtilityA1
Process for the preparationof prostaglandins and analogues thereof
Priority: May 24, 2001Filed: May 24, 2002Published: Dec 9, 2004
Est. expiryMay 24, 2021(expired)· nominal 20-yr term from priority
C07F 7/1892C07D 307/935C07C 405/00C08F 295/00C07F 7/1804
41
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Claims
Abstract
Disclosed are processes for the synthesis and purification of prostaglandins and analogues thereof, especially analogues of PGF 2α .
Claims
exact text as granted — not AI-modified1 - 101 (canceled)
102 . A process for the synthesis of a compound of Formula (I-A) or (I-B):
comprising the steps of:
(1) subjecting a compound of Formula (X):
wherein
A represents C 6 to C 10 aryl which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of (i) halo, (ii) C 1 to C 6 alkyl and (iii) unsubstituted C 6 to C 10 aryl,
comprising subjecting a compound of Formula (X):
to an oxidation reaction in the presence of a catalytic amount of a stable organic nitroxyl radical,
(2) subjecting a compound of Formula (IX) as defined above to reaction with a compound having the formula:
wherein B represents a substituent selected from the group consisting of:
(i) C 1 to C 6 alkyl, (ii) C 7 to C 16 aralkyl, wherein the aryl group may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C 1 to C 6 alkyl, halo and CF 3 and (iii) —(CH 2 ) n OR a , wherein n represents 1, 2 or 3 and R a represents a C 6 to C 10 aryl group which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C 1 to C 6 alkyl, halo or CF 3 , and
each R′″ is the same or different and each represents a C 1 to C 6 alkyl group,
the process being carried out in the presence of lithium chloride and an organic base to form the compound of Formula (VIII):
(3) reducing the side chain oxo group of the compound of Formula (VIII) with a reducing agent to form a compound of Formula (VII):
(4) deprotecting the hydroxyl group of the compound of Formula (VII) to form the corresponding hydroxy-substituted compound of Formula (VI):
(5) when the dashed line in the compound of Formula (I-A) or (I-B) is absent: hydrogenating the double bond of a compound of Formula (VI), to form a compound of Formula (VI-A):
(6) subjecting the compound of Formula (VI) or (VI-A) to reaction with a silylating agent of formula
wherein R x , R y and R z are the same or different and each independently represents C 1 to C 6 alkyl, C 6 to C 10 aryl or C 7 to C 16 aralkyl, to form a compound of Formula (V):
wherein R′ represents:
(7) reducing the lactone oxo group of the compound of Formula (V) to form a compound of Formula (IV):
(8) subjecting the compound of Formula (IV) to a Wittig reaction with an ylide, the ylide being formed from the reaction of a compound of formula:
HO
2
C
(
CH
2
)
4
P
⊕
(
R
W
)
3
X
⊖
HO 2 C(CH 2 ) 4 P(R w ) 3 X
with a strong base, wherein R w represents C 1 to C 6 alkyl or C 6 to C 10 aryl and X represents F, Cl, Br or I,
to form a compound of Formula (IIIa) or (IIIb) or a mixture thereof:
(9) for compounds of Formula (I-B): subjecting a compound of Formula (IIIa) or Formula (IIb) or a mixture thereof, to reaction with an alkyl halide of formula R″-Hal, wherein R″ represents a C 1 to C 6 alkyl group or a C 3 to C 8 cycloalkyl group, and “Hal” represents chloro, bromo or iodo, in the presence of DBU [1,8-diaza-bicyclo(5.4.0)undec-7-ene], to form a compound of Formula (IIa) or (IIb):
or a mixture thereof; and
(10) removing the protecting groups from: (a) the compound of Formula (IIIa) or (IIIb) or a mixture thereof to form the compound of Formula (I-A), or (b) a compound of Formula (IIa) or (IIb) or a mixture thereof to form the compound of Formula (I-B).
103 . A process according to claim 102 for the synthesis of a compound of Formula (I-B) wherein the dashed line is absent, the process comprising carrying out steps (1) and (2) as defined in claim 1 , carrying out the following steps (3′), (4′) and (5′):
(3′) subjecting the double bond of the compound of Formula (VIII) to a hydrogenation reaction to form a compound of Formula (XIII):
(4′) reducing the side chain oxo group of the compound of Formula (XIII) to form a compound of Formula (XIV):
(5′) deprotecting the hydroxyl group of the compound Formula (XIV) to form a compound of Formula (VI-A):
subjecting the above compound of Formula (VI) to reaction steps (6), (7), (8), (9) and (10) as defined in claim 102 .
104 . A process according to claim 102 for the synthesis of a compound of Formula (I-A) or (I-B) the process comprising producing a compound of Formula (IIIa) or Formula (IIIb) or a mixture thereof according to claim 1 :
and further carrying out the steps of:
(9a) subjecting the compound of Formula (IIIa) or (IIIb) or a mixture thereof, to reaction with at least one molar equivalent of silylating agent to form a compound of Formula (XI):
(10a) for compounds of Formula (I-B): subjecting the compound of Formula (XI) to a transesterification reaction with an alcohol having the formula R″—OH, wherein R″ represents C] to C 6 alkyl or C 3 to C 8 cycloalkyl optionally in the presence of a weak acid catalyst to form the compound of Formula (XII):
(11a) removing the protecting groups R′ from either (a) the compound of Formula (XI) to form the compound (I-A) or (b) the compound of Formula (XII) to form the compound (I-B).
105 . A process according to claim 102 for the production of a compound of Formula (I-B) comprising carrying out steps (1) to (9) as defined in claim 1 to form a compound of formula (IIa) or (IIb) or a mixture thereof:
and further carrying out the steps of:
(10b) subjecting the compound of Formula (IIa) or (IIb) of a mixture thereof to reaction with at least one molar equivalent of silylating agent to form a compound of Formula (XII):
(11b) removing the protecting groups R′.
106 . A process according to claim 103 for the synthesis of a compound of Formula (I-A) or (I-B) the process comprising producing a compound of Formula (IIIa) or Formula (IIIb) or a mixture thereof according to claim 2 :
and further carrying out the steps of:
(9a) subjecting the compound of Formula (IIIa) or (IIIb) or a mixture thereof, to reaction with at least one molar equivalent of silylating agent to form a compound of Formula (XI):
(10a) for compounds of Formula (I-B): subjecting the compound of Formula (XI) to a transesterification reaction with an alcohol having the formula R″—OH, wherein R″ represents C 1 to C 6 alkyl or C 3 to C 8 cycloalkyl optionally in the presence of a weak acid catalyst to form the compound of Formula (XII):
and
(11a) removing the protecting groups R′ from either (a) the compound of Formula (XI) to form the compound (I-A) or (b) the compound of Formula (XII) to form the compound (I-B).
107 . A process according to claim 103 for the production of a compound of Formula (I-B) comprising carrying out steps (1) to (9) as defined in claim 2 to form a compound of formula (IIa) or (IIb) or a mixture thereof:
and further carrying out the steps of:
(10b) subjecting the compound of Formula (IIa) or (IIb) of a mixture thereof to reaction with at least one molar equivalent of silylating agent to form a compound of Formula (XII):
and
(11b) removing the protecting groups R′.
108 . A process for the production of a compound of Formula (IX):
wherein
A represents C 6 to C 10 aryl which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of (i) halo, (ii) C 1 to C 6 alkyl and (iii) unsubstituted C 6 to C 10 aryl,
comprising subjecting a compound of Formula (X):
to an oxidation reaction in the presence of a catalytic amount of a stable organic nitroxyl radical.
109 . A process for the preparation of a compound of Formula (XI):
wherein the groups R′ are the same and each represents the substituent:
wherein R x , R y and R z are the same or different and each independently represents C 1 to C 6 alkyl, C 6 to C 10 aryl or C 7 to C 16 aralkyl;
the process comprising reacting a compound of Formula (IIIa) or Formula (IIIb), or a mixture thereof, to reaction with at least a molar equivalent of silylating agent having the formula:
wherein R x , R y and R z are as defined above and X represents F, Cl, Br or I.
110 . A process for the production of a compound of Formula (XII):
wherein
each R′ is preferably the same and each represents the substituent:
wherein
R x , R y and R z are the same or different and each independently represents C 1 to C 6 alkyl, C 6 to C 10 aryl or C 7 to C 16 aralkyl; and
R″ represents C 1 to C 6 alkyl or C 3 to C 8 cycloalkyl
the process comprising subjecting a compound of Formula (IIa) or Formula (IIb), or a mixture thereof, to reaction with at least one molar equivalent of silylating agent having the formula:
wherein R x , R y and R z are as defined above and the group X represents F, Cl, Br or I.
111 . A process for the preparation of a compound of Formula (XII):
wherein:
each R′ is preferably the same and each represents the substituent:
wherein R x , R y and R z are the same or different and each independently represents C 1 to C 6 alkyl, C 6 to C 10 aryl or C 7 to C 16 aralkyl; and
R″ represents C 1 to C 6 alkyl or C 3 to C 8 cycloalkyl;
the process comprising subjecting a compound of Formula (XI):
wherein the groups R′ are preferably the same and each represents the substituent:
wherein R x , R y and R z are the same or different and each independently represents C 1 to C 6 alkyl, C 6 to C 10 aryl or C 7 to C 16 aralkyl;
to a transesterification reaction with an alcohol having the formula R″—OH, wherein R″ represents C 1 to C 6 alkyl or C 3 to C 8 cycloalkyl.
112 . A process for the production of a compound of Formula (I-A):
wherein
B represents a substituent selected from the group consisting of:
(i) C 1 to C 6 alkyl, (ii) C 7 to C 16 aralkyl, wherein the aryl group may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C 1 to C 6 alkyl, halo and CF 3 and (iii) (CH 2 ) n OR a , wherein n represents 1, 2 or 3 and R a represents a C 6 to C 10 aryl group which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C 1 to C 6 alkyl, halo or CF 3 ;
the process comprising removing the silyl protecting groups, R′, from a compound selected from the group consisting of
(i) a compound of Formula (IIIa), Formula (IIIb) or a mixture thereof:
(ii) a compound of Formula (XI):
wherein B and R′ are as defined in any preceding claim.
113 . A process for the production of a compound of Formula (I-B):
wherein
B represents a substituent selected from the group consisting of:
(i) C 1 to C 6 alkyl, (ii) C 7 to C 16 aralkyl, wherein the aryl group may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C 1 to C 6 alkyl, halo and CF 3 and (iii) —(CH 2 ) n OR a , wherein n represents 1, 2 or 3 and R a represents a C 6 to C 10 aryl group which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C 1 to C 6 alkyl, halo or CF 3 ; and
R″ represents, C 1 to C 6 alkyl or C 3 to C 8 cycloalkyl;
the process comprising removing the silyl protecting groups R′ from a compound of Formula (XII):
wherein B and R″ are as defined as above.
114 . A process according to claim 102 wherein the oxidation reaction is carried out by electrooxidation.
115 . A process according to claim 102 wherein the oxidation reaction is carried out in the presence of at least one mole of co-oxidant selected from the group consisting of m-chloroperbenzoic acid, high valent metal salts, sodium bromite, sodium or calcium hypochlorite, N-chloro-succinimide or hypervalent iodine compounds such as [bis(acetoxy)iodo]benzene.
116 . A process according to claim 102 wherein the nitroxyl radical is a completely α-substituted piperidin-1-oxy radical, such as TEMPO free radical.
117 . A process according to claim 102 wherein the reducing agent for reducing the side chain oxo group is selected from the group consisting of borane-dimethylsulfide complex, lithium tri-sec-butylborohydride and sodium borohydride.
118 . A process according to claim 102 wherein the reduction of the side chain oxo group is carried out in the presence of a chiral oxazaborolidine catalyst (Corey catalyst) to form a single enantiomer of the compound of Formula (VII).
119 . A process according to claim 102 wherein the reduction of the side chain oxo group is carried out in the presence of oxa(R)-tetrahydro-1-methyl-3,3-diphenyl-1H, 3H-pyrrole-[1,2-c][1,3,2]-oxazaborole.
120 . A process according to claim 102 wherein the hydroxyl deprotection step to produce the compound of formula (VI) is carried out in the presence of a base selected from the group consisting of K 2 CO 3 , Na 2 CO 3 and Li 2 CO 3 .
121 . A process according to claim 102 wherein hydrogenation reaction is carried out by catalytic hydrogenation in the presence of a catalyst comprising palladium, platinum or rhodium optionally in the presence of sodium nitrite.
122 . A process according to claim 102 wherein the silylating agent is selected from the group consisting of trimethylsilyl chloride, triethylsilyl chloride and tert-butyldimethylsilyl chloride.
123 . A process according to claim 102 wherein the reducing agent in step (7) is di-iso-butylaluminium hydride.
124 . A process according to claim 102 wherein the removal of the protecting group R′ is carried out using a weak acid selected from the group consisting of acetic acid, citric acid or pyridinium p-toluene sulfonate.
125 . A process according to claim 102 wherein A represents phenyl.
126 . A process according to claim 102 wherein R w represents phenyl and X represents Br.
127 . A process according to claim 102 wherein the group R″ represents isopropyl.
128 . A process according to claim 102 wherein B is selected from the group consisting of (i) C 1 to C 6 alkyl, (ii) C 7 to C 16 aralkyl wherein the aryl group is unsubstituted and (iii) —(CH 2 ) n OR a , wherein n represents 1, 2 or 3 and R a represents a C 6 to C 10 aryl group which is substituted with a substituent selected from halo or CF 3 .
129 . A process according to claim 102 wherein B represents a substituent selected from the group consisting of:
130 . A process according to claim 102 wherein the wavy line in side chain of compounds of any of Formulae (VII), (VI), (VI-A), (V), (IV), (IIIa), (IIIb), (IIa), (IIb), (XI), (XII) or (XIV) represents a single enantiomer.
131 . A process according to claim 102 for the synthesis of a compound selected from the group consisting of:
132 . A compound of Formula (XIII):
wherein A represents unsubstituted C 6 to C 10 aryl, and
B represents a substituent selected from the group consisting of:
(i) C 1 to C 6 alkyl, (ii) C 7 to C 16 aralkyl, wherein the aryl group may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C 1 to C 6 alkyl, halo and CF 3 and (iii) (CH 2 ) n OR a , wherein n represents 1, 2 or 3 and R a represents a C 6 to C 10 aryl group which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C 1 to C 6 alkyl, halo or CF 3 .
133 . A compound of Formula (XIV):
or a single enantiomer thereof, wherein
A represents unsubstituted C 6 to C 10 aryl and
B represents a substituent selected from the group consisting of:
(i) C 1 to C 6 alkyl, (ii) C 7 to C 16 aralkyl, wherein the aryl group may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C 1 to C 6 alkyl, halo and CF 3 and (iii) —(CH 2 ) n OR a , wherein n represents 1, 2 or 3 and R a represents a C 6 to C 10 aryl group which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C 1 to C 6 alkyl, halo or CF 3 .
134 . A process for the purification of latanoprost by HPLC comprising the use as an eluent, of a mixture comprising one or more hydrocarbons, one or more alcohols and, optionally, acetonitrile.
135 . A process according to claim 134 wherein the eluent comprises at least one hydrocarbon, at least one alcohol and acetonitrile.
136 . A process according to claim 134 wherein the eluent comprises a hydrocarbon or a mixture of hydrocarbons in an amount range of 80-99 volume percent and an alcohol or a mixture of alcohols in an amount range of 1-20 volume percent.
137 . A process according to claim 134 wherein the eluent comprises a hydrocarbon or a mixture of hydrocarbons in an amount range of 88-98 volume percent and an alcohol or a mixture of alcohols in an amount range of 2-12 volume percent.
138 . A process according to claim 134 wherein the eluent comprises a hydrocarbon or a mixture of hydrocarbons in an amount range of 85-99 volume percent, an alcohol or a mixture of alcohols in an amount of 0.5-10 volume percent and acetonitrile in an amount of 0.5-5 volume percent.
139 . A process according to claim 134 wherein the hydrocarbon is hexane or heptane.
140 . A process according to claim 134 wherein the alcohol component comprises at least one C 1 to C 8 straight chain, branched or cyclic alkanol.
141 . A process according to claim 134 wherein the alcohol comprises propan-2-ol.
142 . Latanoprost substantially free of the 15(S)-cis isomer, the 15(S)-trans isomer and the 15(R)-trans isomer.
143 . Latanoprost according to claim 142 containing less than 0.3% in total of any combination of: 15(S)-cis isomer, 15(S)-trans isomer and 15(R)-trans isomer.
144 . Latanoprost according to claim 142 containing less than 0.1% each of 15(S)-cis isomer, 15(S)-trans isomer and 15(R)-trans isomer.
145 . Latanoprost having a purity of greater than 98%.
146 . Latanoprost according to claim 145 having a purity of greater than 99%.
147 . Latanoprost according to claim 145 having a purity of greater than 99.5%.
148 . Latanoprost according to claim 145 having a purity of greater than 99.8%.Cited by (0)
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