Europaisches Patentamt
`
`European Patent Office
`
`Office europeen des brevets
`
`111111111111111111111111111111111111111111111111111111111111111111111111111
`
`@ Publication number:
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`0427680 A1
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`®
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`EUROPEAN PATENT APPLICATION
`
`@ Application number: 90810854.1
`
`@ Date of filing: 07.11.90
`
`@ Int. C1.5: C07D 498/18, A61 K 31133,
`/1(C07D498/18,311 :00,273:00,
`221 :00)
`
`Humboldtstrasse 3
`W·7850 Lorrach(DE)
`@ DE
`
`Applicant: SANDOZ·ERFINDUNGEN
`Verwaltungsgesellschaft m.b.H.
`Brunner Strasse 59
`A·1235 Wien(AT)
`@AT
`® Inventor: Baumann, Karl
`Simmeringer Hauptstrasse 36/2/29
`A·1110 Vienna(AT)
`Inventor: Emmer, Gerhard
`Theresiengasse 25
`A-1180 Vienna(AT)
`
`@ Priority: 09.11.89 DE 3937336
`16.11.89 DE 3938132
`23.12.89 DE 3942831
`23.12.89 DE 3942833
`05.03.90 DE 4006819
`
`@ Date of publication of application:
`15.05.91 Bulletin 91/20
`
`@ Designated Contracting States:
`AT BE CH DE OK ES FR GB GR IT LI LU NL SE
`
`@ Applicant: SANDOZ LTD.
`Lichtstrasse 35
`CH·4002 Basel(CH)
`@ BE CH OK ES FR GB GR IT LI LU NL SE
`
`Applicant: SANDOZ·PATENT ·GMBH
`
`® Heteroatoms·containing tricyclic compounds.
`
`@ The invention concerns the compounds of formula I
`
`Xerox Copy Centre
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`29
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`24
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`23
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`I
`
`wherein the substituents have various significances.
`They are prepared by several processes including epimenzmg replacement, treatment with cyanogen
`bromide or thiophosgene, treatment with an acid having a non-nucleophilic anion, treatment with dimethylsulfox(cid:173)
`ide and acetic anhydride, acylation, treatment with an oxalyl derivative and ammonia, methylation, oxidation,
`deprotection and protection.
`They possess interesting pharmacological activity as antiinflammatory, immunosuppressant, anti proliferative
`and chemotherapeutic drug resistance reversing agents.
`
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`HETEROATOMS·CONT AINING TRICYCLIC COMPOUNDS
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`The invention relates to the field of macrolides. It concerns the compounds of formula I
`
`CB3
`
`CR3 .
`
`o
`
`I
`
`(a)
`
`.•• 'CR,
`
`OCR3
`
`wherein
`either R1 is a group (a) of formula
`
`B
`
`wherein Rs is chloro, bromo, iodo or azido and
`R6 is hydroxy or methoxy;
`R2 is oxo and there is a single bond in 23,24 position; optionally protected hydrory and there is a single or
`a double bond in 23,24 position; or absent and there is a double bond in 23,24 position; and
`R4-
`is hydroxy and there is a single bond in 10,11 position; or absent and there is a double bond in 10,11
`position;
`or R1 is a group (b) or (d) of formula
`
`3
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`5
`
`10
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`15
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`20
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`25
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`30
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`35
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`40
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`45
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`EP 0427680 A1
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`NC-O
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`B
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`(b)
`
`and
`
`B
`
`(d)
`
`OBC
`
`wherein R6 is as defined above;
`R2 is as defined above; and
`R4 is hydroxy and there is a single bond in 10,11 position;
`or R, is a group (c) of formula
`
`B
`
`(c)
`
`5
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`10
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`15
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`20
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`25
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`35
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`40
`
`wherein R6 is as defined above and
`is oxo; optionally protected hydroxy; methoxy; methylthiomethoxy; isobutanoyloxy; aminooxalyloxy;
`R7
`RsRsCHCOO- wherein Rs is optionally protected hydroxy or optionally protected amino and Rs is hydrogen
`30 or methyl; or p-tolyloxythiocarbonyloxy;
`R2 is oxo and there is a single bond in 23,24 position; absent and there is a double bond in 23,24 position;
`or is optionally protected hydroxy, methoxy, methylthiomethoxy, isobutanoyloxy, aminooxalyloxy or RsRsCH
`COO- wherein Rs and Rs are as defined above, and there is a single or a double bond in 23,24 position;
`whereby for group (c)
`1) when R7 is oxo, unprotected hydroxy or methoxy
`then R2 is other than absent and other than unprotected hydroxy or methoxy, and
`there is a single bond in 23,24 position;
`2) when R6 is methoxy and R7 is methylthiomethoxy
`then R2 is other than absent and other than unprotected hydroxy;
`3) when R6 is methoxy and R7 is protected hydroxy
`then R2 is other than optionally protected hydroxy; and
`4) when R6 is hydroxy
`then R7 is other than optionally protected hydroxy; and
`R4 is hydroxy and there is a single bond in 10,11 position; and
`R3 is methyl, ethyl, n-propyl or allyl;
`in free form and, where such forms exist, in salt form,
`hereinafter referred to as "the compounds of the invention".
`As is evident from formula I and the definition of the substituents when there is a single bond in 10,11
`position the carbon atom to which the methyl group in 11 position is attached has the .B-configuration and
`there is a hydrogen atom with the a-configuration attached to the carbon atom in 11 position; when there is
`a double bond in 10,11 position this methyl group lies in the plane of the paper and there is no hydrogen
`atom in 11 position. When R2 is oxo no hydrogen atom is attached to the carbon atom in 24 position. When
`R7 is oxo the hydrogen atom shown in group (c) attached to the same carbon atom as R7 is absent.
`R, preferably is a group (c) or (d). R2 preferably is unprotected hydroxy and there is a single bond in
`55 23,24 position. R3 preferably is ethyl or allyl. R4- preferably is hydroxy. Rs preferably is chiaro. R6
`preferably is methoxy. RJ preferably is isobutanoyloxy, aminooxalyloxy or RsRsCHCOO-. Rs preferably is
`unprotected hydroxy or unprotected amino, especially unprotected hydroxy. Rs preferably is hydrogen.
`is other than hydrogen the carbon atom to which it is attached preferably has the (8)
`When Rs
`
`45
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`4
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`configuration.
`Protected hydroxy preferably is hydroxy protected by a conventional hydroxy-protecting group such as
`formyl, tert-butoxycarbonyl, or trialkylsilyl; it especially is tert-butyldimethylsilyloxy.
`Optionally protected hydroxy as defined above under formula I for R2 and R7 should not be understood
`as including a group R2 or R7 which is otherwise specified, such as e.g. aminooxalyloxy or Rs RsCHCOO-.
`Protected amino preferably is amino protected by a conventional amino-protecting group such as
`benzyloxycarbonyl or trialkylsilyl; it especially is tert-butoxycarbonyl.
`A compound of the invention preferably is in free form. It preferably is in unprotected form.
`A subgroup of compounds of the invention is the compounds Ip1, i.e. the compounds of formula I
`10 wherein
`R1 is a group (a) wherein R6 is methoxy and
`either Rs is chloro or bromo and
`R.,. is hydroxy and there is a single bond in 10,11 position
`or Rs is azido and
`R.,. is hydroxy and there is a single bond in 10,11 position or absent and there is a double bond in 10,11
`position;
`R2 is optionally protected hydroxy and there is a single or a double bond in 23,24 position; and
`R3 is as defined above under formula I;
`in free form and, where such forms exist, in salt form.
`A further subgroup of compounds of the invention is the compounds Ip2, i.e. the compounds of
`formula I wherein
`is oxo; optionally protected hydroxy; methoxy;
`is methoxy and R7
`R1
`is a group (c) wherein R6
`methylthiomethoxy; aminooxalyloxy; RsCH2COO- wherein Rs
`is optionally protected amino; or p-tolylox(cid:173)
`ythiocarbonyloxy;
`is absent and there is a double bond in 23,24 position; or optionally protected hydroxy, methoxy,
`25 R2
`methylthiomethoxy or aminooxalyloxy and there is a single or double bond in 23,24 position;
`whereby
`1) when R7 is oxo, unprotected hydroxy or methoxy
`then R2 is other than absent and other than unprotected hydroxy or methoxy, and
`there is a single bond in 23,24 position;
`2) when R7 is methylthiomethoxy
`then R2 is other than absent and other than unprotected hydroxy; and
`3) when R7 is protected hydroxy
`then R2 is other than optionally protected hydroxy; and
`R4-
`is hydroxy and there is a single bond in 10,11 position; and
`R3 is as defined above under formula I;
`in free form and, where such forms exist, in salt form.
`A further subgroup of compounds of the invention is the compounds Ip3, i.e. the compounds of
`formula I wherein
`R1 is a group (b) wherein R6 is methoxy,
`R2 is optionally protected hydroxy and there is a single bond in 23,24 position; or absent and there is a
`double bond in 23,24 position;
`R.,. is hydroxy and there is a single bond in 10,11 position; and
`Ra is as defined above under formula I;
`in free form and, where such forms exist, in salt form.
`A further subgroup of compounds of the invention is the compounds Ip.,., i.e. the compounds of
`formula I wherein
`R1 is a group (d),
`R2 is optionally protected hydroxy and there is a single bond in 23,24 position; or absent and there is a
`50 double bond in 23,24 position;
`RI\. is hydroxy and there is a single bond in 10,11 position; and
`R3 is as defined above under formula I;
`in free form and, where such forms exist, in salt form.
`A preferred subgroup of compounds of the invention is the compounds of formula I wherein
`R1 is a group (a) wherein Rs is as defined above under formula I and R6 is methoxy;
`R2 is optionally protected hydroxy and there is a single bond in 23,24 position;
`R.,. is hydroxy and there is a single bond in 23,24 position; or absent and there is a double bond in 10,11
`position; and
`
`35
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`R3 is ethyl or allyl.
`A further preferred group of compounds of the invention is the compounds of formula I wherein
`Rl is a group (b) wherein R6 is methoxy;
`R2 is optionally protected hydroxy and there is a single bond in 23,24 position; or absent and there is a
`double bond in 23,24 position;
`R4- is hydroxy and there is a single bond in 10,11 position; and
`R3 is ethyl or allyl.
`A further preferred group of compounds of the invention is the compounds of formula I wherein
`Rl is a group (c) wherein R6 is methoxy and R7 is as defined above under formula I;
`10 R2 is oxo and there is a single bond in 23,24 position; or optionally protected hydroxy, methylthiomethoxy,
`aminooxalyloxy , RsCH2COO- wherein Rs is optionally protected amino, and there is a single or a double
`bond in 23,24 position;
`whereby
`1) when R7 is oxo, unprotected hydroxy or methoxy
`then R2 is other than unprotected hydroxy or methoxy, and there is a single bond in 23,24 position;
`2) when R7 is methylthiomethoxy
`then R2 is other than unprotected hydroxy; and
`3) when R7 is protected hydroxy
`then R2 is other than optionally protected hydroxy;
`R4- is hydroxy and there is a single bond in 10,11 position; and
`R3 is ethyl or allyl.
`A further preferred subgroup of compounds of the invention is the compounds of formula I wherein
`Rl is a group (d),
`R2 is optionally protected hydroxy and there is a single bond in 23,24 position; or absent and there is a
`25 double bond in 23,24 position;
`R4- is hydroxy and there is a single bond in 10,11 position; and
`R3 is ethyl or allyl.
`A further subgroup of compounds of the invention is the compounds Jq, i.e. the compounds of formula
`I wherein
`30 either Rl is a group (a) wherein Rs is chloro, bromo, iodo or azido and R6 is hydroxy or methoxy,
`R2 is oxo and there is a single bond in 23,24 position; optionally protected hydroxy and there is a single or
`a double bond in 23,24 position; or absent and there is a double bond in 23,24 position; and
`R .. is hydroxy and there is a Single bond in 10,11 position; or absent and there is a double bond in 10,11
`position;
`35 or Rl is a group (b) or (d) wherein R6 is hydroxy or methoxy;
`R2 is as defined above for this subgroup; and
`R .. is hydroxy and there is a single bond in 10,11 position;
`or Rl is a group (c) wherein
`R6 is hydroxy or methoxy and
`is aminooxalyloxy; Rs Rs CHCOO- wherein Rs
`is optionally protected hydroxy or optionally protected
`40 R7
`amino and R9 is hydrogen or methyl; or p-tolyloxythiocarbonyloxy;
`is methylthiomethoxy, isobutanoyloxy, amninooxalyloxy or Rs RsCHCOO- wherein Rs and Rs are as
`R2
`defined above for this subgroup, and there is a single or double bond in 23,24 position;
`and
`45 R .. is hydroxy and there is a single bond in 10,11 position; and
`R3 is methyl, ethyl, n-propyl or allyl,
`in free form and, where such forms exist, in salt form.
`A further subgroup of compounds of the invention is the compounds Jr, i.e. the compounds of formula
`I wherein
`50 either Rl is a group (a) as defined above under formula I; and
`R2 and R .. have the significance indicated above under group (a);
`or Rl is a group (b) or (d) as defined above under formula I; and
`R2 and R4- have the significance indicated above under groups (b) and (d);
`or Rl is a group (c) as defined above under formula I wherein
`55 R6 is as defined above under formula I and
`R7 with the exception of optionally protected hydroxy has the significance indicated above under group (c);
`whereby for group (c)
`1) when R7 is oxo or methoxy
`
`6
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`then R2 is other than absent and other than methoxy, and there is a single bond in 23,24 position; and
`2) when R6 is methoxy and R7 is methylthiomethoxy
`then R2 is other than absent; and
`R4 has the significance indicated above under group (c); and
`R3 is as defined above under formula I;
`in free form and, where such forms exist, in salt form.
`In a subgroup of compounds Ir R7
`is other than oxo or methoxy; in a further subgroup when R6
`is
`methoxy then R7 is other than methylthiomethoxy; in a further subgroup R2 is other than absent and other
`than methoxy.
`A further subgroup of compounds of the invention is the compounds of formula Is
`
`29
`
`Is
`
`•••. CBl
`
`OCB 3
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`wherein
`either R1s is a group (a) wherein Rs is chloro, bromo, iodo or azido and RG is methoxy;
`R2s is hydroxy optionally protected by tert-butyldimethylsilyloxy and there is a single bond in 23,24 position:
`and
`45 R4s is hydroxy and there is a single bond in 10,11 position; or absent and there is a double bond in 10,11
`position;
`or R1s is a group (b) wherein R6 is methoxy, or a group (d);
`R2s is hydroxy optionally protected by tert-butyldimethylsilyloxy and there is a single bond in 23,24 position:
`or absent and there is a double bond in 23,24 position; and
`50 R4s is hydroxy and there is a single bond in 10,11 position;
`or R1s is a group (c) wherein
`R6 is methoxy and
`R7
`tert-butyldimethylsilyloxy; methoxy; methylthiomethoxy;
`is oxo; hydroxy optionally protected by
`isobutanoyloxy; aminooxalyloxy; Rs R9 CHCOO- wherein Rs
`is hydroxy optionally protected by tert-butyl-
`55 dimethylsilyloxy or amino optionally protected by tert-butoxycarbonyl and R9 is hydrogen or methyl; or p(cid:173)
`tolyloxythiocarbonyloxy;
`R2s is oxo and there is a single bond in 23,24 position; absent and there is a double bond in 23,24 position;
`or is hydroxy optionally protected by tert-butyldimethylsilyloxy, methoxy, methylthiomethoxy, aminoox-
`
`7
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`is
`
`is amino optionally protected by tert-butoxycarbonyl and Rs
`alyloxy or RsR9CHCOO- wherein Rs
`hydrogen, and there is a single bond in 23,24 position;
`whereby for group (c)
`1) when R7 is oxo, unprotected hydroxy or methoxy
`then R2s is other than absent and other than unprotected hydroxy or methoxy, and
`there is a single bond in 23,24 position;
`2) when R7 is methylthiomethoxy
`then R2s is other than absent and other than unprotected hydroxy;
`and
`3) when R7 is hydroxy protected by tert-butyldimethylsilyloxy
`then R2s is other than hydroxy optionally protected by tert-butyldimethylsilyloxy; and
`R4s is hydroxy and there is a single bond in 10,11 position; and
`Ras is ethyl or allyl,
`in free form and. where such forms exist, in salt form.
`A compound of the invention can be obtained by a process comprising
`a) for the preparation of a compound of formula I wherein
`Rl is a group (a) as defined above under formula I,
`R2 and R3 are as defined above under formula I and
`R4 is hydroxy
`(Le. a compound la),
`replacing under simultaneous epimerization the hydroxy group by chlorine. bromine, iodine or azido in a
`corresponding compound having unprotected hydroxy in 33 position (i.e. a compound IIa. of formula lIa
`
`ao
`
`a
`
`.
`ca,
`
`24
`23
`.. '---""\
`
`o
`
`IIa
`
`····CR,
`
`oca,
`
`8
`
`5
`
`10
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`15
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`20
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`25
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`30
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`35
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`wherein R2 and Rs are as defined above under formula I and
`RG is hydroxy or methoxy):
`b) for the preparation of a compound of formula I wherein
`R1 is a group (b) as defined above under formula I,
`R2 and Rs are as defined above under formula I and
`R4 is hydroxy
`(Le. a compound Ib),
`treating a corresponding compound lIa with cyanogen bromide in the presence of a base or
`treating a corresponding compound lIa with thiophosgene, reacting the resultant product with an
`inorganic azide and allowing the resultant unstable intermediate having a group
`
`N--N C--()-
`II
`I
`N
`S
`
`is oxo or
`
`in 33 position (Le. a compound lib)
`to decompose to a corresponding compound Ib;
`c} for the preparation of a compound of formula I wherein
`R1 is a group (d) as defined above under formula I,
`R2 and Rs are as defined above under formula I and
`R4- is hydroxy
`(Le. a compound Ie),
`treating a corresponding compound Ib with an acid having a non-nucleophilic anion;
`d) for the preparation of a compound of formula I wherein
`R1
`is a group (c) wherein R6
`is as defined above under formula I, one of R2 and R7
`methylthiomethoxy and the other is protected hydroxy,
`R3 is as defined above under formula I and
`R4 is hydroxy
`(i.e. a compound Id),
`treating a corresponding compound wherein
`one of the substituents in 24 and 33 position is hydroxy and the other is protected hydroxy,
`(Le. a compound lie)
`with dimethylsulfoxide and acetanhydride;
`e} for the preparation of a compound of formula I wherein
`R1 is a group (c) wherein
`R6 is as defined above under formula I and
`R7
`is isobutanoyloxy, aminooxalyloxy, Ra R9 CHCQQ- as defined above under formula I or p-tolylox(cid:173)
`ythiocarbonyloxy,
`R2 and R3 are as defined above under formula I and
`R4 is hydroxy
`(Le. a compound Ie),
`appropriately acylating a corresponding compound lIa;
`f} for the preparation of a compound of formula I wherein
`R1 is a group (c) wherein
`R6 is as defined above under formula I and
`R7 is aminooxalyloxy,
`R2 is optionally protected hydroxy or is aminooxalyloxy,
`R3 is as defined above under formula I and
`R4 is hydroxy
`(i.e. a compound If),
`treating with a appropriate oxalyl derivative and thereafter with ammonia a corresponding compound
`having a optionally protected hydroxy group in 33 pOSition and a protected hydroxy group in 24 position
`(Le. a compound lid);
`g} for the preparation of a compound of formula I wherein
`R1 is a group (c) wherein R6 is as defined above under formula I,
`R2 and R7 are as defined above under formula I with the proviso that one of R2 and R7 is methoxy,
`Ra is as defined above under formula I and
`
`9
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`10
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`R4 is hydroxy
`(Le. a compound Ig),
`methylating a corresponding compound having a hydroxy group in 24 or 33 position
`(Le. a compound lie);
`h) for the preparation of a compound of formula I wherein
`R1 is a group (c) wherein RG is as defined above under formula I,
`R2 and R7 are as defined above under formula I with the proviso that one of R2 and R7 is oxo,
`R, is as defined above under formula I and
`R4 is hydroxy
`(Le. a compound Ih),
`oxidizing a corresponding compound having a hydroxy group in 24 or 33 position
`(Le. a compound IIf); and
`- when a resultant compound of formula I has a protected hydroxy and/or a protected amino group,
`optionally splitting off the protecting group(s) to give a corresponding compound of formula I having one
`or more unprotected hydroxy and/or unprotected amino group(s)
`(Le. a compound Ij),
`is a group (a), a water molecule may be simultaneously split off and a compound of
`- whereby when R1
`formula I is obtained wherein
`R1 is a group (a) as defined above under formula I,
`R2 is unprotected hydroxy and there is a single or double bond in 23,24 position; and
`R4 is absent and there is a double bond in 10,11 position (Le. a compound Ii); or
`- optionally protecting an unprotected hydroxy and/or unprotected amino group in a resultant compound
`of formula I as appropriate to give a corresponding compound of formula I having one or more protected
`hydroxy and/or protected amino groups(s) (Le. a compound Ik),
`and recovering the resultant compound of formula I in free form and, where such forms exist, in salt
`form.
`The process variants of the invention can be effected in a manner analogous to known procedures.
`Process variant a) is a substitution reaction under simultaneous epimerization. It is preferably effected in
`an inert solvent such as tetrahydrofurane or toluene. Preferably for the substitution by halogen the reaction
`is effected with tetrachloro-, tetrabromo- or tetraiodomethane in the presence of triphenylphosphine, and for
`the substitution by azido with azodicarboxylic acid ester, preferably diethyl ester, and hydrazoic acid. A
`hydroxy group in 24 position may be in protected form. As protecting group known hydroxy protecting
`groups such as tert-butyldimethylsilyl may be used. A protecting group may subsequently be split off in
`accordance with known procedures, e.g. with hydrofluoric acid in acetonitrile. Upon deprotection a water
`35 molecule may, depending on the reaction conditions chosen, simultaneously be split off in position 10,11
`and a double bond formed. The individual compounds can be separated from such a resultant mixture in
`conventional manner, e.g. chromatographically.
`Compounds la may be further processed by e.g. oxidation or dehydration to corresponding compounds
`wherein R .. is absent; for example, oxidation of compounds la wherein R2 is hydroxy leads to corresponding
`40 compounds wherein R4 is absent and R2 is oxo.
`Process variant b) is a cyanidation reaction. It preferably is effected rn an inert solvent such as a
`chlorinated hydrocarbon, e.g. dichloromethane. The temperature preferably is about room temperature. The
`base is e.g. 4-dimethylaminopyridine.
`A compound of formula I obtained accordance to process variants a) and b} above may be isolated
`from the reaction mixture and purified in accordance with known methods. When R2 is hydroxy and there is
`a single bond in 23,24 position a water molecule may be simultaneously split off. A corresponding mixture
`of compounds Ib is obtained wherein either R2 is hydroxy and there is a single bond in 23,24 position or R2
`is absent and there is a double bond in 23,24 position. The individual compounds can be separated from
`such a resultant mixture in conventional manner, e.g. chromatographically.
`The second procedure according to process variant b} is effected by reaction with thiophosgene,
`preferably in the presence of an acid scavenger such as 4-dimethylaminopyridine. Preferably an inert
`solvent such as acetonitrile is used. The temperature preferably is about room temperature. The subse(cid:173)
`quent reaction with a inorganic azide is preferably effected with sodium azide. The resultant compounds lib
`are unstable and decompose already at room temperature to compounds Ib, under splitting off of nitrogen
`55 and sulfur. This reaction step preferably is effected in an inert solvent such as an aromatic hydrocarbon,
`e.g. benzene. Temperature preferably is elevated, e.g. about 50· C.
`In process variant c} a ring contraction takes place. Protecting groups which are present may be
`simultaneously split off. Preferably an inert solvent such as acetonitrile is used. Preferably hydrofluoric acid
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`is used as acid having a non-nucleophilic anion. Temperature preferably is about room temperature.
`Process variant d) is a Swern oxidation. The reaction preferably is effected with compound IIc dissolved
`in dimethylsulfoxide and acetic anhydride. Duration of reaction is prolonged, e.g. about 5 hours. Tempera(cid:173)
`ture preferably is about room temperature.
`Process variant e) is an acylation. It is preferably effected in an inert solvent such as acetonitrile. The
`acylating agent preferably is an activated acyl derivative, such as a acyl halogen ide or anhydride. An acid
`scavenger such as dimethylaminopyridine or pyridine is employed. Further, a compound lIa may also be
`reacted with a carboxylic acid such as glycine protected at the amino moiety by e.g. tert-butoxycarbonyl, or
`with a compound of formula Rs R2 CHCOOH wherein Rg is protected hydroxy and R9 is hydrogen or methyl,
`10 and a carbodiimide such as N-ethyl-N' -(3-dimethylaminopropyl)carbodiimide or N,N' -dicyclo-hexylcar(cid:173)
`bodiimide, where indicated in the presence of a base, such as 4-dimethylaminopyridine, preferably in an
`inert solvent such as acetonitrile or in a chlorinated hydrocarbon. An amino protecting group may
`subsequently be split off together with any hydroxy protecting group which may be present. If in the starting
`compound IIa R2 is hydroxy and there is a single bond in 23,24 position, upon acylation splitting off of a
`15 water molecule in 23,24 position may occur and a compound Ie be formed wherein R2 is absent and there
`is a double bond in 23,24 position.
`Process variant f) is an acylation. It is preferably effected in an inert solvent such as acetonitrile.
`Temperature preferably is reduced, e.g. about 0 to 50 C. The oxalyl derivative preferably is an oxalyl
`halogenide, e.g. chloride. Upon completion of the reaction the mixture is stirred with ammonia.
`Process variant g) is a methylation. It preferably is effected in an inert solvent such as a chlorinated
`hydrocarbon, e.g. dichloromethane. The methylating agent preferably is diazomethane in the presence of
`e.g. borotrifluoride-etherate. Temperature preferably is from about O· to about room temperature.
`Process variant h} is an oxidation. The oxidizing agent is e.g. tetrapropylammonium perruthenate. The
`temperature preferably is about room temperature.
`The optional deprotection process variant may also be effect in conventional manner. For splitting off of
`e.g. tert-butyldimethylsilyl it is effected by treatment with e.g. hydrofluoric acid in a solvent such as
`acetonitrile. Depending on the reaction conditions selected (duration, temperature, etc.) the splitting can be
`steered in such a manner that either all or only some protecting group are removed. Partial deprotection is
`particularly indicated where a definite hydroxy group is to be subsequently reacted in a later reaction.
`The optional protection step variant may also be effected in conventional manner along similar lines.
`Thus for subsequent reactions involving a hydroxy group, particularly a hydroxy group in position 24
`and/or 33, selective protection of only one of the two free hydroxy groups or selective deprotection of only
`one of the two protected hydroxy groups may be effected in such a manner that reaction occurs only at the
`desired position. Mixtures of end products may be obtained thereby; such mixtures can be separated in
`35 conventional manner, e.g chromatographically. Resultant end products still containing protecting groups can
`be subsequently deprotected. Reaction conditions may alternatively be selected such that simultaneously
`with or immediately after reaction the protecting groups are removed (one pot process).
`The compounds of formula I may be isolated and purified from the reaction mixture in conventional
`manner.
`Insofar as their preparation is not specifically described herein, e.g. in the Examples; the compounds
`used as starting materials are known or can be obtained in conventional manner from known compounds,
`e.g. starting from appropriate Streptomyces strains such as Streptomyces tsukubaensis No. 9993 described
`in e.g. Fujisawa EP 184162. Samples can be obtained from the Fermentation Research Institute, Tsukuba,
`Ibaraki 305, Japan under provisions of the Budapest Treaty under deposit No. FERM BP-927. This strain
`45 has been redeposited on April 27, 1989 e.g. as disclosed in Sandoz EP356399, with the Agricultural
`Research Culture Collection International Depository, Peoria, Illinois 61604, USA under the provisions of the
`Budapest Treaty under deposit No. NRRL 18488.
`The following Examples illustrate the invention and are not limitative. All temperatures are in degrees
`Centigrade. All NMR spectra are in CDCb, ppm. The abbreviations have the following meanings:
`50 BOC: tert-butoxycarbonyl;
`cfr: colourless foamy resin:
`db: double bond;
`Et: ethyl;
`FK 506: the compound of formula
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`.. . ·CR,
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`i.e. 17 cx-allyl-1 {3, 14cx-dihydroxy-12-[2' -(4" (R)-hydroxy-3" (R)-methoxycyclohex-1 "(R)-yl)-1' -methyl-trans-vinyl]-
`23cx,25 .s-dimethoxy-13cx, 19 ,21 cx,27 f3-tetramethyl-11 ,28-dioxa-4-azatricyclo[22.3.1 .04,9 ]octacos-18-trans-ene-
`2,3,10,16-tetraone (according to the atom numbering in EP 184162; however, in the Examples the atom
`numbering of formula I is used throughout);
`40 FR 520: as FK 506, but with •• ·CH2CH3 (ethyl) in place of allyl in position 21 in the formula;
`iBuoyloxy: isobutanoyloxy [(H3C)2CHCOO-];
`iPr: isopropyl;
`na: not applicable;
`N3: azido;
`45 OMe (or MeO): methoxy;
`OtBDMS: tert-butyldimethylsilyloxy;
`sb: single bond;
`tBu: tert-butyl.
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`Example 1: 24-tert-Butyldimethylsilyloxy-33-epi-33-chloro-FK506
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`[Formula 1: R1 = a group (a) wherein Rs = chloro, R6 = OMe; R2 = OtBDMS, single bond in 23,24
`55 position; Ra = allyl; R4 = OH, single bond in 10,11 position]
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`[Process variant a), replacement with epimerization]
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`0.092 9 24·tert·butyldimethylsilyloxy·FK506 is heated for 15 hours under refluxing with 0.037 9
`triphenylphosphine in 4 ml of. tetrachloromethane. The solvent is evaporated to dryness under reduced
`pressure and the residue is purified by column chromatography over silicagel using a mixture of hexane
`and acetic acid ethyl ester (2:1) as the eluant. The title compound is obtained (colourless foam):
`1H·NMR: about 2:3 mixture of conformers:
`main conformer: 4.56 (m, W1/2 = 7 Hz, H-33).
`The starting material is obtained as follows:
`a) 20 9 FK 506 is dissolved in 400 ml of dry dimethylformamide, 5.08 9 imidazole and 11.25 9 tert(cid:173)
`butyldimethylchlorosilane is added in portions and the mixture is stirred for 110 hours at room
`temperature. The reaction mixture is diluted with acetic acid ethyl ester and washed five times with
`water. The organic phase is dried over sodium sulfate and the solvent distilled off under reduced
`pressure. The resultant crude product is purified by chromatography over silicagel using hexane/acetic
`acid ethyl ester 3:1 as the eluant. 24,33·Bis·(tert-butyldimethylsilyloxy)-FK 506 is obtained:
`13C-NMR: main conformer: 69.7 (C-24); 75.1 (C-33); S4.1 (C-32); 164.6 (C-S); 168.9 (C-1); 196.4 (C-9);
`209.3 (C-22);
`minor conformer: 70.9 (C-24); 75.3 (C-33); 84.1 (C-32); 165.8 (C-8); 168.2 (C-1); 191.2 (C-9); 210.0 (C-
`22);
`b) 0.5 9 24,33-bis-(tertbutyldimethylsilyloxy)-FK506 is dissolved at o· under stirring into a mixture of 10
`ml of acetonitrile and 0.5 ml of 40 % hydrofluoric acid. After 2 hours at that temperature the reaction
`medium is diluted with dichloromethane. The solution is successively washed with saturated aqueous
`sodium bicarbonate solution and water and the organic phase is dried over sodium sulfate, and the
`solvent is evaporated under reduced pressure. The resultant residue is purified by column chromatog(cid:173)
`raphy over silicagel (eluant: dichloromethane/methanol 9:1). 24-tert-Butyldimethylsilyloxy·FK 506 is
`obtained as a colourless foam:
`13C-NMR: main conformer: 69.7 (C-24); 73.6 (C-33); 84.1 (C-32); 164.6 (C-8); 168.9 (C-1); 196.4 (C-g);
`209.2 (C-22);
`minor conformer: 70.7 (C-24); 73.6 (C-33); 84.2 (C-32); 165.8 (C-8); 168.2 (C-1); 191.4 (C-9); 209.2 (C-
`22).
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`Example 2: 24·tert·Butyldimethylsilyloxy·33·epi·33-azido·FK506
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`[Formula I: R1 : a group (a) wherein Rs : azido, R6 :