WO2000073288A1 - Method for preparing 5-substituted oxazoles - Google Patents
Method for preparing 5-substituted oxazoles Download PDFInfo
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- WO2000073288A1 WO2000073288A1 PCT/US2000/013817 US0013817W WO0073288A1 WO 2000073288 A1 WO2000073288 A1 WO 2000073288A1 US 0013817 W US0013817 W US 0013817W WO 0073288 A1 WO0073288 A1 WO 0073288A1
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- 0 *c1ncc[o]1 Chemical compound *c1ncc[o]1 0.000 description 6
- VMWHXCGXKXICJJ-VOTSOKGWSA-N CN(C)/C=C/c(ccc([N+]([O-])=O)c1)c1OC Chemical compound CN(C)/C=C/c(ccc([N+]([O-])=O)c1)c1OC VMWHXCGXKXICJJ-VOTSOKGWSA-N 0.000 description 2
- JBPUGFODGPKTDW-SFHVURJKSA-N COc1cc(NC(Nc2cc(CNC(O[C@@H]3COCC3)=O)ccc2)=O)ccc1-c1cnc[o]1 Chemical compound COc1cc(NC(Nc2cc(CNC(O[C@@H]3COCC3)=O)ccc2)=O)ccc1-c1cnc[o]1 JBPUGFODGPKTDW-SFHVURJKSA-N 0.000 description 1
- AOIXGUQZJVAHKJ-UHFFFAOYSA-N COc1cc([N+]([O-])=O)ccc1-c1cnc[o]1 Chemical compound COc1cc([N+]([O-])=O)ccc1-c1cnc[o]1 AOIXGUQZJVAHKJ-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/44—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by —CHO groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Definitions
- the invention provides a method for the preparation of 5-substituted oxazoles in high yield using inexpensive, widely available reagents.
- the method is particularly useful in the preparation of intermediates necessary in the synthesis of a class of IMPDH inhibitors, in particular VX-497, which is currently in clinical trials.
- the invention also provides compounds that represent novel intermediates useful in the methods of this invention.
- Oxazoles moieties may be linked to the remainder of a more complex molecule in one of three ways. Connections of the 2-substitutued are usually prepared by reaction of a 2-substituted oxazole possessing a leaving group (Lv) at C-2 with a nucleophile (Nu) [R. Go pper et al . Chem. Ber . , 92, pp. 1928-1931 (1959) ] .
- Lv leaving group
- Nu nucleophile
- a third process for the preparation of 5-aryl- oxazoles employs a reaction between an isonitrile and an aldehyde [A. M. van Leusen, Tetrahedron Lett., pp. 2369- 2372 (1972)]. This is the method set forth in PCT publication WO 97/40028 for the synthesis of intermediates useful in the production of IMPDH inhibitors. An example of this method uses p- toluenesulfonylmethyl isocyanide ("TosMIC").
- the present invention fills this need by providing a new method for the production of oxazoles of the 5-substituted type which are useful as intermediates in the production of molecules containing such moieties.
- the method involves the reaction of a compound of the formula:
- Y is Ci-Cio straight or branched alkyl or a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms independently selected from N, 0, or S, and wherein Y may contain up to 4 independent, non-electrophilic substituents ;
- X is selected from Cl, Br or I;
- R is selected from hydrogen or C ⁇ -C straight or branched alkyl ; and R' is hydrogen or Ci-Cio straight or branched alkyl .
- the method of this invention is particularly useful in the synthesis of a class of IMPDH inhibitors containing an oxazole moiety that is linked to the rest of the molecule via its 5-position.
- IMPDH inhibitors are described in detail in WO 97/40028 and WO 98/40381, the disclosures of which are herein incorporated by reference.
- the present invention also provides novel compounds that are precursors of and used in the present method of synthesizing the 5-substituted oxazole moieties of this invention.
- substituted refers to the replacement of one or more hydrogen radicals in a given structure with a radical selected from a specified group.
- substituents may be either the same or different at every position.
- monocyclic or bicyclic ring system consisting of 5 to 6 members per ring
- substituents those substituents may be at any position of the ring system, unless otherwise specified.
- such ring systems may optionally comprise up to 4 heteroatoms selected from N, 0 or S .
- heteroatoms may replace any carbon atoms in these ring systems as long as the resulting compound is chemically stable.
- the invention provides a method for the production of an oxazole of the formula:
- Y is C 1 -C1 0 straight or branched alkyl or a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms independently selected from N, 0, or S, and wherein Y may contain up to 4 independently selected, non-electrophilic substituents;
- X is selected from Cl, Br or I;
- R is selected from hydrogen C 1 -C 4 straight or branched alkyl ; and R' is hydrogen or C 1 -C 10 straight or branched alkyl .
- Electrophilic substituents include, for example, halogens, nitriles, esters, sulfonyl esters, ketones and aldehydes. Other electrophilic substituents that must not be present on Y are well known in the art.
- R is H or CH 3 . Even more preferred is when R is H.
- X is Br.
- Y is phenyl optionally substituted at the 4-position with nitro and optionally substituted at the 2-position with methoxy .
- this method is used to produce a compound of the formula:
- Scheme 1 may be synthesized by the route set forth in Scheme 1, below if it is not commercially available.
- Scheme 1 may be synthesized by the route set forth in Scheme 1, below if it is not commercially available.
- the invention provides a method of synthesizing a compound of the formula:
- the amount of DMF used is between about 5 to 15 ml per gram of
- the amount of (CH 3 )2-N-CH(OCH 3 )2 be between about 2.5 to 5.0 grams per gram of O P N ' OCH ⁇ 3 , _
- the temperature of the reaction in step a) is preferably between about 100 to 120°C.
- the amount of water added upon completion of the reaction is preferably between about 6 to 30 ml per
- step b) it is preferred that the amount of HCl and water be between about 2 to 5 ml of concentrated HCl and 4 to 8 ml of water, respectively, per gram of
- step b) be carried out at a temperature of between about 15 to 35°C.
- step c) the preferred amount of acetic acid and bromine is between about 5 to 15 ml of acetic acid and between about 1.0 to 1.5 grams of bromine per gram of
- step c) is carried out at a temperature of between about 18 to 35°C. It is further preferred that the reaction in step c) be quenched by the addition of between about 5 to 15 ml water per gram of
- the invention provides the individual compounds produced in steps a) , b) and c) , above .
- the method for producing a 5-substituted oxazole is utilized in the synthesis of compounds which have IMPDH inhibitory activity.
- Such compounds have the formula:
- A is selected from (Ci-C ⁇ ) -straight or branched alkyl, or (C2-C 6 ) -straight or branched alkenyl or alkynyl ; and A optionally comprises up to 2 substituents, wherein: the first of said substituents, if present, is selected from Ri or R 3 , and the second of said substituents, if present, is Ri; each of B and B' is independently selected from a saturated, unsaturated or partially saturated monocyclic or bicyclic ring system optionally comprising up to 4 heteroatoms selected from N, 0, or S and wherein each of B and B' optionally comprises up to 3 substituents, wherein: the first of said substituents, if present, is selected from R l t R 2 , R 4 or R 5 , the second of said substituents, if present, is selected from R or R 4 , and the third of said substituents, if present, is Ri; and D is selected from C(0), C(S), or S
- R 3 is selected from a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, 0, or S, and wherein a CH 2 adjacent to any of said N, 0, or S heteroatoms is optionally substituted with C(0); and each R 3 optionally comprises up to 3 substituents, wherein: the first of said substituents, if present, is selected from R l r R 2 , R 4 or R 5 , the second of said substituents, if present, is selected from R l t or R 4 , and the third of said substituents, if present, is Ri; each R 4 is independently selected from OR 5 , OC(0)R 6 , OC(0)R 5 , OC(0)OR 6 , OC(0)OR 5 , OC(0)N(R 6 ) 2 , OP(0)(OR 6 ) 2 , SR 6 , SR 5 , S(0)R 6 , S(0)R 5
- R is a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, 0, or S, and wherein a CH adjacent to said N, 0 or S maybe substituted with C(0); and each R 7 optionally comprises up to 2 substituents independently chosen from H, (C1-C 4 ) -straight or branched alkyl, (C 2 -C ) straight or branched alkenyl, 1 , 2-methylenedioxy, 1 , 2-ethylenedioxy, or (CH 2 ) n -Z; wherein n is 0, 1 or 2; and
- Z is selected from halogen, CN, N0 2 , CF 3 , OCF 3 , OH, S(C ⁇ -C 4 ) -alkyl, SO (C1-C4) -alkyl , S0 2 (C ⁇ -C 4 ) -alkyl , NH 2 , NH(C ⁇ -C 4 ) -alkyl, N ( (C 1 -C 4 ) -alkyl) 2 , N ( (C 1 -C 4 ) -alkyl) R 8 , COOH, C(0)0(C ⁇ -C 4 ) -alkyl or 0 (C1-C4) -alkyl; Rg is an amino protecting group; E is oxygen; G is hydrogen; and
- G' is selected from hydrogen or C ⁇ -C 4 -straight or branched alkyl ; wherein any carbon atom in any A, R 2 or R is optionally replaced by 0, S, SO, S0 2 , NH, or N(C ⁇ -C 4 )- alkyl .
- the method for producing a 5- substituted oxazole is used to synthesize a compound of the formula:
- the method for producing a 5-substituted oxazole is utilized in the synthesis of another class of compounds which have IMPDH inhibitory activity.
- Such compounds have the formula: ( I I I ) , wherein :
- A' is a saturated, unsaturated or partially saturated monocyclic or bicyclic ring system optionally comprising up to 4 heteroatoms selected from N, 0, and S wherein each A' optionally comprises up to 4 substituents independently selected from R 2 ⁇ , R 24 and R 2 s; each R 21 is halogen, CN, N0 2 , CF 3 , 0CF 3 , OH, R 23 , OR 23 , 1, 2-methylenedioxy, 1 , 2-ethylenedioxy, SR 2 3, S(0)R3, S(0 2 )R 2 3, NH 2 , NHR 23 , N(R 23 ) 2 , NR 23 R 29 , COOH, or COOR 23 ; each R 23 is independently (C 1 -C 4 ) -straight or branched alkyl, or (C 2 -C 4 ) -straight or branched alkenyl or alkynyl; each R 2 is independently (Ci-C ⁇ ) -straight or branched al
- R 2 6 is a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, 0, and S, and wherein a CH 2 adjacent to any of said N, 0, or S heteroatoms is optionally substituted with C(0); and each R 26 optionally comprises up to 3 substituents, each substituent independently selected from R 2 ⁇ ; each R 27 is independently H, (C 1 -C 4 ) -straight or branched alkyl, or (C -C ) straight or branched alkenyl; and each R 2 -7 optionally comprises a substituent that is
- R 2 8,' R 28 is a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, 0, and S, and wherein a CH 2 adjacent to said N, 0 or S maybe substituted with C(0); and each R 2 g optionally comprises up to 2 substituents independently chosen from H, (C 1 -C 4 ) -straight or branched alkyl, (C 2 -C 4 ) straight or branched alkenyl, 1 , 2-methylenedioxy, 1 , 2-ethylenedioxy and (CH 2 ) n -R2i; wherein n is 0, 1 or 2 ; R 2 g is an amino protecting group; and wherein any carbon atom in any R 2 , R 4 or R 27 is optionally replaced by 0, S, SO, S0 2 , NH, or N(C ⁇ -C 4 )- alkyl .
- the method for producing a 5-substituted oxazole is utilized in the synthesis of yet another class of compounds which have IMPDH inhibitory activity.
- Such compounds have the formula:
- R 3 ⁇ is (C ⁇ -C 6 ) -straight or branched alkyl, wherein up to 4 hydrogen atoms in said alkyl are optionally and independently replaced by R 33 ;
- R32 is selected from hydrogen, -CF 3 , - (Ci-C ⁇ ) -straight or branched alkyl, - (d-C 6 ) -straight or branched alkyl-Ar, or -Ar; or wherein R 3i and R 32 are taken together to form a 3- tetrahydrofuranyl moiety that is substituted at the 5 position by -OR 36 ; each R 33 is independently selected from halo, -OR , or -N(R 35 ) 2 ;
- R34 is selected from hydrogen, - (C ⁇ -C 6 ) -straight alkyl, - (d-C 6 ) -straight alkyl-Ar, -C (0) - (C ⁇ -C 6 ) -straight or branched alkyl, -C(0)-Ar, or - (d-C 6 ) -straight alkyl- CN; each R 35 is independently selected from hydrogen,
- R 36 is selected from -C(0)-CH 3 , -CH 2 -C (0) -OH, -CH 2 -C (0) -0-tBu, -CH 2 -CN, or -CH 2 -C ⁇ CH;
- Ar is selected from phenyl , 1-naphthyl, 2-naphthyl, indenyl , azulenyl, fluorenyl, anthracenyl, 2-furyl, 3- furyl , 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- pyridyl , pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl, 2-pyrazolinyl, pyrazolidinyl , isoxazolyl, isotriazolyl , 1, 2 , 3-oxadiazolyl , 1 , 2 , 3-triazolyl , 1,3,4- thiadiazolyl , pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5- triazinyl, 1, 3 , 5-trithianyl, indolizinyl, in
- reaction of a 2-methyl-5- nitroanisole with N,N-dimethylformamide dimethyl acetal in DMF at 120°C gives A997-146, which was then hydrolyzed to aryl-acetaldehyde A997-154.
- An advantage of this hydrolysis is that it is performed in water without the need for organic solvent. Bromination of A997-154 is carried out in glacial acetic acid, then VRT-039536 is obtained by heating the ⁇ -bromo-aryl-acetaldehyde in formic acid in the presence of ammonium formate. More details of the synthesis are provided below.
- A997-154 A 5 L, 4-necked, round- bottomed flask was fitted with a thermocouple, overhead mechanical stirrer, and addition funnel. The flask was charged with 152.0 g (0.6847 mol) of A997-146, suspended in 600.0 mL of H 2 0, and 100.0 mL of concentrated HCl was added dropwise over 15 minutes causing the maroon suspension to turn yellow-brown. After 60 minutes the suspension was cooled to 5°C, and the solid collected by vacuum filtration to give 118.0 g of the aryl- acetaldehyde (88% yield) .
- VRT-039536 A 3 L, 4-necked, round- bottomed flask was fitted with a heating mantle, thermocouple, overhead mechanical stirrer, and reflux condenser. The flask was charged with the 244.3 g (0.8916 mol) of the moist A997-155, and suspended in
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Abstract
The invention provides a method for the preparation of 5-substituted oxazoles in high yield using inexpensive, widely available reagents. The method is particularly useful in the preparation of intermediates necessary in the synthesis of a class of IMPDH inhibitors, in particular VX-497, which is currently in clinical trials. The invention also provides compounds that represent novel intermediates useful in the methods of this invention.
Description
METHOD FOR PREPARING 5-SUBSTITUTED OXAZOLES
TECHNICAL FIELD OF THE INVENTION
The invention provides a method for the preparation of 5-substituted oxazoles in high yield using inexpensive, widely available reagents. The method is particularly useful in the preparation of intermediates necessary in the synthesis of a class of IMPDH inhibitors, in particular VX-497, which is currently in clinical trials. The invention also provides compounds that represent novel intermediates useful in the methods of this invention.
BACKGROUND OF THE INVENTION Oxazoles pervade many areas of synthetic organic chemistry, and found in many natural products and pharmaceuticals [For reviews on oxazole chemistry, see: I. J. Turchi et al . , Chem. Rev . , 1975, pp. 389-437 (1975); Oxazoles, I. J. Turchi, ed. , Wiley-Interscience, New York, 1986; and Heterocyclic Compounds Vol. 5, R. C. Elderfield, ed. ; Wiley, New York, 1957]. Of particular importance in the synthesis of oxazoles for therapeutic agents is the linking of the oxazole moiety to the remainder of the molecule.
Oxazoles moieties may be linked to the remainder of a more complex molecule in one of three ways. Connections of the 2-substitutued are usually prepared by reaction of a 2-substituted oxazole possessing a leaving group (Lv) at C-2 with a nucleophile (Nu) [R. Go pper et al . Chem. Ber . , 92, pp. 1928-1931 (1959) ] .
For the preparation of oxazoles of the 4- substituted type, an ?-halo ketone is reacted with ammonium formate in formic acid. For example, 4-phenyl oxazole has been prepared from phenacyl bromide in this fashion [H. Bredereck et al . , Chem. Ber . , 87, pp. 700, 706 (1954)].
There are a few known methods for the preparation of 5-substituted oxazoles. These include dehydration of an N-phenacyl-formamide [Bachstez, Chem. Ber. , 47, p. 3165 (1914)]
These two methods are less than desirable because in certain syntheses, the immediate precursors to the 5- substituted oxazoles are difficult to produce.
A third process for the preparation of 5-aryl- oxazoles employs a reaction between an isonitrile and an aldehyde [A. M. van Leusen, Tetrahedron Lett., pp. 2369- 2372 (1972)]. This is the method set forth in PCT publication WO 97/40028 for the synthesis of intermediates useful in the production of IMPDH inhibitors. An example of this method uses p- toluenesulfonylmethyl isocyanide ("TosMIC"). Although this reagent yields the desired intermediate nitro- oxazole in good yield and with less synthetic difficulty, TosMIC is relatively expensive. Thus this process is less than desirable for the production of commercial quantities of the ultimate product containing the 5- substituted oxazole. Thus, there is still a need for producing an oxazole of the 5-substituted variety in good yield, without synthetic difficulty and at a reasonable cost.
SUMMARY OF THE INVENTION The present invention fills this need by providing a new method for the production of oxazoles of the 5-substituted type which are useful as intermediates in the production of molecules containing such moieties. The method involves the reaction of a compound of the formula:
Y is Ci-Cio straight or branched alkyl or a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms independently selected from N, 0, or S, and wherein Y may contain up to 4 independent, non-electrophilic substituents ; X is selected from Cl, Br or I;
R is selected from hydrogen or Cι-C straight or branched alkyl ; and R' is hydrogen or Ci-Cio straight or branched alkyl .
The method of this invention is particularly useful in the synthesis of a class of IMPDH inhibitors containing an oxazole moiety that is linked to the rest of the molecule via its 5-position. Such IMPDH inhibitors are described in detail in WO 97/40028 and WO 98/40381, the disclosures of which are herein incorporated by reference. The present invention also provides novel compounds that are precursors of and used in the present method of synthesizing the 5-substituted oxazole moieties of this invention.
DETAILED DESCRIPTION OF THE INVENTION Definitions
The following definitions are used throughout the application.
The term "substituted" refers to the replacement of one or more hydrogen radicals in a given
structure with a radical selected from a specified group. When more than one hydrogen radical may be replaced with a substituent selected from the same specified group, the substituents may be either the same or different at every position.
The term "monocyclic or bicyclic ring system consisting of 5 to 6 members per ring" refers to 5 or 6 member monocyclic rings and 8, 9 and 10 membered bicyclic ring structures, wherein each bond in each ring may be possess any degree of saturation that is chemically feasible. When such structures contain substituents, those substituents may be at any position of the ring system, unless otherwise specified.
As specified, such ring systems may optionally comprise up to 4 heteroatoms selected from N, 0 or S .
Those heteroatoms may replace any carbon atoms in these ring systems as long as the resulting compound is chemically stable.
According to one embodiment, the invention provides a method for the production of an oxazole of the formula:
Y is C1-C10 straight or branched alkyl or a monocyclic or a bicyclic ring system consisting of 5 to 6
members per ring, wherein said ring system optionally comprises up to 4 heteroatoms independently selected from N, 0, or S, and wherein Y may contain up to 4 independently selected, non-electrophilic substituents; X is selected from Cl, Br or I; and
R is selected from hydrogen C1-C4 straight or branched alkyl ; and R' is hydrogen or C1-C10 straight or branched alkyl . Those of skill in the art will be well aware that the presence of an electrophilic substituent on Y will interfere with the desired reaction by causing a side reaction. Electrophilic substituents include, for example, halogens, nitriles, esters, sulfonyl esters, ketones and aldehydes. Other electrophilic substituents that must not be present on Y are well known in the art. According to one preferred embodiment, R is H or CH3. Even more preferred is when R is H.
According to another preferred embodiment, X is Br.
In yet another preferred embodiment, Y is phenyl optionally substituted at the 4-position with nitro and optionally substituted at the 2-position with methoxy . In the most preferred embodiment, this method is used to produce a compound of the formula:
reacting a compound of the
with NH4C02H and HC02H at a temperature of between about 80°C and 120°C. Preferably, between about 4 to 10 ml HC02H and between about 0.5 to 1.0 gram
NH4CO2H are used per gram of
_ τhe reaction is typically quenched by the addition of between about 20 to 30 ml water per gram of
Of course, it should be understood that if any of the above intermediate compounds are commercially
available, the synthesis of
may begin with that intermediate and follow the subsequent steps set forth in Scheme 1.
In another embodiment, the invention provides a method of synthesizing a compound of the formula:
O '2oN, ' CHn3, w_tn (CH3)2-N-CH(OCH3)2 in the presence of N,N-dimethylformamide ("DMF") and heat, followed by the addition of water to yield a compound of the formula:
b) reacting
HC1 and water to produce a compound of the formula:
acid to produce
Preferably, in step a) , the amount of DMF used is between about 5 to 15 ml per gram of
O 2 PN' OCHn3, ^ It a]_so preferred that the amount of (CH3)2-N-CH(OCH3)2 be between about 2.5 to 5.0 grams per
gram of OPN' OCHπ 3, _ The temperature of the reaction in step a) is preferably between about 100 to 120°C. And the amount of water added upon completion of the reaction is preferably between about 6 to 30 ml per
In step b) , it is preferred that the amount of HCl and water be between about 2 to 5 ml of concentrated HCl and 4 to 8 ml of water, respectively, per gram of
O '2PNI ' OCHn,3 _ It is also preferred that step b) be carried out at a temperature of between about 15 to 35°C.
In step c) the preferred amount of acetic acid and bromine is between about 5 to 15 ml of acetic acid and between about 1.0 to 1.5 grams of bromine per gram of
O 2PN' OwCHn,3 Preferably, step c) is carried out at a temperature of between about 18 to 35°C. It is further preferred that the reaction in step c) be quenched by the addition of between about 5 to 15 ml
water per gram of
In addition, the invention provides the individual compounds produced in steps a) , b) and c) , above .
In another aspect of the present invention, the method for producing a 5-substituted oxazole is utilized in the synthesis of compounds which have IMPDH inhibitory activity. Such compounds have the formula:
A is selected from (Ci-Cε) -straight or branched alkyl, or (C2-C6) -straight or branched alkenyl or alkynyl ; and A optionally comprises up to 2 substituents, wherein: the first of said substituents, if present, is selected from Ri or R3 , and the second of said substituents, if present, is Ri; each of B and B' is independently selected from a saturated, unsaturated or partially saturated monocyclic or bicyclic ring system optionally comprising up to 4
heteroatoms selected from N, 0, or S and wherein each of B and B' optionally comprises up to 3 substituents, wherein: the first of said substituents, if present, is selected from Rl t R2, R4 or R5, the second of said substituents, if present, is selected from R or R4 , and the third of said substituents, if present, is Ri; and D is selected from C(0), C(S), or S(0)2; wherein: each Ri is independently selected from 1,2- methylenedioxy, 1 , 2-ethylenedioxy, R or (CH2)n _Z; wherein n is 0, 1 or 2; and Z is selected from halogen, CN, N02 , CF3 , 0CF3 , OH, SR6, S(0)R6, S02R6, N(R6)2, N(R6)R8, C00R6 or OR6 ; each R2 is independently selected from (Cι~C4)- straight or branched alkyl, or (C2-C ) -straight or branched alkenyl or alkynyl; and each R2 optionally comprises up to 2 substituents, wherein: the first of said substituents, if present, is selected from Rl t R4 or R5; and the second of said substituents, if present, is Ri;
R3 is selected from a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, 0, or S, and wherein a CH2 adjacent to any of said N, 0, or S heteroatoms is optionally substituted with C(0); and each R3 optionally comprises up to 3 substituents, wherein: the first of said substituents, if present, is selected from Rl r R2 , R4 or R5,
the second of said substituents, if present, is selected from Rl t or R4 , and the third of said substituents, if present, is Ri; each R4 is independently selected from OR5, OC(0)R6, OC(0)R5, OC(0)OR6, OC(0)OR5, OC(0)N(R6)2, OP(0)(OR6)2, SR6 , SR5, S(0)R6, S(0)R5, S02R6, S02R5, S02N(R6)2, S02NR5R6, S03R6, C(0)R5, C(0)OR5, C(0)R6, C(0)OR6, NC(0)C(0)R6, NC(0)C(0)R5, NC(0)C(O)OR6, NC(0)C(0)N(R6)2, C(0)N(R6)2, C (0) N (0R6) R6, C(0)N(0R6)R5, C(NOR6)R6, C(NOR6)R5, N(R6)2, NR6C(0)Rι, NR6C(0)R6, NR6C(0)R5, NR6C(0)OR5, NR6C(0)OR5, NR6C (0) N (R6) 2 , NR6C(0)NR5R6, NR6S02R6, NR6S02R5, NR6S02N (R6) 2 , NR6S02NR5R6, N(OR6)R6, N(OR6)R5, P(0) (OR6)N(R5)2, and P(0)(OR6)2; each R5 is a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, O, or S, and wherein a CH2 adjacent to said N, 0 or S maybe substituted with C(0); and each R5 optionally comprises up to 3 substituents, each of which, if present, is Ri; each R6 is independently selected from H, (Cι-C )- straight or branched alkyl, or (C2-C4) straight or branched alkenyl; and each R6 optionally comprises a substituent that is R7;
R is a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, 0, or S, and wherein a CH adjacent to said N, 0 or S maybe substituted with C(0); and each R7 optionally comprises up to 2 substituents independently chosen from H, (C1-C4) -straight or branched alkyl, (C2-C ) straight or branched alkenyl, 1 , 2-methylenedioxy, 1 , 2-ethylenedioxy, or (CH2)n-Z;
wherein n is 0, 1 or 2; and
Z is selected from halogen, CN, N02 , CF3 , OCF3 , OH, S(Cι-C4) -alkyl, SO (C1-C4) -alkyl , S02 (Cι-C4) -alkyl , NH2 , NH(Cι-C4) -alkyl, N ( (C1-C4) -alkyl) 2, N ( (C1-C4) -alkyl) R8, COOH, C(0)0(Cι-C4) -alkyl or 0 (C1-C4) -alkyl; Rg is an amino protecting group; E is oxygen; G is hydrogen; and
G' is selected from hydrogen or Cι-C4-straight or branched alkyl ; wherein any carbon atom in any A, R2 or R is optionally replaced by 0, S, SO, S02 , NH, or N(Cι-C4)- alkyl .
Methods for synthesizing the desired end- product compounds of formula I or II from the 5- substituted oxazole intermediate are set forth in detail in WO 97/40028, the disclosure of which is herein incorporated by reference.
More preferably, the method for producing a 5- substituted oxazole is used to synthesize a compound of the formula:
VX-497.
According to another embodiment, the method for producing a 5-substituted oxazole is utilized in the synthesis of another class of compounds which have IMPDH inhibitory activity. Such compounds have the formula:
( I I I ) , wherein :
A' is a saturated, unsaturated or partially saturated monocyclic or bicyclic ring system optionally comprising up to 4 heteroatoms selected from N, 0, and S wherein each A' optionally comprises up to 4 substituents independently selected from R2ι, R24 and R2s; each R21 is halogen, CN, N02 , CF3 , 0CF3 , OH, R23, OR23, 1, 2-methylenedioxy, 1 , 2-ethylenedioxy, SR23, S(0)R3, S(02)R23, NH2, NHR23, N(R23)2, NR23R29, COOH, or COOR23 ; each R23 is independently (C1-C4) -straight or branched alkyl, or (C2-C4) -straight or branched alkenyl or alkynyl; each R2 is independently (Ci-Cδ) -straight or branched alkyl, or (C2-Ce) -straight or branched alkenyl or alkynyl; and each R24 optionally comprises up to 2 substituents, wherein: the first of said substituents, if present, is R2ι, R25 or R28, and the second of said substituents, if present, is Ri; each R25 is independently selected from OR26, OC(0)R27, OC(0)R26, OC(0)OR27, OC(0)OR26, OC (0) N (R27) 2 ,
0P(0) (OR27)2, SR27, SR26, S(0)R27, S(0)R26, S02R27, S02R26, S02N(R27)2, S02NR26R27, S03R27, C(0)R26, C(0)OR26, C(0)R27, C(0)OR27, NC(0)C(0)R27, NC(0)C(0)R26, NC (0) C (0) OR27 , NC(0)C(0)N(R27)2, C(0)N(R27)2, C (0) N (OR27) R27 , C (O) N (OR27) R26, C(NOR27)R27, C(NOR27)R25, N(R27)2, NR27C(0)R26, NR27C(0)R27, NR6C(0)R26, NR27C(0)OR27, NR27C (0) OR26 , NR27C (O) N (R27) 2 , NR27C(0)NR26R27, NR27S02R27, NR27S02R26, NR27S02N (R27) 2 ,
NR27S02NR26R27, N(OR27)R27, N(0R27)R26, P (0) (OR27) N (R27) 2 , P(0) (OR27)2, P(0) (N(R27)2)2, and P(0) (OR27)R27-
R26 is a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, 0, and S, and wherein a CH2 adjacent to any of said N, 0, or S heteroatoms is optionally substituted with C(0); and each R26 optionally comprises up to 3 substituents, each substituent independently selected from R2ι; each R27 is independently H, (C1-C4) -straight or branched alkyl, or (C -C ) straight or branched alkenyl; and each R2-7 optionally comprises a substituent that is
R28,' R28 is a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, 0, and S, and wherein a CH2 adjacent to said N, 0 or S maybe substituted with C(0); and each R2g optionally comprises up to 2 substituents independently chosen from H, (C1-C4) -straight or branched alkyl, (C2-C4) straight or branched alkenyl, 1 , 2-methylenedioxy, 1 , 2-ethylenedioxy and (CH2)n-R2i; wherein n is 0, 1 or 2 ; R2g is an amino protecting group; and wherein any carbon atom in any R2 , R4 or R27 is optionally replaced by 0, S, SO, S02 , NH, or N(Cι-C4)- alkyl .
Methods for synthesizing the desired end- product compounds of formula III from the 5-substituted oxazole intermediate are set forth in detail in W0
98/40381, the disclosure of which is herein incorporated by reference.
According to another embodiment, the method for producing a 5-substituted oxazole is utilized in the synthesis of yet another class of compounds which have IMPDH inhibitory activity. Such compounds have the formula:
R32 is selected from hydrogen, -CF3, - (Ci-Cβ) -straight or branched alkyl, - (d-C6) -straight or branched alkyl-Ar, or -Ar; or wherein R3i and R32 are taken together to form a 3- tetrahydrofuranyl moiety that is substituted at the 5 position by -OR36; each R33 is independently selected from halo, -OR , or -N(R35)2;
R34 is selected from hydrogen, - (Cι-C6) -straight alkyl, - (d-C6) -straight alkyl-Ar, -C (0) - (Cι-C6) -straight or branched alkyl, -C(0)-Ar, or - (d-C6) -straight alkyl- CN; each R35 is independently selected from hydrogen,
- (Ci-Cβ) -straight or branched alkyl, - (Ci-Cε) -straight or branched alkyl-Ar, - (Cι-C6) -straight alkyl-CN, -(d-C6)-
straight alkyl-OH, - (Cι-C6) -straight alkyl-0R34, -C(0)-(Cι- C6) -straight or branched alkyl, -C(0)-Ar, -S (0) 2- (d-C6) - straight or branched alkyl, or -S(0)2-Ar; or two R5 moieties, when bound to the same nitrogen atom, are taken together with said nitrogen atom to form a 3 to 7- membered heterocyclic ring, wherein said heterocyclic ring optionally contains 1 to 3 additional heteroatoms independently selected from N, 0, or S;
R36 is selected from -C(0)-CH3, -CH2-C (0) -OH, -CH2-C (0) -0-tBu, -CH2-CN, or -CH2-C≡CH; and
Ar is selected from phenyl , 1-naphthyl, 2-naphthyl, indenyl , azulenyl, fluorenyl, anthracenyl, 2-furyl, 3- furyl , 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- pyridyl , pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl, 2-pyrazolinyl, pyrazolidinyl , isoxazolyl, isotriazolyl , 1, 2 , 3-oxadiazolyl , 1 , 2 , 3-triazolyl , 1,3,4- thiadiazolyl , pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5- triazinyl, 1, 3 , 5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl , benzo [b] thiophenyl , lH-indazolyl , benzimidazolyl , benzthiazolyl , purinyl, 4H-quinolizinyl , quinolinyl, isoquinolinyl , 1,2,3, 4-tetrahydro-isoquinolinyl , cinnolinyl, phthalazinyl , quinazolinyl , quinoxalinyl , 1, 8-naphthyridinyl , peridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl or other chemically feasible monocyclic, bicyclic or tricyclic ring systems, wherein each ring consists of 5 to 7 ring atoms and wherein each ring comprises 0 to 3 heteroatoms independently selected from N, 0 and S; wherein any Ar or heterocyclic ring is optionally substituted with 1 to 3 substituents independently selected from halo, hydroxy, nitro, cyano, amino, (C1-C4)-
straight or branched alkyl; 0- (C1-C4) -straight or branched alkyl, (C -C4) -straight or branched alkenyl or alkynyl, or 0- (C2-C4) -straight or branched alkenyl or alkynyl; and any Ar or heterocyclic ring is optionally benzofused.
Methods for synthesizing the desired end- product compounds of formula IV from the 5-substituted oxazole intermediate are analagous to those set forth in WO 97/40028. . In order that this invention be more fully understood, the following examples are set forth. These examples are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.
EXAMPLE 1 Synthesis of a 5-Aryl Oxazole
The synthesis is outlined in Scheme 2, below.
Scheme 2:
VRT-039536 VRT-025591
As can be seen above, reaction of a 2-methyl-5- nitroanisole with N,N-dimethylformamide dimethyl acetal in DMF at 120°C gives A997-146, which was then hydrolyzed to aryl-acetaldehyde A997-154. An advantage of this hydrolysis is that it is performed in water without the need for organic solvent. Bromination of A997-154 is carried out in glacial acetic acid, then VRT-039536 is obtained by heating the α-bromo-aryl-acetaldehyde in formic acid in the presence of ammonium formate. More details of the synthesis are provided below.
Preparation of A997-146: A 5 L, 4-necked, round-bottomed flask was fitted with a heating mantle, thermocouple, overhead mechanical stirrer, nitrogen inlet, and a reflux condenser was vented to a mineral oil bubbler. The flask
was charged with 172.0 g (1.029 mol) of 2-methyl-5- nitroanisole , 1.250 L of N, N-dimethylformamide, and 331.9 g (2.785 mol) of N, N-dimethylformamide dimethyl acetal (DMFDMA) . The mixture was heated to 120°C and monitored by TLC (Si02 3:1 hexanes : EtOAc) until the 2-methyl-5- nitroanisole had been consumed (about 24 hours heating at
120 °C) . The maroon mixture was cooled to ambient temperature, and 1.250 L of H20 was added slowly over 60 minutes producing a thick maroon precipitate. The solid was collected by vacuum filtration, and washed with water until the filtrate passing into the flask was colorless. The maroon solid was dried, and 211.0 g of the desired enamine was obtained (92% yield).
Preparation of A997-154: A 5 L, 4-necked, round- bottomed flask was fitted with a thermocouple, overhead mechanical stirrer, and addition funnel. The flask was charged with 152.0 g (0.6847 mol) of A997-146, suspended in 600.0 mL of H20, and 100.0 mL of concentrated HCl was added dropwise over 15 minutes causing the maroon suspension to turn yellow-brown. After 60 minutes the suspension was cooled to 5°C, and the solid collected by vacuum filtration to give 118.0 g of the aryl- acetaldehyde (88% yield) .
Preparation of A997-155: A 3 L, 4-necked, round- bottomed flask was fitted with a thermocouple, overhead mechanical stirrer, and addition funnel. The flask was charged with 118.0 g (0.6051 mol) of A997-154 suspended in 750.0 mL of glacial acetic acid. To this suspension was added 136.5 g (0.8531 mol) of Br2 dropwise over 60 minutes. The solution was then stirred for 12 hours at
which time 800.0 L H20 was added followed by cooling of the suspension to 10°C. The resulting yellow solid was washed with HO, and collected by vacuum filtration to give 244.3 g of the ?-bromo-aryl-acetaldehyde as a moist solid.
Preparation of VRT-039536: A 3 L, 4-necked, round- bottomed flask was fitted with a heating mantle, thermocouple, overhead mechanical stirrer, and reflux condenser. The flask was charged with the 244.3 g (0.8916 mol) of the moist A997-155, and suspended in
1.200 L of 96% formic acid. The suspension was cooled in an ice-water bath to 17°C, and 225.0 g (3.568 mol) of ammonium formate was added at a rate such that the solution temperature never exceeded 20°C. Once the ammonium formate was added, the cooling bath was replaced with a heating mantle and the mixture heated at 100°C for 2 hours . The resulting brown-red mixture was cooled to ambient temperature, and poured into 2.500 L of H20. The pH of the solution was adjusted to pH ~ 6 by addition of 6 M NaOH, and the solids were collected by vacuum filtration to give the nitro-oxazole as a brown-yellow powder .
While we have hereinbefore presented a number of embodiments of this invention, it is apparent that my basic construction can be altered to provide other embodiments which utilize the methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the claims appended hereto rather than the specific embodiments which have been presented hereinbefore by way of example.
Claims
We claim:
1. A method for preparing an oxazole of the formula:
Y is Ci-Cio straight or branched alkyl or a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms independently selected from N, 0, or S, and wherein Y may contain up to 4 independently selected, non-electrophilic substituents;
X is selected from Cl, Br or I; and
R is selected from hydrogen Cι~C straight or branched alkyl ; and R' is hydrogen or Ci-Cio straight or branched alkyl .
2. The method according to claim 1, wherein R is H or CH3.
3. The method according to claim 2 , wherein R is H.
4. The method according to claim 1, wherein X is Br .
5. The method according to claim 1, wherein Y is phenyl optionally substituted at the 4-position with nitro and optionally substituted at the 2-position with methoxy .
A method for producing a compound of the formula:
A method of synthesizing a
compound of the formula:
comprising the steps of:
reacting a compound of the formula:
O '2PNI ' OCHπ 3, W1t (CH3)2-N-CH(OCH3)2 in the presence of N,N-DIMETHYLFORMAMIDE and heat, followed by the addition of water to yield a compound of the formula:
b) reacting
HCl and water to produce a compound of the formula:
acid to produce
A compound of the formula:
A compound of the formula:
10. A compound of the formula:
11. A method of synthesizing a compound of the formula :
II), through an intermediate of the formula:
producing said intermediate by reacting
with NH4C02R and RC0H at a temperature of between about 80°C and 160°C, wherein:
Y is Ci-Cio straight or branched alkyl or a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms independently selected from N, 0, or S, and wherein Y may contain up to 4 independently selected, non-electrophilic substituents;
X is selected from Cl, Br or I; and
R is selected from hydrogen Cι-C4 straight or branched alkyl ;
R' is hydrogen or Ci-Cio straight or branched alkyl;
A is selected from (Cι-C6) -straight or branched alkyl, or (d-d) -straight or branched alkenyl or alkynyl; and A optionally comprises up to 2 substituents, wherein: the first of said substituents, if present, is selected from R1 or R3 , and the second of said substituents, if present, is Ri; each of B and B' is independently selected from a saturated, unsaturated or partially saturated monocyclic
or bicyclic ring system optionally comprising up to 4 heteroatoms selected from N, 0, or S and wherein each of B and B' optionally comprises up to 3 substituents, wherein: the first of said substituents, if present, is selected from Ri, R2 , R4 or R5, the second of said substituents, if present, is selected from Ri or R4 , and the third of said substituents, if present, is Ri; and
D is selected from C(O), C(S), or S(0)2; wherein: each Ri is independently selected from 1,2- methylenedioxy, 1, 2-ethylenedioxy, R6 or (CH2)n-Z; wherein n is 0, 1 or 2 ; and
Z is selected from halogen, CN, N02, CF3 , 0CF3, OH, SR6, S(0)R6, S02R6, N(R6)2, N(R6)R8, COOR6 or OR6 ; each R2 is independently selected from (C1-C4)- straight or branched alkyl, or (C2-C ) -straight or branched alkenyl or alkynyl; and each R2 optionally comprises up to 2 substituents, wherein: the first of said substituents, if present, is selected from Ri, R4 or R5; and the second of said substituents, if present, is Ri;
R3 is selected from a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, 0, or S, and wherein a CH2 adjacent to any of said N, 0, or S heteroatoms is optionally substituted with C(0); and each R3 optionally comprises up to 3 substituents, wherein:
the first of said substituents, if present, is selected from R1( R2 , R or R5, the second of said substituents, if present, is selected from Rl r or R , and the third of said substituents, if present, is Ri; each R4 is independently selected from OR5, OC(0)R6, OC(0)R5, OC(0)OR6, OC(0)OR5, OC(0)N(R6)2, OP(0)(OR6)2, SR6, SR5, S(0)R6, S(0)R5, S02R6, S02R5, S02N(R6) , S02NR5R5, S03R6, C(0)R5, C(0)OR5, C(0)R6, C(0)OR6, NC(0)C(0)R6, NC(0)C(0)R5, NC(0)C(0)OR6, NC(0)C(0)N(R6)2, C(0)N(R6)2, C (0) N (OR6) R6, C(0)N(OR6)R5, C(NOR6)R6, C(NOR6)R5, N(R5)2, NR6C(0)Rι, NR6C(0)R5, NR6C(0)R5, NR6C(0)OR6, NR6C(0)OR5, NR6C (0) N (R6) 2 , NR6C(0)NR5R6, NR6S02R6, NR6S02R5, NR6S02N (R6) 2 , NRgSOsNRsRe, N(OR6)R6, N(OR6)R5, P (0) (0R6) N (R6) 2 , and P(O) (OR6)2; each R5 is a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, 0, or S, and wherein a CH2 adjacent to said N, 0 or S maybe substituted with C(0); and each R5 optionally comprises up to 3 substituents, each of which, if present, is Ri; each R5 is independently selected from H, (C1-C4)- straight or branched alkyl, or (C2-C ) straight or branched alkenyl; and each R6 optionally comprises a substituent that is R ;
R7 is a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, 0, or S, and wherein a CH2 adjacent to said N, 0 or S maybe substituted with C(0); and each R7 optionally comprises up to 2 substituents independently chosen from H, (C1-C4) -straight or branched alkyl, (C -C ) straight or
branched alkenyl, 1 , 2-methylenedioxy, 1 , 2-ethylenedioxy, or (CH2)n-Z; wherein n is 0, 1 or 2 ; and
Z is selected from halogen, CN, N0 , CF3 , OCF3, OH, S(Cι-d) -alkyl, SO (C1-C4) -alkyl, S02 (d-C4) -alkyl , NH2 , NH(Cι-C4) -alkyl, N ( (Cι-C4 ) -alkyl ) 2 , N ( (d-C4) -alkyl ) R8 , COOH, C (0)0 (Cι-C4) -alkyl or 0 (C1-C4) -alkyl ;
R8 is an amino protecting group;
E is oxygen;
G is hydrogen; and
G' is selected from hydrogen or Cι-C4-straight or branched alkyl ; wherein any carbon atom in any A, R2 or R6 is optionally replaced by 0, S, SO, S02 , NH, or N(d-C4)- alkyl .
12. The method according to claim 11, wherein said compound has the formula:
13. The method according to claim 12, wherein said intermediate has the formula:
14. A method of synthesizing a compound of the
Y is Ci-Cio straight or branched alkyl or a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms independently selected from N, 0, or S, and wherein Y may contain up to 4 independently selected, non-electrophilic substituents;
X is selected from Cl, Br or I; and
R is selected from hydrogen C1-C4 straight or branched alkyl ;
R' is hydrogen or C1-C10 straight or branched alkyl;
A' is a saturated, unsaturated or partially saturated monocyclic or bicyclic ring system optionally comprising up to 4 heteroatoms selected from N, 0, and S wherein each A' optionally comprises up to 4 substituents independently selected from R21, R24 and R25;
each R2ι is halogen, CN, N02 , CF3 , OCF3 , OH, R23, OR23, 1, 2-methylenedioxy, 1 , 2-ethylenedioxy, SR23, S(0)R2 , S(02)R23, NH2, NHR23, N(R23)2, NR23R29, COOH, or COOR23; each R23 is independently (C1-C4) -straight or branched alkyl, or (C2-C ) -straight or branched alkenyl or alkynyl; each R24 is independently (Ci- ) -straight or branched alkyl, or (C2-d) -straight or branched alkenyl or alkynyl; and each R24 optionally comprises up to 2 substituents, wherein: the first of said substituents, if present, is R2ι, R25 or R28, and the second of said substituents, if present, is Ri; each R25 is independently selected from OR26, OC(0)R27, OC(0)R26, OC(0)OR27, OC(0)OR26, OC (0) N (R27) 2 , OP(O) (OR27)2, SR27, SR26, S(0)R27, S(0)R26, S02R27, S02R26,
S02N(R27)2, S02NR26R27, SO3R27, C(0)R26, C(0)OR26, C(0)R27,
C(0)0R27, NC(0)C(0)R27, NC(0)C(0)R26, NC (0) C (0) OR27, NC(0)C(0)N(R27)2, C(0)N(R27)2, C (0) N (OR27) R27 , C (0) N (OR27) R26 , C(NOR27)R27, C(NOR27)R26, N(R27)2, NR27C(0)R26, NR27C(0)R27, NR6C(0)R26, NR27C(0)OR27, NR27C (0) OR26 , NR27C (0) N (R27) 2 , NR27C(0)NR26R27, NR27SO2R27, NR27S02R26, NR27S02N (R27) 2 , NR27S02NR26R27, N(OR27)R27, N(OR27)R26, P(0) (OR27) N (R27) 2 , P(0) (OR27)2, P(0) (N(R27)2)2, and P(0) (OR27)R27.
R26 is a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, 0, and S, and wherein a CH2 adjacent to any of said N, 0, or S heteroatoms is optionally substituted with C(0); and each R26 optionally comprises up to 3 substituents, each substituent independently selected from R2χ;
each R7 is independently H, (C1-C4) -straight or branched alkyl, or (C2-C4) straight or branched alkenyl; and each R7 optionally comprises a substituent that is
R28;
R28 is a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, 0, and S, and wherein a CH2 adjacent to said N, 0 or S maybe substituted with C(0); and each R28 optionally comprises up to 2 substituents independently chosen from H, (C1-C4) -straight or branched alkyl, (C2-C ) straight or branched alkenyl, 1, 2-methylenedioxy, 1, 2-ethylenedioxy and (CH2)n-R2ι; wherein n is 0, 1 or 2 ;
Rg is an amino protecting group; and wherein any carbon atom in any R23, R4 or R27 is optionally replaced by 0, S, SO, S02 , NH, or N(d-C4)- alkyl .
15. A method of synthesizing a compound of the formula:
producing said intermediate by reacting
with NHC02R and RC02H at a temperature of between about 80°C and 160°C, wherein:
Y is Ci-Cio straight or branched alkyl or a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms independently selected from N, 0, or S, and wherein Y may contain up to 4 independently selected, non-electrophilic substituents;
X is selected from Cl, Br or I; and
R is selected from hydrogen Cι~C4 straight or branched alkyl ;
R' is hydrogen or Ci-Cio straight or branched alkyl;
R3ι is (Ci-Cβ) -straight or branched alkyl, wherein up to 4 hydrogen atoms in said alkyl are optionally and independently replaced by R33;
R32 is selected from hydrogen, -CF3, - (Ci-d) -straight or branched alkyl, - (Cι-C6) -straight or branched alkyl-Ar, or -Ar; or wherein R31 and R32 are taken together to form a 3- tetrahydrofuranyl moiety that is substituted at the 5 position by -OR36; each R33 is independently selected from halo, -OR34, or -N(R35)2;
R34 is selected from hydrogen, - (Cι-C6) -straight alkyl, - (Cι-C6) -straight alkyl-Ar, -C (0) - (Cι-C6) -straight
or branched alkyl, -C(0)-Ar, or - (Ci- ) -straight alkyl- CN; each R35 is independently selected from hydrogen, - (Ci-d) -straight or branched alkyl, - (Ci- ) -straight or branched alkyl-Ar, - (d-C6) -straight alkyl-CN, -(d-C6)- straight alkyl-OH, - (Cι-C6) -straight alkyl-OR34, -C(0)-(Cι- C6) -straight or branched alkyl, -C(0)-Ar, -S (0) 2- (Cι-C6) - straight or branched alkyl, or -S(0)2-Ar; or two R35 moieties, when bound to the same nitrogen atom, are taken together with said nitrogen atom to form a 3 to 7- membered heterocyclic ring, wherein said heterocyclic ring optionally contains 1 to 3 additional heteroatoms independently selected from N, 0, or S;
R36 is selected from -C(0)-CH3, -CH2-C (0) -OH, -CH2-C(0) -0-tBu, -CH2-CN, or -CH2-C≡CH; and
Ar is selected from phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- pyridyl , pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl, 2-pyrazolinyl , pyrazolidinyl, isoxazolyl, isotriazolyl, 1 , 2 , 3-oxadiazolyl , 1 , 2 , 3-triazolyl, 1,3,4- thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5- triazinyl, 1, 3 , 5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b] thiophenyl, lH-indazolyl, benzimidazolyl, benzthiazolyl , purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, 1,2,3, 4-tetrahydro-isoquinolinyl, cinnolinyl, phthalazinyl , quinazolinyl, quinoxalinyl , 1, 8-naphthyridinyl, peridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl or other chemically feasible monocyclic, bicyclic or tricyclic ring systems, wherein each ring consists of 5 to 7 ring
atoms and wherein each ring comprises 0 to 3 heteroatoms independently selected from N, 0 and S; wherein any Ar or heterocyclic ring is optionally substituted with 1 to 3 substituents independently selected from halo, hydroxy, nitro, cyano, amino, (C1-C4)- straight or branched alkyl; O- (C1-C4) -straight or branched alkyl, (C2-C ) -straight or branched alkenyl or alkynyl, or 0- (C2-C4) -straight or branched alkenyl or alkynyl; and any Ar or heterocyclic ring is optionally benzofused.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU50312/00A AU5031200A (en) | 1999-05-28 | 2000-05-18 | Method for preparing 5-substituted oxazoles |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13643099P | 1999-05-28 | 1999-05-28 | |
| US60/136,430 | 1999-05-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2000073288A1 true WO2000073288A1 (en) | 2000-12-07 |
Family
ID=22472825
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2000/013817 Ceased WO2000073288A1 (en) | 1999-05-28 | 2000-05-18 | Method for preparing 5-substituted oxazoles |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU5031200A (en) |
| WO (1) | WO2000073288A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7553836B2 (en) | 2006-02-06 | 2009-06-30 | Bristol-Myers Squibb Company | Melanin concentrating hormone receptor-1 antagonists |
| EP2181704A2 (en) | 2002-12-30 | 2010-05-05 | Angiotech International Ag | Drug delivery from rapid gelling polymer composition |
| EP2298776A1 (en) | 2005-10-26 | 2011-03-23 | Bristol-Myers Squibb Company | Thienopyrimidinone derivatives as melanin concentrating hormone receptor-1 antagonists |
| US7989433B2 (en) | 2008-05-29 | 2011-08-02 | Bristol-Myers Squibb Company | Substituted thieno[3,2-D]pyrimidines as melanin concentrating hormone receptor-1 antagonists |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4093654A (en) * | 1977-03-31 | 1978-06-06 | Hoffmann-La Roche Inc. | Production of pyridoxine intermediates from diketene |
| US4632930A (en) * | 1984-11-30 | 1986-12-30 | E. I. Du Pont De Nemours And Company | Antihypertensive alkyl-arylimidazole, thiazole and oxazole derivatives |
| EP0307141A2 (en) * | 1987-09-10 | 1989-03-15 | MERCK SHARP & DOHME LTD. | Oxazoles and thiazoles for the treatment of senile dementia |
| WO1997040028A1 (en) * | 1996-04-23 | 1997-10-30 | Vertex Pharmaceuticals Incorporated | Urea derivatives as inhibitors of impdh enzyme |
| WO1998040381A1 (en) * | 1997-03-14 | 1998-09-17 | Vertex Pharmaceuticals Incorporated | Inhibitors of impdh enzyme |
-
2000
- 2000-05-18 AU AU50312/00A patent/AU5031200A/en not_active Abandoned
- 2000-05-18 WO PCT/US2000/013817 patent/WO2000073288A1/en not_active Ceased
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4093654A (en) * | 1977-03-31 | 1978-06-06 | Hoffmann-La Roche Inc. | Production of pyridoxine intermediates from diketene |
| US4632930A (en) * | 1984-11-30 | 1986-12-30 | E. I. Du Pont De Nemours And Company | Antihypertensive alkyl-arylimidazole, thiazole and oxazole derivatives |
| EP0307141A2 (en) * | 1987-09-10 | 1989-03-15 | MERCK SHARP & DOHME LTD. | Oxazoles and thiazoles for the treatment of senile dementia |
| WO1997040028A1 (en) * | 1996-04-23 | 1997-10-30 | Vertex Pharmaceuticals Incorporated | Urea derivatives as inhibitors of impdh enzyme |
| WO1998040381A1 (en) * | 1997-03-14 | 1998-09-17 | Vertex Pharmaceuticals Incorporated | Inhibitors of impdh enzyme |
Non-Patent Citations (2)
| Title |
|---|
| H. BREDERECK ET AL.: "Oxazol-Synthesen aus alpha-Halogen-ketonen", CHEMISCHE BERICHTE, vol. 87, no. 5, 1954, pages 700 - 7, XP002148209 * |
| M. BACHSTEZ: "Über einige Thiazole und Oxazole", BERICHTE DER DEUTSCHEN CHEMISCHEN GESELLSCHAFT, vol. 47, 1914, pages 3163 - 9, XP002148208 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2181704A2 (en) | 2002-12-30 | 2010-05-05 | Angiotech International Ag | Drug delivery from rapid gelling polymer composition |
| EP2298776A1 (en) | 2005-10-26 | 2011-03-23 | Bristol-Myers Squibb Company | Thienopyrimidinone derivatives as melanin concentrating hormone receptor-1 antagonists |
| US8618115B2 (en) | 2005-10-26 | 2013-12-31 | Bristol-Myers Squibb Company | Substituted thieno[3,2-d]pyrimidinones as MCHR1 antagonists and methods for using them |
| US7553836B2 (en) | 2006-02-06 | 2009-06-30 | Bristol-Myers Squibb Company | Melanin concentrating hormone receptor-1 antagonists |
| US7956049B2 (en) | 2006-02-06 | 2011-06-07 | Bristol-Myers Squibb Company | Melanin concentrating hormone receptor-1 antagonists |
| US7989433B2 (en) | 2008-05-29 | 2011-08-02 | Bristol-Myers Squibb Company | Substituted thieno[3,2-D]pyrimidines as melanin concentrating hormone receptor-1 antagonists |
Also Published As
| Publication number | Publication date |
|---|---|
| AU5031200A (en) | 2000-12-18 |
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