AU3764399A

AU3764399A - Solid supported synthesis of sulfonated 2-oxopiperazines

Info

Publication number: AU3764399A
Application number: AU37643/99A
Authority: AU
Inventors: Adam Golebiowski; Sean Rees Klopfenstein
Original assignee: Procter and Gamble Co
Current assignee: Procter and Gamble Co
Priority date: 1998-04-29
Filing date: 1999-04-27
Publication date: 1999-11-16
Also published as: NO20005303D0; EP1073644A1; CA2328934A1; NO20005303L; WO1999055684A1; IL139121A0; JP2002513010A

Description

WO 99/55684 PCT/US99/09091 1 Solid Supported Synthesis of Sulfonated 2-Oxopiperazines TECHNICAL FIELD The subject invention relates to methods for synthesizing sulfonated 2 oxopiperazine and homologous compounds, including libraries of such compounds, using a solid-support resin to facilitate purification of intermediates. BACKGROUND OF THE INVENTION Many of the first combinatorial libraries were developed around the well documented solid supported syntheses of peptides and transformations of amino acid resin esters. As a consequence, several syntheses of hydantoins and diketopiperazines have been reported. See a) Gordon, D. W.; Steele, J.; Bioorg. Med Chem. Lett., vol. 5 (1995), p. 47; b) Kowalski, J.; Lipton, M. A.; Tetrahedron Lett., vol. 37 (1996), p. 5839; c) Scott, B. O.; Siegmund, A. C.; Marlowe, C. K.; Pei, Y.; Spear, K. L.; Mol. Diversity, vol. 1 (1995), p. 125; d) Goodfellow, V. S.; Laudeman, C. P.; Gerrity, J. I.; Burkard, M.; Strobel, E.; Zuzack, J. S.; McLeod, D. A.; Mol. Diversity, vol. 2 (1996), p. 97; e) Fresno, M.; Alsina, J.; Royo, M.; Barany, G.; Albericio, F.; Tetrahedron Lett., vol. 39 (1998), p. 2639. The latter class of compounds possesses a rigid scaffold and has proven to be an effective screening tool, but also has several limitations, solubility and metabolic stability. There are only a few reports on the synthesis of piperazines and 2-oxopiperazines on solid support. See a) Goff, D. A.; Zuckremann, R. N.; Tetrahedron Lett., vol. 37 (1996), p. 6247; b) Dankwardt, S. M.; Sherry, R. N.; Krstenansky, J.; Tetrahedron Lett., vol. 36 (1995), p. 4923; c) Goff, D. A.; Tetrahedron Lett., vol. 39 (1998), p.

14 7 3 . SUMMARY OF THE INVENTION WO 99/55684 PCT/US99/09091 2 The subject invention involves processes for making sulfonated 2 oxopiperazine compounds: O HN

R

3

N\SO

2 R2 using a solid-support resin, comprising the following steps: (a) starting with a N-protected cc-amino acid ester of a solid-support resin: O O R] BINH removing the N-protecting group, and reacting the unprotected ester with a sulfonyl chloride: R 2

-SO

2 C1, to provide: O

R

1 NH L SO2R2 (b) reacting this through a Mitsunobu reaction with a N-protected a-amino alcohol: BINHCH(R 3

)CH

2 OH, to provide: WO 99/55684 PCT/US99/09091 3 0 O Ri

N",SO

2 R2 BINH R 3 (c) removing the N-protecting group, and cyclizing the above sulfonated 2 oxopiperazine from the resin. The subject invention also includes the above processes where the above ca amino acid ester is replaced by a -amino acid ester (or longer homologous ester) and/or the above ac-amino alcohol is replaced by a -amino alcohol (or longer homologous alcohol), such that the final products are the homologous 7-member or 8-member (or larger) ring compounds. Also, in the above structures, R 3 may also be attached to the N from the amino alcohol (eliminating the H attached thereto), thus resulting in a fused-ring product. DETAILED DESCRIPTION OF THE INVENTION As used herein unless specified otherwise, "alkyl" means a hydrocarbon chain which is branched, linear or cyclic, saturated or unsaturated (but not aromatic), substituted or unsubstituted. The term "alkyl" may be used alone or as part of another word where it may be shortened to "alk" (e.g., in alkoxy, alkylacyl). Preferred linear alkyl have from one to about twenty carbon atoms, more preferably from one to about six carbon atoms, more preferably still from one to about four carbon atoms; most preferred are methyl or ethyl. Preferred cyclic and branched alkyl have from three to about twenty carbon atoms, more preferably from three to about six carbon atoms. Preferred cyclic alkyl have one hydrocarbon ring, but may have two, three, or more, fused hydrocarbon rings. Preferred alkyl are unsaturated with from one to about three double or triple bonds; preferably they are mono unsaturated with one double bond; more preferred alkyl are saturated. Preferred WO 99/55684 PCT/US99/09091 4 substituents of alkyl include alkyl, aryl, aryloxy, alkoxy, alkyl or aryl ester. More preferred alkyl are unsubstituted. As used herein, "heteroatom" means a nitrogen, oxygen, or sulfur atom. As used herein, "alkylene" means a linear alkyl which is attached to other moieties both ends of the alkylene, and "heteroalkylene" means an alkylene having one or more heteroatoms between carbons or/and at one or both ends of the alkylene. As used herein unless specified otherwise, "aryl" means an aromatic hydrocarbon ring which is substituted or unsubstituted. The term "aryl" may be used alone or as part of another word (e.g., in aryloxy, arylacyl). Preferred aryl have from six to about ten carbon atoms in the aromatic ring(s), and a total of from about six to about twenty, preferably to about twelve, carbon atoms. Preferred aryl is phenyl or naphthyl; most preferred is phenyl. Preferred substituents of aryl include alkyl, aryl, alkoxy, aryloxy, alkyl or aryl ester, halo, nitro, amino, cyano, acyl, alkyl- or arylacyl. More preferred aryl are unsubstituted. As used herein unless specified otherwise, "heterocycle" means a cyclic hydrocarbon chain with one or more heteroatoms in the hydrocarbon ring(s). The ring(s) may be saturated, unsaturated, or aromatic. Preferred heterocycles have from one to about six heteroatoms in the ring(s), more preferably one or two or three heteroatoms, most preferably one heteroatom. Preferred heterocycles have from three to about twelve carbon plus heteroatoms in the ring(s), more preferably from three to about seven; and a total of from three to about twenty carbon plus heteroatoms, more preferably from three to about ten. Preferred heterocycles have one ring, but may have two, three, or more, fused rings. Heterocycles are unsubstituted or substituted. Preferred heterocycle substituents are the same as for alkyl. As used herein unless specified otherwise, "heteroaryl" means an aromatic heterocycle. Preferred heteroaryls have from one to about six heteroatoms in the ring(s), more preferably one or two or three heteroatoms, most preferably one heteroatom. Preferred heteroaryls have from five to about twelve carbon plus heteroatoms in the aromatic ring(s), more preferably from five to about nine; and a total of from five to about twenty carbon plus heteroatoms, more preferably from WO 99/55684 PCT/US99/09091 5 five to about ten. Preferred heteroaryls have one ring, but may have two or more fused rings, at least one of which contains at least one ring heteroatom. Heteroaryls are unsubstituted or substituted. Preferred heteroaryl substituents are the same as for aryl. The subject invention processes use solid-support resins capable of linking with the carboxy moiety of amino acids. Preferred resins for use in the subject processes have hydroxyalkylene linking moieties. Particularly preferred are Merrifield or Wang resins such as polystyrene based resin Merrifield (100-200 mesh), 2%DVB - catalog number 01-64-0104, available from Calbiochem Novabiochem Corp., San Diego, California, a hydroxymethylpolystyrene resin. N-protected amino acids can be readily esterified to the above-mentioned resins. Alternatively, such resins are commercially available with N-protected amino acids already esterified to the resin (e.g. Boc-Gly-Merrifield resin catalog number 04-12-2507, available from Calbiochem-Novabiochem Corp.). N-protecting groups on the above-mentioned amino acids are well known; they include t-butyloxycarbonyl (Boc) and 9-fluorenylmethoxycarbonyl (Fmoc); most preferred is Boc. In the structures depicted herein, "Bi" is used to indicate a N protecting group. A subject invention process involves starting with a N-protected amino acid ester of a solid-support resin: O O n BINH R The N-protecting group is generally present on amino acid esters of resins because it is needed to properly esterify the amino acid onto the resin. The subject process first requires removing this N-protecting group; this can be accomplished using any WO 99/55684 PCT/US99/09091 6 known method. (If the N-protecting group is not present, this procedure can be skipped.) The resulting unprotected amino acid ester of a solid-support resin is reacted with a sulfonyl chloride:

R

2

-SO

2 Cl 2 to provide: O n

R

1 NH So R 2R2 3 This reaction is preferably carried out under basic conditions (e.g. diisopropylethyl amine) in a halogenated solvent (e.g. dichloromethane). In structures herein, R 1 can be any moiety that provides stable intermediates and final products for the subject processes. Preferred R 1 include hydrogen, alkyl, aryl, heterocycle, heteroaryl, alkyl or aryl amine, alkyl or aryl ester. More preferred

R

1 are hydrogen and alkyl having from one to about four carbon atoms, the alkyl preferably being saturated, linear or branched, unsubstituted or substituted with one or more, preferably one, moiety selected from hydroxy, methoxy, ethoxy, thio, methylthio, ethylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, guanido, carboxy, carbamoyl, phenyl, hydroxyphenyl, indole, and imidazo. Still more preferred R 1 are the side chains of the natural amino acids. In structures herein, R 2 can be any moiety that provides stable intermediates and final products for the subject processes. Preferred R 2 include hydrogen, alkyl, aryl, heterocycle, heteroaryl, alkyl or aryl amine, alkyl or aryl ester; more preferred

R

2 are aryl and heterocycle.

WO 99/55684 PCT/US99/09091 7 In structures herein, n is an integer from 0 to about 5, preferably from.0 to about 3; more preferably n is 0 or 1, most preferably 0. The next step of a subject invention involves a Mitsunobu reaction of 3 with a N-protected amino alcohol: BINH BI H

R

3 H m R m 4 or 7 to provide: 0 0 n n BlNm m2 BIHN BI-N \ SO 2

R

2 SO2 2 4 SO2R 5 or 8 Mitsunobu reactions are disclosed in a) Hughes, D., " The Mitsunobu Reaction", Organic Reactions, vol. 42, Paquette, L.A., ed.; 1992, John Wiley & Sons, NY, pp. 335-656; b) Swayze, E. E., Tetrahedron Lett., vol.38 (1997), p. 8643. In structures, herein, R 3 can be any moiety that provides stable intermediates and final products for the subject processes. Preferred R 3 include hydrogen, alkyl, aryl, heterocycle, heteroaryl, alkyl or aryl amine, alkyl or aryl acyl, alkyl or aryl ester, alkyl or aryl sulfonyl. More preferred R 3 are hydrogen and alkyl having from one to about four carbon atoms, the alkyl preferably being saturated, linear or branched, unsubstituted or substituted with one or more, preferably one, moiety selected from hydroxy, methoxy, ethoxy, thio, methylthio, ethylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, guanido, carboxy, WO 99/55684 PCT/US99/09091 8 carbamoyl, phenyl, hydroxyphenyl, indole, and imidazo. Still more preferred R 3 are the side chains of the natural amino acids. In structures herein, R 4 is an alkylene or heteroalkylene moiety. R 4 has from 3 to about 10 carbon plus heteroatoms in the ring (incorporating R 4 ), preferably 3 or 4 carbon plus heteroatoms in the ring, more preferably 3 or 4 carbon atoms and no heteroatoms in the ring. (Of course, such ring has at least the one N depicted in 8.) Preferred R 4 is saturated and unsubstituted or substituted with one moiety selected from hydroxy, methoxy, ethoxy, thio, methylthio, ethylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, carboxy, and carbamoyl. Most preferred

R

4 is n-propylene. In structures herein, m is an integer from 1 to 5, preferably from 1 to 3; more preferably m is 1 or 2, most preferably 1. The next step of a subject invention process involves removing the N protecting group from 5 or 8 by any known method (similar to the analogous procedure above). The next step of a subject invention process involves cyclizing the product: 0 HN n Nn R1R R N R N S SCR 2 S2R 2 6 or 9 from the resin. This cyclizing/cleavage from resin reaction is carried out in acidic conditions in a mildly polar solvent at an elevated temperature. Cleavage and cyclization is preferably achieved in a solution of acetic acid in 2-butanol. The cleavage and cyclization reaction is not highly dependent on the amino acid or amino aldehyde used. The temperature required for maximum cleavage and cyclization is typically from about 25 oC to about 700C. The subject invention processes are useful for making compounds individually or in libraries of separate or mixtures of compounds. The synthesis of WO 99/55684 PCT/US99/09091 9 libraries of compounds of structure 6 and/or 9 can readily be carried out using a multiple cell procedure, e.g., 96 plate format (e.g., Robbins Block), where different compounds having different combinations of R 1 , R 2 and R 3 or R 4 can be made in each cell simultaneously. Also, libraries of mixtures of compounds of structure 6 and/or 9 can be made by reacting reagents which are mixtures rather than single compounds. Both types of libraries are useful for rapid screening of numerous compounds for pharmacological and other activities. An exemplary process of the subject invention is depicted in the following scheme: O O ' O) R 1 1. TFA, DCM R 1 O R 2_ 0 -'O R NHBoc 2. R2-SO 2 C NH I 10

SO

2

R

2 11 HNBoc 1. Ph3P H , R3 0 R 12 R- . N SO2R 2. DIAD S0 2 R2 BocHN

R

3 13 O 1. TFA, DCM HN R 0 R3 N \ 2 2. 2M AcOH/2-BuOH S0 2 R 14 A Boc-amino acid attached via an ester link to Merrifield resin 10 is used as starting material. The amino group is deprotected and sulfonamide 11 is formed. The resin is washed with dilute acetic acid in order to remove any residual amine. Mitsunobu reaction with Boc-proctected amino alcohol 12 leads to alkylated product 13. To ensure the completion of this process, alkylation is WO 99/55684 PCT/US99/09091 10 repeated once more. Finally, the Boc group is removed and 2-oxopiperazine 14 is cleaved from the resin (2M AcOH in 2-BuOH). The following examples of the synthesis of 2-oxopiperazines using Boc prolinol and Boc-alaninol are typical. Boc-Ala-Merrifield resin ester (1.070 g, 0.74 mmol, 0.69 mmol/g, NovaBiochem) is rinsed several times with dichloromethane (DCM). It is then treated with trifluoroacetic acid (95%; TFA/H 2 0) for 1 h at room temperature. The resin is washed with DCM several times, then with 5% diisopropylethylamine (DIPEA) in DCM, and again with DCM. The suspended resin (DCM ca. 5 mL) is treated with DIPEA (645 mg, 869 L, 5 mmol) and 4-methoxybenzenesulfonyl chloride (762 mg, 3.7 mmol, 5 eq) and vigorously shaken for 16 h, filtered and washed (DCM, methanol and again DCM several times, acetic acid (1% in DCM), DCM several times, and finally methanol) and dried under vacuum for 20 h at room temperature to give resin ester 15 (1.121 g, new loading, 0.61 mmol/g): O HN 0 0 15 Resin ester 15 (200 mg, 0.122 mmol, 0.61 mmol/g) is rinsed several times with tetrahydrofuran (THF). Triphenylphosphine (Ph 3 P) (0.37 mmol, 97 mg, 3 eq) and (S)-1-(tert-butoxycarbonyl)-2-pyrrolidinemethanol (N-Boc-L-prolinol) (0.37 mmol, 75 mg, 3 eq) are dissolved in THF (ca. 4 mL) and added to the reactor, followed by diisopropyl azodicarboxylate (DIAD) (0.37 mmol, 75 mg, 73 pL, 3 eq). The reaction mixture is vigorously shaken for 8 h and filtered. The resin is washed several times with THF. Then the alkylation procedure is repeated one more time. The crude resin product from the previous step is rinsed several times with DCM and then treated with trifluoroacetic acid (95%; TFA/iH 2 0) for 1 h at room WO 99/55684 PCT/US99/09091 11 temperature. The resin is washed with DCM and methanol and finally suspended in 2M AcOH/2-BuOH and vigorously shaken at 50 0 C for 15 h and filtered. The resin is washed a few more times with DCM and methanol; filtrates are collected and evaporated. The oily residue is co-evaporated with chloroform (in order to remove traces of acetic acid and butanol) to give a purified product of 16: O o o 16 Compound 17 is prepared using a similar process. Resin ester 15 (300 mg, 0.183 mmol, 0.61 mmol/g) is rinsed several times with tetrahydrofuran (THF). Triphenylphosphine (Ph 3 P) (0.56 mmol, 148 mg, 3 eq), N-Boc-L-alaninol (0.56 mmol, 113 mg, 3 eq) are dissolved in THF (ca. 9 mL) and added to the reactor, followed by diisopropyl azodicarboxylate (DIAD) (0.56 mmol, 113 mg, 110 [IL, 3 eq). The reaction mixture is vigorously shaken for 8 h and filtered. The resin is washed several times with THF. The alkylation procedure is repeated one more time. The crude resin product from the previous step is rinsed several times with DCM and then treated with trifluoroacetic acid (95%; TFA/H 2 0) for 1 h at room temperature. The resin is washed with DCM and methanol and finally suspended in 2M AcOH/2-BuOH and vigorously shaken at 70 0 C for 48 h and filtered. The resin is washed a few more times with DCM and methanol; filtrates are collected and evaporated. The oily residue is co-evaporated with chloroform (in order to remove traces of acetic acid and butanol) to give a purified product of 17: WO 99/55684 PCT/US99/09091 12 0 HN N S o 0 17 While particular embodiments of the subject invention have been described, it will be obvious to those skilled in the arts that various changes and modifications of the subject invention can be made without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, all such modifications that are within the scope of this invention.

Claims

1. A process for making compounds having the structure: 0 0 HN n N n R N R n mN \SQ2R2 S2R 2 6 or 9 wherein R1, R2, R 3 and R 4 are selected such that compounds L 2,3,4, 5, 6, 7, 8, and 9 are sufficiently stable to carry out the process, n is an integer from 0 to 5, m is an integer from 1 to 5, and BI is a N-protecting group, comprising the following steps: (a) from a N-protected amino acid ester of a solid-support resin: O O n BINH R 1 1 removing the N-protecting group BI and substituting therefor a hydrogen to give an unprotected amino acid ester of a solid-support resin; or starting with such unprotected resin ester; (b) reacting the unprotected resin ester from step (a) with sulfonyl chloride: R 2 -SO 2 CI 2 to provide: WO 99/55684 PCT/US99/09091 14 O n RI NH I S02R 2 3 (c) reacting 3 with a N-protected alcohol: BINH BI H H R 3 R m R m 4 or 7 to provide: O O 0 n ~n Ol n On N1 NR BIHN S 2 BI-N m SO 2 R 2 R3S2 R4 R 3 5 or 8 (d) removing the N-protecting group from 5 or 8; and (e) cleaving and cyclizing 6 or 9 from the resin.

2. The process of Claim 1 wherein: (a) R 1 is selected from hydrogen, alkyl, aryl, heterocycle, heteroaryl, alkyl or aryl amine, alkyl or aryl ester; (b) R 2 is selected from hydrogen, alkyl, aryl, heterocycle, heteroaryl, alkyl or aryl amine, alkyl or aryl ester; WO 99/55684 PCT/US99/09091 15 (c) R 3 is selected from hydrogen, alkyl, aryl, heterocycle, heteroaryl, alkyl or aryl amine, alkyl or aryl ester, alkyl or aryl acyl, alkyl or aryl sulfonyl; and (d) R 4 is alkylene or heteroalkylene.

3. The process of Claim I or 2 wherein n is 0 or 1, preferably 0; and m is I or 2, preferably 1.

4. The process of any of Claims 1 - 3 wherein in step (c) the amino alcohol has structure 4, resulting in product with structures 6 from step (e).

5. The process of any of Claims 1 - 3 wherein in step (c) the amino alcohol has structure 7, resulting in product with structures 9 from step (e).

6. The process of any of Claims 1 - 5 wherein: (a) R 1 is hydrogen or alkyl, the alkyl having from one to four carbon atoms and being saturated, linear or branched, unsubstituted or substituted with one moiety selected from the group consisting of hydroxy, methoxy, ethoxy, thio, methylthio, ethylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, guanido, carboxy, carbamoyl, phenyl, hydroxyphenyl, indole, and imidazo; (b) R 2 is selected from hydrogen, alkyl, aryl, and heterocycle; (c) R 3 is hydrogen or alkyl, the alkyl having from one to four carbon atoms and being saturated, linear or branched, unsubstituted or substituted with one moiety selected from the group consisting of hydroxy, methoxy, ethoxy, thio, methylthio, ethylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, guanido, carboxy, carbamoyl, phenyl, hydroxyphenyl, indole, and imidazo; and (d) R 4 is saturated alkylene having from three to four carbon atoms, the alkylene being unsubstituted or substituted with one moiety selected WO 99/55684 PCT/US99/09091 16 from the group consisting of hydroxy, methoxy, ethoxy, thio, methylthio, ethylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, carboxy, and carbamoyl.

7. The process of any of Claims 1 - 6 wherein each N-protecting group is Boc or Fmoc, steps (a) and (d) are each preferably carried out in a TFA solution, and step (e) is preferably carried out in an acetic acid/2- butanol solution.

8. The process of any of Claims 1 - 7 wherein the resin is hydroxymethylpolystyrene.

9. A library of compounds having structure: 0 O HN n N n S2 SO2R 6 or 9 or both, wherein R 1 , R 2 , R 3 and R 4 are selected such that the compounds are stable; preferably wherein: (a) R 1 is selected from hydrogen, alkyl, aryl, heterocycle, heteroaryl, alkyl or aryl amine, alkyl or aryl ester; (b) R 2 is selected from hydrogen, alkyl, aryl, heterocycle, heteroaryl, alkyl or aryl amine, alkyl or aryl ester; (c) R 3 is selected from hydrogen, alkyl, aryl, heterocycle, heteroaryl, alkyl or aryl amine, alkyl or aryl ester, alkyl or aryl acyl, alkyl or aryl sulfonyl; and (d) R 4 is alkylene or heteroalkylene. WO 99/55684 PCT/US99/09091 17

10. The library of compounds of Claim 9, preferably with all compounds having structure 6, wherein: (a) n is from 0 to 2, preferably 0; (b) m is from 1 to 3, preferably 1; (c) R 1 is hydrogen or alkyl, the alkyl having from one to four carbon atoms and being saturated, linear or branched, unsubstituted or substituted with one moiety selected from the group consisting of hydroxy, methoxy, ethoxy, thio, methylthio, ethylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, guanido, carboxy, carbamoyl, phenyl, hydroxyphenyl, indole, and imidazo; (d) R 2 is selected from hydrogen, alkyl, aryl, and heterocycle; (e) R 3 is hydrogen or alkyl, the alkyl having from one to four carbon atoms and being saturated, linear or branched, unsubstituted or substituted with one moiety selected from the group consisting of hydroxy, methoxy, ethoxy, thio, methylthio, ethylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, guanido, carboxy, carbamoyl, phenyl, hydroxyphenyl, indole, and imidazo;.and (f) R 4 is saturated alkylene having from three to four carbon atoms, the alkylene being unsubstituted or substituted with one moiety selected from hydroxy, methoxy, ethoxy, thio, methylthio, ethylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, carboxy, and carbamoyl.