CA2207102A1 - Process for the preparation of amidino phenyl pyrrolidine .beta.-alanine urea analogs - Google Patents
Process for the preparation of amidino phenyl pyrrolidine .beta.-alanine urea analogsInfo
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- CA2207102A1 CA2207102A1 CA002207102A CA2207102A CA2207102A1 CA 2207102 A1 CA2207102 A1 CA 2207102A1 CA 002207102 A CA002207102 A CA 002207102A CA 2207102 A CA2207102 A CA 2207102A CA 2207102 A1 CA2207102 A1 CA 2207102A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/38—2-Pyrrolones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
- C07C323/43—Y being a hetero atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur 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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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
The invention herein is directed to a process for producing a lactam of formula (2) from a methionine analog of the formula (1) by treating the methionine analog with trimethylsulfonium halide or trimethylsulfoxonium halide in the presence of a base in a suitable aprotic solvent. The invention herein is further directed to the preparation of amidinophenyl pyrrolidinyl .beta.-alanine urea analogs using such methionine and lactam compounds as intermediates, which .beta.-alanine urea analogs are useful as antithrombotics.
Description
CA 02207102 1997-06-0~
W O 96/17827 PCTnUS9S/149~8 Process for the Preparation of Amidino Phenyl Pyrrolidine ~-Alanine Urea Analogs BACKGROUND OF THE INVENTION
The invention herein is directed to the cyclization of a methionine analog to a lactam using new reaction reagents and conditions. The invention herein is further directed to the enantioselective synthesis of ethyl 3-t[ttl-t4-(aminoiminomethyl)phenyl]-2-oxo-3(s)-pyrrolidinyl]amino]carbonyl]amino]propionate acetate and related ~-alanine analogs. Such compounds are useful as antithrombotic agents.
More specifically the invention herein is directed to the conversion of a methionine analog such as \~
Z~ ~
(Z = H, -CN, -CONH2 or -CO2Me) to a lactam such as ~ ~NR
using reagent and reaction conditions which are beneficial in comparison to previously disclosed methodology for achieving such a conversion.
CA 02207102 1997-06-0~
WO g6/17827 ~ J95114948 Friedinger et al., J. Org. Chem ., 47, (104-109), 1982 disclose general methods for the synthesis of lactam-constrained dipeptide analogs using three different paths from protected chiral ~-amino acids to lactams. Included within this disclosure is a method for cyclizing methionine analogs to lactams via an alkylative cyclization involving a two step procedure using highly volatile and toxic methyl iodide and highly reactive sodium hydride as reagents.
It would be desirable to provide a process for conversion of a methionine analog to a lactam via conditions which do not employ volatile, toxic or highly reactive reagents and which produces a lactam having high enantiomeric purity.
lS
SU~IARY OF THE INVENTION
The invention herein is directed to a process for producing a lactam of the formula r-~
Z 3~N~''NHR
wherein R is a protecting group such as t-butoxycarbonyl (BOC) or carbobenzyloxy (CBZ) and Z is H, -CN, -CONH, or CO2alkyl, from a methionine analog of the formula S
H ~¦
z~ O
CA 02207102 1997-06-0~
WO g6/17827 ~ 9~114948 by treating the methionine analog with trimethylsulfonium halide or trimethylsulfoxonium halide in the presence of an inorganic or aminergic base, such as alkali metal hydroxides, alkoxides or carbonates or a tertiary amine, diazabicycloundecane (DBU), or Hunig's base [diisopropylethylamine (DIEA)], in a suitable aprotic solvent.
The invention herein is further directed to the preparation of amidinophenyl pyrrolidinyl ~-alanine urea analogs using such methionine and lactam compounds as intermediates, which ~-alanine urea analogs are useful as antithrombotics.
DETAILED DESCRIPTION OF THE INVENTION
The invention herein is directed to a process for producing a lactam of the formula 1~
Z ~ N ~ NHR
wherein R is a protecting group such as t-butoxycarbonyl (BOC) or carbobenzyloxy (CBZ) and Z is H, -CN, -CONH2 or CO2alkyl from a methionine analog of the formula S
H ~
3 o ,~' --~NR
by treating the methionine analog with trimethylsulfonium halide or trimethylsulfoxonium halide (such as trimethylsulfonium iodide or trimethylsulfoxonium CA 02207102 1997-06-0~
~VO g6/17827 chloride) in the presence of an inorganic or aminergic base in a suitable aprotic solvent.
The invention herein is further directed to the preparation of amidinophenyl pyrrolidinyl ~-alanine urea analogs using such methionine and lactam compounds as intermediates, which ~-alanine urea analogs are useful as anti-thrombotics. Such process includes treating a methionine analog of the formula H r Z~ O
(wherein Z is -CN or -CONH2) with trimethylsulfonium halide or trimethylsulfoxonium halide in the presence of a base, preferably potassium carbonate, in an aprotic solvent, preferably DMS0, to afford a lactam of the formula r~
Z~ O
dehydrating when Z is -CONH2 and deprotecting the lactam, reacting the resulting product with a ~-amino ester in the presence of CDI to produce a urea of the formula o O ~ OR6 ~N/~N~NlR
NC--~J O H H
CA 02207102 1997-06-0~
W O g6117827 PCTnUS9S/14g48 treating the urea with hydroxylamine to produce an amidoxime, hydrogenating the amidoxime; and isolating a compound of the formula o H2N~N~N~N~
wherein Rl is hydrogen, alkyl, aryl, arylalkyl, a heterocyclyl radical containing 1 to 3 heteroatoms or a heterocyclylalkyl and ~ is selected from alkyl, aryl, arylalkyl or acyloxymethyl.
The general synthetic scheme is outlined in Scheme 1.
15 Starting from commercially available materials, a suitably protected methionine (R = BOC, CBZ) is condensed with a substituted or unsubstituted aniline in the presence of a suitable amino acid coupling reagent (e.g. isobutyl chloroformate, 2-chloro-1-methylpyridinium iodide, 1,1'-carbonyldiimidazole (CDI) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) and a tertiary amine base (e.g. N-methylmorpholine, N-methylpiperazine or triethylamine) in a suitable aprotic solvent (e.g.
dimethylformamide (DMF), tetrahydrofuran (THF) or CH~Cl2) at a temperature ranging from -15~C to 25OC to give the methionine analog 1.
Methionine analog 1 is cyclized to lactam 2 via a novel set of reaction conditions. Treatment of compound 1 with trimethylsulfonium halide or trimethylsulfoxonium halide in the presence of an inorganic or aminergic base (e.g. alkali metal hydroxide, alkali metal alkoxides, - alkali metal carbonates or tertiary amines such as DBU or Hunig's base), preferably in the presence of potassium carbonate in a suitable aprotic solvent (e.g. DMF, CA 02207102 1997-06-0~
WO96/17827 PCT~S95/14948 dimethylacetamide (DMA), DMSO or THF) at a temperature ranging from 35~C to 90~C affords lactam 2. Historically, this conversion was accomplished by an alkylative cyclization in a two step procedure requiring highly S volatile and toxic methyl iodide and highly reactive sodium hydride respectively as the principle reagents [c.f. Freidinger, R.M. et al., J. Orq. Chem., 47, 104-109 (1982); Kottirsch, G. et al., Bioorq. Med. Chem. Letters, 3, 167S-1680 (1993)]. Further, the extent of racemization in the later process was dependant upon the workup conditions. In the present invention, neither strong alkylators nor strong bases are required and the product is produced having high enantiomeric purity.
The lactam 2 can be dehydrated when Z is -CONH2 to lS the nitrile 3 using standard reagents (e.g.
trifluoroacetic anhydride (TFAA), trichloroacetic anhydride or thionyl chloride) in the presence of an amine base (e.g. Et3N, pyridine, N-methylmorpholine or N,N-diisopropylethylamine) in an aprotic solvent (e.g. THF, EtOAc, pyridine or DME).
Aromatic analogs of methionine undergo cyclization as illustrated in Table 1. For example, the nitrile compound lb, prepared by dehydrating la (TFAA, Et3N), was cyclized to lactam 10. Also, the carbomethoxyanilides ld and le 2S undergo cyclization without subsequent hydrolysis of the ester function. This is important to note since ester containing intermediates cyclized under the Freidinger conditions undergo hydrolysis of the ester.
WO g6/17827 1 ~ 4948 H ~
"NBOC Me3S X /K2Co3 ~N~""'NBOC
Me3SO X /K2CO3 Z O H
1 a-e 2 a-e compound compound, ~neld 1 a, Z = 4-CONH2 2a, 75%
1 b, Z = 4-CN 1 O, 88%
1c, Z = 4-H 2c, 38%
1 d, Z = 3-CO2Me 2d, 53%
1 e, Z = 4-CO2Me 2e, 79%
-CA 02207102 1997-06-0~
WOg6/17827 PCT~S9S114948 DeprotectiOn of the protecting group R with HCl or trifluoroacetic acid (TFA) (R = BOC) or H2, Pd/C (R = CBZ) affords aminolactam 4. For R = BOC, excess anhydrous HCl or concentrated HCl (2.0 - 5.0 equivalents) in solvent (e.g. EtOAc, MeO-t-Bu, 1,4-dioxane or THF) at 5 to 50~C
for 0.5 - 23 hours affords product as the hydrochloride salt. Additionally the free base could be isolated as a precipitate by adding 1 equivalent of base (e.g. lN NaOH) to an aqueous solution of the hydrochloride salt.
Synthesis of the urea product 5 is accomplished by sequential addition of an appropriate ~-amino ester and aminolactam 4 to a suitable phosgene equivalent (e.g.
triphosgene, diphosgene, phosgene, 1,1'-carbonyldiimidazole) in a suitable solvent (e.g. CH2Cl2, CHC13, ClCH2CH2Cl, DMF, DMA, pyridine, dioxane, THF, benzene, toluene). Reaction of 5 with hydroxylamine hydrochloride in the presence of a suitable base (e.g.
Et3N, (i-Pr)2NEt, NaOAc, NaOEt, NaOH) in a suitable solvent (e.g. MeOH, EtOH, H2O, DMF, DMA) provides the amidoxime intermediate 6. This material is hydrogenolyzed in the presence of a suitable catalyst (e.g. Pd/C, Pt/C, Pd(OH)2) in a suitable solvent (e.g. MeOH, EtOH, i-PrOH or HOAc) in the presence of an acid counterion (e.g. HOAc, HCl, HBr, methanesulfonic acid (MsOH), succinic acid, citric acid, H3PO4, malic acid) affording the target compound 7 as the corresponding acid salt.
W 096/17827 ~ gS/14948 ~S ~S
~NH2 ~cou~irq ro~g~, H
/[W HO~R ~ BOC, CBZ ~ NR
Me3S X/K2C03 ~ ~N/~NHR whonZis-CONH~
Me3SO X /K2C03 Z
NC~N/~>~NR d~tprotect, { 3~ ~ H2N R~
O ~OEt H~OH HCI
pho~g~ ~ NC~ ~H H
~0 HO-NH~N~NJ~N~
6 HN~ ~NJ~NJ~
HY
(x- is l . cr, Br') Yis a p~,.,.~ ceF~ salt Rt iS H, alk~4, alkenyl, alkynyl, ar~, or a ",onoc~lic heterocyclyl cu. ' ~ing 1 to 3 OINJS) CA 02207102 1997-06-0~
WO g6/17827 ~ 3~114948 The preferred method of preparing a preferred antithrombotic agent, namely, ethyl 3-[[[[1-[4-(aminoiminomethyl)phenyl]-2-oxo-3(S)-pyrrolidinyl]amino]carbonyl]amino]propionate acetate is illustrated in Scheme 2 and Scheme 2a. Treatment of commercially available N-BOC-L-methionine and 4-aminobenzamide with 2-chloro-1-methylpyridinium iodide (CMPI) and N-methylmorpholine (NMM) in DMF affords the methionine amide lA.
In the novel cyclization step, heating a mixture of lA, trimethylsulfonium iodide and powdered K2C03 (potassium carbonate) in DMSO at 70~C gives the chiral lactam 2A.
Formation of the nitrile 10 is carried out by dehydrating the primary amide with a standard reagent (trifluoroacetic anhydride/Et3N) in THF. Removal of the BOC protecting group with HCl/EtOAc affords the amine hydrochloride 11. Sequential addition of ~-alanine ethyl ester hydrochloride and compound 11 to 1,1'-carbonyldiimidazole in DMF/pyridine (1:1) affords the unsymmetrical urea 12.
Treatment of 12 with hydroxylamine hydrochloride/triethylamine in ethanol gives the benzamidoxime 13. Hydrogenolysis of 13 with 4% palladium on carbon in acetic acid gives the target compound 14 as the acetate salt.
In Scheme 2B another preferred method is illustrated, wherein intermediate lA is dehydrated to intermediate 1B.
Subsequent cyclization of lB to 10 is accomplished as described for the conversion of lA to 2A. Intermediate 1o is then utilized further as demonstrated in Scheme 2 and 2a.
W Og6/17827 ~ S/14948 H N ~ N Boc O f W O H
Me3S r/1<2CO3 ~p ''N Boc DMSO/70~C o~ H TFAAlEt3N
NCJC~N/~""'N E30C conc. HCUEtOAc ~3~ 0 HCI
W O 96/17827 PCTnUSgS/14948 SCHEME 2 a "NH2 CDUH2CH2CH2CO2Et HC
NCJ~ o HCI DMF/pyr (1:1 ) N/~ H2NOH HCUEt3N
~ "'N N EtOH/65 C
/--\ ~ _~OEt 4%Pd/C, H2 60psi HI~N~ ............................... 60 CIHOAC
Ho,N O
HN~,~ ? H H
H2N HOAc 14 WO g6/17827 1 ~ J.,3S/14g48 SCHEME 2 b H r 1A TFA~VEt3N, ~0~N~I'"'N BOC
Me3S I A<2C~3 . 10 DMSO/70~C
CA 02207102 1997-06-0~
WOs6/17827 PCT~S95/14948 As illustrated in Scheme 3, classical resolution of commercially available ethyl 3-aminobutanoate with (R)-mandelic acid affords enantiomerically pure mandelate salt 1s after three recrystallizations from EtOAc. Sequential treatment of a suspension of 1,1'-carbonyldiimidazole with 11 then 15 affords the unsymmetrical urea 16. Treatment of 16 with hydroxylamine hydrochloride/triethylamine gives the benzamidoxime 17 which undergoes hydrogenolysis in HOAc to give the target compound 18.
WO g6/17827 P~ 9~/14948 ~OEt (P)-mandelicacid ~C0 H2N EtOAc H3N--~3~N~ H CDU15 ~ NC 11 DMFlpyr(1:1) NCJ3~N? J~ ~ H~NOH HCVEt3N .
o ~OEt 4% Pd/C. H260 psi "NJ~NJ~ 60~C/HOAc HO HN~N~."
H2N HOAc L8 WO96/17827 PCT~S9S114948 The Arndt-Eistert homologation (Scheme 4) of N-BOC-D-phenylglycine affords the chiral ~-amino ester 19.
Treatment of 19 with dry HCl affords the amine hydrochloride 20. Elaboration of 20 as outlined in Scheme 2a affords the target compound 21.
WO g6/17827 PCr/US9S/14948 .
1~l ,~02H 1) IBCF/NMM ~OEt BOC-N ~ 2) CH2N2 BOC-N~
~ 3) Agbenzoate/EtOH H
HCI fJ~OE~
HCI/EtOAc I Scheme 2a H2N~
N~0~N?"""
H2N HOAc CA 02207102 1997-06-0~
W O 96/17827 1~ s/l4948 The ~-amino acids and esters can be purchased or prepared from commercially available starting materials using known methods as illustrated in Scheme 5. The racemic ~-heteroaryl ~-amino acids can be prepared from the appropriate aryl aldehyde, malonic acid, and ammonium acetate (Method 1) [Johnson and Livak, J. Am. Chem. Soc., Z29 (1936)]. The racemic ~-alkyl ~-amino acids can be prepared from the corresponding alkene and chlorosulfonyl isocyanate (CSI) which goes through the ~-lactam as shown in Method 2 [W. A. Szabo, Aldrichimica Acta, 23 (1977); R.
Graf, Angew. Chem. Int. Ed., 172 (1968)]. The ~-lactam can be opened to the ethyl ester by treatment with anhydrous HCl in ethanol. An alternative method to form racemic ~-amino esters is shown in Method 3. Nucleophiles can be added to 4-benzoyloxy-2-azetidinone to afford a variety of 3-substituted ~-amino esters after treatment with anhydrous HCl in ethanol tK. Prasad et al., Vol. 19, Heterocvcles, 2099 (1982)]. The racemic ~-amino acids and esters can be resolved using classical methods described in the literature [E. Fischer, H. Scheibler, R. Groh, Ber., 2020 (1910); E. Fischer, H. Scheibler, Annalen, 337 (1911) ] .
Chiral ~-amino acids and esters can also be prepared using many different approaches including the following methods: 1) homologation of suitably protected ~-amino acids using the Arndt-Eistert reaction as shown in Method 4 [Meier and Zeller, Anqew. Chem. Int. Ed., 32-43 (1975);
M. Rodriguez et al., Tetrahedron Lett., 5153 (1990); W. J.
Greenlee, J. Med. Chem. 434 (1985) and references therein], 2) through the addition of an amine to ~
unsaturated esters bearing a chiral auxiliary as shown in Method 5 [J. d'Angelo, J. Maddaluno, J. Am. Chem. Soc., 8112-14, (1986)], 3) through an enantioselective hydrogenation of a dehydroamino acid as shown in Method 6 [see: Asymmetric Synthesis, Vol 5, (J. D. Morrison, Ed.) WOg6117827 PCT~S9S114948 Academic Press, New York, 1985], and 4) through the addition of enantiomerically pure amines to ~
unsaturated esters as shown in Method 7 [S. G. Davies, o.
Ich;hAra, Tetrahedron: AsYmmetr~, 183-186 (1991)].
WO g6/17827 PCr/US9S/14948 SCHE~SE 5 Method 1 ~CO2H
CH2(CO2H)2 + R1CHO ~ NH40Ac ~
(R1 is a~yl or heteroary~ H2N R1 Method 2 0 ~CO2Et CISO2N=C=O + ~R~ ~,R1 H2N R~
Method 3 )R1 ~ ~ EHtCOH ' OCOPh R~ H2N R
(R1 is alkyl, aryl, heterocyclyl, alkenyl, alkynyl) Method 4 CO2H 1) Fommmixed COCHN2 ~ CO2Et anhydride ¦ A~
BOC-N~R1 2) CH2N2 H EtOH BOC-N~R~
~ Indicates Chiral Center Retention of stereoche, l I,~t (R~ is alkyl, aryl, heterocyclyl, arylalkyl, heteroaryblkyl) Method 5 CO2-Xc CO2Et 1~ Ph2cHNH2 1 1 ) Hydrogenolysis R~ Ph2CHN ~ R1 2) NaOH
Xc = 8-(p-phenoxyphenyl)-menthyl CO2H
H2N~R
(R1 is alk~l, aryl, arylalkyl, heterocyclyl, heteroarylalkyl~
WO g6/17827 rcrlusssll4s4s SCHEME 5 f Cont ' d Method 6 CO2Et ~CO2Et Enantioselective .
R4COHN R~ HydrogenaUon R4CON R~
~ Indicates Chiral Center (R4 is alkyl or alkoxy) (R~ is alkyl, aryl, arylalkyl) Method 7 CO2Et )~ + PhlN' ~ PhlN~R, R1 PhJ
1) Hydrogenolysis 2) NaOH H2N~R, (R~ is alkyl, aryl, heterocyclyl, arylalkyl, heteroarylalkyl) CA 02207102 1997-06-0~
W O 96117827 PCTnUS9S/14948 As used herein the term "lower alkyl" refers to a straight or branched chain hydrocarbon radical having from 1 to about 6 carbon atoms. Examples of such "lower alkyl"
radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neo-pentyl, hexyl, isohexyl and the like.
As used herein the term "lower alkenyl" refers to unsaturated acyclic hydrocarbon radicals containing at least one double bond and 2 to about 6 carbon atoms.
Examples of such groups include, ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl and the like.
As used herein the term "lower alkynyl" refers to unsaturated acyclic hydrocarbon radicals containing one or more triple bonds and 2 to about 6 carbon atoms. Examples of such groups are ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
The term aryl as used herein denotes carbocyclic aromatic ring systems composed of one or more aromatic rings. Preferred aryl groups are those consisting of one, two or three benzene rings. The term embraces aromatic radicals such as phenyl, naphthyl and biphenyl.
The term acyloxymethyl embraces groups of the formula o ~ wherein R7 is alkyl or aryl as defined R7~-~ocH
above.
As used herein the phrase "heterocyclyl radical containing 1 to 3 heteroatoms" refers to monocyclic or bicyclic radicals wherein 1 to 3 carbon atoms have been replaced with a heteroatom selected from oxygen, nitrogen or sulfur. Such rings can be saturated or unsaturated and include heteroaromatics.
The following non-limiting examples describe and illustrate methods for carrying out the process of the CA 02207102 1997-06-0~
WO 96117827 ~ 114948 present invention, as well as other aspects of the present invention, and the results achieved thereby in further detail. Both an explanation of, and the actual procedures for, the various aspects of the present invention are described where appropriate. These examples are intended to be merely illustrative of the present invention, and not limiting thereof in either scope or spirit. Those of skill in the art will readily understand that known variations of the conditions and processes described in these examples can be used to perform the process of the present invention.
Unless otherwise indicated all starting materials and equipment employed were commercially available.
CA 02207102 1997-06-0~
WO g6/17827 ~ S/14948 Exam~le 1 Preparation of N-~(4-aminocarbonYl)phenyll-4-methylthio-2~S) -r r (1 .1-dimethYlethox~)carbonyllaminolbutanamide rlA).
H - ~ CH3 H2N~N~NJ~o~cH3 A. To a solution of L-BOC-methionine (100.0 g, 0.40 mol), 4-aminobenzamide (57.3 g, 0.42 mol) and CMPI (102.6 g, 0.40 mol) in 250 ml of DMF at 0~C, under nitrogen, was added NMM (88 mL, 0.8 mol) over two minutes. The reaction mixture was stirred and allowed to gradually warm to room temperature while stirring for 4 hours. The reaction was quenched by the addition of 0.1 N HCl (750 mL) over about 10 minutes. After stirring for about 30 minutes, the white precipitate was filtered, washed with H2O and dried affording 123.3 g (84%) of product [m.p. 193.5-195~C
(dec.)].
[~]D25 = -23.0~ (MeOH, c=10.85 mg/ml) Anal. calc'd. for C~7H25N3O4S-0.33H20:
Calc'd.: C, 54.67; H, 6.93; N, 11.25; S, 8.59.
Found: C, 54.63; H, 7.02; N, 11.05; S, 8.63.
B. The following compounds were made in a like manner substituting other anilines for 4-aminobenzamide:
CA 02207102 1997-06-0~
W O g6/17827 p~ 3~/14g48 N-phenyl-4-methylthio-2(S)-[t(1,1-dimethylethoxy)-carbonyl]amino]~utanamide (~c), H-NMR (300 MHz, CD30D) ~ 1.44 (s, 9H), 1.90-2.05 (m, 2H), 2.08 (s, 3H), 2.S8 (m, 2H), 4.34 (m, lH), 7.08 (t, J = 8 Hz, lH), 7.29 (t, J = 8 Hz, 2H), 7.57 (d, J = 8 Hz, 2H).
N-[(3-methoxycarbonyl)phenyl]-4-methylthio-2(s)-[[( dimethylethoxy)carbonyl]amino]butanamide (ld), IH-NMR (300 MHz, CDCl3) ~ 1.43 (s, 9H), 2.00-2.25 (m, 2H), 2.08 (s, 3H), 2.63 (m, 2H), 3.82 (s, 3H), 4.65 (m, lH), 6.18 (d, J = 7 Hz, lH, exchangeable), 7.24 (t, J = 8 Hz, lH), 7.71 (m, 2H), 8.19 (s, 2H), 9.58 (s, lH, exchangeable).
N-[(4-methoxycarbonyl)phenyl]-4-methylthio-2(s)-[[( dimethylethoxy)carbonyl]amino]butanamide (le), H-NMR (300 MHz, CDCl3) ~ 1.42 (s, 9H), 2.00-2.25 (m, 2H), 2.10 (s, 3H), 2.64 (m, 2H), 3.90 (s, 3H), 4.62 (m, lH), 6.03 (d, J = 7 Hz, lH, exchangeable), 7.58 (d, J = 8 Hz, 2H), 7.88 (d, J = 8 Hz, 2H), 9.53 (s, lH, exchangeable).
C. Preparation of N-(4-cyanophenyl)-4-methylthio-2(S)-[[(1,1-dimethylethoxy)carbonyl]amino]butanamide (lb), To an ice cooled, stirred suspension of compound la (10.00 g, 27.23 mmol) and triethylamine (16.5 g, 0.163 mol) in 40 mL of THF was added TFAA (7.88 g, 37.53 mmol) at a rate to keep the internal temperature between 5-10~C.
The resulting solution was stirred at 0~C for 20 minutes then quenched at 0~C by slowly adding 45 mL of 2N HCl.
After the subsequent addition of 40 mL of saturated NaCl, the mixture was extracted with EtOAc, washed with saturated NaHCO3, dried (MgSO4), treated with decolorizing charcoal (ca. lg) and filtered through a bed of silica gel using EtOAc as eluent. Removal of the solvent under WO g6/17827 PCr/US9S114g48 reduced pressure produced a golden yellow oil which was dried to 9.50 g of a gummy foam under high vacuum.
H-NMR (300 MHz, CDCl3) ~ 1.47 (s, 9H), 2.02 (m, 2H), 2.13 (s, 3H), 2.18 (m, lH), 2.63 (t, J = 7 Hz, 2H), 4.44 (m, lH), 5.34 (broad, lH, exchangeable), 7.57 (d, J = 8 Hz, 2H), 7.63 (d, J = 8 Hz, 2H), 9.07 (s, lH, exchangeable).
CA 02207102 1997-06-0~
W O96/17827 PCTnUSg5/14948 Example 2 Preparation of 1-~(4-aminocarbonYl)~henyll-3(S)- r r dimethylethoxY)carbonyllaminolpyrrolidin-2-one (2~) H2N~ ? " ~
A. To a solution of the product of example la (3.00 g, 8.16 mmol) in DMSO (6 mL) was added trimethylsulfonium iodide (5.00 g, 24.48 mmol) and powdered K2CO3 (1.69 g, 12.24 mmol). The reaction mixture was stirred at 80~C
under nitrogen for 3 hours, cooled to room temperature and diluted with H2O (30 mL). The white precipitate was filtered, washed with H2O and dried affording 1.94 g (75%) of product which was used directly in the preparation of the compound of Example 3. An analytical sample was prepared by recrystallizing the product from 1 part hot i-PrOH and diluting with 3 parts H2O [m.p. 225-226~C (dec)].
[~]D25 - -14.1~ (MeOH, c=9.90 mg/mL) Anal. calc'd. for C~6H2~N3O4-1 H20:
Calcd.: C, 56.96; H, 6.87; N, 12.46.
Found: C, 56.78; H, 6.56; N, 12.36.
B. The following compounds were made in a like manner substituting other products of Example 1 (lb-le) for Compound 1~:
N-(4-cyanophenyl)-3(S)-[t(1,1-dimethylethoxy)carbonyl]-amino]pyrrolidin-2-one (3), H-NMR (300 MHz, CDC13) ~ 1.47 (s, 9H), 2.08 (m, J = lH), 2.80 (m, lH), 3.82 (m, 2H), 4.38 (m, lH), 5.20 (broad s, CA 02207102 1997-06-0~
WO g6/17827 PCr/US9S114g48 lH, exchangeable), 7.68 (d, J = 8 Hz, 2H), 7.82 (d, J = 8 Hz, 2H).
N-phenyl-3(S)-[[(l,l-dimethylethoxy)carbonyl]amino]-pyrrolidin-2-one (2c), H-NMR (300 MHz, CDCl3) ~ 1.43 (s, 9H), 2.00 (m, lH), 2.80 (m, lH), 3.81 (m, 2H), 4.36 (m, lH), 5.23 (broad, lH, exchangeable), 7.18 (t, J = 8 Hz, lH), 7.39 (t, J = 8 Hz, 2H), 7.64 (d, J = 8 Hz, 2H).
N-[(3-methoxycarbonyl)phenyl]-3(S)-[[(l,l-dimethylethoxy)carbonyl]amino]pyrrolidin-2-one (2d), H-NMR (300 MHz, CDC13) ~ 1.47 (s, 9H), 2.04 (m, lH), 2.80 (m, lH), 3.85 (m, 2H), 3.93 (s, 3H), 4.38 (m, lH), 5.23 (broad, lH, exchangeable), 7.47 (t, J = 8 Hz, lH), 7.86 (m, lH), 8.10 (m, 2H).
N-[(4-methoxycarbonyl)phenyl]-3(S)-[[(l,l-dimethylethoxy)carbonyl]amino]pyrrolidin-2-one (2e), IH-NMR (300 MHz, CDCl3) ~ 1.48 (s, 9H), 2.04 (m, lH), 2.80 (m, lH), 3.83 (m, 2H), 3.92 (s, 3H), 4.38 (m, lH), 5.20 (broad, lH, exchangeable), 7.75 (d, J = 8 Hz, 2H), 8.06 (d, J = 8 Hz, 2H).
CA 02207102 1997-06-0~
PCT~S9S/14948 Exam~le 3 PreDaration of 1-(4-cYano~henYl~-3(S)-[ r ~
dimethYlethoxy~carbonyllamino1p~rrolidin-2-one.
NC~ ? " $
To a suspension of the product of example 2a (2.0 g, 6.27 mmol) and triethylamine (5.23 mL, 37.6 mmol) in THF
(20 mL) at 0~C was added neat trifluoroacetic anhydride (3.87 g, 18.8 mmol) dropwise over 5 minutes. The solution was stirred at 0~C for an additional 1 hour, warmed to room temperature then quenched by adding 20 mL of water.
The reaction mixture was partially concentrated to approximately 1/2 the volume of THF whereupon the product precipitated. The precipitate was filtered, washed with water and dried affording 1.60 g (8S%) of product (m.p.
152-153.5~C).
[~]D25 = -11.4~ (MeOH, c=9.65 mg/mL) Anal. calc'd. for Cl6HIgN3O-l H20:
Calc'd.: C, 60.17; H, 6.63; N, 13.16.
Found: C, 59.75; H, 6.30; N, 13.14.
CA 02207102 1997-06-0~
W 096/17827 PCTnUS9S/14g48 Exam~le 4 Pre~aration of 1-(4-cyano~henvl)-3(S)-aminoPYrrolidin-2-one H~drochloride.
~
NC~N~..""NH HCI
HCl gas was bubbled through a solution of the product of example 3 (62.0 g, 206 mmol) in EtOAc (750 mL) at ambient temperature for 15 minutes. After an additional 30 minutes, the precipitated product was filtered, washed with EtOAc and dried affording 46.7 g (96%) [m.p. 253-254.5~C (dec.), >99.9% e. e.]. Enantiomeric purity was determined by chiral HPLC analysis using a Crownpak CR(-) column (15 cm x 4.0 mm) and isocratic elution with 1%
aqueous HCl04 at 1.2 mL/min. The detector was set at 254 nm.
[~]D25 = -20.8~ (MeOH, c = 10.63 mg/mL) Anal. calc'd. for Cl~H~2N3OCl-l/4H20:
Calculated: C, 54.55; H, 5.20; N, 17.35.
Found: C, 54.51; H, 4.98; N, 17.40.
CA 02207102 1997-06-0~
WO g6/17827 ~ lU:,9S/14948 Exam~le S
Pre~aration of Ethyl 3-~ r ~ ~l-r4-cyanOphenyl)-2-Oxo-3 rs)-~rrolidinYllaminolcarbonYllamino1propionate.
s O
~ ~ t~ H
To a suspension of 1,1'-carbonyldiimidazole (572 mg, 3.55 mmol) in pyridine (2.5 mL) at 5~C under nitrogen was added solid ethyl 3-amino-propionate hydrochloride (545 mg, 3.55 mmol). The resulting solution was stirred at 5~C
for 15 minutes, diluted with 2.5 mL of DMF and removed from the ice bath. The product of example 4 (700 mg, 2.96 mmol) was added all at once and the reaction mixture was stirred at 7S-80~C for 2 hours. After cooling to room temperature, the resulting solution was diluted with 15 mL
of 1 N HCl. The white precipitate was filtered, washed with H2O and dried. Trituration and filtration from methyl t-butyl ether afforded 844 mg of product (m.p.
168.5-169~C). Extractive work up of the filtrate with EtOAc afforded an additional 110 mg of product (94%
overall).
[~]D25 = +9.5~ (MeOH, c=9.45 mg/mL) Anal. calc'd- for C~7H20N4O4:
Calculated: C, 59.29; H, 5.85; N, 16.27.
Found: C, 58.94; H, 5.71; N, 16.13.
W 096/17827 rCTrUS95/14948 ExamPle 6 PreParation of EthYl 3-~ r rl-r4-(amino(hYdroxYimino~-methYl)~henyll-2-oxo-3(S)-Pyrrolidinyllaminolcarbon aminolProPionate.
o HzN~ ~ 'NJ~Ng~
To a suspension of the product of example 5 ( 104 g 304 mmol) and hydroxylamine hydrochloride (42 g, 607 mmol) in EtOH (900 mL) was added triethylamine (61 g, 607 mmol).
The reaction mixture was heated to 60-65~C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and diluted with H2O. The precipitate was filtered, washed with H2O and dried affording 110 g (96%) of product (m.p. 188-190~C).
~Cr]D25 = -2.8 (MeOH, c = 10. 53 mg/mL) Anal. calc'd. for Cl6Hl9N3O: C, 54.10; H, 6.14; N, 18.56.
Found: C, 53.76; H, 6.14; N, 18. 52.
CA 02207102 1997-06-0~
3~ 4g48 WO g6/17827 Exam~le 7 Preparation of EthYl 3-~ r r rl-~4-(aminoiminOmethYl)~henyl~-2-oxo-3(S)-pyrrolidinYllamino1carbonYllaminolpro~ionate Acetate.
O
H2N~N~"""N~N
NH
To a suspension of the product of example 6 (250 g, 663 mmol) in HOAc (1 L) was added 100 g of 4% Pd/C (50%
wet). The mixture was hydrogenated at 60~C using 60 psi H2 for 1.37 hours. The catalyst was filtered and the solvent evaporated under reduced pressure. The syrupy product was diluted sequentially while stirring with 500 mL MeOH, 1.5 L EtOH and 800 mL of CH3CN. The white solid was filtered, washed with CH3CN and dried affording 219 g of product. The mother liquor was concentrated and the residue dissolved in H2O and treated with decolorizing charcoal (5 g). After filtration and removal of the solvent under reduced pressure, the residue was dissolved in a minimal amount of HOAc and diluted sequentially with 150 mL of i-PrOH and 150 mL of CH3CN. The precipitate was filtered, washed with i-PrOH/CH3CN (1:1) and dried affording an additional 35 g of product (91% overall) [m.p. 213-214~C (dec.)]. Enantiomeric purity was determined by chiral HPLC using a Chiralcel-OD column and EtOH/Heptane/TFA (20:80:0.1) as the mobile phase and was determined to be >99.9% e. e WO96/17827 PCT~S9S/14948 [~]D25 = +13.2 (MeOH, c = 9.43 mg/mL) Anal. calc'd. for C~9H2~N5O~: C, 54.15; H, 6.46; N, 16.62.
Found: C, 54.08~ H, 6.57; N, 16.57.
WO g6/17827 1 ~ S/l4948 ExamPle 8 Preparation of Eth~l 3(R)-aminobutanoate (R)-mandelate.
OH
(~ H3N~
A solution of ethyl 3-aminobutyrate hydrochloride (4.5 g, 26.8 mmol) in 27 mL of lN NaOH was extracted 2X
with EtOAc. The organic fraction was dried (Na2S04) and concentrated under reduced pressure. Recrystallization of the residue 3X from EtOAc afforded 1.93 g (51%) of product as a single chiral diastereomer as determined by NMR
spectroscopy (m.p. 125-125~C). IH-NMR (300 MHz, CDCl3) 1.00 (d, J = 7Hz, 3H), 1.27 (t, J = 7Hz, 3H), 2.23-2.45 (m, 2H), 3.13 (m, lH), 4.13 (q, J = 7Hz, 2H), 4.85 (s, lH), 7.17-7.33 (m, 3H), 7.41 (d, J = 8Hz, 2H).
Anal. calc'd. for C~4H2lNO5: C, 59.35; H, 7.47; N, 4.94.
Found: C, 59.03, H, 7.51; N, 4.83.
CA 02207102 1997-06-0~
W O g6/17827 ~IU~3~114948 - 36 -Exam~le 9 Preparation of EthYl 3(R)-~ r ~ r 1- (4-cYanoPhenYl)-2-oxo-3(S)-~YrrolidinYll-aminolcarbonYllaminolbutanoate.
~ ? NlN--To a suspension of 1,1'-carbonyldiimidazole (178 mg, 1.1 mmol) in pyridine (2.5 mL) at 5~C under nitrogen was added the product of example 4 (260 mg, 1.1 mmol). The resulting solution was stirred at 5~C for 15 minutes, diluted with 2.5 mL of DMF and removed from the ice bath.
The product of example 8 (375 mg, 1.32 mmol) was added all at once and the reaction mixture stirred at 75-80~C for 2 hours. After cooling to room temperature, the resulting solution was diluted EtOAc and washed with lN HCl, saturated NaHCO3 and dried (MgSO4). Evaporation of the solvent afforded 295 mg (73%) of product (m.p. 177.5-179~C). IH-NMR (300 MHz, CDCl3) ~ 1.20-1.30 (m, 6H), 2.05 (m, lH), 2.53 (m, 2H), 2.83 (m, lH), 3.83 (m, 2H), 4.15 (q, J = 7Hz, 2H), 4.19 (m, lH), 4.48 (m, lH), 7.68 (d, J =
8Hz, 2H), 7.82 (d, J = 8Hz, 2H).
Anal. calc'd. for C~8H22N4O4-0.1 H20:
Calculated: C, 60.02; H, 6.21; N, 15.56.
Found: C, 60.29; H, 6.21; N, 15.06.
W O g6/17827 ~ S114948 Exam~le 10 Pre~aration of Ethvl 3rR)-~ r 4-(aminorhydroxvimino)-methyl)~henyl~-2-oxo-3rS)-pYrrolidinYllaminolcarbonyll-aminolbutanoate.
o Il ~ /~ "NlN
H2N~ O
,N
The title compound was prepared from the product of example 9 (250 mg, 0.63 mmol) in a manner similar to example 6 affording 203 mg (83%) of product [m.p. 165-167~C (dec.)]. IH-NMR (300 MHz, d6-DMSO) ~ 1.06 (d, J =
7Hz, 3H), 1.28 (t, J = 7Hz, 3H), 1.88 (m,- lH), 2.30-2.53 (m, 3H), 3.75 (m, 2H), 3.95 (m, lH), 4.05 (q, J = 7Hz, 2H), 4.40 (m, lH), 7.56 (s, 4H).
Anal. calc'd. for CI~H25N505-1/3H20:
Calculated: C, 54.40; H, 6.51; N, 17.64.
Found: C, 54.76; H, 6.71; N, 17.21.
WO g6/17827 rcrlusssll4s4s ExamPle 11 Pre~aration of EthYl 3 rR) - r r r r 1- r 4-(aminoiminomethYl~-~henyl~-2-oxo-3rS)-pyrrolidinYl~amino1carbonvllamino~-butanoate Acetate o H2N~N/~ ............ , NH
The title compound was prepared from the product of example 10 (150 mg, 0.38 mmol) in a manner similar to example 7 affording 131 mg (77~) of product [m.p. 208-209~C (dec.)].
IH-NMR (300 MHz, d6-DMSO) ~ 1.08 (d, J = 7Hz, 3H), 1.19 (t, J = 7Hz, 3H), 1.39 (s, 3H), 1.94 (m, lH), 2.30-2.53 (m, 3H), 3.80 (m, 2H), 3.95 (m, lH), 4.06 (q, J = 7Hz, 2H), 4.43 (m, lH), 7.86 (d, J = 8Hz, 2H), 7.91 (d, J = 8Hz, 2H).
Anal. calc'd. for C2oH29N506-3/4 H20:
Calculated: C, 53.50; H, 6.85; N, 15.60.
Found: C, 53.34; H, 6.46; N, 15.35.
CA 02207102 1997-06-0~
WOg6/17827 PCT~S9Stl4948 ExamPle 12 Pre~aration of EthYl ~(S)-r r (l.l-dimethYlethOxy)carbOnYl~-~ aminolbenzene~roDanoate.
O
CH3 O ~ OEt H C ~ O ~ N
To a stirred solution of N-BOC-D-phenylglycine (5.02 g, 20 mmol), N-methylmorpholine (2.02 g, 20 mmol) in EtOAc (100 mL) at 0~C was added isobutyl chloroformate 15 (2.73 g, 20 mmol). After 15 minutes the reaction mixture was filtered to remove the amine salts then an ethereal solution of diazomethane (60 mL, 30 mmol) was added. The cooling bath was removed and the reaction mixture stirred at ambient temperature for 2 hours. The reaction mixture was purged with nitrogen for 15 minutes to remove the excess diazomethane. The reaction mixture was diluted with EtOAc, washed with lN HCl, saturated NaHCO3, and dried (MgSO4). Evaporation of the solvent afforded the crude diazoketone which was dissolved in EtOH (100 mL) and then treated sequentially with AgO2CPh (1.6 g, 7 mmol) and triethylamine (6.06 g, 60 mmol). After 20 hours the reaction mixture was concentrated and chromatographed (silica gel, 15% EtOAc/hexanes) affording 4.90 g (85%) of product as a colorless oil. IH-NMR (300 MHz, CDCl3) ~ 1.17 30 (t, J = 7 Hz, 3H), 1.43 (s, 9H), 2.73-2.92 (m, 2H), 4.07 (q, J = 7 Hz, 2H), 5.10 (m, lH), 5.48 (m, lH), 7.22-7.39 (m, 5H).
WOg6/17827 ~ S/14948 Exam~le 13 Preparation of EthYl ~(S)-aminobenzene~ro~anoate HYdrochloride .
O
~OEt H2N~ ~ HCI
Dry HCl gas was bubbled through a solution of the product of example 12 (3.0 g, 10.2 mmol) in EtOAc (50 mL) at ambient temperature for 15 minutes. After stirring for 15 an additional 30 minutes, the solvent was removed under reduced pressure affording 2.30 g (98%) of product as a yellow oil. IH-N~ (300 MHz, d6-DMSO) ~ 1.03 (t, J = 7Hz, 3H), 3.02 (dd, J = 10Hz, J = 15Hz, lH), 3.25 (dd, J = 6Hz, J = 15Hz, lH), 3.96 (m, 2H), 4.55 (m, lH), 7.3-7.6 (m, 5H), 8.93 (s, 3H).
PCT~S9S/149 Exam~le 14 Preparation of Ethyl ~(s)-r r r rl-r4-cYanOphenyl)-2-oxo-3 r S ~ -~Yrrol idinYllaminolcarbonYl~amino~benzeneproDanoate.
~N?"""N~N~
The title compound was prepared from the product of example 13 (685 mg, 2.9 mmol) and the product of example 4 (600 mg, 2.9 mmol) in a manner similar to example 5 affording 1.09 g (91%) of product (m.p. 108-109~C).
H-NMR (300 MHz, CDCl3) ~ 1.16 (t, J = 7Hz, 3H), 2.00 (m, lH), 2.77-2.93 (m, 3H), 3.81 (m, 2H), 4.05 (q, J = 7Hz, 2H), 4.50 (m, lH), 5.26 (m, lH), 7.20-7.35 (m, 5H), 7.66 (d, J = 8Hz, 2H), 7.80 (d, J = 8Hz, 2H).-Anal. calc'd. for C23H24N4O4 1/3H2O:
Calculated: C, 64.79; H, 5.83; N, 13.14 Found: C, 64.65; H, 5.58; N, 13.18.
WO g6/17827 PCrtUSgStl4948 ExamPle 15 PreParation of Ethyl ~(S)-~rl-r4-(amino(hydroxyimino~-methYl)~henY11-2-oxo-3(S)-PYrrolidinyllamino]carbon aminolbenzenePro~anoate.
o H2N~ H H--,N
HO
The title compound was prepared from the product of example 14 (450 mg, 1.07 mmol) in a manner similar to example 6 affording 431 mg (89%) of product [m.p. 192-193~C (dec.)]. IH-NMR (300 MHz, d6-DMSO) ~ 1.10 (t, J =
7Hz, 3H), 1.87 (m, lH), 2.49 (m, lH), 2.77 (m, 2H), 3.74 (m, 2H), 4.00 (q, J = 7Hz, 2H), 4.41 (m, lH), 5.10 (m, lH), 7.20-7.40 (m, 5H), 7.69 (s, 4H).
Anal. calc'd. for C23N2~N5O5-1/2H2O:
Calculated: C, 59.73; H, 6.10; N, 15.14 Found: C, 59.67; H, 6.38; N, 14.85.
W O96117827 PCTnUS9S/14948 ExamPle 16 Preparation of EthYl ~(S)-r r r rl-~4-(aminoiminomethyl)-phen~ll-2-oxo-3(S)-PYrrolidin~llaminolcarbonyllaminol-benzenePropanoate Acetate.
H2N ~ ~ H H
NH
The title compound was prepared from the product of example 15 (400 mg, 0.88 mmol) in a manner similar to example 7 affording 335 mg (76%) of product [m.p. 210-211~C (dec.)]. IH-NMR (d6-DMSO) ~ 1.14 (t, J = 7Hz, 3H), 1.93 (s, 3H), 2.03 (m, lH), 2.47 (m, lH), 2.80 (m, 2H), 3.84 (m, 2H), 4.04 (m, 2H), 4.50 (m, lH), 5.05 (t, J =
7Hz, lH), 7.23-7.44 (m, 5H), 7.92 (d, J = 8Hz, 2H), 7.97 (d, J = 8Hz, 2H).
Anal. calc'd. for C,5H3~NsO6-1/2H70:
Calculated: C, 59.28; H, 6.37; N, 13.83 Found: C, 58.96; H, 6.21; N, 13.92.
W O 96/17827 PCTnUS9S/149~8 Process for the Preparation of Amidino Phenyl Pyrrolidine ~-Alanine Urea Analogs BACKGROUND OF THE INVENTION
The invention herein is directed to the cyclization of a methionine analog to a lactam using new reaction reagents and conditions. The invention herein is further directed to the enantioselective synthesis of ethyl 3-t[ttl-t4-(aminoiminomethyl)phenyl]-2-oxo-3(s)-pyrrolidinyl]amino]carbonyl]amino]propionate acetate and related ~-alanine analogs. Such compounds are useful as antithrombotic agents.
More specifically the invention herein is directed to the conversion of a methionine analog such as \~
Z~ ~
(Z = H, -CN, -CONH2 or -CO2Me) to a lactam such as ~ ~NR
using reagent and reaction conditions which are beneficial in comparison to previously disclosed methodology for achieving such a conversion.
CA 02207102 1997-06-0~
WO g6/17827 ~ J95114948 Friedinger et al., J. Org. Chem ., 47, (104-109), 1982 disclose general methods for the synthesis of lactam-constrained dipeptide analogs using three different paths from protected chiral ~-amino acids to lactams. Included within this disclosure is a method for cyclizing methionine analogs to lactams via an alkylative cyclization involving a two step procedure using highly volatile and toxic methyl iodide and highly reactive sodium hydride as reagents.
It would be desirable to provide a process for conversion of a methionine analog to a lactam via conditions which do not employ volatile, toxic or highly reactive reagents and which produces a lactam having high enantiomeric purity.
lS
SU~IARY OF THE INVENTION
The invention herein is directed to a process for producing a lactam of the formula r-~
Z 3~N~''NHR
wherein R is a protecting group such as t-butoxycarbonyl (BOC) or carbobenzyloxy (CBZ) and Z is H, -CN, -CONH, or CO2alkyl, from a methionine analog of the formula S
H ~¦
z~ O
CA 02207102 1997-06-0~
WO g6/17827 ~ 9~114948 by treating the methionine analog with trimethylsulfonium halide or trimethylsulfoxonium halide in the presence of an inorganic or aminergic base, such as alkali metal hydroxides, alkoxides or carbonates or a tertiary amine, diazabicycloundecane (DBU), or Hunig's base [diisopropylethylamine (DIEA)], in a suitable aprotic solvent.
The invention herein is further directed to the preparation of amidinophenyl pyrrolidinyl ~-alanine urea analogs using such methionine and lactam compounds as intermediates, which ~-alanine urea analogs are useful as antithrombotics.
DETAILED DESCRIPTION OF THE INVENTION
The invention herein is directed to a process for producing a lactam of the formula 1~
Z ~ N ~ NHR
wherein R is a protecting group such as t-butoxycarbonyl (BOC) or carbobenzyloxy (CBZ) and Z is H, -CN, -CONH2 or CO2alkyl from a methionine analog of the formula S
H ~
3 o ,~' --~NR
by treating the methionine analog with trimethylsulfonium halide or trimethylsulfoxonium halide (such as trimethylsulfonium iodide or trimethylsulfoxonium CA 02207102 1997-06-0~
~VO g6/17827 chloride) in the presence of an inorganic or aminergic base in a suitable aprotic solvent.
The invention herein is further directed to the preparation of amidinophenyl pyrrolidinyl ~-alanine urea analogs using such methionine and lactam compounds as intermediates, which ~-alanine urea analogs are useful as anti-thrombotics. Such process includes treating a methionine analog of the formula H r Z~ O
(wherein Z is -CN or -CONH2) with trimethylsulfonium halide or trimethylsulfoxonium halide in the presence of a base, preferably potassium carbonate, in an aprotic solvent, preferably DMS0, to afford a lactam of the formula r~
Z~ O
dehydrating when Z is -CONH2 and deprotecting the lactam, reacting the resulting product with a ~-amino ester in the presence of CDI to produce a urea of the formula o O ~ OR6 ~N/~N~NlR
NC--~J O H H
CA 02207102 1997-06-0~
W O g6117827 PCTnUS9S/14g48 treating the urea with hydroxylamine to produce an amidoxime, hydrogenating the amidoxime; and isolating a compound of the formula o H2N~N~N~N~
wherein Rl is hydrogen, alkyl, aryl, arylalkyl, a heterocyclyl radical containing 1 to 3 heteroatoms or a heterocyclylalkyl and ~ is selected from alkyl, aryl, arylalkyl or acyloxymethyl.
The general synthetic scheme is outlined in Scheme 1.
15 Starting from commercially available materials, a suitably protected methionine (R = BOC, CBZ) is condensed with a substituted or unsubstituted aniline in the presence of a suitable amino acid coupling reagent (e.g. isobutyl chloroformate, 2-chloro-1-methylpyridinium iodide, 1,1'-carbonyldiimidazole (CDI) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) and a tertiary amine base (e.g. N-methylmorpholine, N-methylpiperazine or triethylamine) in a suitable aprotic solvent (e.g.
dimethylformamide (DMF), tetrahydrofuran (THF) or CH~Cl2) at a temperature ranging from -15~C to 25OC to give the methionine analog 1.
Methionine analog 1 is cyclized to lactam 2 via a novel set of reaction conditions. Treatment of compound 1 with trimethylsulfonium halide or trimethylsulfoxonium halide in the presence of an inorganic or aminergic base (e.g. alkali metal hydroxide, alkali metal alkoxides, - alkali metal carbonates or tertiary amines such as DBU or Hunig's base), preferably in the presence of potassium carbonate in a suitable aprotic solvent (e.g. DMF, CA 02207102 1997-06-0~
WO96/17827 PCT~S95/14948 dimethylacetamide (DMA), DMSO or THF) at a temperature ranging from 35~C to 90~C affords lactam 2. Historically, this conversion was accomplished by an alkylative cyclization in a two step procedure requiring highly S volatile and toxic methyl iodide and highly reactive sodium hydride respectively as the principle reagents [c.f. Freidinger, R.M. et al., J. Orq. Chem., 47, 104-109 (1982); Kottirsch, G. et al., Bioorq. Med. Chem. Letters, 3, 167S-1680 (1993)]. Further, the extent of racemization in the later process was dependant upon the workup conditions. In the present invention, neither strong alkylators nor strong bases are required and the product is produced having high enantiomeric purity.
The lactam 2 can be dehydrated when Z is -CONH2 to lS the nitrile 3 using standard reagents (e.g.
trifluoroacetic anhydride (TFAA), trichloroacetic anhydride or thionyl chloride) in the presence of an amine base (e.g. Et3N, pyridine, N-methylmorpholine or N,N-diisopropylethylamine) in an aprotic solvent (e.g. THF, EtOAc, pyridine or DME).
Aromatic analogs of methionine undergo cyclization as illustrated in Table 1. For example, the nitrile compound lb, prepared by dehydrating la (TFAA, Et3N), was cyclized to lactam 10. Also, the carbomethoxyanilides ld and le 2S undergo cyclization without subsequent hydrolysis of the ester function. This is important to note since ester containing intermediates cyclized under the Freidinger conditions undergo hydrolysis of the ester.
WO g6/17827 1 ~ 4948 H ~
"NBOC Me3S X /K2Co3 ~N~""'NBOC
Me3SO X /K2CO3 Z O H
1 a-e 2 a-e compound compound, ~neld 1 a, Z = 4-CONH2 2a, 75%
1 b, Z = 4-CN 1 O, 88%
1c, Z = 4-H 2c, 38%
1 d, Z = 3-CO2Me 2d, 53%
1 e, Z = 4-CO2Me 2e, 79%
-CA 02207102 1997-06-0~
WOg6/17827 PCT~S9S114948 DeprotectiOn of the protecting group R with HCl or trifluoroacetic acid (TFA) (R = BOC) or H2, Pd/C (R = CBZ) affords aminolactam 4. For R = BOC, excess anhydrous HCl or concentrated HCl (2.0 - 5.0 equivalents) in solvent (e.g. EtOAc, MeO-t-Bu, 1,4-dioxane or THF) at 5 to 50~C
for 0.5 - 23 hours affords product as the hydrochloride salt. Additionally the free base could be isolated as a precipitate by adding 1 equivalent of base (e.g. lN NaOH) to an aqueous solution of the hydrochloride salt.
Synthesis of the urea product 5 is accomplished by sequential addition of an appropriate ~-amino ester and aminolactam 4 to a suitable phosgene equivalent (e.g.
triphosgene, diphosgene, phosgene, 1,1'-carbonyldiimidazole) in a suitable solvent (e.g. CH2Cl2, CHC13, ClCH2CH2Cl, DMF, DMA, pyridine, dioxane, THF, benzene, toluene). Reaction of 5 with hydroxylamine hydrochloride in the presence of a suitable base (e.g.
Et3N, (i-Pr)2NEt, NaOAc, NaOEt, NaOH) in a suitable solvent (e.g. MeOH, EtOH, H2O, DMF, DMA) provides the amidoxime intermediate 6. This material is hydrogenolyzed in the presence of a suitable catalyst (e.g. Pd/C, Pt/C, Pd(OH)2) in a suitable solvent (e.g. MeOH, EtOH, i-PrOH or HOAc) in the presence of an acid counterion (e.g. HOAc, HCl, HBr, methanesulfonic acid (MsOH), succinic acid, citric acid, H3PO4, malic acid) affording the target compound 7 as the corresponding acid salt.
W 096/17827 ~ gS/14948 ~S ~S
~NH2 ~cou~irq ro~g~, H
/[W HO~R ~ BOC, CBZ ~ NR
Me3S X/K2C03 ~ ~N/~NHR whonZis-CONH~
Me3SO X /K2C03 Z
NC~N/~>~NR d~tprotect, { 3~ ~ H2N R~
O ~OEt H~OH HCI
pho~g~ ~ NC~ ~H H
~0 HO-NH~N~NJ~N~
6 HN~ ~NJ~NJ~
HY
(x- is l . cr, Br') Yis a p~,.,.~ ceF~ salt Rt iS H, alk~4, alkenyl, alkynyl, ar~, or a ",onoc~lic heterocyclyl cu. ' ~ing 1 to 3 OINJS) CA 02207102 1997-06-0~
WO g6/17827 ~ 3~114948 The preferred method of preparing a preferred antithrombotic agent, namely, ethyl 3-[[[[1-[4-(aminoiminomethyl)phenyl]-2-oxo-3(S)-pyrrolidinyl]amino]carbonyl]amino]propionate acetate is illustrated in Scheme 2 and Scheme 2a. Treatment of commercially available N-BOC-L-methionine and 4-aminobenzamide with 2-chloro-1-methylpyridinium iodide (CMPI) and N-methylmorpholine (NMM) in DMF affords the methionine amide lA.
In the novel cyclization step, heating a mixture of lA, trimethylsulfonium iodide and powdered K2C03 (potassium carbonate) in DMSO at 70~C gives the chiral lactam 2A.
Formation of the nitrile 10 is carried out by dehydrating the primary amide with a standard reagent (trifluoroacetic anhydride/Et3N) in THF. Removal of the BOC protecting group with HCl/EtOAc affords the amine hydrochloride 11. Sequential addition of ~-alanine ethyl ester hydrochloride and compound 11 to 1,1'-carbonyldiimidazole in DMF/pyridine (1:1) affords the unsymmetrical urea 12.
Treatment of 12 with hydroxylamine hydrochloride/triethylamine in ethanol gives the benzamidoxime 13. Hydrogenolysis of 13 with 4% palladium on carbon in acetic acid gives the target compound 14 as the acetate salt.
In Scheme 2B another preferred method is illustrated, wherein intermediate lA is dehydrated to intermediate 1B.
Subsequent cyclization of lB to 10 is accomplished as described for the conversion of lA to 2A. Intermediate 1o is then utilized further as demonstrated in Scheme 2 and 2a.
W Og6/17827 ~ S/14948 H N ~ N Boc O f W O H
Me3S r/1<2CO3 ~p ''N Boc DMSO/70~C o~ H TFAAlEt3N
NCJC~N/~""'N E30C conc. HCUEtOAc ~3~ 0 HCI
W O 96/17827 PCTnUSgS/14948 SCHEME 2 a "NH2 CDUH2CH2CH2CO2Et HC
NCJ~ o HCI DMF/pyr (1:1 ) N/~ H2NOH HCUEt3N
~ "'N N EtOH/65 C
/--\ ~ _~OEt 4%Pd/C, H2 60psi HI~N~ ............................... 60 CIHOAC
Ho,N O
HN~,~ ? H H
H2N HOAc 14 WO g6/17827 1 ~ J.,3S/14g48 SCHEME 2 b H r 1A TFA~VEt3N, ~0~N~I'"'N BOC
Me3S I A<2C~3 . 10 DMSO/70~C
CA 02207102 1997-06-0~
WOs6/17827 PCT~S95/14948 As illustrated in Scheme 3, classical resolution of commercially available ethyl 3-aminobutanoate with (R)-mandelic acid affords enantiomerically pure mandelate salt 1s after three recrystallizations from EtOAc. Sequential treatment of a suspension of 1,1'-carbonyldiimidazole with 11 then 15 affords the unsymmetrical urea 16. Treatment of 16 with hydroxylamine hydrochloride/triethylamine gives the benzamidoxime 17 which undergoes hydrogenolysis in HOAc to give the target compound 18.
WO g6/17827 P~ 9~/14948 ~OEt (P)-mandelicacid ~C0 H2N EtOAc H3N--~3~N~ H CDU15 ~ NC 11 DMFlpyr(1:1) NCJ3~N? J~ ~ H~NOH HCVEt3N .
o ~OEt 4% Pd/C. H260 psi "NJ~NJ~ 60~C/HOAc HO HN~N~."
H2N HOAc L8 WO96/17827 PCT~S9S114948 The Arndt-Eistert homologation (Scheme 4) of N-BOC-D-phenylglycine affords the chiral ~-amino ester 19.
Treatment of 19 with dry HCl affords the amine hydrochloride 20. Elaboration of 20 as outlined in Scheme 2a affords the target compound 21.
WO g6/17827 PCr/US9S/14948 .
1~l ,~02H 1) IBCF/NMM ~OEt BOC-N ~ 2) CH2N2 BOC-N~
~ 3) Agbenzoate/EtOH H
HCI fJ~OE~
HCI/EtOAc I Scheme 2a H2N~
N~0~N?"""
H2N HOAc CA 02207102 1997-06-0~
W O 96/17827 1~ s/l4948 The ~-amino acids and esters can be purchased or prepared from commercially available starting materials using known methods as illustrated in Scheme 5. The racemic ~-heteroaryl ~-amino acids can be prepared from the appropriate aryl aldehyde, malonic acid, and ammonium acetate (Method 1) [Johnson and Livak, J. Am. Chem. Soc., Z29 (1936)]. The racemic ~-alkyl ~-amino acids can be prepared from the corresponding alkene and chlorosulfonyl isocyanate (CSI) which goes through the ~-lactam as shown in Method 2 [W. A. Szabo, Aldrichimica Acta, 23 (1977); R.
Graf, Angew. Chem. Int. Ed., 172 (1968)]. The ~-lactam can be opened to the ethyl ester by treatment with anhydrous HCl in ethanol. An alternative method to form racemic ~-amino esters is shown in Method 3. Nucleophiles can be added to 4-benzoyloxy-2-azetidinone to afford a variety of 3-substituted ~-amino esters after treatment with anhydrous HCl in ethanol tK. Prasad et al., Vol. 19, Heterocvcles, 2099 (1982)]. The racemic ~-amino acids and esters can be resolved using classical methods described in the literature [E. Fischer, H. Scheibler, R. Groh, Ber., 2020 (1910); E. Fischer, H. Scheibler, Annalen, 337 (1911) ] .
Chiral ~-amino acids and esters can also be prepared using many different approaches including the following methods: 1) homologation of suitably protected ~-amino acids using the Arndt-Eistert reaction as shown in Method 4 [Meier and Zeller, Anqew. Chem. Int. Ed., 32-43 (1975);
M. Rodriguez et al., Tetrahedron Lett., 5153 (1990); W. J.
Greenlee, J. Med. Chem. 434 (1985) and references therein], 2) through the addition of an amine to ~
unsaturated esters bearing a chiral auxiliary as shown in Method 5 [J. d'Angelo, J. Maddaluno, J. Am. Chem. Soc., 8112-14, (1986)], 3) through an enantioselective hydrogenation of a dehydroamino acid as shown in Method 6 [see: Asymmetric Synthesis, Vol 5, (J. D. Morrison, Ed.) WOg6117827 PCT~S9S114948 Academic Press, New York, 1985], and 4) through the addition of enantiomerically pure amines to ~
unsaturated esters as shown in Method 7 [S. G. Davies, o.
Ich;hAra, Tetrahedron: AsYmmetr~, 183-186 (1991)].
WO g6/17827 PCr/US9S/14948 SCHE~SE 5 Method 1 ~CO2H
CH2(CO2H)2 + R1CHO ~ NH40Ac ~
(R1 is a~yl or heteroary~ H2N R1 Method 2 0 ~CO2Et CISO2N=C=O + ~R~ ~,R1 H2N R~
Method 3 )R1 ~ ~ EHtCOH ' OCOPh R~ H2N R
(R1 is alkyl, aryl, heterocyclyl, alkenyl, alkynyl) Method 4 CO2H 1) Fommmixed COCHN2 ~ CO2Et anhydride ¦ A~
BOC-N~R1 2) CH2N2 H EtOH BOC-N~R~
~ Indicates Chiral Center Retention of stereoche, l I,~t (R~ is alkyl, aryl, heterocyclyl, arylalkyl, heteroaryblkyl) Method 5 CO2-Xc CO2Et 1~ Ph2cHNH2 1 1 ) Hydrogenolysis R~ Ph2CHN ~ R1 2) NaOH
Xc = 8-(p-phenoxyphenyl)-menthyl CO2H
H2N~R
(R1 is alk~l, aryl, arylalkyl, heterocyclyl, heteroarylalkyl~
WO g6/17827 rcrlusssll4s4s SCHEME 5 f Cont ' d Method 6 CO2Et ~CO2Et Enantioselective .
R4COHN R~ HydrogenaUon R4CON R~
~ Indicates Chiral Center (R4 is alkyl or alkoxy) (R~ is alkyl, aryl, arylalkyl) Method 7 CO2Et )~ + PhlN' ~ PhlN~R, R1 PhJ
1) Hydrogenolysis 2) NaOH H2N~R, (R~ is alkyl, aryl, heterocyclyl, arylalkyl, heteroarylalkyl) CA 02207102 1997-06-0~
W O 96117827 PCTnUS9S/14948 As used herein the term "lower alkyl" refers to a straight or branched chain hydrocarbon radical having from 1 to about 6 carbon atoms. Examples of such "lower alkyl"
radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neo-pentyl, hexyl, isohexyl and the like.
As used herein the term "lower alkenyl" refers to unsaturated acyclic hydrocarbon radicals containing at least one double bond and 2 to about 6 carbon atoms.
Examples of such groups include, ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl and the like.
As used herein the term "lower alkynyl" refers to unsaturated acyclic hydrocarbon radicals containing one or more triple bonds and 2 to about 6 carbon atoms. Examples of such groups are ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
The term aryl as used herein denotes carbocyclic aromatic ring systems composed of one or more aromatic rings. Preferred aryl groups are those consisting of one, two or three benzene rings. The term embraces aromatic radicals such as phenyl, naphthyl and biphenyl.
The term acyloxymethyl embraces groups of the formula o ~ wherein R7 is alkyl or aryl as defined R7~-~ocH
above.
As used herein the phrase "heterocyclyl radical containing 1 to 3 heteroatoms" refers to monocyclic or bicyclic radicals wherein 1 to 3 carbon atoms have been replaced with a heteroatom selected from oxygen, nitrogen or sulfur. Such rings can be saturated or unsaturated and include heteroaromatics.
The following non-limiting examples describe and illustrate methods for carrying out the process of the CA 02207102 1997-06-0~
WO 96117827 ~ 114948 present invention, as well as other aspects of the present invention, and the results achieved thereby in further detail. Both an explanation of, and the actual procedures for, the various aspects of the present invention are described where appropriate. These examples are intended to be merely illustrative of the present invention, and not limiting thereof in either scope or spirit. Those of skill in the art will readily understand that known variations of the conditions and processes described in these examples can be used to perform the process of the present invention.
Unless otherwise indicated all starting materials and equipment employed were commercially available.
CA 02207102 1997-06-0~
WO g6/17827 ~ S/14948 Exam~le 1 Preparation of N-~(4-aminocarbonYl)phenyll-4-methylthio-2~S) -r r (1 .1-dimethYlethox~)carbonyllaminolbutanamide rlA).
H - ~ CH3 H2N~N~NJ~o~cH3 A. To a solution of L-BOC-methionine (100.0 g, 0.40 mol), 4-aminobenzamide (57.3 g, 0.42 mol) and CMPI (102.6 g, 0.40 mol) in 250 ml of DMF at 0~C, under nitrogen, was added NMM (88 mL, 0.8 mol) over two minutes. The reaction mixture was stirred and allowed to gradually warm to room temperature while stirring for 4 hours. The reaction was quenched by the addition of 0.1 N HCl (750 mL) over about 10 minutes. After stirring for about 30 minutes, the white precipitate was filtered, washed with H2O and dried affording 123.3 g (84%) of product [m.p. 193.5-195~C
(dec.)].
[~]D25 = -23.0~ (MeOH, c=10.85 mg/ml) Anal. calc'd. for C~7H25N3O4S-0.33H20:
Calc'd.: C, 54.67; H, 6.93; N, 11.25; S, 8.59.
Found: C, 54.63; H, 7.02; N, 11.05; S, 8.63.
B. The following compounds were made in a like manner substituting other anilines for 4-aminobenzamide:
CA 02207102 1997-06-0~
W O g6/17827 p~ 3~/14g48 N-phenyl-4-methylthio-2(S)-[t(1,1-dimethylethoxy)-carbonyl]amino]~utanamide (~c), H-NMR (300 MHz, CD30D) ~ 1.44 (s, 9H), 1.90-2.05 (m, 2H), 2.08 (s, 3H), 2.S8 (m, 2H), 4.34 (m, lH), 7.08 (t, J = 8 Hz, lH), 7.29 (t, J = 8 Hz, 2H), 7.57 (d, J = 8 Hz, 2H).
N-[(3-methoxycarbonyl)phenyl]-4-methylthio-2(s)-[[( dimethylethoxy)carbonyl]amino]butanamide (ld), IH-NMR (300 MHz, CDCl3) ~ 1.43 (s, 9H), 2.00-2.25 (m, 2H), 2.08 (s, 3H), 2.63 (m, 2H), 3.82 (s, 3H), 4.65 (m, lH), 6.18 (d, J = 7 Hz, lH, exchangeable), 7.24 (t, J = 8 Hz, lH), 7.71 (m, 2H), 8.19 (s, 2H), 9.58 (s, lH, exchangeable).
N-[(4-methoxycarbonyl)phenyl]-4-methylthio-2(s)-[[( dimethylethoxy)carbonyl]amino]butanamide (le), H-NMR (300 MHz, CDCl3) ~ 1.42 (s, 9H), 2.00-2.25 (m, 2H), 2.10 (s, 3H), 2.64 (m, 2H), 3.90 (s, 3H), 4.62 (m, lH), 6.03 (d, J = 7 Hz, lH, exchangeable), 7.58 (d, J = 8 Hz, 2H), 7.88 (d, J = 8 Hz, 2H), 9.53 (s, lH, exchangeable).
C. Preparation of N-(4-cyanophenyl)-4-methylthio-2(S)-[[(1,1-dimethylethoxy)carbonyl]amino]butanamide (lb), To an ice cooled, stirred suspension of compound la (10.00 g, 27.23 mmol) and triethylamine (16.5 g, 0.163 mol) in 40 mL of THF was added TFAA (7.88 g, 37.53 mmol) at a rate to keep the internal temperature between 5-10~C.
The resulting solution was stirred at 0~C for 20 minutes then quenched at 0~C by slowly adding 45 mL of 2N HCl.
After the subsequent addition of 40 mL of saturated NaCl, the mixture was extracted with EtOAc, washed with saturated NaHCO3, dried (MgSO4), treated with decolorizing charcoal (ca. lg) and filtered through a bed of silica gel using EtOAc as eluent. Removal of the solvent under WO g6/17827 PCr/US9S114g48 reduced pressure produced a golden yellow oil which was dried to 9.50 g of a gummy foam under high vacuum.
H-NMR (300 MHz, CDCl3) ~ 1.47 (s, 9H), 2.02 (m, 2H), 2.13 (s, 3H), 2.18 (m, lH), 2.63 (t, J = 7 Hz, 2H), 4.44 (m, lH), 5.34 (broad, lH, exchangeable), 7.57 (d, J = 8 Hz, 2H), 7.63 (d, J = 8 Hz, 2H), 9.07 (s, lH, exchangeable).
CA 02207102 1997-06-0~
W O96/17827 PCTnUSg5/14948 Example 2 Preparation of 1-~(4-aminocarbonYl)~henyll-3(S)- r r dimethylethoxY)carbonyllaminolpyrrolidin-2-one (2~) H2N~ ? " ~
A. To a solution of the product of example la (3.00 g, 8.16 mmol) in DMSO (6 mL) was added trimethylsulfonium iodide (5.00 g, 24.48 mmol) and powdered K2CO3 (1.69 g, 12.24 mmol). The reaction mixture was stirred at 80~C
under nitrogen for 3 hours, cooled to room temperature and diluted with H2O (30 mL). The white precipitate was filtered, washed with H2O and dried affording 1.94 g (75%) of product which was used directly in the preparation of the compound of Example 3. An analytical sample was prepared by recrystallizing the product from 1 part hot i-PrOH and diluting with 3 parts H2O [m.p. 225-226~C (dec)].
[~]D25 - -14.1~ (MeOH, c=9.90 mg/mL) Anal. calc'd. for C~6H2~N3O4-1 H20:
Calcd.: C, 56.96; H, 6.87; N, 12.46.
Found: C, 56.78; H, 6.56; N, 12.36.
B. The following compounds were made in a like manner substituting other products of Example 1 (lb-le) for Compound 1~:
N-(4-cyanophenyl)-3(S)-[t(1,1-dimethylethoxy)carbonyl]-amino]pyrrolidin-2-one (3), H-NMR (300 MHz, CDC13) ~ 1.47 (s, 9H), 2.08 (m, J = lH), 2.80 (m, lH), 3.82 (m, 2H), 4.38 (m, lH), 5.20 (broad s, CA 02207102 1997-06-0~
WO g6/17827 PCr/US9S114g48 lH, exchangeable), 7.68 (d, J = 8 Hz, 2H), 7.82 (d, J = 8 Hz, 2H).
N-phenyl-3(S)-[[(l,l-dimethylethoxy)carbonyl]amino]-pyrrolidin-2-one (2c), H-NMR (300 MHz, CDCl3) ~ 1.43 (s, 9H), 2.00 (m, lH), 2.80 (m, lH), 3.81 (m, 2H), 4.36 (m, lH), 5.23 (broad, lH, exchangeable), 7.18 (t, J = 8 Hz, lH), 7.39 (t, J = 8 Hz, 2H), 7.64 (d, J = 8 Hz, 2H).
N-[(3-methoxycarbonyl)phenyl]-3(S)-[[(l,l-dimethylethoxy)carbonyl]amino]pyrrolidin-2-one (2d), H-NMR (300 MHz, CDC13) ~ 1.47 (s, 9H), 2.04 (m, lH), 2.80 (m, lH), 3.85 (m, 2H), 3.93 (s, 3H), 4.38 (m, lH), 5.23 (broad, lH, exchangeable), 7.47 (t, J = 8 Hz, lH), 7.86 (m, lH), 8.10 (m, 2H).
N-[(4-methoxycarbonyl)phenyl]-3(S)-[[(l,l-dimethylethoxy)carbonyl]amino]pyrrolidin-2-one (2e), IH-NMR (300 MHz, CDCl3) ~ 1.48 (s, 9H), 2.04 (m, lH), 2.80 (m, lH), 3.83 (m, 2H), 3.92 (s, 3H), 4.38 (m, lH), 5.20 (broad, lH, exchangeable), 7.75 (d, J = 8 Hz, 2H), 8.06 (d, J = 8 Hz, 2H).
CA 02207102 1997-06-0~
PCT~S9S/14948 Exam~le 3 PreDaration of 1-(4-cYano~henYl~-3(S)-[ r ~
dimethYlethoxy~carbonyllamino1p~rrolidin-2-one.
NC~ ? " $
To a suspension of the product of example 2a (2.0 g, 6.27 mmol) and triethylamine (5.23 mL, 37.6 mmol) in THF
(20 mL) at 0~C was added neat trifluoroacetic anhydride (3.87 g, 18.8 mmol) dropwise over 5 minutes. The solution was stirred at 0~C for an additional 1 hour, warmed to room temperature then quenched by adding 20 mL of water.
The reaction mixture was partially concentrated to approximately 1/2 the volume of THF whereupon the product precipitated. The precipitate was filtered, washed with water and dried affording 1.60 g (8S%) of product (m.p.
152-153.5~C).
[~]D25 = -11.4~ (MeOH, c=9.65 mg/mL) Anal. calc'd. for Cl6HIgN3O-l H20:
Calc'd.: C, 60.17; H, 6.63; N, 13.16.
Found: C, 59.75; H, 6.30; N, 13.14.
CA 02207102 1997-06-0~
W 096/17827 PCTnUS9S/14g48 Exam~le 4 Pre~aration of 1-(4-cyano~henvl)-3(S)-aminoPYrrolidin-2-one H~drochloride.
~
NC~N~..""NH HCI
HCl gas was bubbled through a solution of the product of example 3 (62.0 g, 206 mmol) in EtOAc (750 mL) at ambient temperature for 15 minutes. After an additional 30 minutes, the precipitated product was filtered, washed with EtOAc and dried affording 46.7 g (96%) [m.p. 253-254.5~C (dec.), >99.9% e. e.]. Enantiomeric purity was determined by chiral HPLC analysis using a Crownpak CR(-) column (15 cm x 4.0 mm) and isocratic elution with 1%
aqueous HCl04 at 1.2 mL/min. The detector was set at 254 nm.
[~]D25 = -20.8~ (MeOH, c = 10.63 mg/mL) Anal. calc'd. for Cl~H~2N3OCl-l/4H20:
Calculated: C, 54.55; H, 5.20; N, 17.35.
Found: C, 54.51; H, 4.98; N, 17.40.
CA 02207102 1997-06-0~
WO g6/17827 ~ lU:,9S/14948 Exam~le S
Pre~aration of Ethyl 3-~ r ~ ~l-r4-cyanOphenyl)-2-Oxo-3 rs)-~rrolidinYllaminolcarbonYllamino1propionate.
s O
~ ~ t~ H
To a suspension of 1,1'-carbonyldiimidazole (572 mg, 3.55 mmol) in pyridine (2.5 mL) at 5~C under nitrogen was added solid ethyl 3-amino-propionate hydrochloride (545 mg, 3.55 mmol). The resulting solution was stirred at 5~C
for 15 minutes, diluted with 2.5 mL of DMF and removed from the ice bath. The product of example 4 (700 mg, 2.96 mmol) was added all at once and the reaction mixture was stirred at 7S-80~C for 2 hours. After cooling to room temperature, the resulting solution was diluted with 15 mL
of 1 N HCl. The white precipitate was filtered, washed with H2O and dried. Trituration and filtration from methyl t-butyl ether afforded 844 mg of product (m.p.
168.5-169~C). Extractive work up of the filtrate with EtOAc afforded an additional 110 mg of product (94%
overall).
[~]D25 = +9.5~ (MeOH, c=9.45 mg/mL) Anal. calc'd- for C~7H20N4O4:
Calculated: C, 59.29; H, 5.85; N, 16.27.
Found: C, 58.94; H, 5.71; N, 16.13.
W 096/17827 rCTrUS95/14948 ExamPle 6 PreParation of EthYl 3-~ r rl-r4-(amino(hYdroxYimino~-methYl)~henyll-2-oxo-3(S)-Pyrrolidinyllaminolcarbon aminolProPionate.
o HzN~ ~ 'NJ~Ng~
To a suspension of the product of example 5 ( 104 g 304 mmol) and hydroxylamine hydrochloride (42 g, 607 mmol) in EtOH (900 mL) was added triethylamine (61 g, 607 mmol).
The reaction mixture was heated to 60-65~C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and diluted with H2O. The precipitate was filtered, washed with H2O and dried affording 110 g (96%) of product (m.p. 188-190~C).
~Cr]D25 = -2.8 (MeOH, c = 10. 53 mg/mL) Anal. calc'd. for Cl6Hl9N3O: C, 54.10; H, 6.14; N, 18.56.
Found: C, 53.76; H, 6.14; N, 18. 52.
CA 02207102 1997-06-0~
3~ 4g48 WO g6/17827 Exam~le 7 Preparation of EthYl 3-~ r r rl-~4-(aminoiminOmethYl)~henyl~-2-oxo-3(S)-pyrrolidinYllamino1carbonYllaminolpro~ionate Acetate.
O
H2N~N~"""N~N
NH
To a suspension of the product of example 6 (250 g, 663 mmol) in HOAc (1 L) was added 100 g of 4% Pd/C (50%
wet). The mixture was hydrogenated at 60~C using 60 psi H2 for 1.37 hours. The catalyst was filtered and the solvent evaporated under reduced pressure. The syrupy product was diluted sequentially while stirring with 500 mL MeOH, 1.5 L EtOH and 800 mL of CH3CN. The white solid was filtered, washed with CH3CN and dried affording 219 g of product. The mother liquor was concentrated and the residue dissolved in H2O and treated with decolorizing charcoal (5 g). After filtration and removal of the solvent under reduced pressure, the residue was dissolved in a minimal amount of HOAc and diluted sequentially with 150 mL of i-PrOH and 150 mL of CH3CN. The precipitate was filtered, washed with i-PrOH/CH3CN (1:1) and dried affording an additional 35 g of product (91% overall) [m.p. 213-214~C (dec.)]. Enantiomeric purity was determined by chiral HPLC using a Chiralcel-OD column and EtOH/Heptane/TFA (20:80:0.1) as the mobile phase and was determined to be >99.9% e. e WO96/17827 PCT~S9S/14948 [~]D25 = +13.2 (MeOH, c = 9.43 mg/mL) Anal. calc'd. for C~9H2~N5O~: C, 54.15; H, 6.46; N, 16.62.
Found: C, 54.08~ H, 6.57; N, 16.57.
WO g6/17827 1 ~ S/l4948 ExamPle 8 Preparation of Eth~l 3(R)-aminobutanoate (R)-mandelate.
OH
(~ H3N~
A solution of ethyl 3-aminobutyrate hydrochloride (4.5 g, 26.8 mmol) in 27 mL of lN NaOH was extracted 2X
with EtOAc. The organic fraction was dried (Na2S04) and concentrated under reduced pressure. Recrystallization of the residue 3X from EtOAc afforded 1.93 g (51%) of product as a single chiral diastereomer as determined by NMR
spectroscopy (m.p. 125-125~C). IH-NMR (300 MHz, CDCl3) 1.00 (d, J = 7Hz, 3H), 1.27 (t, J = 7Hz, 3H), 2.23-2.45 (m, 2H), 3.13 (m, lH), 4.13 (q, J = 7Hz, 2H), 4.85 (s, lH), 7.17-7.33 (m, 3H), 7.41 (d, J = 8Hz, 2H).
Anal. calc'd. for C~4H2lNO5: C, 59.35; H, 7.47; N, 4.94.
Found: C, 59.03, H, 7.51; N, 4.83.
CA 02207102 1997-06-0~
W O g6/17827 ~IU~3~114948 - 36 -Exam~le 9 Preparation of EthYl 3(R)-~ r ~ r 1- (4-cYanoPhenYl)-2-oxo-3(S)-~YrrolidinYll-aminolcarbonYllaminolbutanoate.
~ ? NlN--To a suspension of 1,1'-carbonyldiimidazole (178 mg, 1.1 mmol) in pyridine (2.5 mL) at 5~C under nitrogen was added the product of example 4 (260 mg, 1.1 mmol). The resulting solution was stirred at 5~C for 15 minutes, diluted with 2.5 mL of DMF and removed from the ice bath.
The product of example 8 (375 mg, 1.32 mmol) was added all at once and the reaction mixture stirred at 75-80~C for 2 hours. After cooling to room temperature, the resulting solution was diluted EtOAc and washed with lN HCl, saturated NaHCO3 and dried (MgSO4). Evaporation of the solvent afforded 295 mg (73%) of product (m.p. 177.5-179~C). IH-NMR (300 MHz, CDCl3) ~ 1.20-1.30 (m, 6H), 2.05 (m, lH), 2.53 (m, 2H), 2.83 (m, lH), 3.83 (m, 2H), 4.15 (q, J = 7Hz, 2H), 4.19 (m, lH), 4.48 (m, lH), 7.68 (d, J =
8Hz, 2H), 7.82 (d, J = 8Hz, 2H).
Anal. calc'd. for C~8H22N4O4-0.1 H20:
Calculated: C, 60.02; H, 6.21; N, 15.56.
Found: C, 60.29; H, 6.21; N, 15.06.
W O g6/17827 ~ S114948 Exam~le 10 Pre~aration of Ethvl 3rR)-~ r 4-(aminorhydroxvimino)-methyl)~henyl~-2-oxo-3rS)-pYrrolidinYllaminolcarbonyll-aminolbutanoate.
o Il ~ /~ "NlN
H2N~ O
,N
The title compound was prepared from the product of example 9 (250 mg, 0.63 mmol) in a manner similar to example 6 affording 203 mg (83%) of product [m.p. 165-167~C (dec.)]. IH-NMR (300 MHz, d6-DMSO) ~ 1.06 (d, J =
7Hz, 3H), 1.28 (t, J = 7Hz, 3H), 1.88 (m,- lH), 2.30-2.53 (m, 3H), 3.75 (m, 2H), 3.95 (m, lH), 4.05 (q, J = 7Hz, 2H), 4.40 (m, lH), 7.56 (s, 4H).
Anal. calc'd. for CI~H25N505-1/3H20:
Calculated: C, 54.40; H, 6.51; N, 17.64.
Found: C, 54.76; H, 6.71; N, 17.21.
WO g6/17827 rcrlusssll4s4s ExamPle 11 Pre~aration of EthYl 3 rR) - r r r r 1- r 4-(aminoiminomethYl~-~henyl~-2-oxo-3rS)-pyrrolidinYl~amino1carbonvllamino~-butanoate Acetate o H2N~N/~ ............ , NH
The title compound was prepared from the product of example 10 (150 mg, 0.38 mmol) in a manner similar to example 7 affording 131 mg (77~) of product [m.p. 208-209~C (dec.)].
IH-NMR (300 MHz, d6-DMSO) ~ 1.08 (d, J = 7Hz, 3H), 1.19 (t, J = 7Hz, 3H), 1.39 (s, 3H), 1.94 (m, lH), 2.30-2.53 (m, 3H), 3.80 (m, 2H), 3.95 (m, lH), 4.06 (q, J = 7Hz, 2H), 4.43 (m, lH), 7.86 (d, J = 8Hz, 2H), 7.91 (d, J = 8Hz, 2H).
Anal. calc'd. for C2oH29N506-3/4 H20:
Calculated: C, 53.50; H, 6.85; N, 15.60.
Found: C, 53.34; H, 6.46; N, 15.35.
CA 02207102 1997-06-0~
WOg6/17827 PCT~S9Stl4948 ExamPle 12 Pre~aration of EthYl ~(S)-r r (l.l-dimethYlethOxy)carbOnYl~-~ aminolbenzene~roDanoate.
O
CH3 O ~ OEt H C ~ O ~ N
To a stirred solution of N-BOC-D-phenylglycine (5.02 g, 20 mmol), N-methylmorpholine (2.02 g, 20 mmol) in EtOAc (100 mL) at 0~C was added isobutyl chloroformate 15 (2.73 g, 20 mmol). After 15 minutes the reaction mixture was filtered to remove the amine salts then an ethereal solution of diazomethane (60 mL, 30 mmol) was added. The cooling bath was removed and the reaction mixture stirred at ambient temperature for 2 hours. The reaction mixture was purged with nitrogen for 15 minutes to remove the excess diazomethane. The reaction mixture was diluted with EtOAc, washed with lN HCl, saturated NaHCO3, and dried (MgSO4). Evaporation of the solvent afforded the crude diazoketone which was dissolved in EtOH (100 mL) and then treated sequentially with AgO2CPh (1.6 g, 7 mmol) and triethylamine (6.06 g, 60 mmol). After 20 hours the reaction mixture was concentrated and chromatographed (silica gel, 15% EtOAc/hexanes) affording 4.90 g (85%) of product as a colorless oil. IH-NMR (300 MHz, CDCl3) ~ 1.17 30 (t, J = 7 Hz, 3H), 1.43 (s, 9H), 2.73-2.92 (m, 2H), 4.07 (q, J = 7 Hz, 2H), 5.10 (m, lH), 5.48 (m, lH), 7.22-7.39 (m, 5H).
WOg6/17827 ~ S/14948 Exam~le 13 Preparation of EthYl ~(S)-aminobenzene~ro~anoate HYdrochloride .
O
~OEt H2N~ ~ HCI
Dry HCl gas was bubbled through a solution of the product of example 12 (3.0 g, 10.2 mmol) in EtOAc (50 mL) at ambient temperature for 15 minutes. After stirring for 15 an additional 30 minutes, the solvent was removed under reduced pressure affording 2.30 g (98%) of product as a yellow oil. IH-N~ (300 MHz, d6-DMSO) ~ 1.03 (t, J = 7Hz, 3H), 3.02 (dd, J = 10Hz, J = 15Hz, lH), 3.25 (dd, J = 6Hz, J = 15Hz, lH), 3.96 (m, 2H), 4.55 (m, lH), 7.3-7.6 (m, 5H), 8.93 (s, 3H).
PCT~S9S/149 Exam~le 14 Preparation of Ethyl ~(s)-r r r rl-r4-cYanOphenyl)-2-oxo-3 r S ~ -~Yrrol idinYllaminolcarbonYl~amino~benzeneproDanoate.
~N?"""N~N~
The title compound was prepared from the product of example 13 (685 mg, 2.9 mmol) and the product of example 4 (600 mg, 2.9 mmol) in a manner similar to example 5 affording 1.09 g (91%) of product (m.p. 108-109~C).
H-NMR (300 MHz, CDCl3) ~ 1.16 (t, J = 7Hz, 3H), 2.00 (m, lH), 2.77-2.93 (m, 3H), 3.81 (m, 2H), 4.05 (q, J = 7Hz, 2H), 4.50 (m, lH), 5.26 (m, lH), 7.20-7.35 (m, 5H), 7.66 (d, J = 8Hz, 2H), 7.80 (d, J = 8Hz, 2H).-Anal. calc'd. for C23H24N4O4 1/3H2O:
Calculated: C, 64.79; H, 5.83; N, 13.14 Found: C, 64.65; H, 5.58; N, 13.18.
WO g6/17827 PCrtUSgStl4948 ExamPle 15 PreParation of Ethyl ~(S)-~rl-r4-(amino(hydroxyimino~-methYl)~henY11-2-oxo-3(S)-PYrrolidinyllamino]carbon aminolbenzenePro~anoate.
o H2N~ H H--,N
HO
The title compound was prepared from the product of example 14 (450 mg, 1.07 mmol) in a manner similar to example 6 affording 431 mg (89%) of product [m.p. 192-193~C (dec.)]. IH-NMR (300 MHz, d6-DMSO) ~ 1.10 (t, J =
7Hz, 3H), 1.87 (m, lH), 2.49 (m, lH), 2.77 (m, 2H), 3.74 (m, 2H), 4.00 (q, J = 7Hz, 2H), 4.41 (m, lH), 5.10 (m, lH), 7.20-7.40 (m, 5H), 7.69 (s, 4H).
Anal. calc'd. for C23N2~N5O5-1/2H2O:
Calculated: C, 59.73; H, 6.10; N, 15.14 Found: C, 59.67; H, 6.38; N, 14.85.
W O96117827 PCTnUS9S/14948 ExamPle 16 Preparation of EthYl ~(S)-r r r rl-~4-(aminoiminomethyl)-phen~ll-2-oxo-3(S)-PYrrolidin~llaminolcarbonyllaminol-benzenePropanoate Acetate.
H2N ~ ~ H H
NH
The title compound was prepared from the product of example 15 (400 mg, 0.88 mmol) in a manner similar to example 7 affording 335 mg (76%) of product [m.p. 210-211~C (dec.)]. IH-NMR (d6-DMSO) ~ 1.14 (t, J = 7Hz, 3H), 1.93 (s, 3H), 2.03 (m, lH), 2.47 (m, lH), 2.80 (m, 2H), 3.84 (m, 2H), 4.04 (m, 2H), 4.50 (m, lH), 5.05 (t, J =
7Hz, lH), 7.23-7.44 (m, 5H), 7.92 (d, J = 8Hz, 2H), 7.97 (d, J = 8Hz, 2H).
Anal. calc'd. for C,5H3~NsO6-1/2H70:
Calculated: C, 59.28; H, 6.37; N, 13.83 Found: C, 58.96; H, 6.21; N, 13.92.
Claims (24)
1. A process for the preparation of a lactam of the formula:
wherein R is a protecting group selected from the group consisting of t-butoxycarbonyl and carbobenzyloxy, wherein Z is selected from the group consisting of -CN, -CONH2 and CO2alkyl comprising:
treating a methionine analog of the formula with a compound selected from trimethylsulfonium halide and trimethylsulfoxonium halide, in the presence of a base in an aprotic solvent.
wherein R is a protecting group selected from the group consisting of t-butoxycarbonyl and carbobenzyloxy, wherein Z is selected from the group consisting of -CN, -CONH2 and CO2alkyl comprising:
treating a methionine analog of the formula with a compound selected from trimethylsulfonium halide and trimethylsulfoxonium halide, in the presence of a base in an aprotic solvent.
2. A process according to Claim 1 wherein the methionine analog is of the formula
3. A process according to Claim 2 wherein the methionine analog is treated with trimethylsulfonium iodide.
4. A process according to Claim 3 wherein the base is potassium carbonate.
5. A process according to Claim 4 wherein the aprotic solvent is DMSO.
6. A process according to Claim 5 wherein Z is -CN.
7. A process according to Claim 5 wherein Z is -CONH2.
8. A process according to Claim 1 further comprising deprotecting the lactam and coupling the resulting deprotected lactam with a .beta.-amino ester to form a compound of the formula wherein R1 is selected from the group consisting of H, C1-C6 alkyl, aryl and heterocyclyl radicals wherein 1 to 3 carbon atoms are replaced by a nitrogen, oxygen or sulfur; wherein R6 is selected from the group consisting of C1-C6 alkyl, aryl, arylalkyl and acyloxymethyl.
9. A process for the preparation of a compound of the formula wherein R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, aryl, and monocyclic heterocyclyls wherein 1 to 2 carbon atoms are replaced by a nitrogen, oxygen or sulfur atom; R6 is selected from the group consisting of C1-C6 alkyl, aryl, arylalkyl and acyloxymethyl comprising:
treating a methionine analog of the formula wherein R is selected from the group consisting of BOC or CBZ and Z is -CONH2; with a compound selected from trimethylsulfonium halide and trimethylsulfoxonium halide, in the presence of a base in an aprotic solvent to afford a lactam of the formula dehydrating and deprotecting the lactam;
reacting the resulting product with a .beta.-amino ester in the presence of 1,1-carbonyldiimidazole to produce a urea compound of the formula reacting the urea compound with hydroxylamine hydrochloride to produce an amidoxime intermediate, hydrogenating the amidoxime; and isolating a compound of the formula
treating a methionine analog of the formula wherein R is selected from the group consisting of BOC or CBZ and Z is -CONH2; with a compound selected from trimethylsulfonium halide and trimethylsulfoxonium halide, in the presence of a base in an aprotic solvent to afford a lactam of the formula dehydrating and deprotecting the lactam;
reacting the resulting product with a .beta.-amino ester in the presence of 1,1-carbonyldiimidazole to produce a urea compound of the formula reacting the urea compound with hydroxylamine hydrochloride to produce an amidoxime intermediate, hydrogenating the amidoxime; and isolating a compound of the formula
10. A process according to Claim 9 wherein the methionine analog is of the formula .
11. The process according to Claim 10 wherein the methionine analog is treated with trimethylsulfonium iodide.
12. The process according to Claim 11 wherein the base is potassium carbonate.
13. The process according to Claim 12 wherein the aprotic solvent is DMSO.
14. The process according to Claim 10 wherein the .beta.-amino ester is .beta.-alanine ethyl ester.
15. The process according to Claim 12 wherein the .beta.-amino ester is .beta.-alanine ethyl ester.
16. A process for the preparation of a compound of the formula wherein R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, aryl, and heterocyclyl radicals wherein 1 to 3 carbon atoms are replaced by a nitrogen, oxygen or sulfur atom; R6 is selected from the group consisting of C1-C6 alkyl, aryl, arylalkyl and acyloxymethyl comprising:
treating a methionine analog of the formula wherein R is selected from the group consisting of BOC or CBZ and Z is -CN; with a compound selected from trimethylsulfonium halide and trimethylsulfoxonium halide, in the presence of a base in an aprotic solvent to afford a lactam of the formula deprotecting the lactam;
reacting the resulting product with a .beta.-amino ester in the presence of 1,1-carbonyldiimidazole to produce a urea compound of the formula reacting the urea compound with hydroxylamine hydrochloride to produce an amidoxime intermediate, hydrogenating the amidoxime; and isolating a compound of the formula .
treating a methionine analog of the formula wherein R is selected from the group consisting of BOC or CBZ and Z is -CN; with a compound selected from trimethylsulfonium halide and trimethylsulfoxonium halide, in the presence of a base in an aprotic solvent to afford a lactam of the formula deprotecting the lactam;
reacting the resulting product with a .beta.-amino ester in the presence of 1,1-carbonyldiimidazole to produce a urea compound of the formula reacting the urea compound with hydroxylamine hydrochloride to produce an amidoxime intermediate, hydrogenating the amidoxime; and isolating a compound of the formula .
17. A process according to Claim 16 wherein the methionine analog is of the formula .
18. A process according to Claim 17 wherein the .beta.-amino ester is .beta.-alanine ethyl ester.
19. A process according to Claim 17 wherein the methionine analog is treated with trimethylsulfonium iodide.
20. A process according to Claim 19 wherein the base is potassium carbonate.
21. A process according to Claim 20 wherein the aprotic solvent is DMSO.
22. A process according to Claim 21 wherein the .beta.-amino ester is .beta.-alanine ethyl ester.
23. A compound of the formula wherein R1 is selected from the group consisting of H, C1-C6 alkyl, aryl, and a heterocyclyl radical wherein 1 to 3 carbon atoms are replaced by nitrogen, oxygen or sulfur; and wherein R6 is selected from the group consisting of C1-C6 alkyl, aryl, arylalkyl and acyloxymethyl.
24. A compound of the formula wherein Z is H, -CN, -CONH2 or CO2alkyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002207102A CA2207102A1 (en) | 1994-12-05 | 1995-12-04 | Process for the preparation of amidino phenyl pyrrolidine .beta.-alanine urea analogs |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/349,333 | 1994-12-05 | ||
| CA002207102A CA2207102A1 (en) | 1994-12-05 | 1995-12-04 | Process for the preparation of amidino phenyl pyrrolidine .beta.-alanine urea analogs |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2207102A1 true CA2207102A1 (en) | 1996-06-13 |
Family
ID=4160826
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002207102A Abandoned CA2207102A1 (en) | 1994-12-05 | 1995-12-04 | Process for the preparation of amidino phenyl pyrrolidine .beta.-alanine urea analogs |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2207102A1 (en) |
-
1995
- 1995-12-04 CA CA002207102A patent/CA2207102A1/en not_active Abandoned
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Effective date: 20070423 |