Removal of boronic acid protecting groups by transesterification
First Claim
1. A method for the preparation of a compound of formula (II)
whereinR1 isa) hydrogen,b) an N-terminal protecting group,c) --SO2 (CH2)m -aryl, wherein aryl is phenyl, napthyl or biphenyl substituted with one, two or three substituents selected from the group consisting of halo (F, Cl, Br, I,), --CN, C1-C10-alkyl, C3-C8-cycloalkyl, C2-C10-alkenyl, C2-C10-alkynyl, -OR7, --NO2, --CF3, --S(O)r R8, --NR6 R7, --COR7, --CO2 R7, --CONR6 R7 ;
X is a peptide of 1-20 amino acids;
R2 isa) C1-C10-alkyl,b) C2-C10-alkyl-Y,c) --(CH2)n -aryl, wherein aryl is as defined above;
Y isa) --NHC(NH)NH2,b) --NH2,c) --SC(NH)NH2,d) --OR9,e) --SR9 ;
R5 and R6 are independentlya) H,b) C1-C8-alkyl,c) C1-C8-alkoxy,d) C3-C8-cycloalkyl,e) --CO2 R7,f) --(CH2)m -phenyl;
R7 isa) H,b) phenyl,c) benzyl,d) C1-C8-alkyl;
R8 isa) phenyl,b) C1-C4-alkyl,c) C1-C4-alkoxy,d) --CF3 ;
R9 isa) H,b) C1-C2-alkyl,c) phenyl or phenyl optionally substituted with a substituent selected from the group consisting of halo (F, Cl, Br, I), --CN, C1-C10-alkyl, C3-C8-cycloalkyl, C2-C10-alkenyl, C2-C10-alkynyl, --OR7, --NO2, --CF3, --S(O)r R8, --NR6 R7, --COR7, --COR7, --CO2 R7, --CONR6 R7 ;
n is 0or 1;
m is 0 to 2;
r is 0 to 2;
comprising suspending a compound of the formula
space="preserve" listing-type="equation">R.sup.1 -X.sub.n --NHCH (R.sup.2)--BR.sup.3 R.sup.4 (I)wherein R1, R2, X, Y, R5, R6, R7, R8, R9, n, m and r are as defined above; and
R3 and R4 area) C1-C8-alkoxy, orb) when taken together R3 and R4 form a cyclic boronic ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, a heteroatom selected from the group consisting of N, S, or O,in a mixture of water and a water-immiscible organic solvent in which said compound of formula (II) is less soluble than in water, said mixture containing an organic boronic acid acceptor which is more soluble in the water-immiscible organic solvent than in water and is selected from the group consisting of phenyl boronic acid, butyl boronic acid, pentyl boronic acid, hexyl boronic acid or cyclohexyl boronic acid, said organic boronic acid acceptor being present in a amount equal to at least 1 equivalent of said compound of formula (I), wherein the amount of water present in said mixture is sufficient to completely dissolve the compound of formula (II) formed and the amount of water-immiscible organic solvent present in said mixture is sufficient to completely dissolve said organic boronic acid acceptor and the boronic ester reaction product formed;
stirring the resulting reaction mixture for approximately one hour before allowing the reaction mixture to separate into two distinct phases;
separating the phases; and
recovering the compound of formula (II) from the separated aqueous phase.
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Abstract
A method for the removal of ester protecting groups from α-amino boronic acid is disclosed for the preparation of compounds of formula (II) below
R.sup.1 -X.sub.n -NHCH (R.sup.2)-B(OH).sub.2
100 Citations
8 Claims
- 1. A method for the preparation of a compound of formula (II)
- space="preserve" listing-type="equation">R.sup.1 -X.sub.n --NHCH(R.sup.2)-B(OH).sub.2 (II)
wherein R1 is a) hydrogen, b) an N-terminal protecting group, c) --SO2 (CH2)m -aryl, wherein aryl is phenyl, napthyl or biphenyl substituted with one, two or three substituents selected from the group consisting of halo (F, Cl, Br, I,), --CN, C1-C10-alkyl, C3-C8-cycloalkyl, C2-C10-alkenyl, C2-C10-alkynyl, -OR7, --NO2, --CF3, --S(O)r R8, --NR6 R7, --COR7, --CO2 R7, --CONR6 R7 ; X is a peptide of 1-20 amino acids; R2 is a) C1-C10-alkyl, b) C2-C10-alkyl-Y, c) --(CH2)n -aryl, wherein aryl is as defined above; Y is a) --NHC(NH)NH2, b) --NH2, c) --SC(NH)NH2, d) --OR9, e) --SR9 ; R5 and R6 are independently a) H, b) C1-C8-alkyl, c) C1-C8-alkoxy, d) C3-C8-cycloalkyl, e) --CO2 R7, f) --(CH2)m -phenyl; R7 is a) H, b) phenyl, c) benzyl, d) C1-C8-alkyl; R8 is a) phenyl, b) C1-C4-alkyl, c) C1-C4-alkoxy, d) --CF3 ; R9 is a) H, b) C1-C2-alkyl, c) phenyl or phenyl optionally substituted with a substituent selected from the group consisting of halo (F, Cl, Br, I), --CN, C1-C10-alkyl, C3-C8-cycloalkyl, C2-C10-alkenyl, C2-C10-alkynyl, --OR7, --NO2, --CF3, --S(O)r R8, --NR6 R7, --COR7, --COR7, --CO2 R7, --CONR6 R7 ; n is 0or 1; m is 0 to 2; r is 0 to 2; comprising suspending a compound of the formula
space="preserve" listing-type="equation">R.sup.1 -X.sub.n --NHCH (R.sup.2)--BR.sup.3 R.sup.4 (I)wherein R1, R2, X, Y, R5, R6, R7, R8, R9, n, m and r are as defined above; and R3 and R4 are a) C1-C8-alkoxy, or b) when taken together R3 and R4 form a cyclic boronic ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, a heteroatom selected from the group consisting of N, S, or O, in a mixture of water and a water-immiscible organic solvent in which said compound of formula (II) is less soluble than in water, said mixture containing an organic boronic acid acceptor which is more soluble in the water-immiscible organic solvent than in water and is selected from the group consisting of phenyl boronic acid, butyl boronic acid, pentyl boronic acid, hexyl boronic acid or cyclohexyl boronic acid, said organic boronic acid acceptor being present in a amount equal to at least 1 equivalent of said compound of formula (I), wherein the amount of water present in said mixture is sufficient to completely dissolve the compound of formula (II) formed and the amount of water-immiscible organic solvent present in said mixture is sufficient to completely dissolve said organic boronic acid acceptor and the boronic ester reaction product formed;
stirring the resulting reaction mixture for approximately one hour before allowing the reaction mixture to separate into two distinct phases;
separating the phases; and
recovering the compound of formula (II) from the separated aqueous phase.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8)
Specification
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- Resources
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Current AssigneeBristol-Myers Squibb Pharma Company (Bristol-Myers Squibb Company)
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Original AssigneeDu Pont De Nemours (Belgium) Bvba (DuPont de Nemours, Inc.)
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InventorsKettner, Charles A.
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Primary Examiner(s)BRUST, JOSEPH
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Application NumberUS08/036,378Time in Patent Office671 DaysField of Search562/7, 558/228, 558/289, 558/295, 558/298, 558/384, 548/405, 530/331, 530/330US Class Current548/405CPC Class CodesC07F 5/025 Boronic and borinic acid co...C07K 1/088 containing other elements, ...C07K 5/06191 containing heteroatoms diff...Y02P 20/55 Design of synthesis routes,...
