CN106146351B - Method for producing biaryl substituted 4-amino-butyric acids or derivatives thereof - Google Patents

Method for producing biaryl substituted 4-amino-butyric acids or derivatives thereof Download PDF

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CN106146351B
CN106146351B CN201510156552.6A CN201510156552A CN106146351B CN 106146351 B CN106146351 B CN 106146351B CN 201510156552 A CN201510156552 A CN 201510156552A CN 106146351 B CN106146351 B CN 106146351B
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袁建栋
徐安佗
王萌
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Borui Biomedical Suzhou Co ltd
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Abstract

The present invention relates to a process for the preparation of biaryl substituted 4-amino-butyric acid or derivatives thereof, which process comprises reacting (ii) with hydrogen in the presence of a transition metal catalyst and a chiral ligand to form (i), wherein the transition metal catalyst is a rhodium catalyst and wherein the chiral ligand is a chiral phosphine ligand of a conformationally rigid cyclic structure to which phosphorus may be bonded or which is part of the cyclic structure, and further preparing a biaryl substituted 4-amino-butyric acid or derivative thereof from compound (i).
Figure 615277DEST_PATH_IMAGE001

Description

Method for producing biaryl substituted 4-amino-butyric acids or derivatives thereof
Technical Field
The present invention relates to a process for the preparation of biaryl substituted 4-aminobutyric acids or derivatives thereof and their use in the preparation of NEP inhibitors.
Background
Endogenous Atrial Natriuretic Peptide (ANP) has diuretic, natriuretic and vasodilatory properties in mammals. Native ANP is metabolically inactivated, in particular by degradative enzymes of the neutral endopeptidase (NEP, EC 3.4.24.11), which is also responsible for the metabolic inactivation of, for example, enkephalin.
In the prior art, it is known that biaryl substituted phosphonic acid derivatives are useful as inhibitors of Neutral Endopeptidase (NEP), for example as inhibitors of mammalian ANP-degrading enzymes, so that the diuretic, natriuretic and vasodilatory properties of ANP in mammals can be prolonged and enhanced by inhibiting the degradation of ANP to less active metabolites. Thus, NEP inhibitors are particularly useful in the treatment of conditions and disorders responsive to inhibition of neutral endopeptidase (EC 3.4.24.11), particularly cardiovascular disorders such as hypertension, renal insufficiency, including edema and salt retention, pulmonary edema, and congestive heart failure.
Methods for preparing NEP-inhibitors are known. WO2008031567 discloses a preparation method as follows:
Figure GDA0002503687450000011
wherein R is1And R1' is independently hydrogen or an amine protecting group and R2Is a carboxyl group or an ester group. The process is a reaction with hydrogen in the presence of a transition metal catalyst and a chiral ligand, the transition metal being selected from group 8 or 9 of the periodic table. The chiral ligand is a Mandyphos ligand, a Walphos ligand, a Josiphos ligand, or a Solphos ligand. Except Solphos ligand, the ligands are ferrocene chiral phosphine ligands. However, the selectivity of this process is not very high, and although some examples show that the% ee is 99%, some examples show that the% ee is 89%, which means that the stability of this process is not very high and the selectivity cannot be guaranteed.
Disclosure of Invention
It is an object of the present invention to provide a better hydrogenation process in a process for the preparation of NEP inhibitors or prodrugs thereof, and in particular it is an object of the present invention to provide an alternative process for the preparation of compounds of formula (i) or salts thereof, which compounds are useful as intermediates in the preparation of NEP inhibitors or prodrugs thereof, in particular NEP inhibitors comprising a γ -amino-biphenyl- α -methylalkanoic acid or acid ester backbone thereof.
Figure GDA0002503687450000021
Wherein R is1And R1' is independently hydrogen or an amine protecting group and R2Is a carboxyl group or an ester group. R1Preferably an amine protecting group. R1Further' is preferably hydrogen. Or, R1And R1Together may form a cyclic structure (and thus a difunctional cyclic amine protecting group). Term(s) for"amine protecting group" includes any group that reversibly protects an amino functional group.
In a particularly preferred embodiment, R1Is tert-Butoxycarbonyl (BOC). More preferably, R1Is tert-Butoxycarbonyl (BOC) and R1' is hydrogen.
The term "ester group" includes any ester of a carboxyl group commonly known in the art. In a preferred embodiment, R2is-COOR3Wherein R is3Is C1-C6An alkyl group. In a particularly preferred embodiment, R2Is COOH.
Figure GDA0002503687450000022
Represents a covalent bond, wherein the stereochemistry of the bond is determined to be either (S) or (R) configuration with respect to the chiral center.
The compounds of formula (I) have a γ -amino-biphenyl- α -methylalkanoic acid skeleton. Some NEP inhibitors are known which have a γ -amino-biphenyl- α -methyl alkanoic acid backbone, such as N- (3-carboxy-1-oxopropyl) - (4S) -p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid. Thus, the present invention provides a novel asymmetric process for the preparation of NEP inhibitors. More importantly, the process has high stereoselectivity.
It is a further object of the present invention to provide a process for the preparation of compounds wherein R is1、R1' and R2A process for the preparation of compounds of formulae (I-a) and (I-b) or salts thereof having a high diastereoisomeric ratio as defined above.
Figure GDA0002503687450000031
It is another object of the present invention to provide a process in which the compound of formula (I-b) or a salt thereof can be completely removed and the compound of formula (I-a) or a salt thereof can be provided in a pure form.
It is a further object of the present invention to provide a hydrogenation step in a process for the preparation of NEP inhibitors or prodrugs thereof, in particular NEP inhibitors comprising a γ -amino-biphenyl- α -methyl alkanoic acid or an acid ester backbone thereof, wherein said hydrogenation step preferably has a high yield and preferably results in a product with high purity.
The object of the present invention can be achieved by using a specific catalyst and a specific chiral ligand in the hydrogenation step in the preparation of NEP inhibitors, in particular NEP inhibitors comprising a γ -amino-biphenyl- α -methylalkanoic acid or an acid ester skeleton thereof, preferably in the hydrogenation of a compound of formula (ii) or a salt thereof, in particular of a compound of formula (ii-a) or a salt thereof,
Figure GDA0002503687450000032
in summary, the present invention provides the following synthetic methods:
Figure GDA0002503687450000033
wherein R is1、R1′、R2As defined above. The method comprises the steps of reacting with hydrogen in the presence of a transition metal catalyst and a chiral ligand, wherein the transition metal catalyst is a rhodium catalyst; wherein the chiral ligand is a chiral phosphine ligand of a conformational rigid ring structure, and the phosphorus may be bonded to or part of the ring structure.
Further, the invention provides a synthesis method as follows:
Figure GDA0002503687450000041
wherein R is1、R1′、R2As defined above. The method comprises the steps of reacting with hydrogen in the presence of a transition metal catalyst and a chiral ligand, wherein the transition metal catalyst is a rhodium catalyst; wherein the chiral ligand is a chiral phosphine ligand of a conformational rigid ring structure, and the phosphorus may be bonded to or part of the ring structure.
Still further, the present invention provides a synthetic method comprising:
Figure GDA0002503687450000042
the method comprises the steps of reacting with hydrogen in the presence of a transition metal catalyst and a chiral ligand, wherein the transition metal catalyst is a rhodium catalyst; wherein the chiral ligand is a chiral phosphine ligand of a conformational rigid ring structure, and the phosphorus may be bonded to or part of the ring structure.
In a preferred embodiment, the compound of formula (I-a) or a salt thereof is further reacted to obtain the NEP inhibitor prodrug N- (3-carboxy-1-oxopropyl) - (4S) -p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (i.e. AHU-377) or a salt thereof.
Figure GDA0002503687450000051
AHU-377
In a preferred embodiment of the present invention, the reaction preferably comprises the following steps:
Figure GDA0002503687450000052
the rhodium catalyst of the present invention is preferably [ Rh (COD) ]2]BF4And [ Rh (COD) ]2Cl]2。
The chiral phosphine ligand with the conformational rigid ring structure is beneficial to limiting the conformational changeability of the ligand, so that the chiral recognition capability is improved, and the chiral phosphine ligand has high enantioselectivity.
The chiral phosphine ligand with the conformation rigid ring structure comprises five-membered, six-membered and seven-membered ring bidentate, tridentate, tetradentate and pentadentate chiral phosphine ligands, and compared with the phosphine ligand used in WO2008031567, the catalyst has high enantioselectivity to asymmetric reaction. WO2008031567 discloses a method with the ee% value of 89:11 to 99:1, and although the ee% value of the method is as high as 99:1 or 98:2, the ee% value of the method is 89:11 or 90:10, which shows that the method is not very high in stability and can not ensure that the selectivity is good.
The chiral phosphine ligand of the conformational rigid ring structure is preferably a BICPO ligand, a phosphine ligand L6, a phosphine ligand L7, a phosphine ligand Tangphos, a phosphine ligand Me-Penn Phos, and has the following structure:
Figure GDA0002503687450000053
the invention has high enantioselectivity because the frame of BICP contains two cyclopentane rings, which limits the conformational changeability of the ligand, thus leading to high enantioselectivity of asymmetric reaction. The rigid structure of BICP provides stronger chiral recognition. And the BICP is easy to synthesize and has lower cost. The key to the system is that two cyclopentane rings in the backbone limit the conformational flexibility of nine-membered rings, and four stereogenic carbon centers in the backbone determine the orientation of the four P-phenyl groups. And the BICPO can be synthesized from BICP, these ligands are all air stable solids and can be easily handled on the bench.
The advantages of the other ligands of the invention are similar to those of BICP and BICPO. By the hydrogenation method, the selectivity of the compound (II) obtained by hydrogenating the compound (I) is further improved, and the ee% values are all higher than 96: 4. This indicates that the hydrogenation process of the present invention is more selective and more stable.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1
Figure GDA0002503687450000061
To a 500mL solution of methanol (240mL) in a reaction flask was added [ Rh (COD)2]BF4(315mg, 0.78mmol) chiral phosphine ligand BICPO (452mg, 0.84mmol) was added and after stirring the mixture for 30 minutes 1(ii-a) (30g,0.078mol) was added in sequence. The hydrogenation was carried out at room temperature under hydrogen for 24 hours. After careful hydrogen evolution, the reaction mixture was washed with methanol and then concentrated in vacuo. The residue was passed through a short silica gel column to remove the catalyst. Measurement of enantiomers by capillary GC or HPLCIsomer content. The conversion of the reaction was 100%, and the ee% was 99%.
Figure GDA0002503687450000062
Example 2
Figure GDA0002503687450000071
To a 500mL solution of methanol (240mL) in a reaction flask was added [ Rh (COD)2]BF4(315mg, 0.78mmol), chiral phosphine ligand L6(475mg, 0.84mmol) was added and the mixture was stirred for 30 minutes, followed by the addition of 1(ii-a) (30g,0.078 mol). The hydrogenation was carried out at room temperature under hydrogen for 24 hours. After careful hydrogen evolution, the reaction mixture was washed with methanol and then concentrated in vacuo. The residue was passed through a short silica gel column to remove the catalyst. Enantiomeric contents were measured by capillary GC or HPLC. The conversion of the reaction was 100%, and the ee% was 96%.
Figure GDA0002503687450000072
Example 3
Figure GDA0002503687450000073
To a 500mL solution of methanol (240mL) in a reaction flask was added [ Rh (COD)2]BF4(315mg, 0.78mmol), chiral phosphine ligand L7(500mg, 0.84mmol) was added and after stirring the mixture for 30 minutes, 1(ii-a) (30g,0.078mol) was added in that order. The hydrogenation was carried out at room temperature under hydrogen for 24 hours. After careful hydrogen evolution, the reaction mixture was washed with methanol and then concentrated in vacuo. The residue was passed through a short silica gel column to remove the catalyst. Enantiomeric contents were measured by capillary GC or HPLC. The conversion of the reaction was 100%, and the ee% was 97%.
Figure GDA0002503687450000081
Example 4
Figure GDA0002503687450000082
To a 500mL solution of methanol (240mL) in a reaction flask was added [ Rh (COD)2]BF4(315mg, 0.78mmol) of the chiral phosphine ligand Tangphos (254mg, 0.84mmol) was added and after stirring the mixture for 30 minutes 1(ii-a) (30g,0.078mol) was added in sequence. The hydrogenation was carried out at room temperature under hydrogen for 24 hours. After careful hydrogen evolution, the reaction mixture was washed with methanol and then concentrated in vacuo. The residue was passed through a short silica gel column to remove the catalyst. Enantiomeric contents were measured by capillary GC or HPLC. The conversion of the reaction was 100%, and the ee% was 98%.
Figure GDA0002503687450000083
Example 5
Figure GDA0002503687450000091
To a 500mL solution of methanol (240mL) in a reaction flask was added [ Rh (COD)2]BF4(315mg, 0.78mmol) and the chiral phosphine ligand Me-Penn Phos (300mg, 0.84mmol) were added and after stirring the mixture for 30 minutes 1(ii-a) (30g,0.078mol) was added in sequence. The hydrogenation was carried out at room temperature under hydrogen for 24 hours. After careful hydrogen evolution, the reaction mixture was washed with methanol and then concentrated in vacuo. The residue was passed through a short silica gel column to remove the catalyst. Enantiomeric contents were measured by capillary GC or HPLC. The conversion of the reaction was 100%, and the ee% was 96%.
Figure GDA0002503687450000092
Example 6
Figure GDA0002503687450000093
To a 500mL solution of methanol (240mL) in a reaction flask was added [ Rh (COD)2Cl]2(553mg, 0.78mmol), the chiral phosphine ligand BICPO (452mg, 0.84mmol) was added and after stirring the mixture for 30 minutes, 1(ii-a) (30g,0.078mol) was added in that order. The hydrogenation was carried out at room temperature under hydrogen for 24 hours. After careful hydrogen evolution, the reaction mixture was washed with methanol and then concentrated in vacuo. The residue was passed through a short silica gel column to remove the catalyst. Enantiomeric contents were measured by capillary GC or HPLC. The conversion of the reaction was 100%, and the ee% was 99%.
Figure GDA0002503687450000101
Example 7
Figure GDA0002503687450000102
To a 500mL solution of methanol (240mL) in a reaction flask was added [ Rh (COD)2Cl]2(553mg, 0.78mmol), chiral phosphine ligand L6(475mg, 0.84mmol) was added, and after the mixture was stirred for 30 minutes, 1(ii-a) (30g,0.078mol) was added in that order. The hydrogenation was carried out at room temperature under hydrogen for 24 hours. After careful hydrogen evolution, the reaction mixture was washed with methanol and then concentrated in vacuo. The residue was passed through a short silica gel column to remove the catalyst. Enantiomeric contents were measured by capillary GC or HPLC. The conversion of the reaction was 100%, and the ee% was 96%.
Figure GDA0002503687450000103
Example 8
Figure GDA0002503687450000104
To a 500mL solution of methanol (240mL) in a reaction flask was added [ Rh (COD)2Cl]2(553mg, 0.78mmol), chiral phosphine ligand L7(500mg, 0.84mmol) was added, and the mixture was stirred for 30 minutes, followed by1(ii-a) (30g,0.078mol) was added. The hydrogenation was carried out at room temperature under hydrogen for 24 hours. After careful hydrogen evolution, the reaction mixture was washed with methanol and then concentrated in vacuo. The residue was passed through a short silica gel column to remove the catalyst. Enantiomeric contents were measured by capillary GC or HPLC. The conversion of the reaction was 100%, and the ee% was 96%.
Figure GDA0002503687450000111
Example 9
Figure GDA0002503687450000112
To a 500mL solution of methanol (240mL) in a reaction flask was added [ Rh (COD)2Cl]2(553mg, 0.78mmol) of chiral phosphine ligand Tangphos (254mg, 0.84mmol) was added and after stirring the mixture for 30 minutes 1(ii-a) (30g,0.078mol) was added in that order. The hydrogenation was carried out at room temperature under hydrogen for 24 hours. After careful hydrogen evolution, the reaction mixture was washed with methanol and then concentrated in vacuo. The residue was passed through a short silica gel column to remove the catalyst. Enantiomeric contents were measured by capillary GC or HPLC. The conversion of the reaction was 100%, and the ee% was 97%.
Figure GDA0002503687450000113
Example 10
Figure GDA0002503687450000121
To a 500ml solution of ethanol (250ml) in a reaction flask, A (383mg, 1mmol) was added, and SOCl was added2(120mg,1.1mmol) and the mixture was stirred for 30 minutes. The reaction was carried out in hydrogen at room temperature for 24 hours. After careful hydrogen evolution, the reaction mixture was washed with methanol and then concentrated in vacuo. Succinic anhydride (110mg, 1mmol) was added, the reaction stirred for 8 hours, the reaction mixture was washed with ethanol and the residue was removed by short silica gel column. By capillary actionTube GC or HPLC measured the enantiomeric content. The conversion of the reaction was 100%, and the ee% was 98%.

Claims (3)

1. A process for the preparation of a compound of formula (i) or a salt thereof, which process comprises:
Figure FDA0002503687440000011
the process is a reaction of a compound (II) or a salt thereof with hydrogen in the presence of a transition metal catalyst and a chiral phosphorus ligand, wherein the transition metal catalyst is [ Rh (COD)2]BF4Wherein the chiral phosphorus ligand is a BICPO ligand, an L6 ligand, an L7 ligand, a Tangphos ligand, a Me-Penn Phos ligand; the structural formulas of the BICPO ligand, the L6 ligand, the L7 ligand, the Tangphos ligand and the Me-Penn Phos ligand are respectively as follows:
Figure FDA0002503687440000012
2. the process as claimed in claim 1, wherein the compound of formula (i) or a salt thereof is further reacted to obtain N- (3-carboxy-1-oxopropyl) - (4S) -p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid or a salt thereof.
3. The process as claimed in claim 1, wherein the compound of formula (i) or a salt thereof is further reacted to obtain N- (3-carboxy-1-oxopropyl) - (4S) -p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester or a salt thereof.
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