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HK1049336B - Synthetic routes for the preparation of rhinovirus protease inhibitors and key intermediates - Google Patents

Synthetic routes for the preparation of rhinovirus protease inhibitors and key intermediates Download PDF

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Publication number
HK1049336B
HK1049336B HK03101461.5A HK03101461A HK1049336B HK 1049336 B HK1049336 B HK 1049336B HK 03101461 A HK03101461 A HK 03101461A HK 1049336 B HK1049336 B HK 1049336B
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formula
compound
reaction
acid
produce
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HK03101461.5A
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HK1049336A1 (en
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Tian Qingping
K. Nayyar Naresh
Babu Srinivasan
Tao Junhua
Jarold Moran Terence
Dagnino Raymond Jr.
J. Mitchell Lennert
Paul Remarchuk Travis
Joseph Melnick Michael
Lee Bender Steven
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阿古龙制药有限公司
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Publication of HK1049336A1 publication Critical patent/HK1049336A1/en
Publication of HK1049336B publication Critical patent/HK1049336B/en

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    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
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    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
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    • 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
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    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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  • Pyridine Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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Abstract

Efficient synthetic routes for the preparation of rhinovirus protease inhibitors of formula (I), as well as key intermediates usefull in those synthetic routes. These compounds of formula (I), as well as pharmaceutical compositions that contain these compounds, are suitable for treating patients or hosts infected with one or more picornaviruses.

Description

Synthetic routes to rhinovirus protease inhibitors and key intermediates
Related application information:
this application is related to U.S. provisional patent application No. 60/150,358, filed on 8/24/1999.
This application also relates to U.S. provisional patent application No. 60/150,365 (attorney docket No. 0125.0027), filed on even 24.8.1999, entitled "efficient process for preparing rhinovirus protease inhibitors, key intermediates used to prepare such inhibitors and continuous membrane reactors", to: tao, s.babu, r.dagnino, jr., q.tiana, t.remarchuk, k.mcgee, n.nayyar and t.moran. The above application also relates to synthetic routes for the preparation of rhinovirus protease inhibitors and key intermediates used in their preparation. This application is based on the above application and is incorporated herein by reference.
Technical field and industrial applicability of the invention:
the present invention relates to an improved process for the preparation of ethyl-3- { (5 '-methylisoxazole-3' -carbonyl) -L-Val ψ (COCH)2) -L- (4-F-Phe) -L- ((S) -pyrrole-Ala) } -E-propionate (also known as AG7088), analogs thereof, and pharmaceutically acceptable salts thereof. The present invention also includes a new group of key intermediates useful in the above process.
Background of the invention:
picornaviruses are a family of tiny, non-enveloped, positive-stranded RNA-containing viruses that can infect humans and other animals. These viruses include human rhinoviruses, human polioviruses, human coxsackieviruses, human echoviruses, human and bovine enteroviruses, encephalomyocarditis viruses, meningitis viruses, foot and mouth viruses, hepatitis a viruses, and the like. Human rhinoviruses are the major cause of common cold.
The natural maturation of picornaviruses requires a 3C enzyme that breaks down proteins. Thus, inhibition of the activity of these proteolytic 3C enzymes represents an important and useful method for treating and curing viral infections of this nature, including the common cold.
Recently, small molecule inhibitors of the enzymatic activity of some picornavirus 3c proteases (i.e., anti-picornavirus compounds) have been discovered. See, e.g., U.S. patent application No. 08/850,398, filed 1997, 5/2/d by Webber et al; U.S. patent application No. 08/991,282, filed 1997 on 16.12.1997 by Dragovich et al; and U.S. patent application No. 08/991,739, filed by Webber et al, 1997, 12, 16. These U.S. patent applications describe certain antipicornaviral compounds and methods for their synthesis, the disclosures of which are incorporated herein by reference.
Recently, a particularly effective anti-picornaviral agent has been disclosed in U.S. patent application No. 60/098,354 (' 354 application), filed by Dragovich et al, 28.8.1998, which is incorporated herein by reference. This application discloses a group of antipicornaviral agents of general formula I. Among these is a particularly promising compound, AG7088, which shows excellent antiviral properties against a variety of rhinovirus serotypes, and is currently undergoing clinical trials in humans. The' 354 application also discloses processes and intermediates for synthesizing these compounds. For example, general procedure V therein discloses a general method for synthesizing compounds of formula I, which comprises reacting a carboxylic acid of formula BB with an amine of formula P to form an amide to give the final product CC, shown below.
The' 354 application also discloses methods of synthesizing intermediates of the general formulae BB and P, and teaches methods of performing the amide forming reactions described above. Thus, the' 354 application teaches the synthesis of a compound from carboxylic acid BB (within the scope of the compounds of formula II described below) and TokyoA compound of formula P (the same as the compound of formula III described below) a suitable method for the synthesis of compounds of formula I. Likewise, two recent publications by Dragovich et al disclose anti-picornaviral agents and suitable synthetic methods therefor. See "structural-based design, synthesis and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structural activity studies of ketomethylene-containing peptidomimetics, "Dragovich et al, Journal of medicinal chemistry, ASAP, 1999; and "structure-based design, synthesis and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 4. Incorporation of P1The lactam moiety as a substitute for L-glutamine ", Dragovich et al, Journal of medicinal chemistry, ASAP, 1999. The above articles are incorporated herein by reference in their entirety.
However, there is still a need to develop improved, more efficient methods and new intermediates for the synthesis of anti-picornaviral agents. In particular, there is a need for improved methods of synthesizing compounds of formula II and III.
Summary of the invention:
the present invention relates to an economical and efficient process for the preparation of an antipicornaviral agent of formula I, e.g. compound AG7088, and intermediates useful in this synthetic process.
Anti-picornaviral agents of formula I include:
wherein R is1H, F, alkyl, OH, SH or O-alkyl;
R2and R3Independently of one another is H;
or
Wherein n is an integer of 0 to 5, A1Is CH or N, A2And each A3Are independently from each other selected from C (R)41)(R41)、N(R41)、S、S(O)、S(O)2And O, A4Is NH or NR41Wherein each R41Independently of one another, is H or lower alkyl, with the proviso that in the above-mentioned radicals A1、A2、(A3)n、A4And C ═ O, up to two consecutive heteroatoms in the ring, and R2And R3At least one of which is
Or
R4Is that
R5And R6H, F, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, independently of one another;
R7and R8Independently of one another, H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR17、-SR17、-NR17R18、-NR19NR17R18or-NR17OR18Wherein R is17、R18And R19Independently of one another, H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or acyl, with the proviso that R7And R8At least one of which is alkyl, aryl, heteroaryl, -OR17、-SR17、-NR17R18、-NR19NR17R18or-NR17OR18；
R9Is a 5-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, N and S;
z and Z1H, F, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C (O) R21、-CO2R21、CN、-C(O)NR21R22、-C(O)NR21OR22、-C(S)R21、-C(S)NR21R22、-NO2、-SOR21、-SO2R21、-SO2NR21R22、-SO(NR21)(OR22)、-SONR21、-SO3R21、-PO(OR21)2、-PO(R21)(R22)、-PO(NR21R22)(OR23)、-PO(NR21R22)(NR23R24)、-C(O)NR21NR22R23or-C (S) NR21NR22R23Wherein R is21、R22、R23And R24Independently of one another, H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or thioacyl, or wherein R21、R22、R23And R24Any two of which taken together with the atom to which they are bound form a heterocycloalkyl group, provided that Z and Z1Not H at the same time;
or Z1And R1Taken together with the atom to which they are bound to form cycloalkyl or heterocycloalkyl, wherein Z1And R1As defined above, but excluding moieties that do not form cycloalkyl or heterocycloalkyl groups;
or Z and Z1Taken together with the atoms to which they are bound to form cycloalkyl or heterocycloalkyl, wherein Z and Z1As defined above, but does not include moieties that cannot form cycloalkyl or heterocycloalkyl groups.
As will be discussed below, these antipicornaviral agents of formula I can be synthesized by subjecting a compound of formula II to an appropriate amide-forming reaction with a compound of formula III. The process of the present invention not only reduces the number of steps required to synthesize the compound of formula III, but more importantly, employs less expensive starting materials and reagents.
These objects, advantages and features of the invention will be more fully understood upon reading the specification.
Detailed description of preferred embodiments of the invention:
in the present application, the following definitions are used:
according to rules adopted in the art, are used in the formulae hereinTo indicate the bond of the moiety or substituent involved to the point of attachment of the core or backbone structure.
When a chiral carbon is included in a chemical structure, both stereoisomeric forms are included unless specific orientation is specified.
"alkyl" means a straight or branched, monovalent, saturated and/or unsaturated group of carbon and hydrogen atoms, such as methyl (Me), ethyl (Et), propyl, isopropyl, butyl (Bu), isobutyl, tert-butyl (t-Bu), ethenyl, pentenyl, butenyl, propenyl, ethynyl, butynyl, propynyl, pentynyl, hexynyl, and the like, which groups may be unsubstituted (i.e., contain only carbon and hydrogen) or substituted with one or more suitable substituents as defined below (e.g., one or more halogens, such as F, Cl, Br or I, preferably F and Cl). "lower alkyl" refers to an alkyl group containing 1 to 4 carbon atoms in its chain.
"cycloalkyl" means a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon ring atoms, which may be saturated or unsaturated, and which may be unsubstituted or substituted with one or more suitable substituents as defined below, and which may be fused to one or more heterocycloalkyl, aryl, or heteroaryl groups, which in turn may be unsubstituted or substituted with one or more substituents. Illustrative examples of cycloalkyl groups include the following groups:
and
"heterocycloalkyl" means a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms including 1,2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen, and sulfur, which may be saturated or unsaturated, and which may be unsubstituted or substituted with one or more suitable substituents as defined below, and which may be fused to one or more cycloalkyl, aryl, or heteroaryl groups, which in turn may be unsubstituted or substituted with one or more suitable substituents. Illustrative examples of heterocycloalkyl groups include the following groups:
and
"aryl" means an aromatic monovalent monocyclic, bicyclic or tricyclic radical containing 6, 10, 14 or 18 carbon atoms, which radical may be substituted or substituted by one or more suitable substituents defined below, and which radical may be fused to one or more cycloalkyl, heterocycloalkyl or heteroaryl radicals, which in turn may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of aryl groups include the following:
and
"heteroaryl" means an aromatic monovalent monocyclic, bicyclic or tricyclic radical containing 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 ring atoms including 1,2, 3, 4 or 5 heteroatoms selected from nitrogen, oxygen and sulfur, which radical may be unsubstituted or substituted by one or more suitable substituents as defined below, and which radical may be fused to one or more cycloalkyl, heterocycloalkyl or aryl radicals, which in turn may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of heteroaryl groups include the following groups:
and
"heterocycle" refers to heteroaryl or heterocycloalkyl (which may each be optionally substituted, as described above).
"acyl" refers to the group-C (O) -R, where R is a substituent as defined below.
"Thioacyl" refers to the group-C (S) -R, wherein R is a substituent as defined below.
"Sulfonyl" means-SO2R groups, wherein R is a substituent as defined below.
"hydroxy" refers to the group-OH.
"amino" refers to the group-NH2。
"alkylamino" refers to the group-NHRaWherein R isaIs an alkyl group.
"dialkylamino" refers to the group-NRaRbWherein R isaAnd RbIndependently of one another, is an alkyl group.
"alkoxy" means a group-ORaWherein R isaIs an alkyl group. Examples of alkoxy groups include methoxy, ethoxy, propoxy, and the like.
"alkoxycarbonyl" refers to the group-C (O) ORaWherein R isaIs an alkyl group.
"alkylsulfonyl" means the radical-SO2RaWherein R isaIs an alkyl group.
"alkylaminocarbonyl" refers to the group-C (O) NHRaWherein R isaIs an alkyl group.
"Dialkylaminocarbonyl" refers to the group-C (O) NRaRbWherein R isaAnd RbIndependently of one another, is an alkyl group.
"mercapto" means the group-SH.
"alkylthio" means the radical-SRaWherein R isaIs an alkyl group.
"carboxy" refers to the group-C (O) OH.
"carbamoyl" refers to the group-C (O) NH2。
"aryloxy" refers to the group-ORcWherein R iscIs an aryl group.
"Heteroaryloxy" means the group-ORdWherein R isdIs a heteroaryl group.
"arylthio" means the radical-SRcWherein R iscIs an aryl group.
"Heteroarylthio" means the radical-SRdWherein R isdIs a heteroaryl group.
"leaving group" (Lv) refers to any suitable group that can be displaced by a substitution reaction. It will be appreciated by those of ordinary skill in the art that any conjugate base of a strong acid may function as a leaving group. Illustrative examples of suitable leaving groups include, but are not limited to, -F, -Cl, -Br, alkyl chlorides, alkyl bromides, alkyl iodides, alkyl sulfonates, alkyl benzene sulfonates, alkyl p-toluene sulfonates, alkyl methanesulfonates, triflates, and any group containing bisulfate, methyl sulfate or sulfonate ions.
Typical protecting groups, reagents and solvents, such as but not limited to those listed in table 1 below, are abbreviated as follows herein and in the claims. Those skilled in the art will appreciate that the compounds listed in the tables may be used interchangeably; for example, the compounds listed under "reagents and solvents" can be used as protecting groups and the like. In addition, other possible protecting groups, reagents and solvents are known to those skilled in the art; these are included in the scope of the present invention.
TABLE 1
Protecting group
Ada adamantane acetyl
Alloc allyloxycarbonyl radical
Allyl Allyl ester
Boc tert-butyloxycarbonyl group
Bzl benzyl radical
Cbz benzyloxycarbonyl
Fmoc fluorenylmethoxycarbonyl
OBzl benzyl ester
OEt ethyl ester
OMe methyl ester
Tos (Tosyl) p-toluenesulfonyl
Trt Triphenylmethyl
Reagents and solvents
ACN acetonitrile
AcOH acetic acid
Ac, sub.20 acetic anhydride
Adacoh adamantane acetic acid
AIBN 2, 2-azobisisobutyronitrile
Alloc-Cl allyloxycarbonyl chloride
BHT 2, 6-di-tert-butyl-4-methylphenol
Boc.sub.20 di-tert-butyl dicarbonate
CDI 1, 1' -carbonyldiimidazole
DIEA diisopropylethylamine
DIPEA N, N-diisopropylethylamine
DMA dimethyl acetamide
DMF N, N-dimethylformamide
DMSO dimethyl sulfoxide
EDTA ethylene diamine tetraacetic acid
Et, sub, 3N Triethylamine
EtOAc ethyl acetate
FDH formate dehydrogenase
FmocOSu 9-fluorenylmethoxycarbonyl N-hydroxysuccinimide ester
HATU N- [ (dimethylamino) -1H-1, 2, 3-triazolo [4, 5-b ] pyri
Picolylmethylene ] -N-methylmethanamine hexafluorophosphate N-oxide
HOBT 1-hydroxybenzotriazole
HF hydrofluoric acid
LDH lactate dehydrogenase
LiHMDS lithium bistrimethylsilylamide
MeOH methanol
Mes (mesyl) methanesulfonyl
MTBE tert-butyl methyl ether
NAD nicotinamide adenine dinucleotide
NADH hydrogen peroxide redox enzyme
NaHMDS sodium bistrimethylsilylamide
NMP 1-methyl-2-pyrrolidone
nin ninhydrin
i-PrOH Isopropanol
Pip piperidine
PPL Lipase
pTSA-p-toluenesulfonic acid monohydrate
Pyr pyridine
TEA Triethylamine
TET triethylenetetramine
TFA trifluoroacetic acid
THF tetrahydrofuran
Triflate (Tf) trifluoromethanesulfonyl
The term "suitable organic moiety" refers to any organic moiety that does not adversely affect the inhibitory activity of the compounds of the present invention, as can be determined by one skilled in the art, for example, by routine experimentation. Illustrative examples of suitable organic moieties include, but are not limited to, hydroxy, alkyl, oxo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl, sulfonyl, mercapto, alkylthio, alkoxy, carboxy, amino, alkylamino, dialkylamino, carbamoyl, arylthio, heteroarylthio, and the like.
The term "substituent" or "suitable substituent" refers to any suitable substituent that can be judged by one skilled in the art, for example, by routine experimentation. Illustrative examples of suitable substituents include hydroxy, halogen, oxo, alkyl, acyl, sulfonyl, mercapto, alkylthio, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxy, amino, alkylamino, dialkylamino, carbamoyl, aryloxy, heteroaryloxy, arylthio, heteroarylthio and the like.
The term "optionally substituted" is used to indicate that the indicated group is unsubstituted or substituted with one or more suitable substituents, and if an optional substituent is specifically indicated, the term indicates that the group is unsubstituted or substituted with the indicated substituent. As defined above, each group can be unsubstituted or substituted (i.e., they are optionally substituted) unless otherwise indicated (e.g., indicating that the group is unsubstituted).
"prodrug" refers to a compound that can be converted under physiological conditions or by solvolysis or metabolism to a particular compound that has pharmaceutical activity.
"pharmaceutically active metabolite" refers to a pharmacologically active product of a particular compound produced in vivo by metabolism.
"solvate" refers to a pharmaceutically acceptable solvate of a given compound that retains the biological potency of the compound. Examples of solvent compounds include combinations of the compounds of the present invention with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
By "pharmaceutically acceptable salt" is meant a salt that retains the biological effectiveness of the free acid or base of the specified compound and does not adversely affect biologically or otherwise. Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, hydroiodide, acetate, propionate, caprate, caprylate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, suberate, caprylate, capryl, Lactate, gamma-hydroxybutyrate, glycolate, tartrate, mesylate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate.
The present invention also provides a method of synthesis comprising one of the synthetic steps listed in the present application. When a synthesis step is at least part of the final synthesis method, then the synthesis method comprises the synthesis step. Thus, the synthesis method may have only one synthesis step, or may also contain additional synthesis steps associated therewith. The synthesis method may contain few additional synthesis steps, or may contain many additional synthesis steps.
If the antipicornaviral agent of formula I produced by the process of the present invention is a base, the desired salt can be prepared by any suitable method known in the art, including subjecting the free base to treatment with a mineral acid such as hydrochloric acid; hydrobromic acid; sulfuric acid; nitric acid; phosphoric acid, or the like, or with an organic acid such as acetic acid; maleic acid; succinic acid; mandelic acid; fumaric acid; malonic acid; pyruvic acid; oxalic acid; glycolic acid; salicylic acid; pyranosyl acids such as glucuronic acid or galacturonic acid; alpha-hydroxy acids such as citric acid or tartaric acid; amino acids, such as aspartic acid or glutamic acid; aromatic acids such as benzoic acid or cinnamic acid; sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid.
If the antipicornaviral agent of formula I produced by the process of the present invention is an acid, the desired salt can be prepared by any suitable method known in the art, including the use of the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary); alkali metal or alkaline earth metal hydroxides, and the like. Illustrative examples of suitable salts include those derived from amino acids such as glycine and arginine; ammonia; primary, secondary and tertiary amines and cyclic amines such as piperidine, morpholine and piperazine derived organic salts; and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
When the compound, salt or solvate thereof is a solid, it will be understood by those skilled in the art that the compounds of formula I and intermediates, salts and solvates thereof used in the process of the invention may exist in different crystalline forms, all of which are included within the scope of the invention and the specified formula.
The antipicornaviral agents of formula I, as well as the intermediates used in the methods of the invention, may exist as individual stereoisomers, racemates and/or mixtures of optical antipodes and/or diastereomers. All such individual stereoisomers, racemates and mixtures thereof are included within the scope of the present invention. However, it is preferred that the intermediate compounds used in the process of the invention are in optically pure form.
It is generally understood by those skilled in the art that optically pure compounds are enantiomerically pure compounds. The term "optically pure" as used herein means that the compound contains at least a sufficient amount of a single enantiomer to provide a compound having the desired pharmacological activity. Preferably "optically pure" means that the compound contains at least 90% of a single isomer (80% enantiomeric excess (hereinafter "e.e.")), more preferably at least 95% (90% e.e.), still more preferably at least 97.5% (95% e.e.), and most preferably at least 99% (98% e.e.). Preferably, the antipicornaviral agent of formula I formed by the method of the present invention is optically pure.
The present invention relates to a process for preparing an anti-picornaviral agent of formula I:
wherein R is1H, F, alkyl, OH, SH or O-alkyl;
R2and R3Independently of one another is H;
or
Wherein n is an integer of 0 to 5, A1Is CH or N, A2And each A3Are independently from each other selected from C (R)41)(R41)、N(R41)、S、S(O)、S(O)2And O, A4Is NH or NR41Wherein each R41Independently of one another, is H or lower alkyl, with the proviso that in the above-mentioned radicals A1、A2、(A3)n、A4And C ═ O, up to two consecutive heteroatoms in the ring, and R2And R3At least one of which is
Or
R4Is that
R5And R6H, F, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, independently of one another;
R7and R8Independently of one another, H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR17、-SR17、-NR17R18、-NR19NR17R18or-NR17OR18Wherein R is17、R18And R19Independently of one another, H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or acyl, with the proviso that R7And R8At least one of which is alkyl, aryl, heteroaryl, -OR17、-SR17、-NR17R18、-NR19NR17R18or-NR17OR18；
R9Is a 5-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, N and S;
z and Z1H, F, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C (O) R21、-CO2R21、CN、-C(O)NR21R22、-C(O)NR21OR22、-C(S)R21、-C(S)NR21R22、-NO2、-SOR21、-SO2R2R21、-SO2NR21R22、-SO(NR21)(OR22)、-SONR21、-SO3R21、-PO(OR21)2、-PO(R21)(R22)、-PO(NR21R22)(OR23)、-PO(NR21R22)(NR23R24)、-C(O)NR21NR22R23or-C (S) NR21NR22R23Wherein R is21、R22、R23And R24Independently of one another, H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or thioacyl, or wherein R21、R22、R23And R24Any two of which taken together with the atom to which they are bound form a heterocycloalkyl group, provided that Z and Z1Not H at the same time;
or Z1And R1Taken together with the atom to which they are bound to form cycloalkyl or heterocycloalkyl, wherein Z1And R1As defined above, but excluding moieties that do not form cycloalkyl or heterocycloalkyl groups;
or Z and Z1Taken together with the atoms to which they are bound to form cycloalkyl or heterocycloalkyl, wherein Z and Z1As defined above, but does not include moieties that cannot form cycloalkyl or heterocycloalkyl groups.
The invention discloses that the compound of formula I can be prepared by reacting a compound of formula II with a compound of formula III to form an amide:
the amide forming reaction may be accomplished by any suitable method, reagents and reaction conditions. Preferably, the various methods disclosed in the' 354 application may be employed. For example, the compound of formula II can be reacted with the compound of formula III in HATU, DIPEA, CH3CN and H2In the presence of O to form the desired compound of formula I. Any suitable purification method may be employed to further purify the compound of formula I.
More preferably, the compound of formula I is prepared by an amide formation reaction comprising the steps of:
(a) reacting a compound of formula II with a compound of formula IIIA in the presence of N-methylmorpholine to form a reaction mixture; then the
(b) Adding a compound of formula Lv-X to the reaction mixture to form a compound of formula I, wherein X is any suitable halide.
Preferably, the more preferred amide formation reaction is used in a process for preparing the compounds of formula I, using some or all of the reagents and reaction conditions disclosed below. Thus, it is preferred to mix the compound of formula II and the compound of formula IIIA in DMF in any suitable vessel. A suitable container is preferably a single-neck flask, which is then covered with any suitable septum and covered with a temperature probe. Before the addition of N-methylmorpholine to the reaction mixture, the appropriate vessel was purged with nitrogen. More preferably, N-methylmorpholine is added in one portion by syringe and the reaction mixture is cooled to about-5 ℃ to 5 ℃. More preferably, the reaction mixture is cooled to about 0 ℃. A solution of a compound of formula Lv-X is then added to the reaction mixture. More preferably, the solution of the compound of formula Lv-X is a DMF solution of the compound of formula Lv-X. Still more preferably the compound of formula Lv-X is CDMT. A solution of the compound of formula Lv-X is added to the reaction mixture by any suitable method to maintain the reaction mixture at a constant temperature. For example, a solution of the compound of formula Lv-X may be added dropwise to the reaction mixture using a syringe. After the end of the addition of the compound of formula Lv-X, the reaction mixture is warmed to about room temperature. The progress of the reaction was monitored by monitoring the disappearance of the compound of formula II by thin layer chromatography (hereinafter referred to as "TLC"). When the reaction is at least substantially complete, the compound of formula I may be precipitated from solution by slowly adding water to the reaction mixture to form a slurry. The compound of formula I may then be isolated from the slurry by any suitable method known to those skilled in the art. For example, the compound of formula I may be isolated from the slurry by filtration. Any suitable purification method known to those skilled in the art may be employed to purify the compound of formula I. More preferably, the compound of formula I is purified by recrystallization.
The invention also discloses two methods for synthesizing the compound of the formula III and the acid addition salt thereof. Of these two methods, the second method is currently preferred because it can be made more cost effective on an industrial scale.
In both methods, the first method is to prepare the compound of formula IV and its acid addition salts from the compound of formula V.
As can be seen by those skilled in the art, the compounds of formula IV are a subgenus of compounds of formula III.
The compound of formula V can be prepared from commercially available gamma-benzyl N-Boc L-glutamate. Any suitable method may be employed to prepare the compounds of formula V. The method disclosed in U.S. patent application No. 08/991,739 is preferably used. U.S. patent application No. 08/991,739 is incorporated herein by reference in its entirety.
The method of the invention comprises the following steps:
(a) cyanomethylation of the compound of formula V with bis (trimethylsilyl) amide and bromoacetonitrile to produce the compound of formula VI;
(b) sequentially reducing, cyclizing and deprotecting a compound of formula VI to produce a compound of formula VII; then the
(c) By reacting a compound with SO3-pyridine complex reaction the compound of formula VII is oxidized and alkylenated to form a reaction mixture, which is then reacted with the phosphorane of formula VIII.
As described above, according to the present invention, the preparation of the compound of formula V from gamma-benzyl N-Boc glutamate can be carried out by any suitable method known in the art.
In addition, cyanomethylation of the compound of formula V can be accomplished using any suitable methods, reagents and reaction conditions. The methods disclosed below are preferred and all or some of the reagents or reaction conditions are used. Thus, the compound of formula V is preferably added dropwise to a stirred THF solution of NaHMDS at-70 ℃ under a nitrogen atmosphere over a period of at least 5 hours, and then mixed with bromoacetonitrile.
Cyanomethylation of the compound of formula V with bis (trimethylsilyl) amide and bromoacetonitrile according to this procedure can produce the compound of formula VI and its epimer in a ratio of 5: 1. However, the compound may be purified by any suitable method. Preferably, the compound of formula VI is purified by filtration followed by chromatography after trituration. Under these preferred conditions, compounds of formula VI can be obtained in an overall yield of 60% with a diastereomeric purity of > 99%.
The three-step reduction, cyclization and deprotection reaction of step (b) to convert a compound of formula VI to a compound of formula VII may be accomplished using any suitable reagents and reaction conditions. Preferably, all or some of the reagents and reaction conditions are used in the methods disclosed below. Thus, the compound of formula VI is preferably reduced by adding cobalt (II) chloride hexahydrate to a tetrahydrofuran/methanol solution of the compound of formula VI. The resulting solution was cooled to 0 ℃ and then sodium borohydride was added portionwise over a period of at least 7 hours. P-toluenesulfonic acid monohydrate was then added to the methanol solution of the crude product and reacted at room temperature for at least about 18 hours. After removal of the solvent, the residue was dissolved in ethyl acetate and washed. Any suitable washing reagent may be used. A preferred washing agent is saturated sodium bicarbonate. An aqueous solution of methanol was then added to the crude product. More preferably, a 2.5% methanol solution is used. The crude product may be isolated from the solution by any suitable method. For example, the crude product can be isolated by filtration and concentration of the filtrate on a rotary evaporator. The product was then dissolved in ethyl acetate, dried, filtered and concentrated to give the crude compound of formula VII. More preferably, the product is dried over magnesium sulfate. The crude compound of formula VII may be further purified by any suitable purification method. More preferably, the crude compound of formula VII is purified by trituration with 1: 1 ethyl acetate and hexane.
If the preferred three-step reduction, cyclization and deprotection reactions disclosed above are employed, the pure compound of formula VII may be obtained in an overall yield of at least about 95%.
In the presence of SO3The oxidation and olefination of the compound of formula VIII to the compound of formula IV using the pyridine complex and the phosphorane of formula VIII may be carried out using any suitable method, reagents and reaction conditions. The methods and all or some of the reagents and reaction conditions disclosed below are preferably employed. Thus, triethylamine is preferably added to the solution of the compound of formula VIII and methyl sulfoxide. The resulting solution was cooled to about 5 ℃ and then sulfur trioxide-pyridine complex was added. The reaction was stirred at about 5 ℃ for at least about 15 minutes. After removing the cooling bath used to cool the solution to about 5 ℃, the reaction solution was stirred for at least about 1 hour. (ethoxycarbonylmethylenetriphenyl) -phosphorane is then added and the reaction mixture is stirred at room temperature for at least about 3 hours. Then, the reaction was quenched with ethyl acetate and extracted. More preferably, the reaction is terminated by adding saturated brine. The combined organic phases are then washed, dried, filtered and concentrated to give the crude compound of formula IV. More preferably, the combined organic phases are washed with saturated brine and then dried over magnesium sulfate.
The compound of formula IV may be purified by any suitable method. Preferably, chromatographic purification and trituration are used. If the preferred purification method is used, yields of 55% to 60% can be achieved.
The second process disclosed in this invention for preparing compounds of formula IV and their acid addition salts comprises the steps of:
(a) carrying out double-anion alkylation reaction on the compound of the formula IX with bromoacetonitrile to generate a compound of the formula X;
(b) hydrogenating the compound of formula X to form an amine of formula XI;
(c) reacting an amine of formula XI with Et3N reacts to generate lactam ester with the formula XII;
(d) reducing the lactam ester of formula XII by a suitable reduction procedure to produce a compound of formula XIII;
(e) oxidizing and alkylenating a compound of formula XIII by reaction with a compound of formula XV to produce a compound of formula XIV; then the
(f) Converting the compound of formula XIV to a compound of formula IV.
Furthermore, it will be appreciated by those skilled in the art that the methods disclosed above may be used to prepare compounds of formula XIV. In particular, steps (a) - (e) disclose a process for preparing a compound of formula XIV.
The compound of formula IX may be prepared by any suitable method known in the art. For example, N-Boc L- (+) -glutamic acid dimethyl ester can be prepared from commercially available L-glutamic acid dimethyl ester hydrochloride or commercially available L-glutamic acid 5-methyl ester according to the literature methods. See, e.g., Shimamoto et al, J.org.chem.1991, 56, 4167 and Duralski et al, Tetrahedron Lett.1998, 30, 3585. These references are incorporated herein by reference in their entirety.
Preferably, the dianionic alkylation reaction is prepared using the methods and all or some of the reagents and reaction conditions disclosed below. Thus, the compound of formula IX is preferably first dissolved in THF to form a solution which is then added dropwise to a stirred solution of LiHMDS at-78 ℃ under an argon atmosphere. The resulting mixture was stirred at about-78 ℃ for 2 hours, and then freshly distilled bromoacetonitrile was added dropwise over 1 hour. The reaction mixture was stirred for an additional 2 hours at about-78 ℃. The reaction was then terminated. More preferably by adding 0.5M HCl and H2And O stops the reaction. The aqueous layer formed was separated and further extracted with methyl tert-butyl ether. The combined organic extracts were washed, dried and then filtered. More preferably, the organic extract is washed with saturated sodium bicarbonate and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure.
The compound of formula IX can be hydrogenated to the amine of formula XI by any suitable method known in the art. The hydrogenation reaction is preferably carried out in the presence of 5% Pd/C. More preferably, the hydrogenation reaction is carried out according to the methods disclosed below using some or all of the reagents and reaction conditions. According to this preferred hydrogenation process, the compound of formula IX is dissolved in HOAc and shaken with 5% Pd/C under a hydrogen pressure of 50psi for 3 days. The mixture was then filtered through celite. The filtrate may then be evaporated under reduced pressure and the residue repeatedly evaporated from methyl tert-butyl ether.
Amines of formula XI with Et3The reaction of N can be accomplished using any suitable conditions. The method disclosed below is preferably employedAnd all or some of the reagents and reaction conditions. Thus, preferably, the amine of formula XI is dissolved in a 1: 1 MeOH/THF mixture, and Et is added to the solution3And N is added. The resulting mixture was stirred at about 45 ℃ for about 10 hours or until the starting material disappeared. Can pass through1HNMR monitors the presence of feedstock. After the solvent was distilled off, methyl t-butyl ether was added. The precipitate is then filtered off. To the filtrate diluted with water was added 0.5M HCl. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed, dried, filtered and concentrated. More preferably, the combined organic phases are washed with brine and then dried over magnesium sulfate. The organic phase can be concentrated on a rotary evaporator. Flash chromatography gives the lactam ester of formula XII.
Any suitable reduction method may be employed to convert the lactam ester of formula XII to the compound of formula XIII. LiBH is preferably used4As a reducing agent. More preferably, the methods disclosed below or a portion thereof, as well as any or all of the reagents and reaction conditions, are employed. Thus, more preferably, LiBH is added4To a stirred solution of the lactam ester of formula XII in THF. Reacting LiBH4The addition was carried out in portions under argon at 0 ℃. The reaction mixture was stirred at 0 ℃ for 10 minutes, then warmed to room temperature and stirred for an additional 2 hours. The reaction was then terminated. More preferably, the reaction is terminated by the dropwise addition of 0.5M HCl under ice bath cooling. The solution was taken up with ethyl acetate and H2And (4) diluting with oxygen. After phase separation, the aqueous phase may be extracted with ethyl acetate. The combined organic layers were washed, dried, filtered and concentrated. More preferably, the combined organic phases are washed with brine and dried over magnesium sulfate. The organic phase can be concentrated on a rotary evaporator. Flash chromatography gives the compound of formula XII.
The compounds of formula XIV can be prepared from compounds of formula XIII using any suitable oxidation and olefination methods. It is preferred to employ the methods disclosed below or a portion thereof, as well as all or some of the reagents and reaction conditions. Thus, according to the invention, benzoic acid, (ethoxycarbonylmethylenetriphenyl) phosphorane and DMSO are added to a solution of the compound of formula XIII in dichloromethane. Dess-Martin p is added to the solution in several portionseriodinane and the reaction mixture is then stirred at room temperature for at least 5 hours until the compound of formula XIII is substantially disappeared. Can pass through1H NMR monitored the presence of the compound of formula XIII. Saturated sodium bicarbonate solution was added and the mixture was stirred for 30 minutes to form a precipitate. The precipitate is filtered off, and the organic phase of the filtrate is separated, washed and then concentrated to give the crude compound of formula XIV. More preferably, the filtrate is washed with brine and then concentrated on a rotary evaporator. The crude compound of formula XIV can be purified by any suitable method. More preferably, the crude compound of formula XIV is purified by flash chromatography and then dissolved in ethyl acetate. Then, an excess of hexane was gradually added to the stirred solution to form a precipitate. The precipitate is filtered off and then dried to give the compound of formula XIV. More preferably, the precipitate is dried in a vacuum oven for at least about 12 hours.
The following examples are provided only for illustrating the present invention and should not be construed as limiting the scope of the present invention as defined by the appended claims.
Example (b):
examples of amide formation reactions between two compounds falling within the scope of formula II and formula III for the preparation of compounds of formula I are illustrated below. In particular, the example described in reaction scheme 1 below illustrates the reaction between 1 and 2 for the preparation of the protease inhibitor AG 7088.
Reaction scheme 1
The following examples disclose the preparation of compound 1 included within the scope of the compounds of formula IV. The first example (as shown in reaction scheme 2 below) illustrates the above disclosed route using the cyanomethylation reaction. A second example (as shown in reaction scheme 3 below) illustrates a second more preferred economically efficient route for preparing the same compound.
Reaction scheme 2
Reaction scheme 3
4 (reaction scheme 2)
A solution of 3(1.0kg, 2.34mol, 1.0 eq) in THF (8.0L) was added dropwise over a period of 5 hours under a nitrogen atmosphere at-70 deg.C to a stirred solution of NaHMDS in THF (1M in THF, 2.96L, 1.28 eq). The resulting solution was stirred at-70 ℃ for 0.5 h, then freshly distilled bromoacetonitrile (320mL, 2.0 equiv.) was added dropwise over a period of 25 min. The reaction mixture was stirred at-70 ℃ for 1 hour until starting material 3 disappeared. The reaction was terminated by adding a saturated ammonium chloride solution (7.0L), and extracted with methyl t-butyl ether (24L). The organic phase was washed with brine (3X 6.0L). The solvent was distilled off under reduced pressure to give a dark brown oil (1.5 kg). The crude product was dissolved in dichloromethane (8.0L) and then passed through a bed of silica gel (600g) and activated carbon (250 g). After rinsing the filter cake with dichloromethane (4.0L), the filtrate was concentrated on a rotary evaporator to give a light brown oil (1.28Kg) which was then dissolved in ethyl acetate (2.5L). To the resulting solution was added excess hexane (14.5L) with vigorous stirring, and a white solid precipitated within 30 minutes. The slurry was cooled in an ice water bath and stirred for 4.5 hours, then filtered to give 4 as a light brown solid (662g, 60%):1H NMR(CDCl3)δ1.46(s，3H)，1.49(s，9H)，1.59(s，3H)，1.75-1.95(m，1H)，2.15-2.31(m，1H)，2.55-3.15(m，3H)，3.36(d，J＝10.8Hz，1H)，3.62-4.10(m，3H)，4.13-4.32(m，3H)，4.70(m，1H)，7.15-7.42(m，5H)。
preparation of 6 (reaction scheme 3)
Compound 6 was prepared from L-glutamic acid dimethyl ester hydrochloride (commercially available from Lancaster) or L-glutamic acid 5-methyl ester (commercially available from Aldrich) according to methods described in the literature.
Preparation of 7 (reaction scheme 3)
A solution of N-Boc L- (+) -glutamic acid dimethyl ester (6, 10g, 36.3mmol, 1 eq) in THF (100mL) was added dropwise to a stirring solution of LiHMDS (77mL, 1M in THF, 77.0mmol, 2.1 eq) at-78 deg.C under argon. The resulting dark mixture was stirred at-78 ℃ for 2 hours, then freshly distilled bromoacetonitrile (13.1g, 109.0mmol, 3 equiv.) was added dropwise over a period of 1 hour. The reaction mixture was stirred at-78 ℃ for 2 hours and the disappearance of starting material (6) was confirmed by TLC analysis. HCl (120mL, 0.5M) and H were added2The reaction was stopped with O (200 mL). The layers were separated and the aqueous layer was extracted with methyl tert-butyl ether (3X 200 mL). The combined organic extracts were washed with saturated sodium bicarbonate (2X 250mL) and brine (2X 250mL), dried over magnesium sulfate and filtered. The solvent was distilled off under reduced pressure to give a brown oil (15.2 g). Flash chromatography on silica gel (3: 1 hexane/ethyl acetate) afforded a colorless oil (7, 6.67g, 10.8mmol, 58%):1H NMR(CDCl3)δ1.46(s，9H)，2.12-2.24(m，2H)，2.77-2.82(m，2H)，2.85-2.91(m，1H)，3.78(s，3H)，3.79(s，3H)，4.32-4.49(m，1H)，5.13(d，J＝6.0Hz，1H)；13CNMR(CDCl3)δ19.4，28.6，34.3，38.6，49.8，53.1，80.9，117.5，155.9，172.4，172.8；HRMS m/z 314.1481(C12H22N2O4calculated value of 314.1486).
Preparation of 8 (reaction scheme 3)
Compound 7(4.60g, 14.6mmol) was dissolved in HOAc (120mL) and shaken with 5% Pd/C (20g) under a hydrogen atmosphere (50psi) for 3 days. The mixture was filtered through celite. The filtrate was evaporated under reduced pressure and the residue was repeatedly evaporated from methyl tert-butyl ether to give a pale pink solid (8, 8.32g) which was used directly in the subsequent step.1H NMR(CD3OD)δ1.47(s，9H)，1.85-2.10(m，4H)，2.60-2.62(m，1H)，2.92-2.96(m，2H)，3.74(s，3H) 3.77(s, 3H), 4.22-4.26(m, 1H); note: experiments have shown that less than 5% Pd/C allows the reaction to be completed, i.e. 1g of 5% Pd/C effectively reduces 2g of 7.
Preparation of 9 (reaction scheme 3)
Crude 8 was dissolved in 1: 1 MeOH/THF (40mL) and Et was added to the solution3N (7 mL). The resulting mixture was stirred at 45 ℃ for 10 hours until it passed1Disappearance of starting material was monitored by H NMR. After evaporation of the solvent on a rotary evaporator, methyl tert-butyl ether (200mL) was added and a white solid precipitated. The solid precipitate was removed by filtration. The filtrate was taken up in 200mL of H2O diluted and then 0.5M HCl (5mL) was added. The phases were separated and the aqueous phase was extracted with ethyl acetate (4X 200 mL). The combined organic phases were washed with brine (2 × 700mL), dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to give a light brown oil. Flash chromatography gave a white solid (9, 2.5g, 8.74mmol, 60%):1H NMR(CDCl3)δ1.37(s，9H)，1.75-1.80(m，2H)，2.04-2.09(m，1H)，2.39-2.42(m，2H)，3.25-3.29(m，2H)，3.67(s，3H)，4.23-4.26(m，1H)，5.47(d，J＝8.0Hz，1H)，6.29(s，1H)；13C NMR(CDCl3)δ28.5，28.6，34.5，38.5，40.7，52.7，52.8，80.3，156.1，173.3，180.0；HRMS m/z286.1564(C13H22N2O5calculated value of 286.1587).
Preparation 5 from 4 (reaction scheme 2)
To a solution of 4(400g, 0.85mol, 1 eq) in tetrahydrofuran (3.0L) was added a solution of cobalt (II) chloride hexahydrate (200g, 0.85mol, 1 eq) in methanol (3.0L). The resulting solution was cooled to 0 ℃ and sodium borohydride (130g, 3.51mol, 4.4 equiv.) was added portionwise over a period of 7 hours. The reaction mixture was warmed to room temperature and stirred for 20 hours while monitoring the disappearance of the starting material (4) by TLC. The reaction was cooled to 0 ℃ and quenched by the addition of 1.0M HCl (14L) and ethyl acetate (12L). The phases were separated and 2.0kg of sodium chloride and 4.0L of ethyl acetate were added to the aqueous phase. The phases were separated and the organic phases were combined, washed with brine (1X 3.0L) and concentrated on a rotary evaporator to give the crude material (440g) which was used directly in the subsequent hydrolysis reaction. To a solution of the crude material (440g, 1 eq) in methanol (800mL) was added p-toluenesulfonic acid monohydrate (4.0g, 0.015 eq). The reaction solution was stirred overnight at room temperature. The solvent was evaporated on a rotary evaporator and the residue was dissolved in ethyl acetate (2.0L) and washed with saturated sodium bicarbonate (2 × 100 mL). The combined aqueous phases were extracted with ethyl acetate (2X 200 mL). All organic phases were combined and concentrated on a rotary evaporator to give 275g of crude product, to which was added a solution of 2.5% methanol (20mL) (780mL) and stirred at room temperature overnight. The particulate solid (chiral auxiliary) was removed by filtration and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in ethyl acetate (1.5L), dried over magnesium sulfate, filtered and concentrated to give a viscous oil. The oil was triturated with 1: 1 ethyl acetate (1L) and hexane (1L) to give 5 as a white solid (104g, 47% total yield from 4).
Preparation 5 from 9 (reaction scheme 3)
To a stirred solution of 9(1.75g, 6.10mmol) in THF (40mL) at 0 deg.C under argon was added LiBH several times4(270mg, 12.2mmol, 2 equiv.). The reaction mixture was stirred at 0 ℃ for 10 minutes, then warmed to room temperature and stirred for an additional 2 hours. The reaction was stopped by the dropwise addition of 0.5M HCl (24mL) with ice bath cooling (note: gas evolution was observed). The solution was taken up in ethyl acetate (100mL) and H2Dilution with O (50 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (6X 150 mL). The combined organic phases were dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to give a light brown oil. Flash chromatography gave a white solid (5, 1.308g, 5.06mmol, 83%):1H NMR(CDCl3)δ1.46(s，9H)，1.61-1.67(m，1H)，1.82-1.91(m，1H)，1.94-2，00(m，1H)，2.43-2.48(m，1H)，2.49-2.55(m，1H)，3.32-3.34(m，3H)，3.58-3.66(m，2H)，3.68-3.79(m，2H)，5.47(d，J＝7.0Hz，1H)，6.24(s，1H)；13C NMR(CDCl3)δ28.8，32.9，38.4，40.8，51.5，66.3，79.8，157.0，181.3；HRMS m/z 258.1652(C13H22N2O5calculated value of (D), 258.1650)。
Preparation of 1 from 5
Method A (reaction scheme 2)
To a solution of 5(50.0g, 0.184mol, 1 eq) in methyl sulfoxide (500mL) was added triethylamine (116 mL). The resulting solution was cooled to 5 ℃ with an ice bath, and sulfur trioxide-pyridine complex (132g) was then added. The reaction solution was stirred at this temperature for 15 minutes. The cooling bath was removed and the reaction was stirred for an additional 1 hour. (ethoxycarbonylmethylenetriphenyl) -phosphorane (112g) was added in one portion and the reaction was stirred at room temperature for 3 hours. The reaction was quenched by the addition of saturated brine (3.0L) and extracted with ethyl acetate (3X 1.5L). The combined organic phases were washed with saturated brine (3 × 1.5L), dried over magnesium sulfate, filtered and concentrated to a dark red oil. The oil was purified by chromatography, then triturated with ethyl acetate (60mL) and excess hexane (240 mL). 1(36.0g, 60%) was obtained as a white solid.
Method B (reaction scheme 3)
To a solution of 5(1.0g, 3.87mmol, 1 eq) in dichloromethane (80mL) was added benzoic acid (1.89g, 15.5mmol, 4 eq), (ethoxycarbonylmethylenetriphenyl) phosphorane (5.39g, 15.5mmol, 4 eq) and DMSO (4.8 mL). Dess-Martin periodinane (4.1g, 9.17mmol, 2.5 equiv.) was added to the solution in several portions, and then the reaction mixture was stirred at room temperature for 5 hours until the starting material 5 disappeared. Saturated sodium bicarbonate was added and the mixture was stirred for 30 minutes. A white solid precipitated and was filtered off. The organic phase of the filtrate was separated, washed with brine (250mL) and then concentrated on a rotary evaporator to give a brown oil which was purified by flash chromatography to give a light brown foam (0.956 g). The foam was dissolved in ethyl acetate (3 mL). To the stirred solution was gradually added an excess of hexane (12mL) and a white solid precipitated. The solid was filtered and then dried in a vacuum oven overnight to give 1(0.69g, 2.11mmol, 55%). Chiral HPLC: 97% pure, 98% de and 100% E isomer;1H NMR(CDCl3)δ1.22(t，J＝7.2Hz，3H)，1.38(s，9H)，1.53-1.58(m，1H)，1.66-1.84(m，1H)，1.85-2.00(m，1H)，2.30-2.50(m，2H)，3.20-3.37(m，2H)，4.13(q，J＝7.2Hz，2H)，4.20-4.35(m，1H)，5.13(d，J＝7.5Hz，1H)，5.68(s，1H)，5.90(dd，J＝1.8，15.6Hz，1H)，6.80(dd，J＝5.1，15.6Hz，1H)；HRMS m/z 326.1846(C16H26N2O6calculated value of 326.1840).
AG7088 was prepared from 1 and 2 (reaction scheme 1).
751mg of Compound 1 was dissolved in DCM (10mL/g of 1) in a single-neck round-bottom flask and then covered with a septum. The flask was then purged with nitrogen and then 1.4mL TFA was added via syringe while the solution was stirred. The progress of the reaction was monitored by TLC with 5% MeOH in DCM until after about 4 hours the starting material disappeared. The solvent and excess TFA were distilled off in vacuo at a pressure of < 50mTorr @45 ℃. The product compound 1A was used immediately in the following procedure.
Compounds 1A and 2 were dissolved in DMF (7mL/g of 2) in a single-necked round-bottomed flask covered with a septum and equipped with a temperature probe. The flask was purged with nitrogen. The resulting solution was divided into two portions. To the first portion was added 1.6mL of N-methylmorpholine by syringe and then cooled to 0 ℃. + -. 5 ℃. 281mg of CDMT were dissolved in the second solution. The CDMT solution was then added dropwise to the first portion of solution via syringe, maintaining the reaction temperature at 0 ℃ ± 5 ℃. The resulting reaction mixture was then warmed to room temperature. The reaction was monitored by TLC (7: 3: 1 hexanes: EtOAc: IPA) for about 1 hour until disappearance of Compound 2. After the reaction was complete, the product AG7088 was precipitated from solution by slowly adding water to the reaction mixture. The resulting slurry was filtered to give > 85% white granulated crystals of compound AG7088 with a purity of > 97%. The product can then be recrystallized by dissolving in hot MeOH/EtOAc 1: 1 followed by slow addition of hexane (2 volumes).
It is to be understood that the foregoing description is intended to be exemplary and explanatory and is intended to illustrate the invention and preferred embodiments thereof. Obvious modifications and variations, without departing from the spirit of the invention, can be ascertained by one skilled in the art through routine experimentation. Accordingly, the invention is not to be seen as limited by the foregoing description, but is only limited by the scope of the appended claims.

Claims (4)

1. A method of synthesizing a compound of formula IA' or an acid addition salt thereof:
the method comprises the following steps:
step A: preparation of a compound of formula IV':
the method comprises the following steps:
(a) cyanomethylation of the compound of formula V with sodium bis (trimethylsilyl) amide and bromoacetonitrile to produce the compound of formula VI';
(b) sequentially reducing, cyclizing and deprotecting the compound of formula VI 'to produce a compound of formula VII'; then the
(c) By reacting a compound with SO3-pyridine complex, and then reacting the reaction mixture formed with Ph3P＝CHCO2Et reaction oxidizes and alkylenates the compound of formula VII';
and B: deprotecting a compound of formula IV 'to produce a compound of formula IVA':
and
and C: subjecting the compound of formula II 'and the compound of formula IVA' to an amide forming reaction
2. A method of synthesizing an anti-picornaviral compound, comprising:
(a) carrying out double anion alkylation reaction on the compound of the formula IX 'by using bromoacetonitrile to prepare a compound of a formula X';
(b) hydrogenating the compound of formula X 'to form an amine of formula XI';
(c) combining formula XIProduct and Et3N to produce a lactam ester of formula XII';
(d) reducing the lactam ester of formula XII 'to produce a compound of formula XIII':
and
(e) passing a compound of formula XIII' through Ph3P＝CHCO2The Et reaction is oxidized and then olefinated to produce the compound of formula XIV'.
3. The method of synthesizing an antipicornaviral compound of claim 2, further comprising:
converting the compound of formula XIV 'to a compound of formula IV'.
4. The method of synthesizing an antipicornaviral compound of claim 3, further comprising:
step A: deprotecting a compound of formula IV 'to produce a compound of formula IVA':
and
and C: subjecting the compound of formula II 'and the compound of formula IVA' to an amide forming reaction.
HK03101461.5A 1999-08-24 2000-08-23 Synthetic routes for the preparation of rhinovirus protease inhibitors and key intermediates HK1049336B (en)

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IL138609A0 (en) 1998-04-30 2001-10-31 Agouron Pharma Antipicornaviral compounds, their preparation and use
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PE20020157A1 (en) 1999-12-03 2002-02-22 Agouron Pharma PYRIDONE DERIVED COMPOUNDS AS PICORNAVIRAL 3C PROTEASE INHIBITORS, COMPOSITIONS, THEIR PHARMACEUTICAL USES AND MATERIALS FOR THEIR SYNTHESIS
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US20230157998A1 (en) 2020-03-06 2023-05-25 Pfizer Inc. Methods of Inhibiting SARS-CoV-2 Replication and Treating Corona Virus Disease 2019
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