CN1168713C - Synthetic reoutes for the preparation of rhionvirus protease inhibitor and key intermediates - Google Patents

Synthetic reoutes for the preparation of rhionvirus protease inhibitor and key intermediates Download PDF

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CN1168713C
CN1168713C CNB008118779A CN00811877A CN1168713C CN 1168713 C CN1168713 C CN 1168713C CN B008118779 A CNB008118779 A CN B008118779A CN 00811877 A CN00811877 A CN 00811877A CN 1168713 C CN1168713 C CN 1168713C
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CN1374947A (en
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田清平
N·K·奈亚
S·巴布
��Ī������
陶军华
��˹��ŵ��
T·J·莫兰
С��׳
R·小达尼诺
L·J·小米彻尔
÷
T·P·雷马楚克
M·J·梅尔尼克
S·L·本德
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    • 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
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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

The synthetic route and the crucial intermediate of preparation rhinovirus proteinase inhibitor
Relevant application materials:
The application relates to U.S. Provisional Patent Application number 60/150,358, and its applying date is on August 24th, 1999.
The application also relates to U.S. Provisional Patent Application number 60/150,365 (lawyer's file number 0125.0027), and its applying date is similarly on August 24th, 1999, denomination of invention is " effective ways of preparation rhinovirus proteinase inhibitor; be used to prepare the key intermediate and the continuous film reactor of this inhibitor ", and invention is artificial: J.Tao, S.Babu, R.Dagnino, Jr., Q.Tian, T.Remarchuk, K.McGee, N.Nayyar and T.Moran.Above-mentioned application also relates to used key intermediate in the synthetic route of preparation rhinovirus proteinase inhibitor and the preparation thereof.The application is based on above-mentioned application and be introduced in the literary composition as a reference.
Technical field of the present invention and industrial applicibility:
The present invention relates to improved preparation ethyl-3-{ (5 '-methyl-isoxazole-3 '-carbonyl)-L-Val ψ (COCH 2)-L-(4-F-Phe)-L-((S)-pyrroles-Ala) }-method of E-propionic ester (being also referred to as AG7088), its analogue and pharmacologically acceptable salt thereof.The present invention also comprises the one group of new key intermediate that is used for aforesaid method.
Background of invention:
Picornavirus be gang can infected person and the small nonencapsulated normal chain of other animal contain RNA viruses.These viruses comprise ERC group virus, human poliovirus, human coxsackievirus, human echovirus, people and bovine enteroviruses, encephalomyocarditis virus, meningitis virus, foot and oral cavity virus, hepatitis A virus (HAV) etc.ERC group virus is the major cause of common cold.
The natural maturity of picornavirus needs protelytic 3C enzyme.Therefore, the activity that suppresses these protelytic 3C enzymes represented a kind of important and useful treatment and cure this character virus infection, comprise the method for common cold.
Recent findings the micromolecular inhibitor (being the compound of antipicornaviral) of enzymic activity of some picornavirus 3c proteolytic enzyme.Referring to, for example Application No. 08/850,398, submitted on May 2nd, 1997 by people such as Webber; Application No. 08/991,282 is submitted on December 16th, 1997 by people such as Dragovich; With Application No. 08/991,739, submit on December 16th, 1997 by people such as Webber.These U.S. Patent applications have been described the compound and the synthetic method thereof of some antipicornaviral, and these apply for that disclosed content is incorporated herein by reference.
Recently, Application No. 60/098,354 (' 354 applications of being submitted on August 28th, 1998 by people such as Dragovich) disclose a kind of especially effectively antipicornaviral agent in, this application is incorporated herein by reference.This application discloses the antipicornaviral agent of one group of general formula I.Comprising a kind of promising especially compound, AG7088, this compound shows splendid ntiviral characteristic to multiple rhinovirus serotype, is carrying out human clinical trials at present.' 354 application also discloses method and the intermediate that is used for synthetic these compounds.For example, general method V wherein discloses the general method of synthetic compound of formula i, and this method comprises reaction that the amine with the carboxylic acid of Formula B B and general formula P forms acid amides to obtain final product C C, and is as follows.
' 354 application also discloses the method for the intermediate of synthetic Formula B B and P, and has instructed the method for carrying out the reaction of above-mentioned formation acid amides.Therefore, ' 354 applications have instructed compound from carboxylic acid BB (within the scope of the general formula I I of the following stated compound) and general formula P (identical with the compound of the general formula III of the following stated) to synthesize the proper method of compound of Formula I.Equally, two parts of nearest publications of people such as Dragovich also disclose antipicornaviral agent and suitable synthetic method thereof.Referring to " irreversible ERC group virus 3C proteinase inhibitor be Base Design, synthetic and biological assessment with the structure.3. the structure-activity of the peptide mimics of ketone group containing methylene radical research ", Dragovich etc., Journal of MedicinalChemistry, ASAP, 1999; " irreversible ERC group virus 3C proteinase inhibitor be Base Design, synthetic and biological assessment with the structure.4. mix P 1The lactan part is as the surrogate of L-glutamine ", Dragovich etc., Journal of MedicinalChemistry, ASAP, 1999.Above-mentioned article is incorporated herein by reference in full.
But, still need to develop improved, the more efficient methods and the new intermediate that are used for synthetic antipicornaviral agent.Specifically, the method that needs improved synthetic general formula I I and III compound.
Summary of the invention:
The present invention relates to the antipicornaviral agent of preparation formula I, economy, the effective means of for example compd A G7088 and the intermediate that is used for this synthetic method.
The antipicornaviral agent of formula I comprises:
Figure C0081187700081
R wherein 1Be H, F, alkyl, OH, SH or O-alkyl;
R 2And R 3Be H independently of one another;
Or
Wherein n is 0 to 5 integer, A 1Be CH or N, A 2With each A 3Be independently from each other C (R 41) (R 41), N (R 41), S, S (O), S (O) 2And O, A 4Be NH or NR 41, each R wherein 41Be H or low alkyl group independently of one another, condition is by A above-mentioned 1, A 2, (A 3) n, A 4In the ring that forms with C=O two successive heteroatomss are arranged at the most, and R 2And R 3In have at least one to be
Figure C0081187700091
Or
R 4Be
Figure C0081187700093
R 5And R 6Be H, F, alkyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl independently of one another;
R 7And R 8Be independently of one another H, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-OR 17,-SR 17,-NR 17R 18,-NR 19NR 17R 18Or-NR 17OR 18, R wherein 17, R 18And R 19Be H, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl or acyl group independently of one another, condition is R 7And R 8In have at least one be alkyl, aryl, heteroaryl ,-OR 17,-SR 17,-NR 17R 18,-NR 19NR 17R 18Or-NR 17OR 18
R 9Be to contain 1 to 3 heteroatomic 5 yuan of heterocycle that are selected from O, N and S;
Z and Z 1Be independently of one another H, F, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-C (O) R 21,-CO 2R 21, CN ,-C (O) NR 21R 22,-C (O) NR 21OR 22,-C (S) R 21,-C (S) NR 21R 22,-NO 2,-SOR 21,-SO 2R 21,-SO 2NR 21R 22,-SO (NR 21) (OR 22) ,-SONR 21,-SO 3R 21,-PO (OR 21) 2,-PO (R 21) (R 22) ,-PO (NR 21R 22) (OR 23) ,-PO (NR 21R 22) (NR 23R 24) ,-C (O) NR 21NR 22R 23Or-C (S) NR 21NR 22R 23, R wherein 21, R 22, R 23And R 24Be H, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, acyl group or sulfo-acyl group independently of one another, perhaps R wherein 21, R 22, R 23And R 24In any two with their institute's bonded atoms lump together the formation Heterocyclylalkyl, condition is Z and Z 1Be not H simultaneously;
Perhaps Z 1And R 1Lump together formation cycloalkyl or Heterocyclylalkyl, wherein Z with their institute's bonded atoms 1And R 1As defined above, but do not comprise the part that can not form cycloalkyl or Heterocyclylalkyl;
Perhaps Z and Z 1Lump together formation cycloalkyl or Heterocyclylalkyl, wherein Z and Z with their institute's bonded atoms 1As defined above, but do not comprise the part that can not form cycloalkyl or Heterocyclylalkyl.
Just as will be discussed, the reaction that can carry out suitable formation acid amides by the compound with the compound of general formula I I and general formula III of the antipicornaviral agent of these formulas I is synthesized.Method of the present invention has not only reduced the required number of steps of synthetic formula III compound, and what is more important, has also adopted comparatively cheap raw material and reagent.
By reading specification sheets, can more fully understand these purposes of the present invention, advantage and characteristics.
The detailed description of the preferred embodiment of the invention:
In this application, used as giving a definition:
According to the rule that adopt this area, in the structural formula of this paper, use
Figure C0081187700101
The key of representing the tie point of related part or substituting group and core or skeleton structure.
When comprising chiral carbon in the chemical structure, do not indicate concrete orientation if having, then comprise two kinds of stereoisomer forms simultaneously.
" alkyl " is meant the saturated and/or unsaturated group of monovalence of the straight or branched of carbon atom and hydrogen atom, for example methyl (Me), ethyl (Et), propyl group, sec.-propyl, butyl (Bu), isobutyl-, the tertiary butyl (t-Bu), vinyl, pentenyl, butenyl, propenyl, ethynyl, butynyl, proyl, pentynyl, hexin base etc., these groups can be unsubstituted (promptly, only carbon containing and hydrogen) or by one or more following defined suitable substituting groups (for example, one or more halogens, for example F, Cl, Br or I, preferred F and Cl) replace." low alkyl group " is meant the alkyl that contains 1 to 4 carbon atom in its chain.
" cycloalkyl " is meant the monocyclic, bicyclic or tricyclic group of nonaromatic monovalence that contains 3,4,5,6,7,8,9,10,11,12,13 or 14 carboatomic ring atoms, this group can be saturated or undersaturated, and can be unsubstituted or replaced by one or more following defined suitable substituting groups, and this group can with one or more Heterocyclylalkyls, aryl or heteroaryl-condensed, these Heterocyclylalkyls, aryl or heteroaryl itself can be again unsubstituted or be replaced by one or more substituting group.The illustrative example of cycloalkyl comprises following group:
Figure C0081187700111
Figure C0081187700112
With
" Heterocyclylalkyl " is meant and contains 3,4,5,6,7,8,9,10,11,12,13,14,15,16,17 or 18 annular atomses, comprising 1,2,3,4 or 5 are selected from nitrogen, the heteroatomic nonaromatic monovalence monocycle of oxygen and sulphur, two ring or three cyclic groups, this group can be saturated or undersaturated, and can be unsubstituted or replaced by one or more following defined suitable substituting groups, and this group can with one or more cycloalkyl, aryl or heteroaryl-condensed, these cycloalkyl, aryl or heteroaryl itself can be again unsubstituted or be replaced by one or more suitable substituting groups.The illustrative example of Heterocyclylalkyl comprises following group:
Figure C0081187700115
With
Figure C0081187700116
" aryl " is meant the monocyclic, bicyclic or tricyclic group of aromatic series monovalence that contains 6,10,14 or 18 carbon atoms, that this group can replace or replaced by one or more following defined suitable substituting groups, and this group can with one or more cycloalkyl, Heterocyclylalkyl or heteroaryl-condensed, these cycloalkyl, Heterocyclylalkyl or heteroaryl itself can be again unsubstituted or be replaced by one or more suitable substituting groups.The illustrative example of aryl comprises following group:
With
Figure C0081187700122
" heteroaryl " is meant and contains 4,5,6,7,8,9,10,11,12,13,14,15,16,17 or 18 annular atomses, comprising 1,2,3,4 or 5 are selected from nitrogen, the monovalence monocycle of the heteroatomic aromaticity of oxygen and sulphur, two ring or three cyclic groups, this group can be unsubstituted or be replaced by one or more following defined suitable substituting groups, and this group can with one or more cycloalkyl, Heterocyclylalkyl or aryl-condensed, these cycloalkyl, Heterocyclylalkyl or aryl itself can be again unsubstituted or be replaced by one or more suitable substituting groups.The illustrative example of heteroaryl comprises following group:
Figure C0081187700123
Figure C0081187700131
Figure C0081187700132
With
" heterocycle " is meant heteroaryl or Heterocyclylalkyl (as mentioned above, it all can optionally be substituted).
" acyl group " is meant-C (O)-R group, and wherein R is following defined substituting group.
" sulfo-acyl group " is meant-C (S)-R group, and wherein R is following defined substituting group.
" alkylsulfonyl " is meant-SO 2The R group, wherein R is following defined substituting group.
" hydroxyl " is meant group-OH.
" amino " is meant group-NH 2
" alkylamino " is meant group-NHR a, R wherein aIt is alkyl.
" dialkyl amido " is meant group-NR aR b, R wherein aAnd R bBe alkyl independently of one another.
" alkoxyl group " is meant group-OR a, R wherein aIt is alkyl.The example of alkoxyl group comprises methoxyl group, oxyethyl group, propoxy-etc.
" alkoxy carbonyl " is meant group-C (O) OR a, R wherein aIt is alkyl.
" alkyl sulphonyl " is meant group-SO 2R a, R wherein aIt is alkyl.
" alkyl amino-carbonyl " is meant group-C (O) NHR a, R wherein aIt is alkyl.
" dialkyl amino carbonyl " is meant group-C (O) NR aR b, R wherein aAnd R bBe alkyl independently of one another.
" sulfydryl " is meant group-SH.
" alkylthio " is meant group-SR a, R wherein aIt is alkyl.
" carboxyl " is meant group-C (O) OH.
" formamyl " is meant group-C (O) NH 2
" aryloxy " is meant group-OR c, R wherein cIt is aryl.
" heteroaryloxy " is meant group-OR d, R wherein dIt is heteroaryl.
" arylthio " is meant group-SR c, R wherein cIt is aryl.
" heteroarylthio " is meant group-SR d, R wherein dIt is heteroaryl.
" leaving group " (Lv) is meant can be by substitution reaction by any suitable group of metathetical.One of ordinary skill in the art will appreciate that any conjugate base of strong acid all can play the effect of leaving group.The illustrative example of suitable leaving group includes but are not limited to,-F ,-Cl ,-Br, alkyl chloride, alkyl bromide, alkiodide, alkyl sulfonic ester, benzene sulfonamide acid esters, alkyl p-toluenesulfonic esters, alkyl methanesulfonates, triflate, and any group that contains bisulfate ion, methyl sulfate or sulfonate ion.
Typical protecting group, reagent and solvent for example but be not limited only to listed those in the following table 1, adopt following abbreviation in the text with in the claim.It will be understood by those skilled in the art that compound listed in the table can exchange use; For example, can be used as protecting group etc. at " reagent and solvent " listed down compound.In addition, other possible protecting group, reagent and solvent are well known by persons skilled in the art; These include within the scope of the invention.
Table 1
Protecting group
Ada diamantane ethanoyl
The Alloc allyloxycarbonyl
The Allyl allyl ester
The Boc tertbutyloxycarbonyl
The Bzl benzyl
The Cbz carbobenzoxy-(Cbz)
The Fmoc fluorenylmethyloxycarbonyl
OBzl benzyl ester
The OEt ethyl ester
The OMe methyl esters
Tos (Tosyl) p-toluenesulfonyl
The Trt trityl group
Reagent and solvent
The ACN acetonitrile
AcOH acetate
Ac.sub.2 0 diacetyl oxide
The AdacOH adamantane acetic acid
AIBN 2, the 2-Diisopropyl azodicarboxylate
Alloc-Cl allyloxy dicarbonyl chloride
BHT 2,6-two-tertiary butyl-4-methylphenol
Boc.sub.2 0 tert-Butyl dicarbonate
CDI 1,1 '-carbonyl dimidazoles
The DIEA diisopropyl ethyl amine
DIPEA N, the N-diisopropyl ethyl amine
The DMA N,N-DIMETHYLACETAMIDE
DMF N, dinethylformamide
The DMSO methyl-sulphoxide
The EDTA ethylenediamine tetraacetic acid (EDTA)
The Et.sub.3N triethylamine
The EtOAc ethyl acetate
The FDH hydrogenlyase
FmocOSu 9-fluorenyl methoxy carbonyl N-hydroxy-succinamide ester
HATU N-[(dimethylamino)-and 1H-1,2,3-triazolo [4,5-b] pyrrole
The pyridine methylene]-N-methyl first ammonium hexafluorophosphate N-oxide compound
The HOBT I-hydroxybenzotriazole
HF hydrofluoric acid
The LDH serum lactic dehydrogenase
The two TMS Lithamides of LiHMDS
MeOH methyl alcohol
Mes (Mesyl) methylsulfonyl
The MTBE t-butyl methyl ether
The NAD Reduced nicotinamide-adenine dinucleotide
The NADH hydrogen peroxide redox enzyme
The two TMS sodium amides of NaHMDS
The NMP 1-Methyl-2-Pyrrolidone
Nin. triketohydrindene hydrate
The i-PrOH Virahol
The Pip piperidines
PPL lipase
PTSA tosic acid monohydrate
The Pyr pyridine
The TEA triethylamine
The TET Triethylenetetramine (TETA)
The TFA trifluoroacetic acid
The THF tetrahydrofuran (THF)
Triflate (Tf) trifyl
Term " suitable organic moiety " is meant that those skilled in the art can be by for example conventional test any organic moiety that judge, that can not have a negative impact to the inhibition activity of The compounds of this invention.The illustrative example of suitable organic moiety includes but are not limited to hydroxyl, alkyl, oxo group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, acyl group, alkylsulfonyl, sulfydryl, alkylthio, alkoxyl group, carboxyl, amino, alkylamino, dialkyl amido, formamyl, arylthio, heteroarylthio etc.
Term " substituting group " or " suitable substituting group " refer to any suitable substituting group that those skilled in the art can judge by for example conventional test.Suitable substituent illustrative example comprises hydroxyl, halogen, oxo group, alkyl, acyl group, alkylsulfonyl, sulfydryl, alkylthio, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, carboxyl, amino, alkylamino, dialkyl amido, formamyl, aryloxy, heteroaryloxy, arylthio, heteroarylthio etc.
Term " selectivity replaces " is used for representing that specified group is unsubstituted or is replaced by one or more suitable substituting groups, if substituting group has optionally been carried out clearly specifying, then this term represents that this group is unsubstituted or appointed substituting group replaces.As defined above, each group all can be (that is, they is that selectivity replaces) that does not replace or replace, (it is unsubstituted for example, indicating this group) except as otherwise noted.
" prodrug " is meant can be under physiological condition or become to have the compound of the specific compound of pharmaceutical activity by solvolysis or metabolic conversion.
" pharmaceutical activity metabolite " is meant the pharmacological activity product of the specific compound that produces in vivo by metabolism.
" solvate " is meant the acceptable solvent thing of appointed compound, and it has kept the biological efficacy of this compound.The example of solvated compounds comprises the binding substances of The compounds of this invention and water, Virahol, ethanol, ethanol, methyl alcohol, DMSO, ethyl acetate, acetate or thanomin.
" pharmacologically acceptable salt " is meant the biological efficacy of the free acid that kept appointed compound or alkali and do not have the salt of disadvantageous effect in biology or others.The example of pharmacologically acceptable salt comprises vitriol, pyrosulphate, hydrosulfate, sulphite, hydrosulphite, phosphoric acid salt, monohydric phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate salt, hydrochloride, hydrobromate, hydriodate, acetate, propionic salt, caprate, octylate, acrylate, formate, isobutyrate, hexanoate, enanthate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butine-1, the 4-diacid salt, hexin-1, the 6-diacid salt, benzoate, chloro benzoate, tolyl acid salt, dinitro-benzoate, hydroxy benzoate, methoxybenzoic acid salt, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenpropionate, benzenebutanoic acid salt, Citrate trianion, lactic acid salt, gamma hydroxybutyrate, glycollate, tartrate, mesylate, propanesulfonic acid salt, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt and mandelate.
The present invention also provides the synthetic method that comprises one of synthesis step listed among the application.When a synthesis step was final synthetic method a part of at least, then synthetic method had comprised this synthesis step.Therefore, synthetic method can only have a synthesis step, perhaps also contains relevant with it additional synthesis step.This synthetic method can contain additional synthesis step seldom, perhaps can contain a lot of additional synthesis steps.
If the antipicornaviral agent of the formula I that is made by method of the present invention is an alkali, then can prepare required salt by any proper method known in the art, comprise free alkali with mineral acid hydrochloric acid for example; Hydrogen bromide; Sulfuric acid; Nitric acid; Processing such as phosphoric acid, or with organic acid acetate for example; Toxilic acid; Succsinic acid; Amygdalic acid; Fumaric acid; Propanedioic acid; Pyruvic acid; Oxalic acid; Oxyacetic acid; Whitfield's ointment; The acid of pyrans glycosyl, for example glucuronic acid or galacturonic acid; Alpha hydroxy acid, for example citric acid or tartrate; Amino acid, for example aspartic acid or L-glutamic acid; Aromatic acid, for example phenylformic acid or styracin; Sulfonic acid, for example processing such as tosic acid or ethyl sulfonic acid.
If the antipicornaviral agent of the formula I that is made by method of the present invention is acid, then can prepare required salt by any proper method known in the art, comprise free acid with inorganic or organic bases amine (primary, the second month in a season or uncle) for example; Processing such as basic metal or alkaline earth metal hydroxides.The illustrative example of suitable salt comprises from amino acid for example glycine and arginine; Ammonia; The primary, the second month in a season and tertiary amine and and the cyclic amine organic salt of piperidines, morpholine and piperazine derivatives for example; And from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium deutero-inorganic salt.
When compound, its salt or solvate are solid, it will be appreciated by those skilled in the art that, formula I compound and intermediate, its salt and solvate used in the method for the present invention can exist with different crystal formations, and all these include in the scope of the present invention and specified molecular formula.
Intermediate used in the antipicornaviral agent of formula I and the method for the present invention can exist with the mixture of one steric isomer, raceme and/or optically active enantiomorph and/or the form of diastereomer.All these one steric isomers, raceme and composition thereof include within the scope of the invention.But used midbody compound is optically pure form in the preferred method of the present invention.
Those skilled in the art are appreciated that usually optically pure compound is the compound of enantiomer-pure.Term used herein " optical purity " is meant that compound contains the single enantiomorph of q.s at least to obtain having the compound of required pharmacological activity.Preferably " optical purity " is meant that compound contains at least 90% single isomer (80% enantiomeric excess (hereinafter referred to as " e.e. ")), more preferably at least 95% (90%e.e.), more preferably at least 97.5% (95%e.e.) still, first-selection at least 99% (98%e.e.).Preferably the antipicornaviral agent of the formula I that is formed by method of the present invention is optically pure.
The present invention relates to the method for the antipicornaviral agent of preparation formula I:
Figure C0081187700181
R wherein 1Be H, F, alkyl, OH, SH or O-alkyl;
R 2And R 3Be H independently of one another;
Or
Figure C0081187700192
Wherein n is 0 to 5 integer, A 1Be CH or N, A 2With each A 3Be independently from each other C (R 41) (R 41), N (R 41), S, S (O), S (O) 2And O, A 4Be NH or NR 41, each R wherein 41Be H or low alkyl group independently of one another, condition is by A above-mentioned 1, A 2, (A 3) n, A 4In the ring that forms with C=O two successive heteroatomss are arranged at the most, and R 2And R 3In have at least one to be
Or
Figure C0081187700194
R 4Be
R 5And R 6Be H, F, alkyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl independently of one another;
R 7And R 8Be independently of one another H, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-OR 17,-SR 17,-NR 17R 18,-NR 19NR 17R 18Or-NR 17OR 18, R wherein 17, R 18And R 19Be H, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl or acyl group independently of one another, condition is R 7And R 8In have at least one be alkyl, aryl, heteroaryl ,-OR 17,-SR 17,-NR 17R 18,-NR 19NR 17R 18Or-NR 17OR 18
R 9Be to contain 1 to 3 heteroatomic 5 yuan of heterocycle that are selected from O, N and S;
Z and Z 1Be independently of one another H, F, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-C (O) R 21,-CO 2R 21, CN ,-C (O) NR 21R 22,-C (O) NR 21OR 22,-C (S) R 21,-C (S) NR 21R 22,-NO 2,-SOR 21,-SO 2R 2R 21,-SO 2NR 21R 22,-SO (NR 21) (OR 22) ,-SONR 21,-SO 3R 21,-PO (OR 21) 2,-PO (R 21) (R 22) ,-PO (NR 21R 22) (OR 23) ,-PO (NR 21R 22) (NR 23R 24) ,-C (O) NR 21NR 22R 23Or-C (S) NR 21NR 22R 23, R wherein 21, R 22, R 23And R 24Be H, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, acyl group or sulfo-acyl group independently of one another, perhaps R wherein 21, R 22, R 23And R 24In any two with their institute's bonded atoms lump together the formation Heterocyclylalkyl, condition is Z and Z 1Be not H simultaneously;
Perhaps Z 1And R 1Lump together formation cycloalkyl or Heterocyclylalkyl, wherein Z with their institute's bonded atoms 1And R 1As defined above, but do not comprise the part that can not form cycloalkyl or Heterocyclylalkyl;
Perhaps Z and Z 1Lump together formation cycloalkyl or Heterocyclylalkyl, wherein Z and Z with their institute's bonded atoms 1As defined above, but do not comprise the part that can not form cycloalkyl or Heterocyclylalkyl.
The invention discloses formula I compound can prepare by the reaction that formula II compound and formula III compound is formed acid amides:
The reaction that forms acid amides can be finished by any suitable method, reagent and reaction conditions.Preferably can adopt disclosed the whole bag of tricks in the application of ' 354.For example, can be with formula II compound and formula III compound at HATU, DIPEA, CH 3CN and H 2The existence of O reaction down generates required formula I compound.Can adopt any suitable purification process to be further purified formula I compound.
More preferably form reaction and come preparation I compound by the acid amides that comprises the steps:
(a) formula II compound and formula III A compound are reacted the formation reaction mixture in the presence of N-methylmorpholine; Then
(b) the compound formation formula I compound of adding formula Lv-X in reaction mixture, wherein X is any suitable halogenide.
Preferably, adopt the method for the preparation I compound of preferred acid amides formation reaction, adopt some or all reagent and the reaction conditions of following discloses.Therefore, preferably formula II compound and formula III A compound are mixed in DMF in any suitable container.The suitable preferably single neck flask of container covers it then and covers with temperature probe with any suitable barrier film.Before in reaction mixture, adding N-methylmorpholine, suitable container is purified with nitrogen.More preferably N-methylmorpholine is cooled to-5 ℃ to 5 ℃ approximately by the disposable adding of syringe and with reaction mixture.More preferably reaction mixture is cooled to about 0 ℃.The solution that in reaction mixture, adds formula Lv-X compound then.More preferably the solution of formula Lv-X compound is the DMF solution of formula Lv-X compound.Still more preferably formula Lv-X compound is CDMT.The solution of formula Lv-X compound is joined in the reaction mixture so that reaction mixture remains on constant temp by any suitable method.For example, the solution of formula Lv-X compound can be added drop-wise in the reaction mixture with syringe.After the reinforced end of formula Lv-X compound, reaction mixture is warming up to about room temperature.By thin-layer chromatography (hereinafter referred to as " TLC) disappearance of the monitoring formula II compound process of coming monitoring reaction.When reaction is when finishing substantially at least, can forms slurries and make formula I compound from solution, separate out precipitation by in reaction mixture, slowly adding entry.Can from slurries, isolate formula I compound by any proper method well known by persons skilled in the art then.For example, can from slurries, isolate formula I compound by filtering.Can adopt any suitable purification process well known by persons skilled in the art to come purifying formula I compound.More preferably formula I compound is carried out purifying by recrystallization.
The invention also discloses two kinds of methods of synthetic formula III compound and acid salt thereof.In these two kinds of methods, second method is present preferable methods, because this method can produce bigger cost effectiveness on technical scale.
In these two kinds of methods, first method is from formula V compound formula IV compound and acid salt thereof.
Those skilled in the art as can be seen, formula IV compound is the subgenus of formula III compound.
Formula V compound can be from commercially available N-Boc L glutamic acid gamma-benzyl ester preparation.Can adopt any suitable method to come preparation formula V compound.Disclosed method in the preferred employing Application No. 08/991,739.Application No. 08/991,739 is incorporated herein by reference in full.
Method of the present invention comprises the steps:
(a) formula V compound is carried out cyano methyl production VI compound with two (TMS) amideses and bromoacetonitrile;
Figure C0081187700222
(b) formula VI compound is reduced successively, cyclisation and deprotection production VII compound; Then
Figure C0081187700231
(c) pass through compound and SO 3-pyridine mixture reaction is formula VII compound oxidation and alkylene formation reaction mixture, then with the positive phosphine reaction of reaction mixture and formula VIII.
Figure C0081187700232
As mentioned above, according to the present invention, can be undertaken by any suitable method known in the art from N-Boc glutamic acid gamma-benzyl ester preparation formula V compound.
In addition, the cyano methylization of formula V compound can be finished with any suitable method, reagent and reaction conditions.Disclosed method below preferred and use whole or some reagent or reaction conditions.Therefore, preferably formula V compound time with at least 5 hours under nitrogen atmosphere is added drop-wise under-70 ℃ in the THF solution of the NaHMDS in the stirring, mixes with bromoacetonitrile then.
Can be with two (TMS) amideses and bromoacetonitrile cyano methylization according to this method with 5: 1 ratio production VI compound and epimer thereof with formula V compound.But this compound can be by any suitable method purifying.Preferably formula VI compound is separated to come purifying by filtering then in the laggard circumstances in which people get things ready for a trip spectrum of grinding.Under these preferred conditions, can obtain the formula VI compound of diastereomer purity＞99% with 60% total recovery.
The three step reduction, cyclisation and the deprotection reaction that formula VI compound are transformed the step (b) of accepted way of doing sth VII compound can be finished with any suitable reagent and reaction conditions.The preferred method that adopts following discloses is used all or some reagent and reaction conditions.Therefore, preferably formula VI compound is reduced by in the tetrahydrofuran (THF)/methanol solution of formula VI compound, adding cobalt chloride (II) hexahydrate.Gained solution is cooled to 0 ℃, at least 7 hours time, adds sodium borohydride then in batches.Adding the tosic acid monohydrate then in the methanol solution of crude product also at room temperature reacts at least about 18 hours.Except that after desolvating, resistates is dissolved in ethyl acetate and washing.Can use any suitable washing reagent.Preferred washing reagent is a saturated sodium bicarbonate.In crude product, add methanol in water then.More preferably use 2.5% methanol solution.Can from solution, isolate crude product by any suitable method.For example, can be by filtering and filtrate concentrating and separating on Rotary Evaporators being gone out crude product.Then product is dissolved in ethyl acetate, drying is filtered and is concentrated the crude product that obtains formula VII compound then.More preferably with the product dried over mgso.Crude product formula VII compound can be further purified by any suitable purification process.More preferably the crude product compound of formula VII is carried out purifying by grinding with 1: 1 ethyl acetate and hexane.
If adopt above disclosed preferred three step reduction, cyclisation and deprotection reactions, can obtain purified formula VII compound with total recovery at least about 95%.
Adopting SO 3In the reaction of the phosphorane of-pyridine mixture and formula VIII with formula VIII compound oxidation and alkylene production IV, can adopt any suitable method, reagent and reaction conditions.Preferred method and whole or some reagent and the reaction conditions that adopts following discloses.Therefore, preferably triethylamine is joined in the solution of formula VIII compound and methyl sulfoxide.Gained solution is cooled to about 5 ℃, adds sulphur trioxide-pyridine mixture then.Reaction solution is stirred at least about 15 minutes down in about 5 ℃.Remove be used for solution is cooled to about 5 ℃ cooling bath after, reaction solution is continued to stir at least about 1 hour.Add (ethoxycarbonyl methylene tri phenyl)-phosphorane then and reaction mixture was at room temperature stirred at least about 3 hours.Then, with ethyl acetate termination reaction and extraction.More preferably by adding the saturated brine termination reaction.With the organic phase washing that merges, drying is filtered the concentrated then crude product formula IV compound that obtains then.More preferably the organic phase that merges is used dried over mgso then with the saturated brine washing.
Formula IV compound can be carried out purifying by any suitable method.Preferred chromatogram purification and the abrasive method of adopting.If adopt preferred purification process, can reach 55% to 60% yield.
The second method of preparation formula IV compound disclosed in this invention and acid salt thereof comprises the steps:
(a) formula IX compound is carried out dianion alkylated reaction production X compound with bromoacetonitrile;
Figure C0081187700251
(b) with the amine of formula X hydrogenation of compounds production XI;
Figure C0081187700252
(c) with amine and the Et of formula XI 3The lactan ester of N reaction production XII;
Figure C0081187700253
(d) with the lactan ester of formula XII compound by suitable method of reducing reduction production XIII;
(e) by formula XIII compound and formula XV compound are reacted with its oxidation and alkylene production XIV compound; Then
Figure C0081187700262
(f) formula XIV compound is transformed accepted way of doing sth IV compound.
In addition, it will be understood by those skilled in the art that above disclosed method can be used for preparation formula XIV compound.Specifically, step (a)-(e) discloses the method for preparation formula XIV compound.
Formula IX compound can be prepared by any proper method known in the art.For example, N-Boc L-(+)-glutamic acid dimethyl ester can prepare according to the method the document from commercially available L-glutamic acid dimethyl ester hydrochloride or commercially available L-L-glutamic acid 5-methyl esters.Referring to, Shimamoto etc. for example, J.Org.Chem.1991,56,4167 and Duralski etc., Tetrahedron Lett.1998,30,3585.These reference are incorporated herein by reference in full.
Preferably, the dianion alkylated reaction adopt the method for following discloses and all or some reagent and reaction conditions be prepared.Therefore, preferably formula IX compound at first is dissolved in THF and forms solution, then with its under argon atmospher in-78 ℃ of solution that are added drop-wise to the LiHMDS in the stirring.The gained mixture in stirring 2 hours approximately-78 ℃ down, was dripped new distillatory bromoacetonitrile then in 1 hour.Reaction mixture was stirred 2 hours in continuing approximately-78 ℃ down.Termination reaction then.More preferably by adding 0.5M HCl and H 2The O termination reaction.Tell formed water layer and further extract with methyl tertiary butyl ether.With the organic extract liquid washing that merges, drying is filtered then.More preferably organic extract liquid is used dried over mgso then with saturated sodium bicarbonate and salt water washing.Remove solvent under reduced pressure.
Formula IX compound can be by the amine of any proper method hydrogenation accepted way of doing sth XI known in the art.Preferably in the presence of 5%Pd/C, carry out hydrogenation.More preferably carry out hydrogenation according to some or all reagent of use of following discloses and the method for reaction conditions.According to this preferred method for hydrogenation, formula IX compound is dissolved in HOAc and and 5%Pd/C jolting 3 days under the hydrogen pressure of 50psi together.Then with the mixture diatomite filtration.Can from methyl tertiary butyl ether, evaporate repeatedly with filtrate evaporated under reduced pressure and with resistates then.
The amine of formula XI and Et 3The reaction of N can be finished with any suitable condition.Preferred method and whole or some reagent and the reaction conditions that adopts following discloses.Therefore, preferably the amine with formula XI is dissolved in 1: 1 MeOH/THF mixture, adds Et then in solution 3N.The gained mixture is disappeared in about 45 ℃ of following stir abouts 10 hours or until raw material.Can pass through 1The existence of HNMR monitoring raw material.After steaming desolventizes, add methyl tertiary butyl ether.Leach precipitation then.In the filtrate of dilute with water, add 0.5M HCl.After the phase-splitting, with the water ethyl acetate extraction.With the organic phase washing that merges, drying is filtered concentrated then.More preferably the organic phase that merges is used dried over mgso then with the salt water washing.Organic phase can be concentrated on Rotary Evaporators.Separate the lactan ester that obtains formula XII through flash chromatography.
Can adopt any suitable method of reducing that the lactan ester of formula XII is transformed accepted way of doing sth XIII compound.The preferred LiBH that uses 4As reductive agent.More preferably adopt the method for following discloses or the part of this method, and any or all of reagent and reaction conditions.Therefore, more preferably, with LiBH 4Join in the THF solution of the formula XII lactan ester in the stirring.With LiBH 4Divide for several times under argon atmospher in 0 ℃ of adding.Reaction mixture in 0 ℃ of stirring 10 minutes, is warming up to room temperature then and continues and stirred 2 hours.Termination reaction then.More preferably come termination reaction by under the ice bath cooling, dripping 0.5M HCl.With solution ethyl acetate and H 2The O dilution.After being separated, can be with the water ethyl acetate extraction.With the organic layer washing that merges, drying is filtered concentrated then.More preferably with the organic phase that merges with the salt water washing and use dried over mgso.Organic phase can be concentrated on Rotary Evaporators.The flash chromatography separation obtains formula XII compound.
Can adopt any suitable oxidation and alkylene method from formula XIII compound formula XIV compound.The preferred method of following discloses or the part of this method of adopting, and whole or some reagent and reaction conditions.Therefore, according to the present invention, phenylformic acid, (ethoxycarbonyl methylene tri phenyl) phosphorane and DMSO are joined in the dichloromethane solution of formula XIII compound.Add Dess-Martin periodinane to this solution mid-score time, reaction mixture is at room temperature stirred disappeared substantially until formula XIII compound at least 5 hours then.Can pass through 1The existence of H NMR monitoring formula XIII compound.Add saturated sodium bicarbonate solution, mixture is stirred generated precipitation in 30 minutes then.Leach precipitation, then the organic phase of filtrate is separated, washing concentrates then and obtains crude product formula XIV compound.More preferably filtrate is concentrated on Rotary Evaporators then with the salt water washing.Can adopt any suitable method purifying crude product formula XIV compound.More preferably crude product formula XIV compound is dissolved in ethyl acetate then by purification by flash chromatography.In the solution that stirs, add excessive hexane then gradually and generate precipitation.Leach precipitation then drying obtain formula XIV compound.More preferably will be deposited in the vacuum drying oven dry at least about 12 hours.
It only is for the present invention being described, should not being seen as the qualification to the defined protection domain of the present invention of claims that following examples are provided.
Embodiment:
The embodiment that acid amides between two kinds of compounds in formula II and the formula III scope forms reaction that belongs to that is used for preparation I compound below has been described.Specifically, the embodiment described in the following reaction scheme 1 illustrated be used to prepare proteinase inhibitor AG7088 1 and 2 between reaction.
Reaction scheme 1
Following examples disclose the preparation that is included in the compound 1 within the formula IV compound scope.First embodiment (as shown in following reaction scheme 2) has illustrated the route of above disclosed use cyano methyl reaction.Second embodiment (as shown in following reaction scheme 3) illustrated the second kind of preferred effective economically route that is used to prepare same compound.
Reaction scheme 2
Reaction scheme 3
Figure C0081187700311
4 preparation (reaction scheme 2)
With THF (8.0L) solution of 3 (1.0kg, 2.34mol, 1.0 equivalents) with time of 5 hours under nitrogen atmosphere in-70 ℃ of THF solution (the THF solution of 1M, 2.96L, 1.28 equivalents) that are added drop-wise to the NaHMDS in the stirring.Gained solution was stirred 0.5 hour in-70 ℃, drip new distillatory bromoacetonitrile (320mL, 2.0 equivalents) with time of 25 minutes then.Reaction mixture is continued to stir 1 hour until raw material 3 disappearances in-70 ℃.Add saturated ammonium chloride solution (7.0L) termination reaction, with methyl tertiary butyl ether (24L) extraction.(3 * 6.0L) wash with salt solution with organic phase.Remove solvent under reduced pressure and obtain dark-brown oil (1.5kg).This crude product is dissolved in the bed that methylene dichloride (8.0L) passes through silica gel (600g) and activated carbon (250g) then.After the rinsing of filter cake usefulness methylene dichloride (4.0L), filtrate is concentrated the oil (1.28Kg) that obtains light brown on Rotary Evaporators, then it is dissolved in ethyl acetate (2.5L).Add excessive hexane (14.5L) under vigorous stirring in the solution that forms, the adularescent solid is separated out in 30 minutes.These slurries with ice-water bath cooling and stirred 4.5 hours, are filtered 4 (662g, 60%) that obtain the light brown solid state then: 1H NMR (CDCl 3) δ 1.46 (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).
6 preparation (reaction scheme 3)
Compound 6 prepares according to the method the document from L-glutamic acid dimethyl ester hydrochloride (can buy from Lancaster) or L-L-glutamic acid 5-methyl esters (can buy from Aldrich).
7 preparation (reaction scheme 3)
THF (100mL) solution of N-Boc L-(+)-glutamic acid dimethyl ester (6,10g, 36.3mmol, 1 equivalent) is added drop-wise under-78 ℃ and argon atmospher in the LiHMDS solution (77mL, the THF solution of 1M, 77.0mmol, 2.1 equivalents) in the stirring.The dark mixture that forms was stirred 2 hours in-78 ℃, drip new distillatory bromoacetonitrile (13.1g, 109.0mmol, 3 equivalents) with time of 1 hour then.Reaction mixture is continued to stir 2 hours in-78 ℃, and analyze the disappearance that confirms raw material (6) by TLC.Add HCl (120mL, 0.5M) and H 2O (200mL) termination reaction.Layering extracts (3 * 200mL) with water layer with methyl tertiary butyl ether.With the organic extract liquid that merges with saturated sodium bicarbonate (2 * 250mL) and salt solution (2 * 250mL) wash, and filter then with dried over mgso.Remove solvent under reduced pressure and obtain brown oil (15.2g).Obtain colourless oil (7,6.67g, 10.8mmol, 58%) through fast silica gel chromatogram (3: 1 hexane/ethyl acetate): 1H NMR (CDCl 3) δ 1.46 (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 (CDCl 3) δ 19.4,28.6,34.3,38.6,49.8,53.1,80.9,117.5,155.9,172.4,172.8; HRMS m/z 314.1481 (C 12H 22N 2O 4Calculated value, 314.1486).
8 preparation (reaction scheme 3)
With compound 7 (4.60g, 14.6mmol) be dissolved in HOAc (120mL) and and 5%Pd/C (20g) together nitrogen atmosphere (50psi) time jolting 3 days.With the mixture diatomite filtration.With filtrate evaporated under reduced pressure and with resistates repeatedly from methyl tertiary butyl ether evaporation obtain the baby pink solid (8,8.32g), it is directly used in subsequently step. 1H NMR (CD 3OD) δ 1.47 (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); Annotate: experiment confirm, the Pd/C less than 5% just can make and react completely, and promptly the 5%Pd/C of 1g just can reduce 7 of 2g effectively.
9 preparation (reaction scheme 3)
Crude product 8 is dissolved in 1: 1 MeOH/THF (40mL) and adds Et in solution 3N (7mL).The mixture that forms is stirred 10 hours until passing through in 45 ℃ 1H NMR monitors raw material and disappears.After steaming on the Rotary Evaporators desolventizes, add methyl tertiary butyl ether (200mL), the adularescent solid is separated out.The solids removed by filtration precipitation.Filtrate is used 200mL H 2The O dilution adds 0.5M HCl (5mL) then.Be separated, (4 * 200mL) extract with ethyl acetate with water.(dried over mgso use in 2 * 700mL) washings, filters the concentrated oil that obtains light brown on Rotary Evaporators then with salt solution with the organic phase that merges.Obtain white solid (9,2.5g, 8.74mmol, 60%) through flash chromatography: 1H NMR (CDCl 3) δ 1.37 (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 (CDCl 3) δ 28.5,28.6,34.5,38.5,40.7,52.7,52.8,80.3,156.1,173.3,180.0; HRMS m/z286.1564 (C 13H 22N 2O 5Calculated value, 286.1587).
From 4 preparations, 5 (reaction scheme 2)
Methyl alcohol (3.0L) solution that in tetrahydrofuran (THF) (3.0L) solution of 4 (400g, 0.85mol, 1 equivalents), adds cobalt chloride (II) hexahydrate (200g, 0.85mol, 1 equivalent).Gained solution is cooled to 0 ℃ and add sodium borohydride (130g, 3.51mol, 4.4 equivalents) in 7 hours time in batches.Reaction mixture is warming up to room temperature and stirred 20 hours, monitor raw material (4) with TLC simultaneously and whether disappear.Reaction solution is cooled to 0 ℃ also by adding 1.0MHCl (14L) and ethyl acetate (12L) termination reaction.Phase-splitting also adds 2.0kg sodium-chlor and 4.0L ethyl acetate to aqueous phase.Phase-splitting merges organic phase, and (1 * 3.0L) washing concentrates on Rotary Evaporators and obtains crude product material (440g), and it is directly used in subsequently hydrolysis reaction with salt solution.In methyl alcohol (800mL) solution of crude product material (440g, 1 equivalent), add tosic acid monohydrate (4.0g, 0.015 equivalent).With the reaction solution stirred overnight at room temperature.Steaming desolventizes and resistates is dissolved in ethyl acetate (2.0L) on Rotary Evaporators, with saturated sodium bicarbonate (2 * 100mL) washings.With water ethyl acetate (2 * 200mL) extractions that merge.Merge all organic phases, on Rotary Evaporators, concentrate and obtain the 275g crude product, to (780mL) solution and the stirred overnight at room temperature that wherein add 2.5% methyl alcohol (20mL).Removing by filter granular solid (chirality assistant agent) concentrates filtrate then on Rotary Evaporators.Resistates is dissolved in ethyl acetate (1.5L), uses dried over mgso, filter the concentrated then heavy-gravity oil that obtains.Should oil obtain white solid 5 (104g, the total recovery from 4 is 47%) by grinding with 1: 1 ethyl acetate (1L) and hexane (1L).
From 9 preparations, 5 (reaction scheme 3)
Under 0 ℃ and the argon atmospher, in stirring 9 (1.75g, THF 6.10mmol) (40mL) solution mid-score time adds LiBH 4(270mg, 12.2mmol, 2 equivalents).Reaction mixture in 0 ℃ of stirring 10 minutes, is warming up to room temperature then and continues and stirred 2 hours.By under the ice bath cooling, dripping 0.5M HCl (24mL) termination reaction (annotating: observed gas and generated).With solution ethyl acetate (100mL) and H 2O (50mL) dilution.Phase-splitting, (6 * 150mL) extract with ethyl acetate with water layer.With the organic phase dried over mgso that merges, filter and on Rotary Evaporators, concentrate the oil that obtains light brown then.Obtain white solid (5,1.308g, 5.06mmol, 83%) through flash chromatography: 1H NMR (CDCl 3) δ 1.46 (s, 9H), 1.61-1.67 (m, 1H), 1.82-1.91 (m, 1H), 1.94-2,00 (m, 1H), and 2.43-2.48 (m, 1H), 2.49-2.55 (m, 1H), and 3.32-3.34 (m, 3H), 3.58-3.66 (m, 2H), and 3.68-3.79 (m, 2H), 5.47 (d, J=7.0Hz, 1H), 6.24 (s, 1H); 13C NMR (CDCl 3) δ 28.8,32.9,38.4,40.8,51.5,66.3,79.8,157.0,181.3; HRMS m/z 258.1652 (C 13H 22N 2O 5Calculated value, 258.1650).
From 5 preparations 1
Method A (reaction scheme 2)
In methyl sulfoxide (500mL) solution of 5 (50.0g, 0.184mol, 1 equivalents), add triethylamine (116mL).Gained solution is cooled to 5 ℃ with ice bath, adds sulphur trioxide-pyridine mixture (132g) then.Reaction solution was stirred 15 minutes under this temperature.Remove cooling bath, reaction solution is continued to stir 1 hour.Disposable adding (ethoxycarbonyl methylene tri phenyl)-phosphorane (112g) and with reaction solution stirring at room 3 hours.By adding saturated brine (3.0L) termination reaction, with ethyl acetate (3 * 1.5L) extractions.(dried over mgso use in 3 * 1.5L) washings, filters the concentrated then wine-colored oil that obtains with saturated brine with the organic phase that merges.Should pass through chromatography purification by oil, and use ethyl acetate (60mL) and excessive hexane (240mL) to grind then.Obtain 1 (36.0g, 60%) of white solid.
Method B (reaction scheme 3)
In methylene dichloride (80mL) solution of 5 (1.0g, 3.87mmol, 1 equivalents), add phenylformic acid (1.89g, 15.5mmol, 4 equivalents), (ethoxycarbonyl methylene tri phenyl) phosphorane (5.39g, 15.5mmol, 4 equivalents) and DMSO (4.8mL).Add Dess-Martin periodinane (4.1g, 9.17mmol, 2.5 equivalents) to this solution mid-score time, then reaction mixture stirring at room 5 hours is disappeared until raw material 5.Add saturated sodium bicarbonate, this mixture was stirred 30 minutes.The adularescent solid is separated out, and leaches this solid.The organic phase of filtrate is separated, with salt solution (250mL) washing on Rotary Evaporators, concentrate then brown oil, it is obtained the foam (0.956g) of light brown by purification by flash chromatography.This foam is dissolved in ethyl acetate (3mL).Add excessive hexane (12mL) gradually in the solution that stirs, the adularescent solid is separated out.With this solid filtering then in vacuum drying oven dried overnight obtain 1 (0.69g, 2.11mmol, 55%).Chirality HPLC:97% is pure, 98%de and 100%E isomer; 1H NMR (CDCl 3) δ 1.22 (t, J=7.2Hz, 3H), 1.38 (s, 9H), 1.53-1.58 (m, 1H), and 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 (C 16H 26N 2O 6Calculated value, 326.1840).
From 1 and 2 preparation AG7088 (reaction scheme 1).
751mg compound 1 is dissolved in DCM (10mL/g 1) in single neck round-bottomed flask cover with barrier film then.With the flask nitrogen purge, in solution stirring, add 1.4mL TFA then then by syringe.With the DCM solution of the 5%MeOH process by the TLC monitoring reaction, raw material disappears after about 4 hours.Desolventize and excessive TFA pressure＜50mTorr@45 ℃ of following vacuum steaming.1A is used for following step immediately with the product compound.
Compound 1A and 2 is dissolved in DMF (7mL/g 2) being coated with barrier film and being equipped with in single neck round-bottomed flask of temperature probe.With the flask nitrogen purge.Gained solution is divided into two parts.In first part, add the 1.6mL N-methylmorpholine by syringe and be cooled to 0 ℃ ± 5 ℃ then.Dissolving 281mg CDMT in second part of solution.Then this CDMT solution is added drop-wise in first part of solution by syringe, keeping temperature of reaction is 0 ℃ ± 5 ℃.Then the gained reaction mixture is warming up to room temperature.(7: 3: 1 hexanes: EtOAc: IPA) about 1 hour of monitoring reaction disappears until compound 2 by TLC.Reaction separates out product A G7088 by slowly add entry in reaction mixture after finishing from solution.The dope filtration that forms is obtained＞the white granular crystallization of 85% compd A G7088 purity＞97%.Then can with this product by be dissolved in heat MeOH: EtOAc slowly adds hexane (2 volume) then and carries out recrystallization in 1: 1.
Should be appreciated that above description is used to demonstrate and explain, its objective is for the present invention and embodiment preferred thereof are described.By the experiment of routine, those skilled in the art can confirm the tangible modification and the change that do not deviate from spirit of the present invention that can carry out.Therefore, the present invention is not by above specification sheets but by defined by the following claims.

Claims (4)

1. the method for synthesis type IA ' compound or its acid salt:
Comprise the steps:
Steps A: preparation formula IV ' compound:
Comprise:
(a) use two (TMS) sodium amides and bromoacetonitrile to carry out the cyano methyl reaction production VI ' compound of formula V ' compound;
(b) formula VI ' compound is reduced successively, cyclisation and deprotection production VII ' compound; Then
Figure C008118770003C1
(c) pass through compound and SO 3The reaction of-pyridine mixture is then with the reaction mixture and the Ph that form 3P=CHCO 2The Et reaction is with formula VII ' compound oxidation and alkylene;
Step B: with formula IV ' compound deprotection production IVA ' compound:
With
Step C: formula II ' compound and formula IVA ' compound are formed the reaction of acid amides
2. synthesize the method for the compound of antipicornaviral, comprising:
(a) formula IX ' compound is carried out dianion alkylated reaction preparation formula X ' compound with bromoacetonitrile;
Figure C008118770004C1
(b) with the amine of formula X ' hydrogenation of compounds production XI ';
(c) with formula XI ' compound and Et 3The lactan ester of N reaction production XII ';
Figure C008118770004C3
(d) with the lactan ester of formula XII ' reduction production XIII ' compound:
Figure C008118770004C4
With
(e) with formula XIII ' compound by with Ph 3P=CHCO 2Et reaction carrying out oxidation, alkylene production XIV ' compound then.
Figure C008118770005C1
3. the method for the compound of the described synthetic antipicornaviral of claim 2, this method also comprises:
Formula XIV ' compound is transformed accepted way of doing sth IV ' compound.
Figure C008118770005C2
4. the method for the compound of the described synthetic antipicornaviral of claim 3, this method also comprises:
Steps A: with formula IV ' compound deprotection production IVA ' compound:
Figure C008118770005C3
With
Step C: formula II ' compound and formula IVA ' compound are formed the reaction of acid amides.
Figure C008118770005C4
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