CN1732165A

CN1732165A - 1-acyl-pyrrolidine derivatives for the treatment of viral infections

Info

Publication number: CN1732165A
Application number: CN 200380107485
Authority: CN
Inventors: 戴维·黑格; 查尔斯·D·哈特利; 彼得·D·豪斯; 德博拉·L·杰克逊; 普里托姆·沙; 马丁·J·斯莱特
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 2002-10-24
Filing date: 2003-10-22
Publication date: 2006-02-08
Also published as: ZA200502945B; GB0224774D0

Abstract

Anti-viral agents of Formula (I) wherein: A represents hydroxy; D represents aryl or heteroaryl; E represents hydrogen, C1-6alkyl, aryl, heteroaryl or heterocyclyl; G represents hydrogen or optionally substituted C1-6alkyl; J represents C1-6alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl;and salts, solvates and esters thereof; provided that when A is esterified to form -OR where R is selected from straight or branched chain alkyl, aralkyl, aryloxyalkyl, or aryl, then R is other than tert-butyl;processes for their preparation, pharmaceutical compositions comprising them, and methods of using them in HCV treatment are provided.

Description

1-acyl group-the pyrrolidin derivatives that is used for the treatment of virus infection

Technical field

The present invention relates to new acyl pyrroline alkane derivatives as antiviral agent.Especially, the present invention relates to new HCV inhibitor.

Background technology

People such as Ikeda, (1997) Journal of the Chemical Society, people such as Perkin Transactions 1:Organic and Bio-Organic Chemistry 22:3339-3344 and Sato, (1995) Journalof the Chemical Society, Perkin Transactions 1, people such as 14:1801-1809 and Sato, (1994) Heterocycles 37 (1): 245-248 discloses as the regioselectivity of bridging Azabicyclic compound 4 ', 5 '-unsubstituted acyl pyrrolidine compound of the reactant in synthetic; But there is not to disclose the medicinal use of this acyl pyrroline hydride compounds.

People such as Ikeda, (1996) Heterocycles 42 (1): people such as 155-158 and Confalone, (1988) Journal of Organic Chemistry 53 (3): people such as 482-487 and De Martino, (1976) Farmaco, Ed.Sci.31 (11): 785-790 discloses 4 ', the 5 '-unsubstituted acyl pyrrolidine compound as the nitrogenous heterocyclic reactant in synthetic of three rings; But there is not to disclose the medicinal use of this acyl pyrroline hydride compounds.People such as Alig, (1992) Journal of Medicinal Chemistry 35 (23): 4393-4407 disclose 4 ', the 5 '-unsubstituted acyl pyrrolidine compound as the synthetic reactant of non-peptide fibrinogen receptor antagonist; But there is not to disclose the medicinal use of this acyl pyrroline hydride compounds.

People such as Padwa, (1992) Journal of the American Chemical society 114 (2): 593-601 disclose the reactant of 4 ', 5 '-unsubstituted acyl pyrrolidine compound as synthetic azomethine inner salt; But there is not to disclose the medicinal use of this acyl pyrroline hydride compounds.People such as Culbertson, (1990) Journal of Medicinal Chemistry 33 (8): people such as 2270-2275 and Crooks, (1979) Journalof the Chemical Society, Perkins Transactions 1,11:2719-2726 discloses respectively as 7-spiral shell amine quinolone and spiral shell [indane-2,2 '-tetramethyleneimine] 4 ', 5 '-unsubstituted acyl pyrrolidine compound of reactant in compound synthetic; But there is not to disclose the medicinal use of this acyl pyrroline hydride compounds.

WO2002/44168, WO96/33170 and EP505868A2 disclose as indoles carboxylic acid amides, N-aroylamino acid acid amides and N-acyl-alpha--amino acid derivative 4 ', 5 '-unsubstituted acyl pyrrolidine compound of the intermediate in synthetic respectively; But there is not to disclose the medicinal use of this acyl pyrroline hydride compounds.

People such as De Caprariis, (1989) Journal of Heterocyclic Chemistry 26 (4): 1023-1027 disclose the intermediate of 3 tetramethyleneimine dicarboxylic acid derivatives as synthetic pyrrolo-[1,4] benzodiazepine _ compound; But there is not to disclose the medicinal use of this tetramethyleneimine dicarboxylic acid derivatives.

WO99/37304 discloses to have factor Xa and suppresses active oxygen azaheterocyclyl derivative (particularly Piperazinone compounds).These derivatives comprise some acyl pyrroline alkane derivatives.Do not mention HCV polymerization enzyme inhibition activity for disclosed compound.

In the world everywhere, the HCV infection is the major cause of human hepatopathy.In the U.S., estimate at 4.5 hundred ten thousand Americans and be subjected to the HCV infection for a long time.Although it is symptomatic having only 30% acute infection, the individual development that is contaminted more than 85% becomes chronic, persistent infection.In 1997, flower spent Gu Jiwei $5.46 1,000,000,000 in the treatment that HCV infects for the U.S..Estimate that the whole world has the people above 20,000 ten thousand to be subjected to chronic infection.30% of the 40-60% of whole chronic hepatopathys and all liver transplantations are infected owing to HCV.In the U.S., chronic HCV infection caused all liver cirrhosis, latter stage hepatopathy and liver cancer in 30%.By 2010, CDC estimated because the caused death toll of HCV increases to bottom line 38,000/ years.

Because height variability, the existence of multiple virogene type and the immunologic opsonin that is proved of viral surface antigen, the vaccine of developing success in the recent period is impossible.Owing to admit that it can be used for treating chronic HCV infection, use alpha-interferon (combining separately or with virazole) widely.Yet, usually follow this treatment to have disadvantageous side effect: influenza-like symptom, leukopenia, thrombocytopenia, by cause depressed of Interferon, rabbit and by the caused anemia of virazole (Lindsay, K.L. (1997) Hepatology 26 (suppl 1): 71S-77S).With compare by other 5 the main caused infection of HCV genotype, this treatment is to having less effect by HCV genotype 1 caused infection (its constitute in the flourishing market that all HCV infect～75%).Unfortunately, have only～patient of 50-80% responds (judging by the reduction of serum HCV rna level and the normalizing of liver enzyme) to this treatment, and in the patient of those treatments, 50-70% recurs in 6 months of stopping to treat.Recently, follow the introducing of the Interferon, rabbit (pegylated interferon) of polyoxyethylene glycol, initial and lasting response rate has all obtained substantial improvement, and the combined treatment of Peg-IFN and virazole has constituted the gold standard of treatment.Yet side effect relevant with combination therapy and patient are revealed the impaired reaction table of genotype 1 and might be improved this treatment of diseases.

1989, (the Choo that identifies by molecular cloning at first, people such as Q-L (1989) Science244:359-362), it is the prevailing pathogenic agent (Kuo, people such as G (1989) Science 244:362-364) of the non-A in blood transfusion back, non--B hepatitis (NANBH) that hepatitis C virus (HCV) now is accepted as widely.Because its genome structure and sequence homology, this virus is designated as the new genus kind in the flaviviridae family.Other member in the picture flaviviridae, arboviruses (as yellow fever virus and dengue fever virus Class1-4) and pestivirus (as bovine viral diarrhea virus, border disease virus and typical hog cholera virus) (Choo, people such as Q-L (1989) Science 244:359-3 for example; Miller, R.H.and R.H.Purcell (1990) Proc.Natl.Acad.Sci.USA 87:2057-2061), HCV is a kind of envelope virus that contains the RNA molecule of straight polarity strand.This HCV genome is the length with about 340 bases, high conservative, about 9.6 kilobase of the non-5 ' non-translational region (NTR) that adds cap are to (kb), its function is internal ribosome entry site (IRES) (people such as Wang CY ' An RNA pseudoknot is an essentialstructural element of the internal ribosome entry site located within the hepatitisC virus 5 ' noncoding region ' RNA-A Publication of the RNA Society.1 (5): 526-537,1995 Jul.).Followed by the zone of open reading frame (ORF) for the single length of coding of this element, this open reading frame coding contain structural and nonstructural viral protein～3000 amino acid whose polypeptide.

When the tenuigenin that enters cell, this RNA directly translate into comprise structural and nonstructural viral protein～3000 amino acid whose polypeptide.The proteolytic ferment of subsequently that this is big polypeptide by host and encoding viral combines and is treated to discrete structural and unstructuredness protein (Rice, C.M. (1996) in B.N.Fields, D.M.Knipe and P.M.Howley (eds) Virology 2 ^NdEdition, p931-960; Raven Press, N.Y.).After the terminator codon of long ORF end, there is the 3 ' NTR that roughly forms by three zones :～40 base zones, it is weak conservative in the range gene type; Many (gathering) uridylic acid of variable-length/poly-pyrimidine sequence; And the 98 base compositions (Kolykhalov, people such as A. (1996) the J.Virology 70:3363-3371 that are also called the high conservative at " 3 ' X-end "; Tanaka, people such as T. (1995) Biochem Biophys.Res.Commun.215:744-749; Tanaka, people such as T. (1996) J.Virology 70:3307-3312; Yamada, people such as N. (1996) Virology223:255-261).Predict that this 3 ' NTR can form stable secondary structure, its HCV growth for chimpanzee is necessary, and it is believed that its function is initiation and regulates viral RNA and duplicate.

The NS5B protein of this HCV (591 amino acid, 65kDa) (Behrens, people such as S.E (1996) EMBO are J.15:12-22) coding RNA-RNA-dependent polysaccharase (RdRp) activity, and contain the standard motif that is present in other RNA viruses polysaccharase.This NS5B protein interior-type (cross 1b conivium～95-98% amino acid (aa) identity) and-type (between genotype 1a and the 1b conivium～85%aa identity) all has quite good conservative property.HCV NS5B RdRp activity to the importance of infectious progeny virion in orangutan, obtained formal confirmation (people such as A.A.Kolykhalov. (2000) Journal of Virology, 74 (4), p.2046-2051).Therefore, prediction inhibition NS5B RdRp activity (inhibition rna replicon) can be treated the HCV infection.

Based on above-mentioned, the ability that they suppress HCV to identification synthetic or biological compound has important demand.

Summary of the invention

The present invention relates to the acyl pyrroline hydride compounds of following representative, comprise the pharmaceutical composition of this compound, and the purposes of this compound in treatment virus infection, particularly HCV infect.

Detailed Description Of The Invention

The invention provides formula (I) compound and its salt, solvate and ester and be used for medical treatment:

Wherein:

The A representation hydroxy;

D represents aryl or heteroaryl;

E represents hydrogen, C _1-6Alkyl, aryl, heteroaryl or heterocyclic radical;

G represents hydrogen or optional by one or more C that are selected from following substituting group replacement _1-6Alkyl: halogen, OR ¹, SR ¹, C (O) NR ²R ³, CO ₂H, C (O) R ⁴, CO ₂R ⁴, NR ²R ³, NHC (O) R ⁴, NHCO ₂R ⁴, NHC (O) NR ⁵R ⁶, SO ₂NR ⁵R ⁶, SO ₂R ⁴, nitro, cyano group, aryl, heteroaryl and heterocyclic radical;

R ¹Represent hydrogen, C _1-6Alkyl, arylalkyl or heteroarylalkyl;

R ²And R ³Be independently selected from hydrogen, C _1-6Alkyl, aryl and heteroaryl; Or R ²And R ³Coupled nitrogen-atoms forms 5 or 6 Yuans saturated cyclic groups together;

R ⁴Be selected from C _1-6Alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl;

R ⁵And R ⁶Be independently selected from hydrogen, C _1-6Alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl; Or R ⁵And R ⁶Coupled nitrogen-atoms forms 5 or 6 Yuans saturated cyclic groups together; With

J represents C _1-6Alkyl, heterocyclic radical alkyl, arylalkyl or heteroarylalkyl;

Condition is as esterification A formation-OR, and when wherein R was selected from the alkyl, aralkyl, aryloxy alkyl of straight or branched or aryl, R was not the tertiary butyl.

As the present invention on the other hand, the medical treatment that provides formula (I) compound or pharmaceutically acceptable salt thereof, solvate or ester to be used for the mankind or animal doctor infects especially for treatment or prophylaxis of viral infections, particularly HCV.

Be to be understood that treatment mentioned in the literary composition (therapy) and/or treatment (treatment) include but not limited to preventing, postpone, prevent, treat and curing of disease.Treatment or prevention that HCV is infected mentioned in the literary composition be should further understand and treatment or prevention HCV-relative disease such as hepatic fibrosis, liver cirrhosis and hepatocellular carcinoma comprised.

According to a further aspect of the invention, provide formula (I) compound or pharmaceutically acceptable salt thereof, solvate or ester to be used for the treatment of and/or prophylaxis of viral infections, particularly the purposes in the medicine of HCV infection in preparation.

In aspect other or another, the invention provides a kind of treatment and suffer from the human or animal patient's that virus infection, particularly HCV infect method, described method comprises the formula of significant quantity (I) compound or pharmaceutically acceptable salt thereof, solvate or ester is delivered medicine to described human or animal patient.

In one aspect of the invention, formula (I) compound is by formula (I ') representative:

Wherein:

The A representation hydroxy;

D represents aryl or heteroaryl;

E represents hydrogen, C _1-6Alkyl, aryl, heteroaryl or heterocyclic radical;

G represents hydrogen or optional by one or more C that are selected from following substituting group replacement _1-6Alkyl: halogen, OR ¹, SR ¹, C (O) NR ²R ³, C (O) R ⁴, CO ₂R ⁴, NR ²R ³, NHC (O) R ⁴, NHCO ₂R ⁴, NHC (O) NR ⁵R ⁶, SO ₂NR ⁵R ⁶, SO ₂R ⁴, nitro, cyano group and heterocyclic radical;

R ¹Represent hydrogen, C _1-6Alkyl, arylalkyl or heteroarylalkyl;

With its salt, solvate and ester; Condition is as the esterified formation-OR of A, and when wherein R was selected from the alkyl, aralkyl, aryloxy alkyl of straight or branched or aryl, R was not the tertiary butyl.

The present invention also provides new formula (I) compound and its salt, solvate and ester in addition, is represented by formula (Ia):

Wherein:

The A representation hydroxy;

D represents aryl or heteroaryl;

E represents hydrogen, C _1-6Alkyl, aryl, heteroaryl or heterocyclic radical;

G represents hydrogen or optional by one or more C that are selected from following substituting group replacement _1-6Alkyl: halogen, OR ¹, SR ¹, C (O) NR ²R ³, CO ₂H, C (O) R ⁴, CO ₂R ⁴, NR ₂R ³, NHC (O) R ⁴, NHCO ₂R ⁴, NHC (O) NR ⁵R ⁶, SO ₂NR ⁵R ⁶, SO ₂R ⁴, nitro, cyano group, aryl, heteroaryl and heterocyclic radical;

R ¹Represent hydrogen, C _1-6Alkyl, arylalkyl or heteroarylalkyl;

Condition is i) E and G not all be hydrogen; With

Ii) this compound is not

4-vinyl-1-(2-nitro benzoyl)-2,2-tetramethyleneimine dicarboxylic acid, diethyl ester;

1-(2-amino benzoyl)-4-(1-hydroxyethyl)-2,2-tetramethyleneimine dicarboxylic acid, diethyl ester;

4-(1-hydroxyethyl)-1-(2-nitro benzoyl)-2,2-tetramethyleneimine dicarboxylic acid, diethyl ester;

Condition is as the esterified formation-OR of A, and when wherein R was selected from the alkyl, aralkyl, aryloxy alkyl of straight or branched or aryl, R was not the tertiary butyl.

In one aspect of the invention, formula (Ia) compound is by formula (Ia ') representative:

Wherein:

The A representation hydroxy;

D represents aryl or heteroaryl;

E represents hydrogen, C _1-6Alkyl, aryl, heteroaryl or heterocyclic radical;

R ¹Represent hydrogen, C _1-6Alkyl, arylalkyl or heteroarylalkyl;

Condition is i) E and G not all be hydrogen; With

Ii) this compound is not

Be to be understood that compound of the present invention can contain one or more unsymmetrical carbons, and can racemize, form diastereoisomeric and optically-active exists.All these racemic compounds, enantiomer and diastereomer are considered within the scope of the invention.

One preferred aspect in, the relative stereochemistry (relative stereochemistry) of formula (I) and/or formula (Ia) racemic compound is by formula (Ip) or (Iq) representative:

(Ip) (Iq)

Three-dimensional relatively chemofacies is to stereochemistry

Wherein A, D, E, G and J such as following formula (I) or (Ia) definition.

Aspect preferred, the absolute stereo chemistry of the chipal compounds of formula (I) and/or formula (Ia) is by formula (Ipp) or (Iqq) representative:

(Ipp) (Iqq)

Absolute stereo chemistry absolute stereo chemistry

Wherein A, D, E, G and J such as following formula (I) or (Ia) definition.

For among formula I, I ', Ia, Ia ', Ip, Ipp, Iq and the Iqq each, if suitable preferred following substituting group:

Preferably, the optional phenyl that replaces of D representative; More preferably optional further substituted tert-butyl-phenyl; Particularly preferred for optional further substituted, preferably by halogen, C _1-3Alkyl or C _1-3Between alkoxyl group, particularly bromine, chlorine, methyl or methoxy-right-tert-butyl-phenyl of replacing; Most preferably D be between-methoxyl group-right-tert-butyl-phenyl (3-methoxyl group-4-tert-butyl-phenyl).

Preferably, E is selected from C _1-6Alkyl, aryl and heteroaryl; More preferably, the optional heteroaryl that replaces of E representative is preferably thiazolyl, pyridyl, pyrazinyl, isoxazolyl and thienyl; Particularly preferred is pyridine-2-base, 5-picoline-2-base, pyrazine-2-base, 1,3-thiazol-2-yl, 5-methyl isophthalic acid, 3-thiazol-2-yl, 5-methoxymethyl-1,3-thiazol-2-yl, 2-chloro-1,3-thiazole-5-base, 2-methoxyl group-1,3-thiazole-5-base, 1,3-thiazoles-4-base, 5-methyl-isoxazole-3-base or thiophene-2-base; Most preferably be 1,3-thiazoles-2-base.

Another preferred aspect, E is selected from C _1-6Alkyl, aryl and heteroaryl; More preferably E represents heteroaryl, is preferably thiazolyl, pyridyl and pyrazinyl; Particularly preferred is pyridine-2-base, pyrazine-2-base, 1,3-thiazoles-2-base, 5-methyl isophthalic acid, 3-thiazol-2-yl, 2-chloro-1,3-thiazoles-5-base, 2-methoxyl group-1,3-thiazoles-5-base or 1,3-thiazoles-4-base; Most preferred is 1,3-thiazoles-2-base.

Preferably, the G representative is optional by halogen, OR ¹, SR ¹, SO ₂R ⁴C with the cyano group replacement _1-6Alkyl; More preferably, the G representative is optional by OR ¹The C that replaces _1-6Alkyl; Particularly preferably, the G representative is optional by OR ¹The methyl that replaces.

Preferably, R ¹Represent hydrogen or C _1-3Alkyl; More preferably, R ¹Represent hydrogen, methyl, ethyl, propyl group or third-2-thiazolinyl, particularly methyl or ethyl.

Preferably, R ⁴Represent C _1-3Alkyl; More preferably, R ⁴Represent methylidene, ethyl or propyl group, particularly methyl or ethyl.

Preferably, J represents C _1-6Alkyl, arylalkyl or heteroarylalkyl; More preferably isobutyl-, third-2-thiazolinyl, benzyl or pyridylmethyl, particularly isobutyl-.

In one aspect of the invention, when D is the phenyl that is replaced by at least two substituting groups, described substituting group be independently selected from hydroxyl, alkoxyl group ,-CO ₂H ,-CO ₂R ⁴Or fluorine; G is hydrogen or C _1-6Alkyl; With J be C _1-6During alkyl; E is aryl, heteroaryl or heterocyclic radical.

Be to be understood that and the present invention includes suitable, convenient and preferably all combinations of group described in the literary composition.

Unless otherwise noted, " alkyl " as used herein refers to the optional alkyl that replaces.This alkyl alkyl can be straight chain, side chain or cyclic, saturated or undersaturated.Wherein when this alkyl alkyl is ring-type, be to be understood that minimumly in this group have 3 carbon atoms.Wherein when this alkyl alkyl when being unsaturated, be to be understood that minimumly in this group have 2 carbon atoms and this group can be for example alkenyl or alkynyl.Preferably, this group is saturated.Preferred moieties is C _1-6Alkyl, more preferably C _1-4Alkyl.Unless otherwise noted, Ren Xuan substituting group comprises C _1-6Alkyl, halogen, OR ¹, SR ¹, C (O) NR ²R ³, C (O) R ⁴, CO ₂H, CO ₂R ⁴, NR ²R ³, NHC (O) R ⁴, NHCO ₂R ⁴, NHC (O) NR ⁵R ⁶, SO ₂NR ⁵R ⁶, SO ₂R ⁴, nitro, cyano group, oxygen base and heterocyclic radical.

" alkoxyl group " as used herein (when as group or group a part of) refers to alkylether radicals, and wherein term " alkyl " definition is the same.The example of alkoxyl group as used herein includes but not limited to methoxyl group, oxyethyl group, positive propoxy, isopropoxy etc.

" aryl " as used herein refers to the optional aromatic group that replaces, and this aromatic group has at least one ring that contains conjugated πDian Zi system, contains up to two conjugation or condensed loop systems." aryl " comprises isocyclic aryl and two aromatic yl group, and it all can be chosen wantonly and be substituted, for example phenyl, naphthyl or xenyl.Preferably " aryl " part is replacement, single replacement, two replacement or trisubstd phenyl.Preferably " aryl " substituting group is selected from: C _1-6Alkyl, halogen, OR ¹, C (O) NR ²R ³, C (O) R ⁴, CO ₂H, CO ₂R ⁴, NR ²R ³, NHC (O) R ⁴, NHCO ₂R ⁴, NHC (O) NR ⁵R ⁶, SO ₂NR ⁵R ⁶, SO ₂R ⁴, nitro, cyano group, oxygen base, heterocyclic radical, CF ₃And NO ₂

" heteroaryl " as used herein refers to and comprises 1-4 5 or 6 Yuans aromatic groups that are selected from the heteroatomic optional replacement of N, O and S, and this group has at least one ring that contains conjugated πDian Zi system, contains up to two conjugation or condensed loop systems.Preferably " heteroaryl " part is replacement, single replacement, two replacement or trisubstituted pyridyl and thiazolyl.Preferably " heteroaryl " substituting group is selected from: C _1-6Alkyl, halogen, OR ¹, C (O) NR ²R ³, C (O) R ⁴, CO ₂H, CO ₂R ⁴, NR ²R ³, NHC (O) R ⁴, NHCO ₂R ⁴, NHC (O) NR ⁵R ⁶, SO ₂NR ⁵R ⁶, SO ₂R ⁴, nitro, cyano group, oxygen base, heterocyclic radical, CF ₃And NO ₂

" heterocyclic " as used herein and " heterocyclic radical " refer to 5 or 6 Yuans saturated cyclic hydrocarbon radical that comprise 1 or 2 heteroatomic optional replacement, and this heteroatoms is selected from: N, it is optional by hydrogen, C _1-6Alkyl, C (O) R ⁴, SO ₂R ⁴, aryl or heteroaryl replace; O; And S, it is chosen wantonly and is replaced by one or two Sauerstoffatom.

Being used for preferred formula of the present invention (I) compound is selected from:

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methyl fluoride-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

2-allyl group-1-(3-bromo-4-tert.-butylbenzene formyl radical)-tetramethyleneimine-2-carboxylic acid;

2-benzyl-1-(3-bromo-4-tert.-butylbenzene formyl radical)-tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-allyloxy methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-propoxy-methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-pseudoallyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-sec.-propyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

(2S, 4S, 5R)-2-isobutyl--1-(3-bromo-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2-carboxylic acid;

(2S, 4S, 5R)-2-isobutyl--1-(3-chloro-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2-carboxylic acid;

(2S, 4S, 5R)-2-isobutyl--1-(3-methyl-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2R, 4R, 5R)-2-benzyl-1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2-carboxylic acid;

Rel-(2R, 4R, 5R)-2-benzyl-1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(pyrazine-2-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(pyrazine-2-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(5-methyl isophthalic acid, 3-thiazol-2-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(2-chloro-1,3-thiazoles-5-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(2-methoxyl group-1,3-thiazoles-5-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-((methylthio group) methyl)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-((methylsulfonyl) methyl)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-(1,1-two fluoro ethyls)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-(1-hydroxyl-1-methylethyl)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2R, 4S, 5R)-2-benzyl-1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2-carboxylic acid;

Rel-(2R, 4S, 5R)-2-benzyl-1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(pyridine-2-yl) tetramethyleneimine-2-carboxylic acid;

(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-(1-hydroxyl-1-methylethyl)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-(1-hydroxyethyl)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-4-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-allyloxy methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-propoxy-methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-cyano methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-(1-hydroxyl-1-methylethyl)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(pyridine-2-yl))-tetramethyleneimine-2-carboxylic acid;

Rel (2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-(1-methoxy ethyl)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxyl group-methyl-5-(pyridine-2-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(5-methyl-isoxazole-3-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(5-methoxymethyl-1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(5-picoline-2-yl) tetramethyleneimine-2-carboxylic acid;

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(thiophene-2-yl) tetramethyleneimine-2-carboxylic acid;

With its salt, solvate and ester and if suitable each enantiomer.

Preferred formula (Ia) compound is selected from:

(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(pyridine-2-yl) tetramethyleneimine-2-carboxylic acid;

With its salt, solvate and ester and if suitable each enantiomer.

In aspect preferred, the invention provides formula (I) and/or (Ia) compound, it is selected from compound and its salt, solvate and ester and if suitable each enantiomer that defines among the embodiment 1-45 hereinafter.In aspect in addition preferred, the invention provides formula (I) compound, it is selected from compound and its salt, solvate and ester and if suitable each enantiomer that defines among the embodiment 1-16 hereinafter.In aspect in addition preferred, the invention provides formula (I) compound, it is selected from compound and its salt, solvate and ester and if suitable each enantiomer that defines among the embodiment 1-14 hereinafter.

Also comprise in the present invention for the pharmacologically acceptable salt complex compound.The present invention also comprises the pharmacologically acceptable salt of formula (I) compound.The suitable pharmacologically acceptable salt of formula (I) compound comprises acid-salt, for example sodium, potassium, calcium, magnesium and tetraalkylammonium salt etc., or with suitable acid for example organic carboxyl acid such as acetate, lactic acid, tartrate, oxysuccinic acid, hydroxyl second (base) sulfonic acid, lactobionic acid and succsinic acid; The list that organic sulfonic acid such as methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid and tosic acid and mineral acid example hydrochloric acid, sulfuric acid, phosphoric acid and thionamic acid etc. form-or two-basic salt.

The invention still further relates to the solvate of formula (I) compound, for example hydrate.

The invention still further relates to the formula (I) and (Ia) the pharmaceutically acceptable ester of compound, carboxylicesters-COOR for example, wherein R is selected from the alkyl of straight or branched, and for example n-propyl, normal-butyl, alkoxyalkyl (as methoxymethyl), aralkyl (as benzyl), aryloxy alkyl (as phenoxymethyl), aryl are (as choosing wantonly by halogen, C _1-4Alkyl or C _1-4Alkoxyl group or the amino phenyl that replaces).Unless otherwise noted, any moieties that is present in this ester class preferably contains 1-18 carbon atom, a particularly 1-4 carbon atom.Any aryl moiety that is present in this ester class preferably contains phenyl group.

Preferably, the present invention relates to formula (I) and (Ia) compound and its salt and solvate.

Should further understand the tautomeric form existence that some compound of the present invention can be different.All tautomers all comprise within the scope of the invention.

Wherein A be the formula (I) of hydroxyl and (Ia) compound can prepare by deprotection by formula (II) compound,

A is the hydroxyl of protection in formula (II), and for example alkoxyl group, benzyloxy or siloxy-are as three-(C _1-4Alkyl)-siloxy-, and D, E, G and J such as following formula (I) or (Ia) definition.Suitable blocking group includes but not limited to T W Greene and P G M Wuts ' Protective Groups in OrganicSynthesis ', 3 ^RdEd (1999), those that describe among the J Wiley and Sons.

For example when A be tert.-butoxy, and D, E, G and J be during as the definition of following formula (I) institute, by with for example trifluoroacetic acid processing of suitable acid.Suitably, this is reflected at solvent and for example carries out in the methylene dichloride.Preferably, temperature is 0-50 ℃, more preferably 20-30 ℃.

For example when A be benzyloxy, and D, E, G and J such as following formula (I) during definition, by for example carrying out hydrogenolysis in the presence of palladium-carbon in appropriate catalyst.Suitably, this is reflected at solvent and for example carries out in the ethanol.Preferably, temperature is 0-50 ℃.

For example when A be allyloxy, and D, E, G and J such as following formula (I) during definition, by with appropriate catalyst for example tetrakis triphenylphosphine palladium (0) and suitable proton source, for example phenyl silane treated.This is reflected at suitable solvent and for example carries out in the methylene dichloride.

For example when A be three (methyl) siloxy-, and D, E, G and J be during as the definition of following formula (I) institute, by with for example tetrabutylammonium fluoride processing of suitable fluoride source.This is reflected at suitable solvent and for example carries out in the tetrahydrofuran (THF).

Wherein A is the formula (I) of hydroxyl or its protection form and (Ia) compound also can be by the defined formula of A, E, G and J such as following formula (I) (III) compound wherein; with suitable acylating reagent; D-C (O)-hal for example; wherein hal is a halogen atom; be preferably chlorine or bromine; and D such as following formula (I) definition, prepared in reaction obtains.

Preferably, this is reflected at for example methylene dichloride of suitable solvent, for example carries out in the presence of the triethylamine at suitable alkali, and removes blocking group subsequently.Suitable blocking group includes but not limited to T W Greene andP G M Wuts ' Protective Groups in Organic Synthesis ', 3 ^RdDescribed in the Ed (1999), J Wiley andSons those.

Wherein the formula (I) of the optional alkyl that replaces of G representative or (II) compound can prepare by suitable processing formula (IIa) compound,

In the formula (IIa), A is hydroxyl or alkoxyl group, benzyloxy or three-(C _1-4Alkyl)-siloxy groups, D, E and J such as following formula (I) definition, and L represents CO ₂Y or COY, wherein Y represents hydrogen or alkyl.

The formula of G representation hydroxy alkyl (II) compound wherein for example, can be by using for example lithium borohydride, sodium borohydride, sodium triacetoxy borohydride, borine/dimethyl sulphide ether complexes or lithium aluminium hydride or its suitable combination of appropriate reductant, for example in tetrahydrofuran (THF) or the methyl alcohol, reducing wherein, L represents CO at suitable solvent or its mixture ₂On behalf of formula (IIa) compound of hydrogen or alkyl, Y or COY and Y obtain.

The formula of G representation hydroxy alkyl (II) compound wherein for example also can L represents CO by making wherein ₂Y or COY and Y represent formula (IIa) compound of hydrogen or alkyl, with suitable organometallic reagent for example methyl-magnesium-bromide or lithium methide, suitable solvent for example in the tetrahydrofuran (THF) prepared in reaction obtain.

For example wherein G represents formula (II) compound of fluoroalkyl, can on behalf of COY and Y, L represent formula (IIa) compound and the suitable fluorination reagent of alkyl by making wherein, diethylamino sulfur trifluoride (diethylaminosulfur trifluoride) for example, suitable solvent for example in the methylene dichloride prepared in reaction obtain.

For example wherein G represents formula (II) compound of thiazolinyl can be by with microcosmic salt for example halogenation microcosmic salt such as Diethylaminoethyl triphenylphosphine, methyl chloride triphenylphosphine, bromination methoxymethyl triphenylphosphine or chlorination methoxymethyl triphenylphosphine, in the presence of for example two (trimethyl silyl) lithium amides of alkali, and at suitable solvent for example in the tetrahydrofuran (THF), handling wherein, on behalf of COY and Y, L represent formula (IIa) compound of hydrogen or alkyl to obtain.

On the other hand, formula (II) compound can prepare by the proper operation of other formula (II) compound.For example the formula of G representation hydroxy alkyl (II) compound wherein can be converted into wherein for example formula of alkyl, haloalkyl or alkoxyalkyl (II) compound of the optional alkyl that replaces of G representative.

The formula of G representation alkoxy alkyl (II) compound wherein for example, can be by using suitable alkali for example sodium hydride and suitable alkylating reagent such as alkiodide, alkylation (for example use methyl iodide to methylate or use iodoethane to ethylize) the wherein formula of G representation hydroxy alkyl (II) compound obtains.This reaction is preferably for example carried out in the dimethyl formamide at suitable solvent.

For example wherein G represents formula (II) compound of haloalkyl, can use suitable halide reagent halogenation wherein the formula of G representation hydroxy alkyl (II) compound obtain, for example at suitable solvent, for example in the methylene dichloride, can hydroxymethyl be changed into methyl fluoride by using for example diethylamino sulfur trifluoride of suitable fluorination reagent.

For example wherein G represents formula (II) compound of cyano methyl, can be by making the wherein formula of G representation hydroxy methyl (II) compound and for example trifluoromethanesulfonic acid anhydride reactant, and for example cyanide salt such as tetrabutyl ammonium cyanide come Processing of Preparation to obtain with nucleophilic reagent subsequently.Wherein G represents C _1-4The formula of alkylthiomethyl (II) compound can use C _1-4The alkyl sulfide alkoxide prepares according to similar methods as nucleophilic reagent.

For example wherein G represents C _1-4The formula of alkyl sulfonyl ylmethyl (II) compound can be by using for example 3-chlorine peroxybenzoic acid, and for example in the methylene dichloride, C is represented in oxidation wherein G at suitable solvent _1-4The formula of alkylthiomethyl (II) compound obtains.

For example wherein G represents formula (II) compound of alkyl, can the desoxydatoin of the formula of G representation hydroxy alkyl (II) compound prepares by making wherein.This desoxydatoin is adapted at finishing in the two step processes, wherein:

Step (i) is by with for example 4-fluorophenyl thiocarbonyl group carbonochloridic acid ester (thionochloroformate) processing of suitable chloro-formic ester, and the formula of G representation hydroxy alkyl (II) compound wherein is converted into the thiocarbonyl group manthanoate.Preferably, this reaction is at suitable solvent for example in the methylene dichloride, suitable alkaline catalysts for example 4-(N, N-dimethylamino) pyridine exist and carry out down.Step (ii) will be by resulting thiocarbonyl group manthanoate in the step (i) with suitable radical initiator AIBN for example, suitable proton source as three (trimethyl silyl) silicomethane in, for example handle in the diox at suitable solvent.Preferably, this temperature is 80-120 ℃.

For example wherein G represents formula (II) compound of undersaturated alkyl group such as 1-methyl ethylene or 2-methoxy-ethylene base, can be in the presence of appropriate catalyst such as palladium-carbon, and in suitable solvent such as ethanol, be converted into the saturated alkyl group of wherein G representative such as formula (II) compound of sec.-propyl or 2-methoxy ethyl by hydrogenation.

For example wherein G represents formula (II) compound of the alkene oxygen base alkyl of alkene oxygen base alkyl or replacement, can be in the presence of appropriate catalyst such as palladium-carbon, and in suitable solvent such as ethanol, be converted into formula (II) compound of the alkoxyalkyl of G representation alkoxy alkyl wherein or replacement by hydrogenation.For example the allyloxy alkyl of allyloxy alkyl or replacement can be converted into the propoxy-alkyl of propoxy-alkyl or replacement.

For example E wherein can be represented 2-chloro-1, formula (II) compound of 3-thiazole-5-base, by with for example sodium hydroxide and the suitable alkoxide heating of suitable alkali, being converted into wherein, E represents 2-alkoxyl group-1, formula (II) compound of 3-thiazole-5-base, for example 2-methoxyl group-1,3-thiazoles-5-base can prepare by using sodium hydroxide and methyl alcohol.

Wherein L represents CO ₂Y wherein Y represents formula (IIa) compound of hydrogen, can represent CO by L wherein ₂On behalf of formula (IIa) compound of alkyl, Y wherein Y obtain.For example wherein L represents CO ₂The formula of Me (IIa) compound can be by hydrolysis as using the suitable alkali such as the alkali catalyzed hydrolysis of sodium methylate, and being converted into wherein in suitable solvent such as methyl alcohol, L represents CO ₂The formula of H (IIa) compound.

Wherein L represents CO ₂Y or COY wherein Y represent formula (IIa) compound of hydrogen or alkyl, can be by formula (IIIa) compound

Wherein L represents CO ₂Y or COY wherein Y represent hydrogen or alkyl, and A, E and J such as following formula (I) definition; With suitable acylating reagent, D-C (O)-hal for example, wherein hal is a halogen atom, is preferably chlorine or bromine, and D such as following formula (I) definition, prepare.Preferably, this reaction is at suitable solvent for example in the methylene dichloride, for example carries out in the presence of the triethylamine at suitable alkali.

On the other hand, wherein on behalf of COY and Y, L represent formula (IIa) compound of hydrogen to represent CO by L wherein ₂On behalf of formula (IIa) compound of hydrogen or alkyl, Y and Y prepare according to two step processes.In first step, wherein L represents CO ₂Y and Y represent formula (IIa) compound of hydrogen or alkyl, with for example lithium aluminium hydride or sodium borohydride processing of appropriate reductant.In second step, with the hydroxyl that suitable oxygenant oxidation generates, this oxygenant is selected from conventional oxidant known in the art, for example the suitable mixture of oxalyl chloride, dimethyl sulfoxide (DMSO) and triethylamine.

Wherein A is that formula (IIa) compound of hydroxyl can be converted into wherein that A is formula (IIa) compound of alkoxyl group, benzyloxy or siloxy-by the hydroxyl protection method of standard.Similarly, wherein A is that formula (IIa) compound of alkoxyl group, benzyloxy or siloxy-can be converted into wherein that A is formula (IIa) compound of hydroxyl by the deprotection method of standard.Suitable blocking group includes but not limited to T W Greeneand P G M Wuts ' Protective Groups in Organic Synthesis ', 3 ^RdDescribed in the Ed (1999), J Wiley and Sons those.

Formula (IIIa) compound can obtain by making formula (IV) compound and formula V compound prepared in reaction,

In formula (IV) E and J such as following formula (I) definition and A such as following formula (II) definition,

L represents CO in formula V ₂Y or COY wherein Y represent hydrogen or alkyl.Preferably, this reaction is, to choose wantonly at Lewis acid catalyst such as lithiumbromide or Silver monoacetate and alkali such as triethylamine, 1 for example in THF or the acetonitrile at suitable solvent, and 8-diazabicylo [5,4,0] 11 carbon-7-alkene (DBU) or tetramethyl guanidine exist and carry out down.Perhaps, this is reflected at suitable solvent for example in THF or the acetonitrile, carries out in the presence of as acetate in acid, and maybe this reaction can be passed through at suitable solvent for example in toluene, dimethylbenzene or the acetonitrile, do not having in the presence of the catalyzer, heating-type (IV) and formula V compound carry out.

Wherein formula (III) compound of the optional alkyl that replaces of G representative can be by at first using suitable N-protected base; after for example benzyloxy carbonyl (CBZ) or tert-butoxycarbonyl are protected the N-atom of pyrrolidine ring,, formula (IIIa) compound obtains by being carried out suitable Processing of Preparation.The formula of G representation hydroxy alkyl (III) compound wherein for example can be by using appropriate reductant such as lithium borohydride or sodium borohydride, and in suitable solvent such as tetrahydrofuran (THF), reducing wherein, L represents CO ₂On behalf of formula (IIIa) compound of alkyl, Y and Y obtain.Carry out the deprotection of N-atom, production (III) compound by standard method.For example when the N-protected base was CBZ, deprotection can be finished by catalytic hydrogenolysis.For example when the N-protected base was tert-butoxycarbonyl, deprotection can be finished by handling with suitable acid such as trifluoroacetic acid.

According to relate to formula (II) compound similar methods above described; wherein G representation hydroxy alkyl and the protected formula of N-atom (III) compound can be converted into wherein the optional alkyl that replaces of G representative for example alkyl, haloalkyl or alkoxyalkyl and the protected formula of N-atom (III) compound.Carry out the deprotection of N-atom by standard method, generate new formula (III) compound.

Formula (IV) compound can be by making formula (VI) compound and formula E-CHO compound, at suitable alkali for example in the presence of the triethylamine, suitable solvent for example in the methylene dichloride prepared in reaction obtain, in formula (VI), J in the following formula (I) institute's definition and A such as following formula (II) middle definition.

Formula (VI) and E-CHO compound are known in the artly maybe can to prepare by the document step of standard.

Wherein A is that formula (I) compound of ester can be by being used for the normative document operation of esterification, is that formula (I) compound of hydroxyl carries out esterification and prepares with A wherein.

Be to be understood that the formula (I) that exists as diastereomer, (Ia), (II), (IIa), (III) and/or (IIIa) compound can randomly for example separate by column chromatography by technology known in the art.

Should be appreciated that to the invention provides a kind of formula (IIa) or (IIIa) method of the C of compound (4)-epimer change of being used for, wherein L represents CO ₂Y or COY wherein Y represent hydrogen or alkyl, and A, E and J such as following formula (I) definition.If it is suitable, for example formula (IIa) and/or (IIIa) rel-(2S of compound, 4S, 5R)-diastereomer can be converted into rel-(2S, 4R, 5R)-diastereomer, and similarly formula (IIa) and/or (IIIa) rel-of compound (2R, 4S, 5R)-diastereomer can be converted into rel-(2R, 4R, 5R)-diastereomer.These rel-(4S, 5R)-diastereomer epimerization like this turn to corresponding rel-(4R, 5R)-diastereomer, can be by with suitable alkali, in the presence of suitable solvent, processing formula (IIa) and/or (IIIa) compound finish.For example, L is represented CO ₂Rel-(the 4S of the formula of Me (IIa) compound, 5R)-diastereomer is converted into rel-(4R, 5R)-diastereomer is in the presence of suitable solvent such as methyl alcohol, by handle with suitable alkali such as sodium methylate rel-(4S, 5R)-diastereomer finishes.

Being to be understood that formula (I), (Ia), (II), (IIa), (III) and/or racemic compound (IIIa) can be chosen wantonly splits into their independent enantiomers.This fractionation can realize easily by standard method known in the art.For example formula (I), (Ia), (II), (IIa), (III) and/or racemic compound (IIIa) can split by the chirality preparation HPLC.Perhaps, containing formula (I), (Ia), (II), (IIa), (III) and/or the racemic compound (IIIa) of suitable acid or base groups such as hydroxy-acid group or amine groups can be by if the suitable diastereo-isomerism salt that forms standard with chiral base or sour reagent respectively splits.This technology is the set technology in this area.For example wherein L is CO ₂The racemic compound of the formula (IIIa) of Me or C (O) Me can use chiral acid as (R)-(-)-1 by in suitable solvent such as Virahol, 1 '-dinaphthalene-2, and 2 '-two bases-hydrogen orthophosphate (hydrogen phosphate) are handled and are split.

Be to be understood that formula (I), (Ia), (II), (IIa), (III) and independent enantiomerism compound (IIIa) can be by the methods of conventional asymmetric synthesis, if suitable use chiral auxiliary(reagent) or chiral catalyst, and the change step of carrying out aforesaid any appropriate functional group in addition comprises addition or removes this arbitrarily chiral auxiliary(reagent) and is prepared.The asymmetric synthesis method of this routine is known in the art, and include but not limited to " Asymmetric Synthesis; " Academic Press, 1984 and/or " Chiral Auxiliaries andLigands in Asymmetric Synthesis ", Wiley, those described in 1995.For example suitable chiral auxiliary(reagent) commonly used comprises chiral alcohol such as menthol or 1-phenylethyl alcohol; Chiral oxazolidinone such as 4-Bian Ji oxazolidine-2-ketone or 4-Yi Bing Ji oxazolidine-2-ketone; Or Chiral Amine such as 1-phenyl ethyl amine or 2-amino-2-phenylethyl alcohol.Suitable chiral catalyst commonly used comprises the part of the basic amine of chirality and chirality such as N-methyl ephedrine, 1-phenyl-2-(1-pyrrolidyl)-1-propyl alcohol, 3-(dimethylamino)-1,7,7-trimethylammonium two rings [2.2.1]-heptan-2-alcohol, 3, two (xenyl phosphino-(phosphanyl))-1-(phenyl methyl) tetramethyleneimine of 4-, chinchonine, chinchonidine, sparteine, hydroquinine or the complexometric reagent of quinine or chirality such as two (oxazolines of chirality) (BOX) part and derivative, choose wantonly in the presence of metal-salt, for example M _mX _xWherein M is silver, cobalt, zinc, titanium, magnesium or manganese, and X is halogenide (for example muriate or bromide), acetate, trifluoroacetate, tosilate, trifluoromethyl sulfonic acid, hexafluorophosphate or nitrate, and m and x are 1 or 2, and choose wantonly at alkali for example in the presence of the triethylamine.All these chiral auxiliary(reagenties or chiral catalyst all are known in the art.The exemplary embodiment for preparing the chirality tetramethyleneimine by the asymmetric synthesis of using chiral auxiliary(reagent) or chiral catalyst includes but not limited to Angew.Chem.Int.Ed., (2002), 41:4236; Tetrahedron:Asymm., (2001), 12:1977; Tetrahedron:Asymm., (2002), 13:2099; J.Am.Chem.Soc., (2002), 124:13400 and Chem.Rev., (1998), those that describe among the 98:863.

One special aspect in, the chirality pyrrolidine compound of formula (IIIb) can react by formula (IV) compound as defined above and formula (Va) compound, and randomly carries out CO by the method that is used to remove chiral auxiliary(reagent) of standard subsequently ₂Y ¹To CO ₂Any conversion of Y prepares,

L in formula (IIIb) ¹Represent CO ₂Y or CO ₂Y ¹Wherein Y represents hydrogen or alkyl, Y ¹Represent chiral auxiliary(reagent) and A, E and J such as following formula (I) definition, and ^*(enantioenriched) chiral centre of enantiomer is rich in representative,

L in formula (Va) ¹Represent chiral ester group CO ₂Y ¹Y wherein ¹Represent chiral auxiliary(reagent).This chiral ester CO ₂Y ¹Can be by chiral alcohol Y ¹OH for example menthol derives by the esterification techniques of standard and obtains.Preferably, the reaction of formula (IV) compound and formula (Va) compound is at suitable solvent for example in THF or the acetonitrile, choose wantonly at Lewis acid catalyst such as lithiumbromide or Silver monoacetate, with alkali such as triethylamine, 1,8-diazabicylo [5,4,0] 11 carbon-7-alkene (DBU) or tetramethyl guanidine carry out under existing.Perhaps, this reaction is at suitable solvent for example in THF or the acetonitrile, carries out in the presence of as acetate in acid, and perhaps this reaction can be passed through at suitable solvent for example in toluene, dimethylbenzene or the acetonitrile, do not having in the presence of the catalyzer, heating-type (IV) and (Va) compound carry out.Be similar to formula (IIIb) and (Va) preparation method of those compound be described in Tetrahedron:Asymm., (1995) are among the 6:2475.

Randomly, thus the main chirality diastereomer of the resulting formula of asymmetric reaction (IIIb) can be further purification technique by routine known in the art, for example by chromatography or carry out the enrichment of enantiomer by fractional crystallization.Favourable crystallization method is the fractional crystallization of the salt example hydrochloric acid salt of main chirality diastereomer.The hydrochloride of formula (IIIb) compound can obtain by for example handling formula (IIIb) compound with anhydrous hydrogen chloride in the ether at suitable solvent.Preferred this reaction is to carry out under-10 to 10 ℃ temperature.

Randomly from L wherein ¹Represent CO ₂Y ¹Group in remove chiral auxiliary(reagent) to obtain wherein L ¹Represent CO ₂If the group of Y can be finished at an easy rate by the method for standard, for example uses hydrolysing agent suitable for sodium hydroxide or alkoxide such as sodium methylate, handles in suitable solvent such as methyl alcohol.

Randomly, can be by finishing by group L with suitable agent treated ¹Conversion to the functional group of group G is converted into formula (IIIb) chipal compounds the chipal compounds of G representation hydroxy alkyl wherein and A, E and J such as the defined formula of following formula (I) (III).For example can be with L wherein ¹Represent CO ₂Y ¹And Y ¹Formula (IIIb) compound is for example handled in the tetrahydrofuran (THF) at suitable solvent with appropriate reductant lithium aluminium hydride for example as defined above.

Randomly; the chipal compounds of formula (IIIb) can be converted into the wherein chipal compounds of the formula of G representation hydroxy alkyl (II) by following method: at first the aforesaid tetramethyleneimine nitrogen-atoms of acidylate to be being converted into formula (IIa) compound with formula (IIIa) compound, and then finishes by group L with suitable agent treated then ¹Conversion to the functional group of group G.For example can be with L wherein ¹Represent CO ₂Y ¹And Y ¹Formula (IIIb) compound as defined above, at suitable solvent for example in the tetrahydrofuran (THF), with appropriate reductant for example lithium aluminium hydride handle.

Should be appreciated that with suitable aforesaid other step of converting, can prepare formula (I) and/or chipal compounds (Ia) by formula (II) or chipal compounds (III).

Be to be understood that any undersaturated alkyl substituent can for example change into saturated alkyl substituent through appropriate catalyst such as palladium-hydrocarbonize by reduction, condition is at first to protect any other responsive substituting group and carry out deprotection subsequently.

Any chemical functional group is carried out suitable operation and protection, come the synthetic of perfect (I) compound with described those methods of experimental section by being similar to as described above those.Suitable blocking group includes but not limited to T W Greene and P G M Wuts ' Protective Groups in OrganicSynthesis ', 3 ^RdDescribed in the Ed (1999), J Wiley and Sons those.

Embodiment

Intermediate 1

2-[N-(1,3-thiazoles-2-methylene) amino]-the 4-methylvaleric acid, the tert-butyl ester

Under nitrogen, with 2-amino-4-methyl-valeric acid tert-butyl ester hydrochloride of stirring (5.00g, 22.34mmol), 1,3-thiazoles-2-formaldehyde (2.53g, 22.34mmol) and triethylamine (3.10mL, methylene dichloride 22.3mmol) (60mL) mixture heating up backflow 19 hours.Reaction mixture is cooled to room temperature, washes twice with water, through Na ₂SO ₄Dry also evaporation prepares the buttery title compound.

¹H NMR (CDCl ₃): δ 8.46 (s, 1H), 7.94 (d, 1H), 7.44 (d, 1H), 4.07 (dd, 1H), 1.89-1.74 (m, 2H), 1.64-1.52 (m, 1H), 1.48 (s, 9H), 0.96 (d, 3H) and 0.90 (d, 3H).

Intermediate 2

Rel-(2S, 4S, 5R)-and 2-isobutyl--5-(1,3-thiazoles-2-yl) tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Relative stereochemistry shown in racemic

Under nitrogen, (0.53g adds methyl acrylate (254 μ L in anhydrous THF (3mL) solution 1.88mmol) to the intermediate 1 of stirring of cooling (0 ℃), 2.83mmol), add subsequently lithiumbromide (0.33g, 3.80mmol) and triethylamine (390 μ L, 2.82mmol).This is reflected in the cooling bath stirred 5 minutes, and stir in envrionment temperature then and spend the night.Add aqueous ammonium chloride solution (15mL), and the mixture that generates is extracted with ethyl acetate (20mL).Merge extract, and water and salt washing, dry then (MgSO ₄).Vacuum evaporating solvent prepares the solid title compound.

MS counts 2 calculation value (C ₁₈H ₂₈N ₂O ₄S+H) ⁺: 369

MS measured value (found) (electrospray): (M+H) ⁺=369.

Intermediate 3

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Relative stereochemistry shown in racemic

To the 3-methoxyl group-4-tert.-butylbenzene formyl chloride that stirs ¹(3.36g, add in anhydrous methylene chloride 37mmol) (50mL) solution intermediate 2 (4g, 24mmol) and triethylamine (2.27mL, 37mmol).Under nitrogen, this mixture was stirred 6 hours, and then with the methylene dichloride dilution, and wash with water.Dry this organic phase (MgSO ₄) and vacuum-evaporation.Come the purifying resistates by recrystallization from methylene dichloride, and wash, prepare the solid title compound with ether.

MS calculated value (C ₃₀H ₄₂N ₂O ₆S+H) ⁺: 559

MS measured value (electrospray): (M+H) ⁺=559.

Document (1): Synthesised from 3-methoxy-4-tert-butylbenzoic acid (J.Org.Chem., 26,1961,1732-1737).

Intermediate 4 and intermediate 4a

Intermediate 4

Rel-(2S, 4R, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

Intermediate 4a

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

In room temperature, (2.3g adds THF (2.93mL, 5.85mmol) solution of 2M lithium borohydride in anhydrous THF (23mL) solution 4.12mmol) to the intermediate 3 that stirs under nitrogen.This solution in stirred overnight at room temperature, and is used the K of 1M then ₂CO ₃Solution (100mL) stops, and extracts with ethyl acetate (100mL, 50mL then).Dry organic phase (the MgSO that merges ₄) and vacuum-evaporation.With the natural gum that generates by using hexanaphthene-ethyl acetate (7: 3v/v) as the silica gel chromatography purifying of eluent; prepare intermediate 4a; rel-(2S; 4S; 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl-5-(1; the 3-thiazol-2-yl) tetramethyleneimine-2-carboxylic acid; the tert-butyl ester; obtain intermediate 4 subsequently; rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl-5-(1; the 3-thiazol-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester.

Intermediate 4

MS calculated value (C ₂₉H ₄₂N ₂O ₅S+H) ⁺: 531

MS measured value (electrospray): (M+H) ⁺=531.

Intermediate 4a

MS calculated value (C ₂₉H ₄₂N ₂O ₅S+H) ⁺: 531

MS measured value (electrospray): (M+H) ⁺=531

Intermediate 5

Rel-(2S, 4R, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

In the solution of the dry DMF (5mL) of intermediate 4 (0.14g), add sodium hydride (60% mineral oil dispersion, 16mg).When the gas of emitting reduces, add iodoethane (0.084mL).Under nitrogen atmosphere,, mixture was stirred 18 hours in envrionment temperature.Add the more sodium hydride dispersion of volume (17mg), and add iodoethane (0.084mL), mixture was further stirred 24 hours.Add methyl alcohol (10mL), and mixture was stirred 10 minutes.Remove volatile matter, and resistates is dissolved in the ethyl acetate (15mL), water (15mL) is washed, and dry then (MgSO ₄).Remove and desolvate, prepare crude product, it by the silica gel chromatography purifying with 5: 1 (v/v) cyclohexane/ethyl acetate wash-outs, is prepared the buttery title compound.

MS calculated value (C ₃₁H ₄₆N ₂O ₅S+H) ⁺: 559

MS measured value (electrospray): (M+H) ⁺=559

Intermediate 6

Rel-(2S, 4R, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 5 similar methods, prepare this title compound by intermediate 4.

MS calculated value (C ₃₀H ₄₄N ₂O ₅S+H) ⁺: 545

MS measured value (electrospray): (M+H) ⁺=545

Intermediate 7

Rel-(2S, 4R, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methyl fluoride-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

In 0 ℃, in the solution of the anhydrous methylene chloride (3mL) of intermediate 4 (0.147g), add diethylamino sulfur trifluoride (0.073mL).Remove cooling bath, and mixture was stirred under envrionment temperature 3 hours.Mixture is cooled to 0 ℃, and is poured in the sodium hydrogen carbonate solution (10mL) that refrigerative is saturated in advance, and use methylene dichloride (2 * 20mL) extractions then.Merge extract, with salt washing and dry (MgSO ₄).Remove and to desolvate, and with resistates by silica gel chromatography purifying with 3: 1 (v/v) cyclohexane/ethyl acetate wash-outs, prepare gummy title compound.

MS calculated value (C ₂₉H ₄₁FN ₂O ₄S+H) ⁺: 533

MS measured value (electrospray): (M+H) ⁺=533

Intermediate 8

Rel-(2S, 4R, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-(4-fluorophenoxy sulfo--ketonic oxygen ylmethyl)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Relative stereochemistry shown in racemic

In the solution of the anhydrous methylene chloride (5mL) of intermediate 4 (0.31g), add 4-fluorophenyl thiocarbonyl group carbonochloridic acid ester (0.125mL), add 4-dimethylaminopyridine (214mg) subsequently.The solution that generates was stored under envrionment temperature 2 days, it is diluted to 50mL, and wash with 0.5M hydrochloric acid, water and the saturated salt of 25mL part successively with methylene dichloride, and dry then (MgSO ₄).Remove and desolvate, and resistates is passed through with 3: the silica gel chromatography purifying of 1v/v cyclohexane/ethyl acetate wash-out prepares foamed title compound.

MS calculated value (C ₃₆H ₄₅N ₂O ₆S ₂+ H) ⁺: 685

MS measured value (electrospray): (M+H) ⁺=685

Intermediate 9

Rel-(2S, 4R, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

To intermediate 8 (add 2,2 in 0.30g) De diox (4mL) solution '-azobis isobutyronitrile (AIBN) (31mg), add three (trimethyl silyl) silicomethane (0.183mL) subsequently.Mixture heating up was refluxed 30 minutes, and keep and be cooled to envrionment temperature and spend the night.Remove volatile matter, and with resistates by with the silica gel chromatography purifying of 6: 1 (v/v) cyclohexane/ethyl acetate wash-outs, prepare the solid title compound.

MS calculated value (C ₂₉H ₄₂N ₂O ₄S+H) ⁺: 515

MS measured value (electrospray): (M+H) ⁺=515

Intermediate 10

Rel-(2S, 4R, 5R)-and 2-isobutyl--4-ethanoyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

Under nitrogen, (3.00g adds methyl vinyl ketone (1.0mL in anhydrous THF (25mL) solution 10.6mmol) to the intermediate 1 of stirring of cooling (0 ℃), 11.7mmol), add subsequently lithiumbromide (1.75g, 20.1mmol) and triethylamine (2.2mL, 15.9mmol).This is reacted in the cooling bath stirred 10 minutes.And under envrionment temperature, stir then and spend the night.Reaction mixture is diluted with ethyl acetate (80mL) and saturated ammonium chloride solution (40mL).Separate two-phase, and water is used ethyl acetate (80mL) extraction once more.Merge extract and wash dry then (MgSO with salt ₄).Vacuum evaporating solvent prepares crude product.It is passed through to use hexanaphthene-ethyl acetate gradient liquid (95: 5v/v to 9: 1v/v) as the silica gel chromatography purifying of eluent, prepare the buttery title compound.

MS calculated value (C ₁₈H ₂₈N ₂O ₃S+H) ⁺: 353.

MS measured value (electrospray): (M+H) ⁺=353.

Intermediate 11

Rel-(2S, 4R, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethanoyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

In 0 ℃, to the 3-methoxyl group-4-tert.-butylbenzene formyl chloride that stirs (0.32g, add in anhydrous methylene chloride 1.41mmol) (5mL) solution intermediate 10 (0.45g, 1.28mmol) and triethylamine (196 μ L, 1.41mmol).This mixture was stirred 16 hours, and use methylene dichloride (40mL) dilution then, and water (40mL) is washed.Dry organic phase (MgSO ₄) and vacuum-evaporation.Resistates is passed through to use hexanaphthene-ethyl acetate gradient liquid (95: 5v/v to 85: 15v/v) as the silica gel chromatography purifying of eluent, prepare the solid title compound.

MS calculated value (C ₃₀H ₄₂N ₂O ₅S+H) ⁺: 543.

MS measured value (electrospray): (M+H) ⁺=543.

Intermediate 12

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-pseudoallyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

In 0 ℃, (0.295g slowly adds THF (0.83mL, 0.83mmol) solution of two (trimethyl silyl) lithium amides of 1.0M in anhydrous THF (3mL) suspension 0.83mmol) to methyl triphenyl phosphine bromide under nitrogen.This solution was stirred 15 minutes down in 0 ℃.Add intermediate 11 (0.32g, anhydrous THF (4mL) solution 0.59mmol) subsequently.This is reacted on 0 ℃ stirred 1 hour down, and be warmed to room temperature then, and stir and spend the night.Reaction mixture is diluted with saturated ammonium chloride solution (40mL) and ethyl acetate (40mL).Then organic phase water (40mL) and salt solution (40mL) are washed dry (MgSO ₄) and vacuum evaporating solvent.Resistates is passed through to use hexanaphthene-ethyl acetate (95: 5v/v) as the silica gel chromatography purifying of eluent, prepare foamed title compound.

MS calculated value (C ₃₁H ₄₄N ₂O ₄S+H) ⁺: 541.

MS measured value (electrospray): (M+H) ⁺=541.

Intermediate 13

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-sec.-propyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

(0.164g, ethanol 0.3mmol) (15mL) solution was through 10% palladium carbon (38mg) hydrogenation 6 hours with intermediate 12.Remove by filter catalyzer and vacuum-evaporation filtrate, prepare foamed title compound.

MS calculated value (C ₃₁H ₄₆N ₂O ₄S+H) ⁺: 543.

MS measured value (electrospray): (M+H) ⁺=543.

Intermediate 14

Rel-(2S, 4R, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-allyloxy methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Relative stereochemistry shown in racemic

In the solution of the dry DMF (5mL) of intermediate 4 (0.200g), add sodium hydride (60% mineral oil dispersion, 24mg).When the gas that produces reduces, add allyl iodide (0.139mL).With mixture under nitrogen atmosphere, stirring 23 hours under the envrionment temperature.Add methyl alcohol (10mL), and mixture was stirred 10 minutes.Remove volatile matter and resistates is dissolved in the ethyl acetate (15mL), water (15mL), salt solution (15mL) is washed then, and dry then (MgSO ₄).Remove and desolvate, prepare thick product, it by the silica gel chromatography purifying with 5: 1 (v/v) cyclohexane/ethyl acetate wash-outs, is prepared gummy title compound.

MS calculated value (C ₃₂H ₄₆N ₂O ₅S+H) ⁺: 571

MS measured value (electrospray): (M+H) ⁺=571.

Intermediate 15

Rel-(2S, 4R, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-propoxy-methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Relative stereochemistry shown in racemic

Ethanol (5mL) solution of intermediate 14 (0.03g) is joined in the 10% palladium carbon (0.10g), and the mixture that generates was stirred 4.5 hours under nitrogen atmosphere.Add more 10% palladium carbon (0.01g) of volume, and under nitrogen atmosphere with mixture restir 18 hours.Remove by filter catalyzer, and wash with ethanol.Merging filtrate and washings, and be evaporated to driedly, prepare gummy title compound.

MS calculated value (C ₃₂H ₄₈N ₂O ₅S+H ⁺): 573

MS measured value (electrospray): (M+H) ⁺=573.

Intermediate 16

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

Under nitrogen in-15 ℃, to the intermediate 4a that stirs (100mg, add in dry DMF 0.2mmol) (5mL) solution sodium hydride (60% mineral oil, 8mg, 0.2mmol).Slurry in-15 ℃ of stirrings 30 minutes, is added methyl iodide (0.25mL, 0.4mmol, 2 equivalents) then, and this reacted to stirring at room in-15 ℃ through 18 hours.

Add methyl alcohol (10mL) and reaction mixture was stirred 15 minutes.Evaporating solvent, and resistates distributed between water and ethyl acetate.Through NaSO ₄Dry organic layer, and evaporation prepare yellow oil.This oily matter is passed through to use hexanaphthene-ethyl acetate (2: 3v/v) as the silica gel chromatography purifying of eluent, prepare the solid title compound.

MS calculated value (C ₃₀H ₄₄N ₂O ₅S+H) ⁺: 545.

MS measured value (electrospray): (M+H) ⁺=545

Intermediate 17

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 16 similar methods, 4a prepares title compound by intermediate.

MS calculated value (C ₃₁H ₄₆N ₂O ₅S+H) ⁺: 559

MS measured value (electrospray): (M+H) ⁺=559.

Intermediate 18

(2S, 4S, 5R)-and 2-isobutyl--5-(1,3-thiazoles-2-yl) tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

[by rel-(5R)-2-isobutyl--5-(1,3-thiazoles-2-yl) tetramethyleneimine-2, the 4-dicarboxylic acid, the 2-tert-butyl ester, the 4-derivation of methyl ester obtains enantiomer A for 2S, 4S]

Chirality, the stereochemistry of absolute stereo chemistry shown in the enantiomer A by determining with reference to intermediate 19

Stage A: in 90 ℃, to the rel-that stirs (2S, 4S, 5R)-2-isobutyl--5-(1,3-thiazoles-2-yl) tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters (intermediate 2; 4.13g, add (R)-1,1 '-dinaphthalene-2,2 '-two bases-hydrogen orthophosphate (3.91g, 2-propyl alcohol (217mL) solution 11.22mmol) in 2-propyl alcohol (20.5mL) solution 11.21mmol)., filter and collect this crystallization after following 19 hours in room temperature, (10mL) washes with the 2-propyl alcohol, and last vacuum-drying, prepares solid.

Stage B: this material is distributed between ethyl acetate and saturated sodium bicarbonate aqueous solution, and filter two-layer then.Separate organic phase, dry (Na ₂SO ₄) and evaporate, prepare the enantiomer A of buttery title compound.

MS calculated value (C ₁₈H ₂₈N ₂O ₄S+H) ⁺: 369

MS measured value (electrospray): (M+H) ⁺=369.

Rel-(2S, 4S, 5R)-2-isobutyl--5-(1, the 3-thiazol-2-yl) tetramethyleneimine-2, the 4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters (intermediate 2) is at Chiralcel OD-H carrier and show the peak of two retention time with the chirality HPLC of the analysis of 5% alcoholic acid n-heptane solution wash-out: 5.7 and 6.9 minutes.Demonstrate this title compound (enantiomer A) corresponding to enantiomer that the second time, wash-out went out.

Determine the absolute stereo chemistry of this compound by reference intermediate 19.

Intermediate 19

(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

[rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, the enantiomer A of 4-methyl esters]

Chirality, the stereochemistry of absolute stereo chemistry shown in the enantiomer A by determining with reference to intermediate 20

To the rel-that stirs (2S, 4S, 5R)-2-isobutyl--5-(1,3-thiazoles-2-yl) tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters (intermediate 18; 1.91g, add in the anhydrous methylene chloride of enantiomer A 5.18mmol) (75mL) solution triethylamine (0.91mL, 6.62mmol) and 3-methoxyl group-4-tert.-butylbenzene formyl chloride (1.39g, 6.14mmol).This mixture was left standstill under room temperature 19 hours, and then with the methylene dichloride dilution, and use saturated sodium bicarbonate aqueous solution (* 2) and washing then successively.Dry organic phase (Na ₂SO ₄) and evaporation, prepare natural gum, with its recrystallization from 1: 3 ethyl acetate/hexanaphthene, prepare the enantiomer A of the title compound of crystalline solid.

MS calculated value (C ₃₀H ₄₂N ₂O ₆S+H) ⁺: 559

MS measured value (electrospray): (M+H) ⁺=559.

By reference intermediate 20, determine the absolute stereo chemistry of this compound.

Intermediate 20

(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

[rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the enantiomer A of the tert-butyl ester]

Chirality, the absolute stereo chemistry shown in the enantiomer A passes through with reference to intermediate 22 and 92 stereochemistry of determining

Under nitrogen in-78 ℃ of dry THF (50mL) solution that stir intermediates 19 (1.00g).Drip THF (1.8mL) solution of 1.0M lithium aluminium hydride.Stir the mixture that generates, and be warmed to-40 ℃ with 2 hours.Mixture is stopped with 1M solution of potassium carbonate (25mL), and (2 * 50mL) extract with ethyl acetate.With the extraction liquid water, then with the salt washing, and dry (MgSO ₄).Remove and desolvate, obtain crude product.It is dissolved among the THF (30mL), under nitrogen, is cooled to-78 ℃, and THF (1.0mL) solution that under agitation drips the 1M lithium aluminium hydride is handled.Mixture was warmed to-20 ℃ with 3 hours.Mixture is stopped with the 1M solution of potassium carbonate, and (2 * 50mL) extract with ethyl acetate.With the extraction liquid water, then with the salt washing, and dry (MgSO ₄).Remove and desolvate, prepare the enantiomer A of title compound.

MS calculated value (C ₂₉H ₄₂N ₂O ₅S+H) ⁺: 531

MS measured value (electrospray): (M+H) ⁺=531

By reference intermediate 22 and 92, determine the absolute stereo chemistry of this compound.This compound is identical with the spectroscopic data (spectroscopically) described in the intermediate 92.

Intermediate 21

(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

[rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the enantiomer A of the tert-butyl ester]

Under nitrogen,, stir dry dimethyl formamide (15mL) solution of intermediate 20 (400mg) in-15 ℃.(60% mineral oil dispersion 32mg), and stirs mixture 20 minutes in-15 ℃ to add sodium hydride.Add methyl iodide (0.25mL), and under nitrogen, the mixture that generates was stirred 24 hours between-15 ℃ and 10 ℃.Add methyl alcohol (10mL), and mixture was stirred 10 minutes.Evaporate this mixture, obtain xanchromatic natural gum, it by the silica gel chromatography purifying with cyclohexane/ethyl acetate mixture (6: 1 to 3: 1) wash-out, is prepared the enantiomer A of lenticular solid title compound.

MS calculated value (C ₃₀H ₄₄N ₂O ₅S+H) ⁺: 545.

MS measured value (electrospray): (M+H) ⁺=545

¹H?NMR(CDCl ₃)：δ7.49(1H，d)，7.19(1H，d)，7.10(1H，d)，6.62(1H，dd)，6.32(1H，s)，5.46(1H，d)，3.56(3H，s)，3.07(3H，s)，3.06(1H，m)，2.96(1H，dd)，2.82(1H，dd)，2.25-2.40(3H，m)，2.11(1H，dd)，1.97(1H，m)，1.58(9H，s)，1.28(9H，s)，1.08(3H，d)，1.07(3H，d)。

Intermediate 22

(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

[rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the enantiomer A of the tert-butyl ester]

Chirality, the stereochemistry that the absolute stereo chemistry shown in the enantiomer A is determined by reference example 16

Under nitrogen,, stir dry dimethyl formamide (15mL) solution of intermediate 20 (400mg) in-15 ℃.(60% mineral oil dispersion 32mg), and stirred the mixture 20 minutes in-15 ℃ to add sodium hydride.Add iodoethane (0.25mL), and under nitrogen, between-15 ℃ and 10 ℃, stirred the mixture that generates 24 hours.Add methyl alcohol (10mL), and mixture was stirred 10 minutes.Evaporating mixture obtains xanchromatic natural gum, and it by the silica gel chromatography purifying with cyclohexane/ethyl acetate mixture (6: 1 to 3: 1) wash-out, is prepared the enantiomer A of crystalloid solid title compound.

MS calculated value (C ₃₁H ₄₆N ₂O ₅S+H) ⁺: 559

MS measured value (electrospray): (M+H) ⁺=559.

¹H?NMR(CDCl ₃)：δ7.49(1H，d)，7.17(1H，d)，7.10(1H，d)，6.63(1H，dd)，6.31(1H，s)，5.45(1H，d)，3.56(3H，s)，3.00-3.20(4H，m)，2.84(1H，dd)，2.25-2.40(3H，m)，2.11(1H，dd)，1.98(1H，m)，1.58(9H，s)，1.28(9H，s)，1.08(3H，d)，1.07(3H，d)，1.00(3H，t).

By reference example 16, determine the absolute stereo chemistry of this compound.

Intermediate 23

(2S, 4S, 5R)-and 2-isobutyl--1-(3-bromo-4-tert.-butylbenzene formyl radical)-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Absolute stereo chemistry shown in the chirality

According to intermediate 19 similar methods, use 3-bromo-4-tert.-butylbenzene formyl chloride to replace 3-methoxyl group-4-tert.-butylbenzene formyl chloride, prepare title compound.

MS calculated value (C ₂₉H ₃₉BrN ₂O ₅S+H) ⁺: 607/609

MS measured value (electrospray): (M+H) ⁺=607/609

Intermediate 24

(2S, 4S, 5R)-and 1-(3-chloro-4-tert.-butylbenzene formyl radical)-2-isobutyl--5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Absolute stereo chemistry shown in the chirality

To the pyrrolidinium (stage A of intermediate 18 that stirs; 1.43g, 1.9mmol) and triethylamine (0.55mL, (0.58g 2.51mmol), and stirred the mixture that generates 19 hours under room temperature to add 3-chloro-4-tert.-butylbenzene formyl chloride in anhydrous methylene chloride 3.96mmol) (18mL) solution.Mixture is diluted with methylene dichloride, wash with saturated sodium bicarbonate aqueous solution, through Na ₂SO ₄Dry also evaporation.Resistates is passed through to use hexanaphthene-ethyl acetate (8: 1v/v) as the silica gel chromatography purifying of eluent, prepare the solid title compound.

MS calculated value (C ₂₉H ₃₉ClN ₂O ₅S+H) ⁺: 563/565

MS measured value (electrospray): (M+H) ⁺=563/565

Intermediate 25

(2S, 4S, 5R)-and 2-isobutyl--1-(3-methyl-4-tert.-butylbenzene formyl radical)-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Absolute stereo chemistry shown in the chirality

To the pyrrolidinium (stage A of intermediate 18 that stirs; 1.14g, 1.59mmol) and triethylamine (0.44mL, (0.56g 2.65mmol), and stirred the mixture that generates 18 hours under room temperature to add 3-methyl-4-tert.-butylbenzene formyl chloride in anhydrous methylene chloride 3.17mmol) (15mL) solution.Mixture is diluted with methylene dichloride, wash with saturated sodium bicarbonate aqueous solution, through Na ₂SO ₄Dry also evaporation.Resistates is passed through to use hexanaphthene-ethyl acetate (8: 1v/v) as the silica gel chromatography purifying of eluent, prepare the solid title compound.

MS calculated value (C ₃₀H ₄₂N ₂O ₅S+H) ⁺: 543

MS measured value (electrospray): (M+H) ⁺=543.

Intermediate 26

(2S, 4S, 5R)-and 2-isobutyl--1-(3-bromo-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Absolute stereo chemistry shown in the chirality

According to intermediate 20 similar methods, use intermediate 23 as initial substance, prepare title compound.

MS calculated value (C ₂₈H ₃₉BrN ₂O ₄S+H) ⁺: 579/581

MS measured value (electrospray): (M+H) ⁺=579/581

Intermediate 27

(2S, 4S, 5R)-and 2-isobutyl--1-(3-chloro-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Absolute stereo chemistry shown in the chirality

According to intermediate 20 similar methods, use intermediate 24 as initial substance, prepare title compound.

MS calculated value (C ₂₈H ₃₉ClN ₂O ₄S+H) ⁺: 535/537

MS measured value (electrospray): (M+H) ⁺=535/537.

Intermediate 28

(2S, 4S, 5R)-and 2-isobutyl--1-(3-methyl-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Absolute stereo chemistry shown in the chirality

According to intermediate 20 similar methods, use intermediate 25 as initial substance, prepare title compound.

MS calculated value (C ₂₉H ₄₂N ₂O ₄S+H) ⁺: 515

MS measured value (electrospray): (M+H) ⁺=515.

Intermediate 29

(2S, 4S, 5R)-and 2-isobutyl--1-(3-bromo-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Absolute stereo chemistry shown in the chirality

According to intermediate 22 similar methods, use intermediate 26 as initial substance, prepare title compound.

MS calculated value (C ₃₀H ₄₃BrN ₂O ₄S+H) ⁺: 607/609

MS measured value (electrospray): (M+H) ⁺=607/609

Intermediate 30

(2S, 4S, 5R)-and 2-isobutyl--1-(3-chloro-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Absolute stereo chemistry shown in the chirality

According to intermediate 22 similar methods, use intermediate 27 as initial substance, prepare title compound.

MS calculated value (C ₃₀H ₄₃ClN ₂O ₄S+H) ⁺: 563/565

MS measured value (electrospray): (M+H) ⁺=563/565

Intermediate 31

2-[N-(1,3-thiazoles-2-methylene) amino]-the 3-phenylpropionic acid, the tert-butyl ester

According to intermediate 1 similar methods, replace 2-amino-4-methyl-valeric acid tert-butyl ester with 2-amino-3-phenylpropionic acid tert-butyl ester, prepare title compound.

¹H NMR (CDCl3): 8.08 (1H, s), 7.80 (1H, d), 7.39 (1H, d), 7.10 (5H, m), 4.11 (1H, dd), 3.25 (1H, dd), 3.06 (1H, dd) and 1.36 (9H, s).

Intermediate 32

Rel-(2R, 4S, 5R)-and 2-benzyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Relative stereochemistry shown in racemic

According to intermediate 2 similar methods, use intermediate 31 as initial substance, prepare title compound.

MS calculated value (C ₂₁H ₂₆N ₂O ₄S+H) ⁺: 403

MS measured value (electrospray): (M+H) ⁺=403

Intermediate 33

Rel-(2R, 4S, 5R)-and 2-benzyl-1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Relative stereochemistry shown in racemic

According to intermediate 3 similar methods, use intermediate 32 as initial substance, prepare title compound.

MS calculated value (C ₃₃H ₄₂N ₂O ₆S+H) ⁺: 593

MS measured value (electrospray): (M+H) ⁺=593

Intermediate 34

Rel-(2R, 4S, 5R)-2-benzyl-1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl

-5-(1,3-thiazoles-2-base-tetramethyleneimine)-2-carboxylic acid, the 2-tert-butyl ester

Relative stereochemistry shown in racemic

Under nitrogen, stir dry tetrahydrofuran (30mL) solution of intermediate 33 (1.08g), and be cooled to 0 ℃.THF (1.8mL) solution that adds the 2M lithium borohydride, and mixture stirred 30 minutes in 0 ℃, and then in stirring at room 2 days.Add 1M solution of potassium carbonate (10mL), and with the mixture ethyl acetate extraction.Dry extraction liquid (Na ₂SO ₄), and remove and desolvate.Resistates by the silica gel chromatography purifying with ethyl acetate/hexanaphthene mixture wash-out, is prepared title compound.

MS calculated value (C ₃₂H ₄₀N ₂O ₅S+H) ⁺: 565

MS measured value (electrospray): (M+H) ⁺=565

Intermediate 35

Rel-(2R, 4R, 5R)-and 2-benzyl-1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester

Relative stereochemistry shown in racemic

Methyl alcohol (30mL) solution of intermediate 33 (1.2g) is handled with 25%w/v methanolizing (methanolic) sodium methylate (0.439mL), and it is warm up to obtaining complete solution.With the mixture that generates in stirred overnight at room temperature.The sodium methoxide solution that adds other equivalent, and with mixture restir 4 hours.Mixture is neutralized with concentrated hydrochloric acid, and be evaporated to dried.Resistates is soluble in water, and use ethyl acetate extraction.Remove and desolvate, and resistates is dissolved in the methyl alcohol (10mL), and add the 2M sodium hydroxide solution.With mixture in stirred overnight at room temperature.Remove and desolvate, and resistates is distributed between water and ethyl acetate.With 2M hydrochloric acid with aqueous phase as acidified to pH be 6, and use ethyl acetate extraction.The extraction liquid that concentrate to merge, and with resistates purifying on silica gel begins that (9: (95: 5v/v) wash-out prepares title compound 1v/v) also progressively to become ethyl acetate-methyl alcohol then with hexanaphthene-ethyl acetate.

MS calculated value (C ₃₂H ₃₈N ₂O ₆S+H) ⁺: 579

MS measured value (electrospray): (M+H) ⁺=579

Intermediate 36

Rel-(2R, 4R, 5R)-and 2-benzyl-1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Relative stereochemistry shown in racemic

Under nitrogen,, stir THF (50mL) solution of intermediate 35 (602mg) in-10 ℃.THF (2mL) solution that adds 2M borine/dimethyl sulphide ether complexes.Mixture is warmed to room temperature and stirs spend the night.Add methyl alcohol, remove and desolvate, and resistates is distributed between 1M solution of potassium carbonate and ethyl acetate.Dry organic layer (Na ₂SO ₄).Remove and desolvate, and resistates is passed through to use hexanaphthene: (7: 3v/v) the silica gel chromatography purifying of wash-out prepares title compound to ethyl acetate.

MS calculated value (C ₃₂H ₄₀N ₂O ₅S+H) ⁺: 565

MS measured value (electrospray): (M+H) ⁺=565

Intermediate 37

Rel-(2R, 4R, 5R)-and 2-benzyl-1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 16 similar methods, use intermediate 36 as initial substance, prepare title compound.

MS calculated value (C ₃₃H ₄₂N ₂O ₅S+H) ⁺: 579

MS measured value (electrospray): (M+H) ⁺=579

Intermediate 38

Rel-(2R, 4R, 5R)-and 2-benzyl-1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 17 similar methods, use intermediate 36 as initial substance, prepare title compound.

MS calculated value (C ₃₄H ₄₄N ₂O ₅S+H) ⁺: 593

MS measured value (electrospray): (M+H) ⁺=593

Intermediate 39

2-[N-(pyrazine-2-methylene) amino]-the 4-methylvaleric acid, the tert-butyl ester

According to intermediate 1 similar methods, use pyrazine-2-formaldehyde to replace 1,3-thiazoles-2-formaldehyde, prepare title compound.

¹H?NMR(CDCl ₃)δ9.31(d，1H)，8.61(m，2H)，8.39(s，1H)，4.08(dd，1H)，1.84(m，2H)，1.59(m，1H)，1.48(s，9H)，0.96(d，3H)，0.92(d，3H)。

Intermediate 40

Rel-(2S, 4S, 5R)-and 2-isobutyl--5-(pyrazine-2-yl) tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Relative stereochemistry shown in racemic

According to intermediate 2 similar methods, use intermediate 39 as initial substance, prepare title compound.

MS calculated value (C ₁₉H ₂₉N ₃O ₄+ H) ⁺: 364

MS measured value (electrospray): (M+H) ⁺=364

Intermediate 41

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-5-(pyrazine-2-yl) tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Relative stereochemistry shown in racemic

According to intermediate 3 similar methods, use intermediate 40 as initial substance, prepare title compound.

MS calculated value (C ₃₁H ₄₃N ₃O ₆+ H) ⁺: 554

MS measured value (electrospray): (M+H) ⁺=554

Intermediate 42

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl-5-(pyrazine-2-yl)-tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 20 similar methods, use intermediate 41 as initial substance, prepare title compound.

MS calculated value (C ₃₀H ₄₃N ₃O ₅+ H) ⁺: 526

MS measured value (electrospray): (M+H) ⁺=526

Intermediate 43

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl-5-(pyrazine-2-yl)-tetramethyleneimine-2-carboxylic acid, the enantiomer A of the 2-tert-butyl ester

Chirality, enantiomer A is as drawn relative stereochemistry

Under nitrogen, stir dry DMF (15mL) solution of intermediate 42 (367mg), and be cooled to-15 ℃.(60% mineral oil dispersion 28mg), and stirs the solution that generates 20 minutes in-15 ℃ to add sodium hydride in this solution.Add methyl iodide (88 μ L) then, and stir this reaction 2.5 hours down in-15 ° to-10 ℃.Add methyl alcohol (10mL) in-10 ℃, and mixture is warmed to room temperature.Mixture is diluted with ethyl acetate, and wash, separate organic phase and dry (MgSO with aqueous ammonium chloride solution ₄).Remove and to desolvate, and with resistates by (1: 4v/v) the silica gel chromatography purifying of wash-out prepares the racemic compound of title compound with ethyl acetate-hexanaphthene.Use preparation type chirality HPLC (stationary phase: chiralpak AD, moving phase: heptane-Virahol 95: 5v/v) it is separated into enantiomer.Obtain this title compound of the enantiomer that goes out as wash-out at first.

MS calculated value (C ₃₁H ₄₅N ₃O ₅+ H) ⁺: 540

MS measured value (electrospray): (M+H) ⁺=540

Intermediate 44

Rel-(2S, 4R, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-5-(pyrazine-2-yl) tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Relative stereochemistry shown in racemic

In the solution of the dry MeOH of intermediate 41 (500mg) (10mL), add sodium methoxide solution (195 μ L, 25%w/v).The solution that generates stirred under room temperature spend the night, subsequently it is extruded (stripped) to dried.With resistates by (1: 1v/v) the silica gel chromatography purifying of wash-out prepares the title compound of white solid with ethyl acetate-hexanaphthene.

MS calculated value (C ₃₁H ₄₃N ₃O ₆+ H) ⁺: 554

MS measured value (electrospray): (M+H) ⁺=554

Intermediate 45

Rel-(2S, 4R, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl-5-(pyrazine-2-yl)-tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 4 similar methods, use intermediate 44 as initial substance, prepare title compound.

MS calculated value (C ₃₀H ₄₃N ₃O ₅+ H) ⁺: 526

MS measured value (electrospray): (M+H) ⁺=526

Intermediate 46

Rel-(2S, 4R, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(pyrazine-2-yl)-tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 16 similar methods, use intermediate 45 as initial substance, prepare title compound.

MS calculated value (C ₃₁H ₄₅N ₃O ₅+ H) ⁺: 540

MS measured value (electrospray): (M+H) ⁺=540

Intermediate 47

2-[N-(5-methyl isophthalic acid, 3-thiazol-2-yl methylene radical) amino]-the 4-methylvaleric acid, the tert-butyl ester

According to intermediate 1 similar methods, use the 5-methyl isophthalic acid, 3-thiazole-2-formaldehyde replaces 1,3-thiazoles-2-formaldehyde, prepares title compound.

¹H NMR (CDCl ₃): δ 8.33 (s, 1H), 7.56 (s, 1H), 4.01 (m, 1H), 2.49 (s, 3H), 1.75 (m, 2H), 1.52 (m, 1H), 1.45 (s, 9H), 0.93 (d, 3H) and 0.88 (d, 3H).

Intermediate 48

Rel-(2S, 4S, 5R)-and 2-isobutyl--5-(5-methyl isophthalic acid, 3-thiazol-2-yl) tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Relative stereochemistry shown in racemic

According to intermediate 2 similar methods, use intermediate 47 as initial substance, prepare title compound.

MS calculated value (C ₁₉H ₃₀N ₂O ₄S+H) ⁺: 383

MS measured value (electrospray): (M+H) ⁺=383

Intermediate 49

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-5-(5-methyl isophthalic acid, 3-thiazol-2-yl) tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Relative stereochemistry shown in racemic

According to intermediate 3 similar methods, use intermediate 48 as initial substance, prepare title compound.

MS calculated value (C ₃₁H ₄₄N ₂O ₆S+H) ⁺: 573

MS measured value (electrospray): (M+H) ⁺=573

Intermediate 50

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl-5-(5-methyl isophthalic acid, 3-thiazol-2-yl) tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 20 similar methods, use intermediate 49 as initial substance, prepare title compound.

MS calculated value (C ₃₀H ₄₄N ₂O ₅S+H) ⁺: 545

MS measured value (electrospray): (M+H) ⁺=545

Intermediate 51

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(5-methyl isophthalic acid, 3-thiazol-2-yl) tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 21 similar methods, use intermediate 50 as initial substance, prepare title compound.

MS calculated value (C ₃₁H ₄₆N ₂O ₅S+H) ⁺: 559

MS measured value (electrospray): (M+H) ⁺=559

Intermediate 52

2-[N-(2-chloro-1,3-thiazoles-5-methylene) amino]-the 4-methylvaleric acid, the tert-butyl ester

According to intermediate 1 similar methods, use 2-chloro-1,3-thiazoles-5-formaldehyde to replace 1,3-thiazoles-2-formaldehyde, prepare title compound.

¹H NMR (CD ₃OD): δ 8.31 (1H, s), 7.61 (1H, s), 3.96 (1H, m), 1.75 (2H, m), 1.55 (1H, m), 1.46 (9H, s), 0.94 (3H, d) and 0.89 (3H, d)

Intermediate 53

Rel-(2S, 4S, 5R)-and 2-isobutyl--5-(2-chloro-1,3-thiazoles-5-yl) tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Relative stereochemistry shown in racemic

According to intermediate 2 similar methods, use intermediate 52 as initial substance, prepare title compound.

MS calculated value (C ₁₈H ₂₇ClN ₂O ₄S+H) ⁺: 403/405

MS measured value (electrospray): (M+H) ⁺=403/405

Intermediate 54

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-5-(2-chloro-1,3-thiazoles-5-yl) tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Relative stereochemistry shown in racemic

According to intermediate 3 similar methods, use intermediate 53 as initial substance, prepare title compound.

MS calculated value (C ₃₀H ₄₁ClN ₂O ₆S+H) ⁺: 593/595

MS measured value (electrospray): (M+H) ⁺=593/595

Intermediate 55

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl-5-(2-chloro-1,3-thiazoles-5-yl) tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 20 similar methods, use intermediate 54 to prepare title compound as initial substance.

MS calculated value (C ₂₉H ₄₁ClN ₂O ₅S+H) ⁺: 565/567

MS measured value (electrospray): (M+H) ⁺=565/567.

Intermediate 56

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(2-chloro-1,3-thiazoles-5-yl) tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 16 similar methods, use intermediate 55 as initial substance, prepare title compound.

MS calculated value (C ₃₀H ₄₃ClN ₂O ₅S+H) ⁺: 579/581

MS measured value (electrospray): (M+H) ⁺=579/581

Intermediate 57

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(2-methoxyl group-1,3-thiazoles-5-yl) tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Relative stereochemistry shown in racemic

Methyl alcohol (0.207mL) solution that in the solution of the methyl alcohol (0.8mL) of intermediate 56 (70mg), adds 1M sodium hydroxide.Mixture in 50 ℃ of heated overnight, and was refluxed 8 hours then.With the preparation HPLC purifying of mixture, contain the water of formic acid (0.1%) and the acetonitrile-water (95: 5v/v), prepare title compound that (B) contains formic acid (0.05%) as two solvent gradient elutions of eluent with (A) by the C18 post.

MS calculated value (C ₃₁H ₄₆N ₂O ₆S+H) ⁺: 575

MS measured value (electrospray): (M+H) ⁺=575

¹H?NMR(CDCl ₃)：δ7.13(1H，d)，6.91(1H，s)，6.66(1H，d)，6.43(1H，s)，5.04(1H，d)，3.99(3H，s)，3.65(3H，s)，3.18(1H，m)3.13(3H，s)，2.94(2H，m)，2.26(1H，m)，2.17(1H，m)，2.05(2H，m)，1.95(1H，m)，1.59(9H，s)，1.32(9H，s)，1.06(6H，d)。

Intermediate 58

Rel-(2S, 4R, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-((methylthio group) methyl)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

Under nitrogen, methylene dichloride (0.5mL) solution of trifluoromethanesulfanhydride anhydride (53mg) and pyridine (15mg) is stirred down in-10 ℃, and with methylene dichloride (1mL) solution-treated of intermediate 4 (100mg) 1.5 hours.Add entry (3mL), collected organic layer, and by Hydrophobic glass material (hydrophobic frit) drying.Remove and to desolvate, and under nitrogen in room temperature with resistates with dimethyl formamide (1.5mL) solution-treated of sodium methyl mercaptide (60mg) 3 days.Solvent removed in vacuo, and resistates distributed between methylene dichloride and salt solution.Dichloromethane solution is used hexanaphthene-ethyl acetate, and (by 15: 1v/v to 12: the silica gel chromatography purifying 1v/v gradient elution) prepares title compound.

MS calculated value (C ₃₀H ₄₄N ₂O ₄S ₂+ H) ⁺: 561

MS measured value (electrospray): (M+H) ⁺=561

Intermediate 59

Rel-(2S, 4R, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-((methylsulfonyl)-methyl)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

In 0 ℃, in methylene dichloride (1mL) solution of intermediate 58 (28.8mg), add methylene dichloride (1mL) solution of 3-chlorine peroxybenzoic acid (21mg).Under nitrogen, mixture was stirred 2.75 hours, and use sodium sulfide solution, sodium hydrogen carbonate solution and washing then successively in 0 ℃, and then by Hydrophobic glass material drying.The solution that generates is used hexanaphthene-ethyl acetate, and (by 2: 1v/v to 1: the silica gel chromatography purifying gradient elution of 1v/v) prepares title compound.

MS calculated value (C ₃₀H ₄₄N ₂O ₆S ₂+ H) ⁺: 593

MS measured value (electrospray): (M+H) ⁺=593

Intermediate 60

Rel-(2S, 4R, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-(1,1-two fluoro ethyls)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

Under nitrogen,, diethylamino sulfur trifluoride (450 μ L) is dropped in methylene dichloride (2.5mL) solution of intermediate 11 (282.3mg) of stirring in 0 ℃.Temperature is risen to room temperature also to be continued to stir to spend the night.After it is cooled to 0 ℃, mixture is poured in the ice-cold saturated sodium hydrogen carbonate solution (12mL).Mixture is extracted with methylene dichloride (40mL), and dry extraction liquid (MgSO ₄).Removing desolvates obtains resistates, and (9: 1v/v) the silica gel chromatography purifying of wash-out prepares title compound by using hexanaphthene-ethyl acetate with it.

MS calculated value (C ₃₀H ₄₂F ₂N ₂O ₄S+H) ⁺: 565

MS measured value (electrospray): (M+H) ⁺=565

Intermediate 61

Rel-(2S, 4R, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-(1-hydroxyl-1-methylethyl)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

Method A: toluene/THF (0.1mL) solution that in the solution of the tetrahydrofuran (THF) (1mL) of intermediate 11 (46mg), adds the 1.4M methyl-magnesium-bromide.Mixture was stirred 70 minutes under nitrogen in 0 ℃, and make it be warmed to room temperature then.Add saturated ammonium chloride solution (2mL), and with the mixture dichloromethane extraction.Dry extraction liquid (MgSO ₄), and remove and desolvate, obtain crude product, with its preparation HPLC purifying by the C18 post, contain the water of formic acid (0.1%) and the acetonitrile-water (95: 5v/v), prepare title compound that (B) contains formic acid (0.05%) with (A) as two solvent gradient elutions of eluent.

MS calculated value (C ₃₁H ₄₆N ₂O ₅S+H) ⁺: 559

MS measured value (electrospray): (M+H) ⁺=559

Method B: with dry tetrahydrofuran (1mL) solution of intermediate 11 (51.7mg) under nitrogen in-78 ℃ of stirrings.Add the ethereal solution (76 μ L) that becomes the 1.5M lithium methide of complex compound with lithiumbromide, and mixture was stirred 2 hours down in-78 ℃.Add ether (the 32 μ L) solution of the 1.5M lithium methide-lithiumbromide complex compound of amount in addition, and continued restir 40 minutes.Add saturated ammonium chloride solution (10mL), and with the mixture dichloromethane extraction.Dry extraction liquid (MgSO ₄).Removing desolvates obtains resistates, and (4: 1v/v) the silica gel chromatography purifying of wash-out prepares title compound by using hexanaphthene-ethyl acetate with it.

Spectroscopic data (Spectroscopic data) is consistent with the spectroscopic data of the product that method A is obtained.

Intermediate 62

Rel-(2S, 4R, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the enantiomer A of the tert-butyl ester

Chirality, enantiomer A; Shown relative stereochemistry

Intermediate 6 is being used heptane-Virahol (98: 2v/v) prepare on the type chirality hplc post as the chiralpak AD of eluent and split, prepare title compound, for the second time the enantiomer that goes out of wash-out.

MS calculated value (C ₃₀H ₄₄N ₂O ₅S+H) ⁺: 545

MS measured value (electrospray): (M+H) ⁺=545

Intermediate 63

Rel-(2R, 4S, 5R)-and 2-benzyl-1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 16 similar methods, use intermediate 34 as initial substance, prepare title compound.

MS calculated value (C ₃₃H ₄₂N ₂O ₅S+H) ⁺: 579

MS measured value (electrospray): (M+H) ⁺=579

Intermediate 64

Rel-(2R, 4S, 5R)-and 2-benzyl-1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 17 similar methods, use intermediate 34 as initial substance, prepare title compound.

MS calculated value (C ₃₄H ₄₄N ₂O ₅S+H) ⁺: 593

MS measured value (electrospray): (M+H) ⁺=593

Intermediate 65

2-[N-(pyridine-2-methylene) amino]-the 4-methylvaleric acid, the tert-butyl ester

According to intermediate 1 similar methods, use pyridine-2-formaldehyde to replace 1,3-thiazoles-2-formaldehyde, prepare title compound.

¹H?NMR(CD ₃OD)：δ8.66(1H，d)，8.37(1H，s)，8.12(1H，d)，7.75(1H，t)，7.34(1H，t)，4.05(1H，m)，1.83(2H，m)，1.55(1H，m)1.48(9H，s)，0.96(3H，d)，0.91(3H，d).

Intermediate 66

Rel-(2S, 4S, 5R)-and 2-isobutyl--5-(pyridine-2-yl) tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Relative stereochemistry shown in racemic

According to intermediate 2 similar methods, use intermediate 65 as initial substance, prepare title compound.

¹H?NMR(CD ₃OD)：δ8.52(1H，d)，7.62(1H，t)，7.29(1H，d)，7.13(1H，t)，4.60(1H，d)，3.37(1H，q)，3.26(3H，s)2.60(1H，dd)，2.01(1H，dd)，1.80(2H，m)，1.54(1H，m)，1.51(9H，s)，0.97(3H，d)，0.90(3H，d).

Intermediate 67

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-5-(pyridine-2-yl)-tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Relative stereochemistry shown in racemic

According to intermediate 3 similar methods, use intermediate 66 as initial substance, prepare title compound.

¹H?NMR(CD ₃OD)：δ8.20(1H，d)，7.92(1H，d)，7.57(1H，t)，7.07(1H，d)，7.03(1H，t)，6.63(1H，d)，6.26(1H，s)，5.42(1H，d)，3.77(1H，m)，3.49(3H，s)，3.33(3H，s)，2.90(1H，t)，2.31(2H，m)，2.14(1H，m)，1.95(1H，m)，1.43(9H，s)，1.25(9H，s)，1.10(6H，d).

Intermediate 68

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl-5-(pyridine-2-yl) tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 20 similar methods, use intermediate 67 as initial substance, prepare title compound.

MS calculated value (C ₃₁H ₄₄N ₂O ₅+ H) ⁺: 525

MS measured value (electrospray): (M+H) ⁺=525

Intermediate 69

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(pyridine-2-yl) tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 16 similar methods, use intermediate 68 as initial substance, prepare title compound.

MS calculated value (C ₃₂H ₄₆N ₂O ₅+ H) ⁺: 539

MS measured value (electrospray): (M+H) ⁺=539

Intermediate 70

(2S, 4R, 5R)-and 2-isobutyl--4-ethanoyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester, (R)-(-)-1,1 '-dinaphthalene-2,2 '-two bases-hydrogen orthophosphate

Chirality; Shown absolute stereo chemistry

(90 ℃) that in the solution of the isopropyl alcohol (30mL) of intermediate 10 (6.51g), add heat (R)-(-)-1,1 '-dinaphthalene-2, the solution of the isopropyl alcohol (337mL) of 2 '-two bases-hydrogen orthophosphate (6.30g).With mixture standing over night under room temperature, and then evaporation concentration to the solvent of about 80mL.It after standing over night under the room temperature, is filtered and collect this title compound.Determine this absolute stereo chemistry by the X-radiocrystallography, and show that this tetramethyleneimine alkali (base) has (2S, 4R, 5R) chirality.

¹H?NMR(CD ₃OD)δ8.03(d，2H)，7.96(d，2H)，7.85(d，1H)，7.72(d，1H)，7.54(d，2H)，7.42(t，2H)，7.26(m，4H)，5.37(d，1H)，3.79(m，1H)，3.10(s，3H)，2.25(dd，1H)，2.22(s，3H)，1.96(m，2H)，1.74(m，1H)，1.53(s，9H)，0.97(d，3H)，0.95(d，3H)。

Intermediate 71

(2S, 4R, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethanoyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Chirality; Shown absolute stereo chemistry

Intermediate 70 (4.2g) is joined in the solution of methylene dichloride (150mL) of 3-methoxyl group-4-tert.-butylbenzene formyl chloride (1.494g), and stir until evenly.Add triethylamine (2.087mL), and with mixture under nitrogen in stirred overnight at room temperature.Methylene dichloride (1mL) solution that adds the 3-methoxyl group-4-tert.-butylbenzene formyl chloride (272mg) of another part, and continued restir 24 hours.Add saturated sodium hydrogen carbonate solution (150mL), and collected organic layer, and dry (MgSO ₄).Remove and desolvate, and (3: 1v/v) the silica gel chromatography purifying of wash-out prepares the solid title compound by hexanaphthene-ethyl acetate with resistates.

MS calculated value (C ₃₀H ₄₂N ₂O ₅S+H) ⁺: 543

MS measured value (electrospray): (M+H) ⁺=543

Intermediate 72

(2S, 4R, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-(1-hydroxyl-1-methylethyl)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Chirality; Shown absolute stereo chemistry

According to similarity method described in the intermediate 61 (method B), replace intermediates 11 with intermediate 71, prepare title compound.

MS calculated value (C ₃₁H ₄₆N ₂O ₅S+H) ⁺: 559

MS measured value (electrospray): (M+H) ⁺=559

Intermediate 73

(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethanoyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Chirality; Shown absolute stereo chemistry

According to embodiment 1 similar methods, use intermediate 71 as initial substance, prepare title compound.

¹H?NMR(CDCl ₃)：δ8.10(d，1H)，7.68(d，1H)，7.39(d，1H)，7.05(d，1H)，6.60(s，1H)，6.27(d，1H)，3.88(m?1H)，3.72，(s，3H)，3.03(dd，1H)，2.79(t，1H)，2.73(dd，1H)，2.32(s，3H)，2.18(dd，1H)，1.86(m，1H)，1.35(s，9H)，1.16(d，3H)，1.04(d，3H)。

Intermediate 74

2-[N-(1,3-thiazoles-4-methylene) amino]-the 4-methylvaleric acid, the tert-butyl ester

According to intermediate 1 similar methods, use 1,3-thiazoles-4-formaldehyde to replace 1,3-thiazoles-2-formaldehyde, prepare title compound.

¹H NMR (CDCl ₃): δ 8.85 (1H, d), 8.49 (1H, s), 8.01 (1H, d), 4.03-3.98 (1H, m), 3.11 (2H, dd), 1.64-1.52 (1H, m), 1.48 (9H, s), 0.96 (3H, d) and 0.91 (3H, d).

Intermediate 75

Rel-(2S, 4S, 5R)-and 2-isobutyl--5-(1,3-thiazoles-4-yl) tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Relative stereochemistry shown in racemic

According to intermediate 2 similar methods, use intermediate 74 as initial substance, prepare title compound.

MS calculated value (C ₁₈H ₂₈N ₂O ₄S+H) ⁺: 369

MS measured value (electrospray): (M+H) ⁺=369

Intermediate 76

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-5-(1,3-thiazoles-4-yl) tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Relative stereochemistry shown in racemic

According to intermediate 3 similar methods, use intermediate 75 as initial substance, prepare title compound.

MS calculated value (C ₃₀H ₄₂N ₂O ₆S+H) ⁺: 559

MS measured value (electrospray): (M+H) ⁺=559

Intermediate 77

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl-5-(1,3-thiazoles-4-yl) tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 20 similar methods, use intermediate 76 as initial substance, prepare title compound.

MS calculated value (C ₂₉H ₄₂N ₂O ₅S+H) ⁺: 531

MS measured value (electrospray): (M+H) ⁺=531

Intermediate 78

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-4-yl) tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 22 similar methods, use intermediate 77 as initial substance, prepare title compound.

MS calculated value (C ₃₁H ₄₆N ₂O ₅S+H) ⁺: 559

MS measured value (electrospray): (M+H) ⁺=559

Intermediate 79

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-4-yl) tetramethyleneimine-2-carboxylic acid, the enantiomer A of the 2-tert-butyl ester

Chirality; Shown relative stereochemistry

By (95: the 5v/v) enantiomer of the preparation type hplc separation of intermediates 78 of the Whelk-01 post of wash-out prepares the title compound as the first wash-out isomer with heptane-ethanol.

MS calculated value (C ₃₁H ₄₆N ₂O ₅S+H) ⁺: 559

MS measured value (electrospray): (M+H) ⁺=559

Intermediate 80

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-allyloxy methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 14 similar methods, replace intermediate 4 with intermediate 4a, prepare title compound.

MS calculated value (C ₃₂H ₄₆N ₂O ₅S+H) ⁺: 571

MS measured value (electrospray): (M+H) ⁺=571

Intermediate 81

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-cyano methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

Under nitrogen,, in the solution of the dry methylene chloride (2mL) of the trifluoromethanesulfanhydride anhydride (51 μ L) that stirs, add methylene dichloride (2mL) solution of intermediate 4 (159mg) and pyridine (23 μ L) in-15 ℃.Mixture was stirred 1.5 hours in 0 ℃.Add entry (5mL) under the vigorous stirring, and with mixture by the Hydrophobic glass material.The dichloromethane solution that so obtains is added in methylene dichloride (2mL) solution of tetrabutyl ammonium cyanide (80mg), and under room temperature, stirred 3 hours.Mixture is passed through with hexanaphthene-ethyl acetate (by 4: 1v/v to 3: the gradient elution of 1v/v) as the silica gel chromatography purifying of eluent, prepare title compound.

MS calculated value (C ₃₀H ₄₁N ₃O ₄S+H) ⁺: 540

MS measured value (electrospray): (M+H) ⁺=540

Intermediate 82

(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-(1-hydroxyl-1-methylethyl)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Absolute stereo chemistry shown in the chirality

Stir tetrahydrofuran (THF) (10mL) solution of intermediate 19 (280mg), and under nitrogen, cool off down in-78 ℃.Toluene/THF (2mL) solution that adds the 1.4M methyl-magnesium-bromide.Remove cooling bath and mixture was stirred 2 hours.Add saturated ammonium chloride solution (10mL), and (2 * 20mL) extract with ethyl acetate with mixture.With extraction liquid water and the salt washing that merges, and dry then (MgSO ₄).Remove and desolvate, and resistates is passed through with hexanaphthene-ethyl acetate (4: 1v/v) as the silica gel chromatography purifying of eluent, prepare title compound.

MS calculated value (C ₃₁H ₄₆N ₂O ₅S+H) ⁺: 559

MS measured value (electrospray): (M+H) ⁺=559

Intermediate 83

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-(1-hydroxyethyl)-5-(1,3-thiazoles-2-base-tetramethyleneimine-2-carboxylic acid, tert-butyl ester

Relative stereochemistry shown in racemic

In the solution of the THF of intermediate 11 (224mg) (3mL) and ethanol (1mL), add sodium borohydride (31mg), and the mixture that generates was stirred under room temperature 5 hours.Remove and desolvate, and resistates is distributed between ethyl acetate and water.Collect organic phase, and dry (MgSO ₄).Remove and desolvate, prepare the title compound of 3: 1 non-enantiomer mixture.

MS calculated value (C ₃₀H ₄₄N ₂O ₅S+H) ⁺: 545

MS measured value (electrospray): (M+H) ⁺=545

Intermediate 84

Rel-(2S, 4R, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-(1-(4-fluorophenoxy thiocarbonyl oxygen base) ethyl)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 8 similar methods, use intermediate 83 as initial substance, prepare title compound.

MS calculated value (C ₃₇H ₄₇FN ₂O ₆S ₂+ H) ⁺: 699

MS measured value (electrospray): (M+H) ⁺=699

Intermediate 85

Rel-(2S, 4R, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

To 1 of intermediate 84 (152mg), add AIBN (14mg) and three (trimethyl silyl) silicomethane (0.089mL) in the solution of 4-diox (3mL).With mixture in 115 ℃ the heating 3.75 hours, and then with it in kept at room temperature overnight.With mixture further in 115 ℃ of reheat 2 hours.Evaporating solvent, and resistates is passed through to use hexanaphthene-ethyl acetate, and (9: 1v/v) the silica gel chromatography purifying of wash-out prepares gummy title compound.

MS calculated value (C ₃₀H ₄₄N ₂O ₄S+H) ⁺: 529

MS measured value (electrospray): (M+H) ⁺=529

Intermediate 86

Rel-(2S, 4R, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-5-(pyridine-2-yl) tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Relative stereochemistry shown in racemic

The sodium methylate (0.51mL) that in the solution of the methyl alcohol (15mL) of intermediate 67 (1.29g), adds the 25%w/v methanolizing.With mixture in stirred overnight at room temperature.Remove and desolvate, and (4: 1v/v) the silica gel chromatography purifying of wash-out prepares title compound by using hexanaphthene-ethyl acetate with resistates.

MS calculated value (C ₃₂H ₄₄N ₂O ₆+ H) ⁺: 553

MS measured value (electrospray): (M+H) ⁺=553

Intermediate 87

Rel-(2S, 4R, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl-5-(pyridine-2-yl) tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Relative stereochemistry shown in racemic

Tetrahydrofuran (THF) (0.98mL) solution that in the solution of the tetrahydrofuran (THF) (10mL) of intermediate 86 (758mg), adds 2M lithium borohydride (lithium borohydridfe).With mixture in stirring at room 18 hours.Remove and desolvate, and resistates is distributed between ethyl acetate and solution of potassium carbonate.Collected organic layer, and water layer further used ethyl acetate extraction.Dry organic solution (the Na that merges ₂SO ₄).Remove and desolvate, and (by 100: 0v/v to 3: the silica gel chromatography purifying of the wash-out gradient elution of 2v/v) prepares title compound by using hexanaphthene-ethyl acetate with resistates.

MS calculated value (C ₃₁H ₄₄N ₂O ₅+ H) ⁺: 525

MS measured value (electrospray): (M+H) ⁺=525

Intermediate 88

Rel-(2S, 4R, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(pyridine-2-yl) tetramethyleneimine-2-carboxylic acid, the 2-tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 16 similar methods, use intermediate 87 as initial substance, prepare title compound.

MS calculated value (C ₃₂H ₄₆N ₂O ₅+ H) ⁺: 539

MS measured value (electrospray): (M+H) ⁺=539

Intermediate 89

(2S, 4S, 5R)-and 2-(isobutyl-)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2, the 4-dicarboxylic acid, 2-(tertiary butyl) ester, 4-[(1R, 2S, 5R)-and 5-methyl-2-(sec.-propyl) cyclohexyl] ester

Absolute stereo chemistry shown in the main diastereomer shown in the diastereomer ratio 85: 15 (hplc of chirality)

(11.24g 53.5mmol) joins (intermediate 1 with L-menthyl acrylate; 13.73g, in the solution of anhydrous THF (165mL) 48.6mmol).Add lithiumbromide (8.43g 97.1mmol), and stirs mixture 5 minutes, drip subsequently triethylamine (10.11mL, 72.9mmol).The mixture that generates in stirring 18 hours under nitrogen under the room temperature, is stopped it then with saturated aqueous ammonium chloride solution, be extracted in the ethyl acetate, and with salt washing, drying (Na ₂SO ₄) and evaporation, prepare scarlet buttery title compound (at the mixture of the diastereomer at tetramethyleneimine C (4)-center).Determine the stereochemistry of the diastereomer that this is main by reference intermediate 90 (as follows).

MS calculated value (C ₂₇H ₄₄N ₂O ₄S+H) ⁺: 493.

MS measured value (electrospray): (M+H) ⁺=493

¹H?NMR(DMSO-d ₆)：δ7.64(1H，d)，7.60(1H，d)，4.72(1H，t)，4.32(1H，m)，3.42(1H，m)，2.46(1H，dd)，2.02(1H，dd)，1.71-1.48(6H，m)，1.41(9H，s)，1.38-1.10(3H，m)，0.97-0.47(4H，br)，0.91(3H，d)，0.84(3H，d)，0.78(6H，d)，0.58(3H，d).

Intermediate 90

(2S, 4S, 5R)-and 2-(isobutyl-)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2, the 4-dicarboxylic acid, 2-(tertiary butyl) ester, 4-[(1R, 2S, 5R)-and 5-methyl-2-(sec.-propyl) cyclohexyl] ester hydrochloride

Chirality; The stereochemistry that shown absolute stereo chemistry is determined by the X-radiocrystallography

In 0 ℃, (75.9mL, (24.84g is in diethyl ether solution 50.4mmol) 75.9mmol) to drop to intermediate 89 with anhydrous hydrogen chloride (diethyl ether solution of 1M).Removal of solvent under reduced pressure, and with the solid that generates by 2-propyl alcohol recrystallization.The solid that generates is washed with ether, and dry, prepared the title compound of crystalline solid.

¹H?NMR(CD ₃OD)：δ7.78(d，1H)，7.76(d，1H)，5.56(d，1H)，4.53(m，1H)，3.84(dd，1H)，3.42(dd，1H)，2.53(dd，1H)，2.11-2.01(m，2H)，1.85-1.70(m，2H)，1.69-1.60(br?m，2H)，1.53(s，9H)，1.45-1.23(br?m，3H)，1.07-0.95(m，1H)，1.03(d，3H)，1.00(d，3H)，0.89(d，3H)，0.83(d，3H)，0.80-0.72(br?m，1H)，0.70(d，3H)0.50(dd，1H)。

Determine the absolute stereo chemistry of this compound by the X-radiocrystallography, and as drawn being shown as (2S, 4S, 5R).

Intermediate 91

(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2, the 4-dicarboxylic acid, 2-(tertiary butyl) ester, 4-[(1R, 2S, 5R)-and 5-methyl-2-(sec.-propyl) cyclohexyl] ester

Chirality; Shown absolute stereo chemistry

(6.16mL, (11.75g, 22.20mmol) (7.57g is in anhydrous methylene chloride 33.4mmol) (190mL) solution with the 4-tertiary butyl-3-methoxy benzoyl chloride 44.4mmol) to drop to intermediate 90 with triethylamine.Reaction mixture in stirring 18 hours under the room temperature, is washed dry (Hydrophobic glass material) and vacuum concentration with saturated sodium bicarbonate aqueous solution under nitrogen.Crude mixture is used hexanaphthene-ethyl acetate (1: 1v/v) as the silica gel chromatography purifying of eluent, prepare gummy title compound then by using toluene.

MS calculated value (C ₃₉H ₅₈N ₂O ₆S+H) ⁺: 683.

MS measured value (electrospray): (M+H) ⁺=683.

¹H?NMR(CD ₃OD)：δ7.42(s，1H)，7.28(d，1H)，6.86(d，1H)，6.51(s，1H)，5.85(d，1H)，4.39(m，1H)，3.92(m，1H)，3.67(s，3H)，3.06(dd，1H)，2.41(dd，1H)，2.26-2.11(m，2H)，2.09-1.90(m，1H)，1.89-1.74(br，1H)，1.66-1.52(br，2H)，1.47(s，9H)，1.35(s，9H)，1.38-1.11(br，4H)，1.08(d，6H)，1.06-0.89(br，1H)，0.86(d，3H)，0.82-0.67(br，1H)，0.76(d，3H)，0.66(d，3H)，0.51-0.35(q，1H)。

Intermediate 92

(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-(hydroxymethyl)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Chirality; Shown absolute stereo chemistry

In room temperature, (0.22mL, (0.15g was in anhydrous diethyl ether 0.22mmol) (3mL) solution 0.22mmol) to drop to intermediate 91 with lithium aluminium hydride (tetrahydrofuran solution of 1M) with 1 minute under nitrogen.By behind this reaction mixture of wet chemical cancellation that drips 1.0M 10 minutes, be extracted in the ethyl acetate twice.Merge extract, wash with water, dry (Na ₂SO ₄), and evaporation prepares natural gum.This crude product is passed through with hexanaphthene-ethyl acetate (2: 1v/v) as the silica gel chromatography purifying of eluent, prepare title compound.

MS calculated value (C ₂₉H ₄₂N ₂O ₅S+H) ⁺: 531.

MS measured value (electrospray): (M+H) ⁺=531.

¹H?NMR(CDCl ₃)：7.57(d，1H)，7.27(d，1H)，7.09(d，1H)，6.69(d，1H)，6.53(s，1H)，5.64(d，1H)，3.59(s，3H)，3.43(dd，1H)，3.26-3.12(br，1H)，2.80(t，1H)，2.34(dd，1H)，2.22-1.82(m，4H)，1.59(s，9H)，1.52-1.30(m，1H)，(s，9H)，1.06(m，6H)。

The spectroscopic data of this compound identical with described in the intermediate 20.

Intermediate 93

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(5-methyl isophthalic acid, 3-thiazol-2-yl) tetramethyleneimine-2-carboxylic acid, the enantiomer A of the 2-tert-butyl ester

Chirality; Relative stereochemistry shown in the enantiomer A

The chirality hplc of intermediate 51 usefulness chiralpak AD posts is separated into enantiomer, with heptane-isopropyl alcohol (95: 5v/v) wash-out.Obtain the title compound of the enantiomer that goes out for wash-out at first.

MS calculated value (C ₃₁H ₄₆N ₂O ₅S+H) ⁺: 559

MS measured value (electrospray): (M+H) ⁺=559

Intermediate 94 and 95

Rel-(2S, 4R, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-(1-methoxy ethyl)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the diastereomer 1 of the tert-butyl ester and diastereomer 2

Relative stereochemistry diastereomer 1-intermediate 94 diastereomer 2-intermediates 95 shown in racemic

(0.84g 1.54mmol) adds sodium hydride (60% mineral oil dispersion in dry DMF (15mL) solution of (mixture of 7: 3 diastereo-isomerism alcohol) to the intermediate 83 that stirs; 0.15g, 3.64mmol).The mixture that generates was stirred under room temperature 1 hour, and under agitation add then methyl iodide (0.75mL, 12.05mmol).After 1 hour, reaction mixture is distributed between ethyl acetate and 1N hydrochloric acid.Isolate water, and with ethyl acetate with its Hui Cui once.Merge organic phase and dry (Na ₂SO ₄), and evaporation obtains natural gum.This material is absorbed on the silica gel in advance, uses hexanaphthene-ethyl acetate (7: subsequently 1v/v) as the silica gel chromatography purifying of eluent.Merge the part in early stage and evaporation then, prepare intermediate 94.

MS calculated value (C ₃₁H ₄₆N ₂O ₅S+H) ⁺: 559.

MS measured value (electrospray): (M+H) ⁺=559.

The part that merges the back, evaporation prepares intermediate 95.

MS calculated value (C ₃₁H ₄₆N ₂O ₅S+H) ⁺: 559.

MS measured value (electrospray): (M+H) ⁺=559

Intermediate 96

(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(pyridine-2-yl) tetramethyleneimine-2-carboxylic acid, the enantiomer A of the 2-tert-butyl ester

Chirality; Relative stereochemistry shown in the enantiomer A

Under nitrogen in-15 ℃, to the intermediate 68 that stirs (845mg, add in dry DMF 1.6mmol) (30mL) solution sodium hydride (60% mineral oil solution, 64mg, 1.6mmol).Slurry was stirred 30 minutes down in-15 ℃, add methyl iodide (0.1mL, 227mg, 1 equivalent) then, and stir this reaction, and made it be warmed to room temperature by-15 ℃ with 18 hours.Add methyl alcohol (30mL), and should react and stir 15 minutes.Evaporating solvent also distributes resistates between water and ethyl acetate.Use Na ₂SO ₄Dry organic layer and evaporation obtain oily matter, and it by the silica gel chromatography purifying with hexanaphthene-ethyl acetate gradient elution, is prepared solid.Use the preparation type chirality HPLC of Welk 01 post to be separated into its enantiomer it, with heptane-Virahol (95: 5v/v) wash-out.Obtain the title compound of the enantiomer that goes out for wash-out at first.

MS calculated value (C ₃₂H ₄₆N ₂O ₅+ H) ⁺: 539

MS measured value (electrospray): (M+H) ⁺=539

Intermediate 97

2-[N-(5-methyl-isoxazole-3-methylene) amino]-the 4-methylvaleric acid, the tert-butyl ester

According to intermediate 1 similar methods, use 5-methyl-isoxazoles-3-formaldehyde to replace 1,3-thiazoles-2-formaldehyde, prepare title compound.

¹H?NMR(CDCl ₃)：δ8.35(1H，s)，6.48(1H，s)，4.00(1H，m)，2.45(3H，s)，1.79(2H，m)，1.53(1H，m)，1.46(9H，s)，0.98(3H，dd)，0.89(3H，dd)

Intermediate 98

Rel-(2S, 4S, 5R)-and 2-isobutyl--5-(5-methyl-isoxazole-3-yl) tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Relative stereochemistry shown in racemic

According to intermediate 2 similar methods, use intermediate 97 as initial substance, prepare title compound.

MS calculated value (C ₁₉H ₃₀N ₂O ₅+ H) ⁺: 367

MS measured value (electrospray): (M+H) ⁺=367

Intermediate 99

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-5-(5-methyl isophthalic acid, 2-oxazole-3-yl)-tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Relative stereochemistry shown in racemic

According to intermediate 3 similar methods, use intermediate 98 as initial substance, prepare title compound.

MS calculated value (C ₃₁H ₄₄N ₂O ₇+ H) ⁺: 557

MS measured value (electrospray): (M+H) ⁺=557

Intermediate 100

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl-5-(5-methyl-isoxazole-3-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 20 similar methods, use intermediate 99 as initial substance, prepare title compound.

MS calculated value (C ₃₀H ₄₄N ₂O ₆+ H) ⁺: 529

MS measured value (electrospray): (M+H) ⁺=529

Intermediate 101

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(5-methyl-isoxazole-3-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 16 similar methods, use intermediate 100 as initial substance, prepare title compound.

MS calculated value (C ₃₂H ₄₈N ₂O ₆+ H) ⁺: 557

MS measured value (electrospray): (M+H) ⁺=557

Intermediate 102

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(5-methyl-isoxazole-3-yl) tetramethyleneimine-2-carboxylic acid, the enantiomer A of the tert-butyl ester

Chirality; Relative stereochemistry shown in the enantiomer A

Preparation type chirality hplc by the Whelko-1 post is separated into its enantiomer with intermediate 101, and with heptane-ethanol (90: 10v/v) wash-out.Obtain the title compound of the enantiomer that goes out for wash-out at first.

MS calculated value (C ₃₂H ₄₈N ₂O ₆+ H) ⁺: 557

MS measured value (electrospray): (M+H) ⁺=557

Intermediate 103

2-bromo-1,3-thiazoles-5-formaldehyde

The acetonitrile (200mL) (slurry) of 2-amino-1,3-thiazoles-5-formaldehyde (13.78g, 0.108mol, 1 equivalent) is added in batches the CuBr of stirring ₂(36.03g, 0.129mol) and nitrite tert-butyl (19mL is in acetonitrile 0.161mL) (550mL) suspension.This is reacted under the room temperature stirred 4 hours, evaporation obtains solid then.It is handled with ethyl acetate (400mL) and 2M HCl (400mL).Add entry (200mL), salt solution (100mL) and ethyl acetate (200mL).Separate two-phase.Water is extracted with ethyl acetate (250mL).Dry organic layer (the MgSO that merges ₄) and evaporation, obtain title compound.

¹H?NMR(CDCl ₃)：δ9.97(1H，s)，8.19(1H，s)

Intermediate 104

(2-bromo-1,3-thiazoles-5-yl) methyl alcohol

(16.34g 0.086mol) is dissolved in the methyl alcohol (300mL), and is cooled to 10 ℃ with intermediate 103.With added in 15 minutes in batches sodium borohydride (1.63g, 0.043mol).Remove cooling bath, and this reaction is warmed to room temperature and stirred 3 hours.Evaporating solvent.Add entry (100mL), add 1N HCl (200mL) subsequently.Add ethyl acetate (450mL), and separate two-phase.Organic layer is washed dry (MgSO with salt solution (450mL) ₄) and concentrate, obtain brown liquid.This crude product is passed through with hexanaphthene-ethyl acetate (80: 20v/v) as the silica gel chromatography purifying of eluent, obtain title compound.

¹H?NMR(CDCl ₃)：δ7.4(1H，s)，4.82(2H，d)，2.96(1H，t)

Intermediate 105

2-bromo-5-(methoxymethyl)-1,3-thiazoles

Under nitrogen, (10.58g 54.80mmol) is dissolved among the DMF (250mL), and this solution is cooled to-15 ℃ with intermediate 104.Add sodium hydride (60% oil dispersion; 3.29g, 82.20mmol), and mixture stirred 25 minutes in-15 ℃ to-10 ℃.Add methyl iodide (6.82mL, 0.109mol), and with this solution in-15 ℃ to-10 ℃ stirrings 4 hours.Should react by adding methyl alcohol (50mL) and stop.Vacuum is removed methyl alcohol, and with resistates water (600mL) dilution, and use the ether extracting twice.Wash organic layer with water twice, dry (MgSO ₄), and the concentrated liquid that obtains.This crude product is passed through with hexanaphthene-ethyl acetate (90: 10v/v) as the silica gel chromatography purifying of eluent, prepare title compound.

¹H?NMR(CDCl ₃)：δ7.45(1H，s)，4.58(2H，s)，3.37(3H，s)

Intermediate 106

5-(methoxymethyl)-1,3-thiazoles-2-formaldehyde

In 3 neck flasks of oven drying, feed nitrogen, and the filling n-BuLi (hexane solution of 1.6M; 21.80mL, 34.54mmol), add exsiccant ether (42mL) subsequently.This solution is cooled to-78 ℃ in ice/acetone bath, and (7.01g, ether 33.86mmol) (28mL) solution keep simultaneously internal temperature to be lower than-68 ℃ to drip intermediate 105 with time of 20 minutes.The reaction mixture that generates was stirred 20 minutes in-78 ℃.Add a dry DMF (3.9mL, 50.79mmol).Should react with 4 hours and slowly be warmed to 15 ℃.Stop this reaction by adding 4N hydrochloric acid (50mL) carefully, temperature is risen be higher than 20 ℃.Add ice/water, add ether (140mL) subsequently.(4 * 70mL) extract with 4N hydrochloric acid with mixture.Merge the aqueous extract that generates.Then with sodium bicarbonate neutralize these extraction liquids to pH be 7, and with the water that generates with ether (2 * 140mL) extractions.Merge ether extraction liquid, dry (MgSO ₄), and vacuum-evaporation carefully, obtain liquid.This crude product is passed through with hexanaphthene-ethyl acetate (80: 20v/v) as the silica gel chromatography purifying of eluent, prepare title compound.

¹H?NMR(CDCl ₃)：δ9.95(1H，s)，7.98(1H，s)，4.72(2H，s)，3.44(3H，s)。

Intermediate 107

2-[N-(5-methoxymethyl-1,3-thiazoles-2-methylene) amino]-the 4-methylvaleric acid, the tert-butyl ester

According to intermediate 1 similar methods, use intermediate 106 to replace 1,3-thiazoles-2-formaldehyde, prepare title compound.

¹H?NMR(CDCl ₃)：δ8.36(1H，s)，7.79(1H，s)，4.65(2H，s)，4.48-4.01(1H，m)，3.39(3H，s)，1.89-1.71，(2H，m)，1.63-1.50(1H，m)，1.47(9H，s)，0.94(3H，d)，0.89(3H，d)

Intermediate 108

Rel-(2S, 4S, 5R)-and 2-isobutyl--5-(5-methoxymethyl-1,3-thiazoles-2-yl) tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Relative stereochemistry shown in racemic

According to intermediate 2 similar methods, use intermediate 107 as initial substance, prepare title compound.

MS calculated value (C ₂₀H ₃₂N ₂O ₅S+H) ⁺: 413

MS measured value (electrospray): (M+H) ⁺=413

Intermediate 109

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-5-(5-methoxymethyl-1,3-thiazoles-2-yl) tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Relative stereochemistry shown in racemic

According to intermediate 3 similar methods, use intermediate 108 as initial substance, prepare title compound.

MS calculated value (C ₃₂H ₄₆N ₂O ₇S+H) ⁺: 603

MS measured value (electrospray): (M+H) ⁺=603

Intermediate 110

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl-5-(5-methoxymethyl-1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 20 similar methods, use intermediate 109 as initial substance, prepare title compound.

MS calculated value (C ₃₁H ₄₆N ₂O ₆S+H) ⁺: 575

MS measured value (electrospray): (M+H) ⁺=575

Intermediate 111

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(5-methoxymethyl-1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 16 similar methods, use intermediate 110 as initial substance, prepare title compound.

MS calculated value (C ₃₂H ₄₈N ₂O ₆S+H) ⁺: 589

MS measured value (electrospray): (M+H) ⁺=589

Intermediate 112

2-[N-(5-picoline-2-methylene) amino]-the 4-methylvaleric acid, the tert-butyl ester

According to intermediate 1 similar methods, use 5-picoline-2-formaldehyde to replace 1,3-thiazoles-2-formaldehyde, prepare title compound.

¹H?NMR(CDCl3)：δ8.47(1H，s)，8.33(1H，s)，8.02(1H，d)，7.55(1H，d)，4.02(1H，m)2.37(3H，s)，1.72-1.9(2H，m)，1.47-1.64(1H，m)，1.47(9H，s)，0.94(3H，d)，0.89(3H，d)。

Intermediate 113

Rel-(2S, 4S, 5R)-and 2-isobutyl--5-(5-picoline-2-yl) tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Relative stereochemistry shown in racemic

According to intermediate 2 similar methods, use intermediate 112 as initial substance, prepare title compound.

MS calculated value (C ₂₁H ₃₂N ₂O ₄+ H) ⁺: 377

MS measured value (electrospray): (M+H) ⁺=377

Intermediate 114

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-5-(5-picoline-2-yl)-tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Relative stereochemistry shown in racemic

According to intermediate 3 similar methods, use intermediate 113 as initial substance, prepare title compound.

MS calculated value (C ₃₃H ₄₆N ₂O ₆+ H) ⁺: 567

MS measured value (electrospray): (M+H) ⁺=567

Intermediate 115

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl-5-(5-picoline-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 20 similar methods, use intermediate 114 as initial substance, prepare title compound.

MS calculated value (C ₃₂H ₄₆N ₂O ₅+ H) ⁺: 539

MS measured value (electrospray): (M+H) ⁺=539

Intermediate 116

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(5-picoline-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 16 similar methods, use intermediate 115 as initial substance, prepare title compound.

MS calculated value (C ₃₃H ₄₈N ₂O ₅+ H) ⁺: 553

MS measured value (electrospray): (M+H) ⁺=553

Intermediate 117

2-[N-(thiophene-2-methylene) amino]-the 4-methylvaleric acid, the tert-butyl ester

According to intermediate 1 similar methods, use thiophene-2-formaldehyde to replace 1,3-thiazoles-2-formaldehyde, prepare title compound.

¹H?NMR(CDCl ₃)：δ8.88(s，1H)，7.43(dd，1H)，7.35(dd，1H)，7.08(dd，1H)，3.94(dd，1H)，1.86-1.72(m，2H)，1.63-1.53(m，1H)，1.47(s，9H)，0.95(d，3H)，0.90(d，3H)。

Intermediate 118

Rel-(2S, 4S, 5R)-and 2-isobutyl--5-(thiophene-2-yl) tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Relative stereochemistry shown in racemic

According to intermediate 2 similar methods, use intermediate 117 as initial substance, prepare title compound.

MS calculated value (C ₁₉H ₂₉NO ₄S+H) ⁺: 368

MS measured value (electrospray) (M+H) ⁺: 368

Intermediate 119

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-5-(thiophene-2-yl) tetramethyleneimine-2,4-dicarboxylic acid, the 2-tert-butyl ester, 4-methyl esters

Relative stereochemistry shown in racemic

According to intermediate 3 similar methods, use intermediate 118 as initial substance, prepare title compound.

MS calculated value (C ₃₁H ₄₃NO ₆S+H) ⁺: 558

MS measured value (electrospray) (M+H) ⁺: 558

Intermediate 120

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl-5-(thiophene-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 20 similar methods, use intermediate 119 as initial substance, prepare title compound.

MS calculated value (C ₃₀H ₄₃NO ₅S+H) ⁺: 530

MS measured value (electrospray) (M+H) ⁺: 530

Intermediate 121

Rel-(2S, 4S, 5R)-and 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(thiophene-2-yl) tetramethyleneimine-2-carboxylic acid, the tert-butyl ester

Relative stereochemistry shown in racemic

According to intermediate 16 similar methods, use intermediate 120 as initial substance, prepare title compound.

MS calculated value (C ₃₁H ₄₅NO ₅S+H) ⁺: 544

MS measured value (electrospray) (M+H) ⁺: 544

Embodiment 1

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

In the solution of the anhydrous methylene chloride (1mL) of intermediate 5 (0.053g), add trifluoroacetic acid (1mL).Mixture is spent the night in 20 ℃ of preservations.Evaporating mixture also grinds resistates with ether, prepare the solid title compound.

MS calculated value (C ₂₇H ₃₈N ₂O ₅S+H) ⁺: 503

MS measured value (electrospray): (M+H) ⁺=503

¹H?NMR(CD ₃OD)：δ7.37(1H，d)，7.23(1H，br?s)，7.14(1H，d)，6.85(1H，s)，6.54(1H，s)，5.37(1H，d)，3.70(3H，s)，3.34-3.47(4H，m)，2.79(1H，m)，2.50(2H，m)，2.31(1H，dd)，1.98(1H，dd)，1.86(1H，m)，1.30(9H，s)，1.13(3H，d)，1.12(3H，t)，1.00(3H，d)。

Embodiment 2

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, prepare title compound by intermediate 6.

MS calculated value (C ₂₆H ₃₆N ₂O ₅S+H) ⁺: 489

MS measured value (electrospray): (M+H) ⁺=489

¹H?NMR(CD ₃OD)：δ7.40(1H，d)，7.26(1H，br?s)，7.17(1H，d)，6.89(1H，d)，6.56(1H，s)，5.38(1H，d)，3.72(3H，s)，3.41(1H，dd)，3.31(3H，s)，2.80(1H，m)，2.51(2H，m)，2.33(1H，m)，2.02(1H，dd)，1.88(1H，m)，1.33(9H，s)，1.15(3H，d)，1.02(3H，d)。1 proton is covered by solvent

Embodiment 3

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methyl fluoride-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, prepare title compound by intermediate 7.

MS calculated value (C ₂₅H ₃₃FN ₂O ₄S+H) ⁺: 477

MS measured value (electrospray): (M+H) ⁺=477

¹H?NMR(CD ₃OD)：δ7.43(1H，d)，7.26(1H，br?s)，7.18(1H，d)，6.91(1H，d)，6.59(1H，s)，5.44(1H，s)，4.33-4.58(2H，m)，3.73(3H，s)，2.93(1H，m)，2.52(2H，m)，2.39(1H，dd)，2.03(1H，m)，1.89(1H，m)，1.33(9H，s)，1.16(3H，d)，1.02(3H，d)

Embodiment 4

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, prepare title compound by intermediate 9.

MS calculated value (C ₂₅H ₃₄N ₂O ₄S+H) ⁺: 459

MS measured value (electrospray): (M+H) ⁺=459

¹H?NMR(CD ₃OD)：δ7.40(1H，d)，7.25(1H，br?s)，7.15(1H，d)，6.89(1H，d)，6.59(1H，s)，5.03(1H，d)，3.73(3H，s)，2.62(1H，m)，2.53(1H，m)，2.43(1H，dd)，2.18(1H，t)，2.04(1H，m)，1.90(1H，m)，1.33(9H，s)，1.15(3H，d)，1.04(3H，d)，1.02(3H，d)

Embodiment 5

2-allyl group-1-(3-bromo-4-tert.-butylbenzene formyl radical)-tetramethyleneimine-2-carboxylic acid

Racemic

2-allyl group-tetramethyleneimine-2-carboxylic acid hydrochloride (J.Chem.Soc.Chem.Commun., 1988,22,1447) (64mg) is dissolved in the methylene dichloride (5mL), and with 3-bromo-4-tert.-butylbenzene formyl chloride ¹(101mg) and triethylamine (139 μ L) handle.Mixture was stirred under room temperature 18 hours.Adding hydrochloric acid (2N, 5mL), and with mixture stirring 5 minutes.Use the PTFE strainer to separate organic phase and concentrated, prepare xanchromatic natural gum.It is passed through C ₁₈The reversed-phase HPLC purifying of post, contain the water of formic acid (0.1%) and (B) contain the acetonitrile-water (95: of formic acid (0.05%) with (A) 5v/v) as two solvent gradient elutions of eluent, and carry out flow point (fractions) by the electrospray mass spectrum and analyze, prepare solid title compound (68mg).

MS calculated value (C ₁₉H ₂₄BrNO ₃+ H) ⁺: 394/396

MS measured value (electrospray): (M+H) ⁺=394/396

¹H?NMR(CDCl ₃)：δ7.75(1H，d)，7.50(1H，d)，7.42(1H，dd)，5.79(1H，m)，5.22-5.28(2H，m)，3.53(2H，m)，3.15(1H，dd)，2.86(1H，dd)，2.70(1H，m)，2.07(1H，m)，1.87(2H，m)，1.52(9H，s)

Document (1): Synthesised from 3-bromo-4-tert-butylbenzoic acid (Aust.J.Chem., 1990,43,807).

Embodiment 6

2-benzyl-1-(3-bromo-4-tert.-butylbenzene formyl radical)-tetramethyleneimine-2-carboxylic acid

Racemic

According to embodiment 5 similar methods, by 2-benzyl-tetramethyleneimine-2-carboxylic acid, prepare title compound.

MS calculated value (C ₂₃H ₂₆BrNO ₃+ H) ⁺: 444/446

MS measured value (electrospray): (M+H) ⁺=444/446

¹H?NMR(CD ₃OD)：δ7.64(1H，d)，7.61(1H，d)，7.36(4H，m)，7.26(2H，m)，3.92(1H，d)，3.39(1H，m)，3.13(1H，d)，2.82(1H，m)2.33(1H，m)，2.19(1H，m)，1.85(1H，m)，1.55(9H，s)，1.35(1H，m)

Embodiment 7

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

(52mg adds trifluoroacetic acid (2mL) in solution 0.098mmol) to intermediate 4.This solution is spent the night in the room temperature placement.Vacuum evaporating solvent and with resistates and CH ₂Cl ₂(* 2) and toluene coevaporation grind with ether then.With the white solid that generates methyl alcohol (the 1mL MeOH solution of the 6.4mg NaOH) solution-treated of the NaOH of 1mL, and under room temperature, stir and spend the night.Vacuum evaporating solvent then, and resistates passed through C ₁₈The reversed-phase HPLC purifying of post contains the water of formic acid (0.1%) and the acetonitrile-water (95: 5v/v) as two solvent gradient elutions of eluent, prepare the solid title compound that (B) contains formic acid (0.05%) with (A).

MS calculated value (C ₂₅H ₃₄N ₂O ₅S+H) ⁺: 475

MS measured value (electrospray): (M+H) ⁺=475

¹H?NMR(CD ₃OD)：δ7.37(1H，d)，7.25(1H，br?s)，7.13(1H，d)，6.86(1H，d)，6.56(1H，s)，5.34(1H，d)，3.71(3H，s)，3.55(1H，dd)，3.46(1H，dd)，2.68(1H，m)，2.49(2H，m)，2.33(1H，dd)，2.02(1H，m)，1.88(1H，m)，1.30(9H，s)，1.14(3H，d)，1.00(3H，d)

Embodiment 8

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-hydroxymethyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 7 similar methods, by intermediate 4a, prepare title compound.

MS calculated value (C ₂₅H ₃₄N ₂O ₅S+H) ⁺: 475

MS measured value (electrospray): (M+H) ⁺=475

¹H?NMR(CD ₃OD)：δ7.82(1H，d)，7.56(1H，d)，7.19(1H，d)，6.68(1H，dd)，6.35(1H，d)，5.69(1H，d)，3.63(3H，s)，3.18(2H，m)，3.01(1H，m)，2.00-2.35(5H，m)，1.30(9H，s)，1.14(3H，d)，1.11(3H，d)。

Embodiment 9

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-allyloxy methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, prepare title compound by intermediate 14.

MS calculated value (C ₂₈H ₃₈N ₂O ₅S+H ⁺): 515

MS measured value (electrospray): (M+H) ⁺=515

¹H?NMR(CD ₃OD)：δ7.38(1H，d)，7.24(1H，br?s)，7.14(1H，d)，6.85(1H，d)，6.54(1H，s)，5.85(1H，m)，5.40(1H，d)，5.19(1H，dd)，5.11(1H，dd)，3.92(2H，m)，3.70(3H，s)，3.46(1H，m)，3.38(1H，m)，2.80(1H，m)，2.52(2H，m)，2.32(1H，dd)，1.99(1H，dd)，1.87(1H，m)，1.30(9H，s)，1.14(3H，d)，1.00(3H，d)。

Embodiment 10

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-propoxy-methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, prepare title compound by intermediate 15.

MS calculated value (C ₂₈H ₄₀N ₂O ₅S+H ⁺): 517

MS measured value (electrospray): (M+H) ⁺=517

¹H NMR (CD ₃OD): δ 7.36 (1H, d), 7.21 (1H, br s), 7.13 (1H, d), 6.84 (1H, d), 6.54 (1H, s), 5.38 (1H, d), 3.70 (3H, s), 3.42 (1H, dd), 3.34 (4H, the m-part is covered by solvent), 2.79 (1H, m), 2.52 (1H, t), 2.29 (1H, dd), 1.97 (1H, dd), 1.86 (1H, m), 1.53 (2H, m), 1.30 (9H, s), 1.14 (3H, d), 1.00 (3H, d), 0.90 (3H, t).

Embodiment 11

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

(51mg adds trifluoroacetic acid (2mL) in the solution of methylene dichloride 0.1mmol) (5mL), and solution is stirred under envrionment temperature spend the night to intermediate 16.Evaporation reaction mixture, and resistates ground with ether, prepare the solid title compound.

MS calculated value (C ₂₆H ₃₆N ₂O ₅S+H) ⁺: 489.

MS measured value (electrospray): (M+H) ⁺=489

The Nmr spectroscopic data demonstrates this compound compare with single enantiomer with embodiment 15 identical-racemic compounds (racemate vs single enantiomer).

Embodiment 12

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 11 similar methods, prepare title compound by intermediate 17.

MS calculated value (C ₂₇H ₃₈N ₂O ₅S+H) ⁺: 503

MS measured value (electrospray): (M+H) ⁺=503.

Spectroscopic data demonstrates this compound and compares with single enantiomer with embodiment 16 identical-racemic compounds.

Embodiment 13

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-pseudoallyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

(74mg 0.14mmol) is dissolved in the trifluoroacetic acid (2mL) with intermediate 12.This is reacted on the room temperature placement spends the night.Vacuum evaporating solvent then, and resistates ground with ether.Filter and collect the solid that generates, and vacuum-drying, prepare title compound.

MS calculated value (C ₂₇H ₃₆N ₂O ₄S+H) ⁺: 485.

MS measured value (electrospray): (M+H) ⁺=485.

¹H?NMR(CD ₃OD)：δ7.36(1H，d)，7.15(2H，m)，6.88(1H，d)，6.51(1H，s)，5.32(1H，d)，4.78(1H，br?s)，4.68(1H，s)，3.69(3H，s)，3.32(1H，m)，2.49(2H，m)，2.33(1H，dd)，2.02(1H，dd)，1.88(1H，m)，1.71(3H，s)，1.30(9H，s)，1.16(3H，d)，1.01(3H，d)。

Embodiment 14

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-sec.-propyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, prepare title compound by intermediate 13.

MS calculated value (C ₂₇H ₃₈N ₂O ₄S+H) ⁺: 487.

MS measured value (electrospray): (M+H) ⁺=487.

¹H?NMR(CD ₃OD)：δ7.38(1H，d)，7.16(2H，m)，6.85(1H，d)，6.46(1H，s)，5.22(1H，d)，3.69(3H，s)，2.51(2H，m)，2.26(2H，m)，1.97(1H，dd)，1.84(1H，m)，1.66(1H，m)，1.31(9H，s)，1.14(3H，d)，1.00(3H，d)，0.93(3H，d)，0.75(3H，d)。

Embodiment 15

(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

[rel-(2S, 4S, 5R)-the enantiomer A of 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid]

Chirality; The stereochemistry of absolute stereo chemistry shown in the enantiomer A by determining with reference to intermediate 21

In the solution of the methylene dichloride (5mL) of intermediate 21 (191mg), add trifluoroacetic acid (5mL), and the solution that generates was placed 18 hours in 20 ℃.Evaporating mixture is extremely done, and resistates is ground with ether, prepares the enantiomer A of solid title compound.

MS calculated value (C ₂₆H ₃₆N ₂O ₅S+H) ⁺: 489.

MS measured value (electrospray): (M+H) ⁺=489

¹H NMR (CD ₃OD): δ 7.87 (1H, d), 7.61 (1H, d), 7.23 (1H, d), 6.72 (1H, dd), 6.37 (1H, s), 5.67 (1H, d), 3.65 (3H, s), 3.21 (2H, m), 3.11 (3H, s), 2.69 (1H, t), 2.17-2.33 (4H, m), 2.05 (1H, m), 1.33 (9H, s), 1.15 (3H, d), 1.13 (3H, d), carboxylic acid proton and solvent exchange.By NMR as can be known, this compound is identical with embodiment 11 (as above).

Determine the absolute stereo chemistry of these compounds by reference intermediate 21, and be shown as above drawn (2S, 4S, 5R).

Embodiment 16

(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

[rel-(2S, 4S, 5R)-the enantiomer A of 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid]

Chirality; The stereochemistry that absolute stereo chemistry shown in the enantiomer A is determined by the X-radiocrystallography

In the solution of the methylene dichloride (5mL) of intermediate 22 (219mg), add trifluoroacetic acid (5mL), and the solution that generates was placed 18 hours in 20 ℃.Evaporating mixture is extremely done, and resistates is ground with ether, prepares the enantiomer A of solid title compound.

MS calculated value (C ₂₇H ₃₈N ₂O ₅S+H) ⁺: 503

MS measured value (electrospray): (M+H) ⁺=503.

¹H NMR (CD ₃OD): δ 7.87 (1H, d), 7.61 (1H, d), 7.23 (1H, d), 6.73 (1H, dd), 6.36 (1H, d), 5.69 (1H, d), 3.65 (3H, s), 3.15-3.30 (4H, m), 2.72 (1H, t), 2.20-2.35 (4H, m), 2.05 (1H, m), 1.33 (9H, s), 1.15 (3H, d), 1.13 (3H, d), 1.09 (3H, t), carboxylic acid proton and solvent exchange.By NMR as can be known, this compound is identical with embodiment 12 (as above).

Determine the absolute stereo chemistry of this compound by the X-radiocrystallography, and be shown as above drawn (2S, 4S, 5R).

Embodiment 17

(2S, 4S, 5R)-2-isobutyl--1-(3-bromo-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2-carboxylic acid

Chirality; As drawn absolute stereo chemistry

According to embodiment 1 similar methods, use intermediate 29 to prepare title compound as initial substance.

MS calculated value (C ₂₆H ₃₅BrN ₂O ₄S+H) ⁺: 551 and 553

MS measured value (electrospray): (M+H) ⁺=551 and 553

¹H?NMR(CD ₃OD)：δ7.83(d，1H)，7.60(d，1H)，7.42(d，1H)，7.09-7.04(m，2H)，5.61(d，1H)，3.28-3.20(m，3H)，3.15(m，1H)，2.72(t，1H)，2.32-2.15(m，4H)，2.02(m，1H)，1.45(s，9H)，1.10(t，6H)，1.06(t，3H)。

Embodiment 18

(2S, 4S, 5R)-2-isobutyl--1-(3-chloro-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2-carboxylic acid

Chirality; As drawn absolute stereo chemistry

According to embodiment 1 similar methods, use intermediate 30 to prepare title compound as initial substance.

MS calculated value (C ₂₆H ₃₅ClN ₂O ₄S+H) ⁺: 507 and 509

MS measured value (electrospray): (M+H) ⁺=507 and 509

¹H?NMR(CD ₃OD)：δ7.82(d，1H)，7.59(d，1H)，7.40(d，1H)，7.00(dd，1H)，6.86(d，1H)，5.63(d，1H)，3.29-3.20(m，3H)，3.20-3.11(m，1H)，2.71(t，1H)，2.31-2.15(m，4H)，2.03-1.97(m，1H)，1.42(s，9H)，1.10(t，6H)，1.06(t，3H)。

Embodiment 19

(2S, 4S, 5R)-2-isobutyl--1-(3-methyl-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Chirality; As drawn absolute stereo chemistry

In 0 ℃, with sodium hydride (60% mineral oil dispersion; 0.061g (0.48g is in dry DMF 0.93mmol) (10mL) solution 1.52mmol) to join the intermediate 28 of stirring.The mixture that generates was stirred 30 minutes in 0 ℃, add subsequently iodoethane (0.37mL, 4.65mmol).In 5 ℃ of stirrings 2 hours, be evaporated to dried then mixture.Resistates is dissolved in the trifluoroacetic acid (8mL), and under room temperature, stirred 19 hours.Evaporate trifluoroacetic acid, and resistates is dissolved in ethyl acetate, wash with water, dry (Na ₂SO ₄) and evaporation.With crude product by with hexanaphthene-ethyl acetate (by 2: 1v/v to 3:, and, prepare the solid title compound then by the ether crystallization gradient elution of 2v/v) as the silica gel chromatography purifying of eluent.

MS calculated value (C ₂₇H ₃₈N ₂O ₄S+H) ⁺: 487

MS measured value (electrospray): (M+H) ⁺=487

¹H?NMR(CD ₃OD)：δ7.81(d，1H)，7.56(d，1H)，7.27(d，1H)，6.85(dd，1H)，6.62(bs，1H)，5.625(d，1H)，3.28-3.19(m，3H)，3.20-3.09(m，1H)，2.69(t，1H)，2.37(s，3H)，2.32-2.14(m，4H)，2.02(m，1H)，1.35(s，9H)，1.12(d，3H)，1.09(d，3H)，1.05(t，3H)。

Embodiment 20

Rel-(2R, 4R, 5R)-2-benzyl-1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, use intermediate 37 as initial substance, prepare title compound.

MS calculated value (C ₂₉H ₃₄N ₂O ₅S+H) ⁺: 523

MS measured value (electrospray): (M+H) ⁺=523

¹H?NMR(CD ₃OD)：δ7.60(m，6H)，7.30(d，1H)，7.16(d，1H)，6.62(d，1H)，6.55(s，1H)，4.82(d，1H)，4.15(d，1H)，3.81(s，3H)，3.39(d，1H)，3.30(s，3H)，3.27(dd，1H)，3.21(dd，1H)，2.89(m，1H)，2.72(t，1H)，2.50(dd，1H)，1.43(s，9H)。

Embodiment 21

Rel-(2R, 4R, 5R)-2-benzyl-1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, use intermediate 38 as initial substance, prepare title compound.

MS calculated value (C ₃₀H ₃₆N ₂O ₅S+H) ⁺: 537

MS measured value (electrospray): (M+H) ⁺=537

¹H?NMR(CD ₃OD)：δ7.36(6H，m)，7.19(1H，d)，7.03(1H，d)，6.48(1H，d)，6.42(1H，s)，4.73(1H，d)，4.02(1H，d)，3.68(3H，s)，3.34(1H，m)，3.25(2H，dd)，3.19(2H，m)，2.76(1H，m)，2.64(1H，t)，2.37(1H，dd)，1.29(9H，s)，1.03(3H，t)

Embodiment 22

Rel-(2S, 4S, 5R)-the enantiomer A of 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(pyrazine-2-yl) tetramethyleneimine-2-carboxylic acid

Chirality; Relative stereochemistry shown in the enantiomer A

According to embodiment 1 similar methods, use intermediate 43 to prepare title compound as initial substance.

MS calculated value (C ₂₇H ₃₇N ₃O ₅+ H) ⁺: 484

MS measured value (electrospray): (M+H) ⁺=484

¹H?NMR(CD ₃OD)：δ8.52(m，2H)，8.30(s，1H)，7.14(d，1H)，6.66(d，1H)，6.35(s，1H)，5.52(d，1H)，3.60(s，3H)，3.34(1H，m)，3.13(m，1H)，2.92(s，3H)，2.70(m，1H)，2.27(m，4H)，2.05(m，1H)，1.27(s，9H)，1.14(d，3H)，1.11(d，3H)。

Embodiment 23

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(pyrazine-2-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, use intermediate 46 to prepare title compound as initial substance.

MS calculated value (C ₂₇H ₃₇N ₃O ₅+ H) ⁺: 484

MS measured value (electrospray): (M+H) ⁺=484

¹H?NMR(CD ₃OD)：δ8.62(s，1H)，8.11(s，1H)，8.08(s，1H)，7.00(d，1H)，6.73(d，1H)，6.40(s，1H)，5.00(d，1H)，3.60(s，3H)，3.29(m，1H)，3.23(m，1H)，3.14(s，3H)，2.62(m，1H)，2.43(m，1H)，2.31(m，2H)，1.99(m，1H)，1.80(m，1H)，1.18(s，9H)，1.05(d，3H)，0.93(d，3H)。

Embodiment 24

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(5-methyl isophthalic acid, 3-thiazol-2-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, use intermediate 51 to prepare title compound as initial substance.

MS calculated value (C ₂₇H ₃₈N ₂O ₅S+H) ⁺: 503

MS measured value (electrospray): (M+H) ⁺=503

¹H NMR (CD ₃OD): δ 7.52 (1H, s), 7.22 (1H, d), 6.72 (1H, d), 6.29 (1H, s), 5.5 (1H, d), 3.64 (3H, s), 3.26-3.15 (2H, m), 3.11 (3H, s), and 2.77-2.67 (1H, m), 2.37 (3H, s), and 2.3-1.94 (5H, m), 1.31 (9H, s), 1.11 (3H, d) and 1.08 (3H, d)

Embodiment 25

Rel-(2S, 4S, 5R)-the enantiomer A of 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(5-methyl isophthalic acid, 3-thiazol-2-yl) tetramethyleneimine-2-carboxylic acid

Chirality; Relative stereochemistry shown in the enantiomer A

According to embodiment 1 similar methods, use intermediate 93 to prepare title compound as initial substance.

MS calculated value (C ₂₇H ₃₈N ₂O ₅S+H) ⁺: 503

MS measured value (electrospray): (M+H) ⁺=503

¹H NMR (CD ₃OD): δ 7.52 (1H, s), 7.22 (1H, d), 6.72 (1H, d), 6.29 (1H, s), 5.5 (1H, d), 3.64 (3H, s), 3.26-3.15 (2H, m), 3.11 (3H, s), and 2.77-2.67 (1H, m), 2.37 (3H, s), and 2.3-1.94 (5H, m), 1.31 (9H, s), 1.11 (3H, d) and 1.08 (3H, d).

Embodiment 26

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(2-chloro-1,3-thiazoles-5-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, use intermediate 56 to prepare title compound as initial substance.

MS calculated value (C ₂₆H ₃₅ClN ₂O ₅S+H) ⁺: 523/525

MS measured value (electrospray): (M+H) ⁺=523/525

¹H?NMR(CD ₃OD)：δ7.42(1H，s)，7.21(1H，d)，6.74(1H，d)，6.46(1H，s)，5.42(1H，s)，3.66(3H，s)，3.19(1H，m)，3.12(1H，m)，3.08(3H，s)，2.88(1H，t)，2.32-2.07(4H，m)，2.00(1H，m)，1.33(9H，s)，1.09(6H，dd).

Embodiment 27

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(2-methoxyl group-1,3-thiazoles-5-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, use intermediate 57 to prepare title compound as initial substance.

MS calculated value (C ₂₇H ₃₈N ₂O ₆S+H) ⁺: 519

MS measured value (electrospray): (M+H) ⁺=519

¹H?NMR(CD ₃OD)：δ7.2(1H，d)，6.89(1H，s)，6.75(1H，d)，6.54(1H，s)，5.23(1H，d)，3.94(3H，s)，3.67(3H，s)，3.16(1H，m)，3.12(3H，s)，3.04(1H，m)，2.96(1H，m)，2.29-2.05(4H，m)，1.98(1H，m)，1.33(9H，s)，1.08(6H，m).

Embodiment 28

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-((methylthio group) methyl)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, use intermediate 58 to prepare title compound as initial substance.

MS calculated value (C ₂₆H ₃₆N ₂O ₄S ₂+ H) ⁺: 505

MS measured value (electrospray): (M+H) ⁺=505

¹H?NMR(CDCl ₃)：δ7.48(1H，d)，7.19(1H，d)，7.11(1H，d)，6.88(1H，d)，6.45(1H，s)，5.22(1H，d)，3.67(3H，s)，3.07(1H，dd)，2.76-2.63(2H，m)，2.63-2.49(2H，m)，2.11-1.96(2H，m)，2.04(3H，s)，1.93-1.81(1H，m)，1.31(9H，s)，1.08(3H，d)，1.04(3H，d)。

Embodiment 29

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-((methylsulfonyl) methyl)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, use intermediate 59 to prepare title compound as initial substance.

MS calculated value (C ₂₆H ₃₆N ₂O ₆S ₂+ H) ⁺: 537

MS measured value (electrospray): (M+H) ⁺=537

¹H?NMR(CDCl ₃)：δ7.40(1H，d)，7.25(1H，d)，7.18(1H，d)，6.85(1H，d)，6.49(1H，s)，5.52(1H，d)，3.69(3H，s)，3.31(1H，dd)，3.22-3.09(2H，m)，2.98-2.89(1H，m)，2.89(3H，s)，2.51(1H，dd)，2.26(1H，t)，2.04(1H，dd)，1.94-1.81(1H，m)，1.31(9H，s)，1.08(3H，d)，1.04(3H，d)。

Embodiment 30

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-(1,1-two fluoro ethyls)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, use intermediate 60 to prepare title compound as initial substance.

MS calculated value (C ₂₆H ₃₄N ₂F ₂O ₄S+H) ⁺: 509

MS measured value (electrospray): (M+H) ⁺=509

¹H?NMR(CDCl ₃)：δ7.59(1H，d)，7.23(1H，d)，7.09(1H，d)，6.93(1H，dd)，6.42(1H，s)，5.57(1H，d)，3.67(3H，s)，3.07(1H，m)，2.96(1H，dd)，2.51(1H，dd)，2.25(1H，dd)，2.13(1H，dd)，1.85(1H，m)，1.59(3H，t)，1.33(9H，s)，1.08(3H，d)，10.3(3H，d)。

Embodiment 31

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-(1-hydroxyl-1-methylethyl)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, use intermediate 61 to prepare title compound as initial substance.

MS calculated value (C ₂₇H ₃₈N ₂O ₅S+H) ⁺: 503

MS measured value (electrospray): (M+H) ⁺=503

¹H?NMR(CDCl ₃)：δ7.44(1H，d)，7.22(1H，d)，7.11(1H，d)，6.94(1H，d)，6.43(1H，s)，5.56(1H，d)，3.67(3H，s)，2.87(1H，dd)，2.65(1H，m)，2.49(1H，dd)，2.20(1H，m)，2.08(1H，dd)，1.87(1H，m)，1.33(9H，s)，1.30(3H，s)，1.08(6H，m)，1.02(3H，d)。

Embodiment 32

Rel-(2S, 4R, 5R)-the enantiomer A of 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Chirality; Relative stereochemistry shown in the enantiomer A

According to embodiment 1 similar methods, use intermediate 62 to prepare title compound as initial substance.

MS calculated value (C ₂₆H ₃₆N ₂O ₅S+H) ⁺: 489

MS measured value (electrospray): (M+H) ⁺=489

¹H?NMR(CD ₃OD)：δ7.41(1H，d)，7.26(1H，s)，7.16(1H，d)，6.88(1H，d)，6.55(1H，s)，5.38(1H，d)，3.71(3H，s)，3.41(1H，m)，3.28-3.35(4H，m)，2.80(1H，m)，2.51(2H，m)，2.33(1H，dd)，2.02(1H，dd)，1.87(1H，m)，1.32(9H，s)，1.15(3H，d)，1.01(3H，d)。

Embodiment 33

Rel-(2R, 4S, 5R)-2-benzyl-1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, use intermediate 63 to prepare title compound as initial substance.

MS calculated value (C ₂₉H ₃₄N ₂O ₅S+H) ⁺: 523

MS measured value (electrospray): (M+H) ⁺=523

¹H?NMR(CD ₃OD)：δ7.82(1H，d)，7.53(1H，d)，7.45(5H，m)，7.21(1H，d)，6.71(1H，d)，6.44(1H，s)，5.12(1H，d)，3.87(1H，d)，3.67(3H，s)，3.34(2H，m)，2.91(3H，s)，2.88(1H，dd)，2.38(1H，m)，2.17(1H，t)，1.85(1H，m)，1.30(9H，s)

Embodiment 34

Rel-(2R, 4S, 5R)-2-benzyl-1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-2-yl)-tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, use intermediate 64 to prepare title compound as initial substance.

MS calculated value (C ₃₀H ₃₆N ₂O ₅S+H) ⁺: 537

MS measured value (electrospray): (M+H) ⁺=537

¹H?NMR(CD ₃OD)：δ7.76(1H，d)，7.51(1H，d)，7.43(5H，m)，7.21(1H，d)，6.73(1H，dd)，6.45(1H，s)，5.13(1H，d)，3.90(1H，d)，3.66(3H，s)，3.35(1H，d)，3.00(3H，m)，2.40(2H，m)，2.20(1H，t)，1.85(1H，m)，1.30(9H，s)，0.93(3H，t)。

Embodiment 35

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(pyridine-2-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, use intermediate 69 to prepare title compound as initial substance.

MS calculated value (C ₂₈H ₃₈N ₂O ₅+ H) ⁺: 483

MS measured value (electrospray): (M+H) ⁺=483

¹H?NMR(CDCl ₃)：δ8.54(1H，d)，7.51(1H，t)，7.30(1H，m)，7.05(1H，d)，6.73(1H，d)，6.60(1H，d)，6.20(1H，s)，5.31(1H，d)，3.48(3H，s)，3.23(1H，m)，3.16(1H，m)，3.01(3H，s)，2.47(1H，dd)，2.37(1H，t)，2.29(1H，dd)，2.18(2H，m)，1.96(1H，m)，1.25(9H，s)，1.16(3H，d)，1.10(3H，d)。

Embodiment 36

(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-(1-hydroxyl-1-methylethyl)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Chirality; Shown absolute stereo chemistry

According to embodiment 1 similar methods, use intermediate 72 to prepare title compound as initial substance.

MS calculated value (C ₂₇H ₃₈N ₂O ₅S+H) ⁺: 503

MS measured value (electrospray): (M+H) ⁺=503

¹H?NMR(CDCl ₃)：δ7.45(1H，d)，7.23(1H，d)，7.10(1H，d)，6.95(1H，d)，6.43(1H，s)，5.56(1H，d)，3.67(3H，s)，2.88(1H，dd)，2.65(1H，m)，2.49(1H，dd)，2.20(1H，dd)，2.08(1H，dd)，1.87(1H，m)，1.34(9H，s)，1.31(3H，s)，1.08(6H，m)，1.03(3H，d)。

Embodiment 37a﹠amp; Embodiment 37b

(2S, 4R, 5R)-diastereomer 1 and the diastereomer 2 of 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-(1-hydroxyethyl)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Chirality; Absolute stereo chemistry shown in the pyrrolidine ring is at pure center isolating diastereomer diastereomer 1﹠amp; The absolute stereo chemistry at the pure center in 2 is unknown

Under nitrogen, (0.025g, (0.065g is in anhydrous THF (5mL) solution 0.133mmol) 0.68mmol) to join refrigerative (0 ℃) intermediate 73 with sodium borohydride.Mixture was stirred 30 minutes in 0 ℃, then in stirring at room 3 hours.With mixture acidifying (2M HCl), and use ethyl acetate extraction.Dry organic solution (Na ₂SO ₄) and evaporation, prepare gummy solid.It is passed through to use the repetition preparation HPLC purifying of C18 post, contain the water of formic acid (0.1%) and the acetonitrile-water that (B) contains formic acid (0.05%) (95:, prepare the mixture of the diastereomer of alcohol with (A) 5v/v) as two solvent gradient elutions of eluent.(90: 10v/v) HPLC as the chiralpak AD post of eluent carries out further purifying with the heptane-ethanol that contains 0.1% trifluoroacetic acid, prepare diastereomer 1 (embodiment 37a) (previous wash-out go out diastereomer), and diastereomer subsequently 2 (embodiment 37b) (wash-out go out diastereomer) after a while.

Embodiment 37a

MS calculated value (C ₂₆H ₃₆N ₂O ₅S+H) ⁺: 489

MS measured value (electrospray): (M+H) ⁺=489

¹H?NMR(CD ₃OD)：δ7.37(d，1H)，7.23(bs，1H)，7.13(d，1H)，6.85(d，1H)，6.55(s，1H)，5.43(d，1H)，3.75-3.68(m，1H)，3.71(s，3H)，3.67-3.60(m，1H)，2.61-2.49(m，2H)，2.23(q，1H)，2.00(dd，1H)，1.93-1.80(m，3H)，1.30(s，9H)，1.15(d，3H)，1.04(d，3H)，0.995(d，3H)。

Embodiment 37b

MS calculated value (C ₂₆H ₃₆N ₂O ₅S+H) ⁺: 489

MS measured value (electrospray): (M+H) ⁺=489

¹H?NMR(CD ₃OD)：δ7.41(s，1H)，7.31(s，1H)，7.18(d，1H)，6.68(d，1H)，6.46(s，1H)，5.50(d，1H)，3.79(m，1H)，3.74-3.66(m，1H)，3.70(s，3H)，2.74-2.64(m，1H)，2.49(bd，1H)，2.39(t，1H)，2.28(dd，1H)，2.00(m，1H)，1.91-1.81(m，1H)，1.32(s，9H)，1.13(d，3H)，1.03(d，3H)，0.99(d，3H)。

Embodiment 38

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-4-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, use intermediate 78 to prepare title compound as initial substance.

MS calculated value (C ₂₇H ₃₈N ₂O ₅S+H) ⁺: 503

MS measured value (electrospray): (M+H) ⁺=503

¹H NMR (CD ₃OD): δ 9.07 (1H, s), 7.17 (1H, d), 7.08 (1H, s), 6.68 (1H, d), 6.35 (1H, s), 5.59 (1H, d), 3.64 (3H, s), 3.25-3.10 (3H, m), 3.05-3.01 (1H, m), 2.78 (1H, t), 2.34-1.98 (5H, m), 1.28 (9H, s), 1.14 (3H, d), 1.10 (3H, d) and 1.03 (3H, t).

Embodiment 39

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(1,3-thiazoles-4-yl))-the enantiomer A of tetramethyleneimine-2-carboxylic acid

Chirality; Relative stereochemistry shown in the enantiomer A

According to embodiment 1 similar methods, use intermediate 79 to prepare title compound as initial substance.

MS calculated value (C ₂₇H ₃₈N ₂O ₅S+H) ⁺: 503

MS measured value (electrospray): (M+H) ⁺=503

¹H NMR (CD ₃OD): δ 9.08 (1H, s), 7.17 (1H, d), 7.08 (1H, s), 6.68 (1H, d), 6.34 (1H, s), 5.59 (1H, d), 3.64 (3H, s), 3.24-3.10 (3H, m), 3.05-3.01 (1H, m), 2.78 (1H, t), 2.34-1.98 (5H, m), 1.28 (9H, s), 1.14 (3H, d), 1.10 (3H, d) and 1.03 (3H, t).

Embodiment 40

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-allyloxy methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, use intermediate 80 to prepare title compound as initial substance.

¹H NMR (CD ₃OD): δ 7.74 (d, 1H), 7.48 (d, 1H), 7.11 (d, 1H), 6.61 (dd, 1H), 6.25 (d, 1H), 5.67 (m, 1H), 5.58 (d, 1H), 5.05 (dd, 1H), 4.99 (dd, 1H), 3.61 (d, 2H), 3.53 (s, 3H), 3.17 (m, 2H), 2.66 (t, 1H), 2.08-2.23 (m, 4H), 1.94 (m, 1H), 1.20 (s, 9H), 1.03 (d, 3H) and 1.00 (d, 3H)

Embodiment 41

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-propoxy-methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

Ethanol (4mL) solution of embodiment 40 (10mg) is joined in the 10% palladium carbon (50mg), and under hydrogen under 1 normal atmosphere, stirred 4 hours in 20 degree.Removing by filter catalyzer also washes with ethanol (10mL).Merging filtrate and washings also remove and desolvate, and prepare title compound.

MS calculated value (C ₂₈H ₄₀N ₂O ₅S+H) ⁺: 517

MS measured value (electrospray): (M+H) ⁺=517

¹H?NMR(CD ₃OD)：δ7.83(1H，d)，7.57(1H，d)，7.20(1H，d)，6.70(1H，d)，6.34(1H，br?s)，5.66(1H，d)，3.62(3H，s)，3.24(2H，m)，3.10(2H，m)，2.73(1H，t)，2.23(4H，m)，2.04(1H，m)，1.45(2H，m)，1.30(9H，s)，1.13(3H，d)，1.10(3H，d)0.84(3H，t)。

Embodiment 42

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-cyano methyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, use intermediate 81 to prepare title compound as initial substance.

MS calculated value (C ₂₆H ₃₃N ₃O ₄S+H) ⁺: 484

MS measured value (electrospray): (M+H) ⁺=484

¹H?NMR(CD ₃OD)：δ7.41(1H，d)，7.23(1H，s)，7.14(1H，d)，6.86(1H，brs)，6.59(1H，s)，5.25(1H，d)，3.72(3H，s)，2.92(1H，m)，2.58(3H，m)，2.44(2H，m)，2.03(1H，m)，1.89(1H，m)，1.30(9H，s)，1.15(3H，d)，1.00(3H，d)。

Embodiment 43

(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-(1-hydroxyl-1-methylethyl)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Chirality; Shown absolute stereo chemistry

According to embodiment 1 similar methods, use intermediate 82 to prepare title compound as initial substance.

MS calculated value (C ₂₇H ₃₈N ₂O ₅S+H) ⁺: 503

MS measured value (electrospray): (M+H) ⁺=503

¹H?NMR(CD ₃OD)：δ7.79(1H，d)，7.52(1H，d)，7.21(1H，d)，6.72(1H，dd)，6.30(1H，d)，5.65(1H，d)，3.63(3H，s)，3.09(1H，m)，2.49(1H，t)，2.29(2H，m)，2.18(1H，dd)，2.02(1H，m)，1.31(9H，s)，1.13(9H，m)，0.76(3H，s)

Embodiment 44

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethyl-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, use intermediate 85 to prepare title compound as initial substance.

MS calculated value (C ₂₆H ₃₆N ₂O ₄S+H) ⁺: 473

MS measured value (electrospray): (M+H) ⁺=473

¹H?NMR(CD ₃OD)：δ7.37(1H，d)，7.20(1H，br?s)，7.13(1H，d)，6.85(1H，d)，6.53(1H，s)，5.07(1H，d)，3.70(3H，s)，2.40-2.55(3H，m)，2.11(1H，m)，2.00(1H，dd)，1.86(1H，m)，1.46(1H，m)，1.38(1H，m)，1.30(9H，s)，1.13(3H，d)，0.99(3H，d)，0.83(3H，t)。

Embodiment 45

Rel-(2S, 4R, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(pyridine-2-yl))-tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, use intermediate 88 to prepare title compound as initial substance.

MS calculated value (C ₂₈H ₃₈N ₂O ₅+ H) ⁺: 483

MS measured value (electrospray): (M+H) ⁺=483

¹H?NMR(CD ₃OD)：δ8.42(1H，d)，7.53(1H，dt)，7.22(1H，dd)，7.17(1H，d)，6.98(1H，d)，6.89(1H，dd)，6.39(1H，d)，5.17(1H，d)，3.67(3H，s)，3.44(2H，m)，3.30(3H，s)，2.69(1H，m)，2.58(1H，dd)，2.52(1H，t)，2.35(1H，dd)，2.10(1H，dd)，1.92(1H，m)，1.32(9H，s)，1.18(3H，d)，1.04(3H，d)。

Embodiment 46

Rel-(2S, 4R, 5R)-diastereomer 1 of 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-(1-methoxy ethyl)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Racemic; Relative stereochemistry shown in the diastereomer 1

According to embodiment 1 similar methods, use intermediate 94 to prepare title compound as initial substance.

MS calculated value (C ₂₇H ₃₈N ₂O ₅S+H) ⁺: 503

MS measured value (electrospray): (M+H) ⁺=503

¹H?NMR(CD ₃OD)：δ7.37(1H，bs)，7.20(1H，bs)，7.14(1H，d)，6.85(1H，d)，6.53(1H，s)，5.42(1H，d)，3.35(3H，s)，3.30(3H，s)，3.19(1H，m)，2.67-2.45(3H，m)，2.21(1H，dd)，1.96(1H，dd)，1.83(1H，m)，1.30(9H，s)，1.12(3H，d)，1.04(3H，d)，0.98(3H，d)。

Embodiment 47

Rel (2S, 4R, 5R)-diastereomer 2 of 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-(1-methoxy ethyl)-5-(1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Racemic; Relative stereochemistry shown in the diastereomer 2

According to embodiment 1 similar methods, use intermediate 95 to prepare title compound as initial substance.

MS calculated value (C ₂₇H ₃₈N ₂O ₅S+H) ⁺: 503

MS measured value (electrospray): (M+H) ⁺=503

¹H NMR (CD ₃OD): δ 7.35 (1H, d), 7.24 (1H, bs), 7.17 (1H, d), 6.87 (1H, d), 6.42 (1H, bs), 5.43 (1H, d), 3.68 (3H, s), 3.40 (1H, m), 3.19 (3H, s), 2.74 (1H, m), 2.49 (1H, bd), 2.36 (1H, t), 2.27 (1H, dd), 1.99 (1H, dd), 1.85 (1H, m), 1.32 (9H, s), 1.13 (3H, d) and 0.99 (6H, d).

Embodiment 48

(2S, 4S, 5R)-the enantiomer A of 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxyl group-methyl-5-(pyridine-2-yl) tetramethyleneimine-2-carboxylic acid

Chirality; Relative stereochemistry shown in the enantiomer A

According to embodiment 1 similar methods, use intermediate 96 to prepare title compound as initial substance.

MS calculated value (C ₂₈H ₃₈N ₂O ₅+ H) ⁺: 483

MS measured value (electrospray): (M+H) ⁺=483

¹H NMR (CD ₃OD): δ 8.54 (1H, d), 7.51 (1H, t), 7.28 (1H, m), 7.06 (1H, d), 6.74 (1H, d), 6.62 (1H, d), 6.20 (1H, s), 5.31 (1H, d), 3.49 (3H, s), 3.15 (1H, m), 3.02 (3H, s), 2.48 (1H, dd), 2.37 (1H, t), 2.33 (1H, m), 2.19 (1H, m), 1.97 (1H, m), 1.26 (9H, s), 1.16 (3H, d) and 1.11 (3H, d).

Embodiment 49

Rel-(2S, 4S, 5R)-the enantiomer A of 2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-ethoxyl methyl-5-(5-methyl-isoxazole-3-yl) tetramethyleneimine-2-carboxylic acid

Chirality; Relative stereochemistry shown in the enantiomer A

According to embodiment 1 similar methods, use intermediate 102 to prepare title compound as initial substance.

MS calculated value (C ₂₈H ₄₀N ₂O ₆+ H) ⁺: 501

MS measured value (electrospray): (M+H) ⁺=501

¹H?NMR(CD ₃OD)：δ7.20(1H，d)，6.74(1H，d)，6.53(1H，s)，6.40(1H，s)，5.28(1H，d)，3.68(3H，s)，3.23(2H，m)，3.06(3H，m)，2.34(3H，s)，2.19(4H，m)，1.99(1H，m)，1.31(9H，s)，1.10(9H，m)。

Embodiment 50

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(5-methoxymethyl-1,3-thiazoles-2-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, use intermediate 111 to prepare title compound as initial substance.

MS calculated value (C ₂₈H ₄₀N ₂O ₆S+H) ⁺: 533

MS measured value (electrospray): (M+H) ⁺=533

¹H NMR (CDCl ₃): δ 7.73 (1H, s), 7.17 (1H, d), 6.66 (1H, d), 6.38 (1H, s), 4.57 (2H, dd), 5.65 (1H, d), 3.62 (3H, s), 3.38-3.22 (2H, m), 3.34 (3H, s), 3.14 (3H, s), 2.63 (1H, t), and 2.42-2.17 (4H, m), 2.01-1.88 (1H, m), 1.29 (9H, s), 1.12 (3H, d) and 1.10 (3H, d).

Embodiment 51

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(5-picoline-2-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, use intermediate 116 to prepare title compound as initial substance.

MS calculated value (C ₂₉H ₄₀N ₂O ₅+ H) ⁺: 497

MS measured value (electrospray): (M+H) ⁺=497

¹H NMR (CDCl ₃): δ 8.36 (1H, s), 7.29 (1H, dd), 7.06 (1H, d), and 6.57-6.65 (2H, m), 6.18 (1H, d) 5.26 (1H, d), 3.49 (3H, s), 3.11-3.27 (2H, m), 3.03 (3H, s), 2.35 (3H, s), 2.08-2.54 (5H, m), and 1.9-2.03 (1H, m), 1.26 (9H, s), 1.15 (3H, d) and 1.09 (3H, d).

Embodiment 52

Rel-(2S, 4S, 5R)-2-isobutyl--1-(3-methoxyl group-4-tert.-butylbenzene formyl radical)-4-methoxymethyl-5-(thiophene-2-yl) tetramethyleneimine-2-carboxylic acid

Relative stereochemistry shown in racemic

According to embodiment 1 similar methods, use intermediate 121 to prepare title compound as initial substance.

MS calculated value (C ₂₇H ₃₇NO ₅S+H) ⁺: 488

MS measured value (electrospray) (M+H) ⁺: 488

¹H?NMR(CDCl ₃)：δ7.25(dd，1H)，7.20(d，1H)，6.96(dd，1H)，6.65(m，2H)，6.35(d，1H)，5.24(d，1H)，3.52(s，3H)，3.23(dd，1H)，3.18(s，3H)，2.83-2.59(brm，4H)，2.20(dd，1H)，1.93-1.80(br?m，2H)，1.76-1.48(br，1H)，1.83(s，9H)，1.07(d，3H)，1.06(d，3H)。

Can prepare compound according to the present invention in any mode easily and be used for administration, therefore the present invention also comprises the pharmaceutical composition that is used for the treatment of, and it comprises the mixture of formula (I) compound or its pharmaceutically useful salt or solvate and one or more pharmaceutically acceptable diluents or carrier.

Compound of the present invention can be different administration, described approach comprises through intravenous administration, through the intraperitoneal administration, through subcutaneous administration, through intramuscular administration, oral administration, topical, percutaneous dosing or mucosal.For the whole body administration, the preferred oral administration.For oral administration, for example this compound can be mixed with conventional oral dosage form such as capsule, tablet and liquid preparation such as syrup, elixir and spissated drops etc.

Perhaps, can adopt injection (administered parenterally), as through intramuscular, through intravenously, through intraperitoneal with through subcutaneous injection.For injection, compound of the present invention is formulated in the liquor, preferably be formulated in physiology compatible buffers or the solution, such as salt brine solution, Han Kesishi (Hank ' s) solution or Ringer's solution.In addition, this compound can be mixed with solid form and dissolving or suspension more immediately before use.Also can prepare freeze dried form.

The whole body administration also can be by through mucous membrane or through the mode of skin.For through mucous membrane or percutaneous dosing, be suitable for the permeate agent that obstacle infiltrated and can be used in the said preparation.This permeate agent is normally known in the art, and comprises, for example is used for the biliary salts and fusidic acid (fusidic acid) derivative of mucosal.In addition, in order to promote infiltration can use washing composition.For example can be by nose spraying, rectal suppository or vaginal suppository mucosal.

For topical, The compounds of this invention can be mixed with as ointment known in the art, salve, gelifying agent or emulsion.

The dosage of all cpds can and consider that following factor measures by standard method: such as this compound (IC ₅₀) effectiveness (potency), (EC ₅₀) render a service and (this compound) biological half-life, patient's age, size and body weight and disease or the illness relevant with the patient.The importance of these and other factor of being considered is that persons skilled in the art are known.

Dosage also depends on the degree of route of administration and oral bioavailability rate.For example for the compound of low oral bioavailability rate, must the higher relatively dosage of administration.Oral administration is the preferred modes of The compounds of this invention.

Said composition is preferably unit dosage form.For oral application, but administration for example tablet or capsule are used (nasal application) for intranasal, but (metered) aerosol dosage of administration metering, for through the skin medication, but administration topical agent or patch (patch), and for transmucosal delivery, but administration is through the agent of cheek paster.In each case, dosage all makes the patient be given single dosage.

Be used for peroral administration each unitary dose and contain 0.01-500mg/Kg aptly, and formula (I) compound or pharmaceutically acceptable salt thereof of preferred 0.1-50mg/Kg, calculate with free alkali (free base).For suck through parenteral, intranasal, per os, through mucous membrane or contain formula (I) compound of 0.01mg-100mg/Kg suitably through the per daily dose of skin approach.Topical formulations contains formula (I) compound of 0.01-5.0% suitably.Once promptly be enough to show required usefulness but effective constituent administration every day 1-6 is less preferred, this is that persons skilled in the art are conspicuous.

Activated formula (I) composition and their pharmacologically acceptable salt can be formulated into syrup, tablet, capsule and lozenge when oral administration.Syrup preparation is usually by this compound in liquid vehicle (for example ethanol, peanut oil, sweet oil, glycerine or water and food flavouring or tinting material) or the suspension or the solution composition of salt.When said composition is the form of tablet, can use any routine to be used to prepare the pharmaceutical carrier of solid chemicals.The example of this carrier comprises Magnesium Stearate, terra alba, talcum, gelatin, gum arabic, stearic acid, starch, lactose and sucrose.When said composition was capsular form, the encapsulated of any routine was suitable, for example used above-mentioned carrier in the hard gelatin capsule shell.When said composition is the capsular form of soft gelatin shell, can consider to use any pharmaceutical carrier that is used to prepare dispersion (dispersion) or suspension routinely, for example moisture natural gum, Mierocrystalline cellulose, silicate or oil, and it is mixed in the soft gelatin capsule shell.

Parenteral composition commonly used is included in the compound in the aseptic moisture or non-aqueous carrier or the solution or the suspension of salt, its optional acceptable oil of parenteral, for example polyoxyethylene glycol, polyvinylpyrrolidone, Yelkin TTS, peanut oil or sesame oil of containing.

Suction composition commonly used is the form of solution, suspension or milk sap, and it can dried powder or the form of aerosol, uses the propelling agent (propellant) of routine to carry out administration as Refrigerant 12 or trichlorofluoromethane.

Suppository formulations commonly used comprises that be activated formula (I) compound or its pharmaceutically useful salt and tackiness agent and/or lubricant when administration in this way, for example polyoxyethylene glycol, gelatin, theobroma oil or other low melting point vegetable wax or fat or their synthetic analogues.

Skin commonly used and percutaneous preparation comprise conventional moisture or non-aqueous carrier, example emulsion, ointment, lotion or paste or be plaster, patch or the film of pastille.

When compound of the present invention according to the present invention during administration, expection does not have unacceptable toxic side effect.

Assay method

The compounds of this invention suppresses the possibility of NS5B wild-type HCV polymerase activity and can for example use one of following external test method to be confirmed:

The vitro detection (A) of HCV RNA-RNA-dependent polymerase activity inhibitor

Will [ ³H]-UMP mixes among the RNA, subsequently the RNA polymkeric substance absorbed on the DEAE glass fiber filter.By (10: the synthetic template that 16 polymers (mer) widow (oligo) U of 1w/w) hybridizing forms is as the homopolymer substrate with polyrA.

Reaction conditions is 22 μ M[ ³H]-UTP (0.75Ci/mMol), 1mM-dithiothreitol (DTT), 3.2mM-MgCl ₂, 20mM-Tris-HCl, pH7.0,10 μ g/mL polyadenylic acid-few U and 90mM-NaCl.Note together adding 50mM-NaCl with enzyme.

With HCV RNA polymerase (recombinant full-lenght NS5B (people such as Lohmann, J.Virol.71 (11), 1997,8416 ' Biochemical properties of hepatitis C virus NS5B RNA-dependentRNA polymerase and identification of amino acid sequence motifs essential forenzymatic activity ') in baculovirus, express and be purified to homogeneous) at 50mM-Hepes, pH7.0,0.5M-NaCl, 20%-glycerine, 0.05%-Triton X-100, the 5mM-dithiothreitol (DTT) is diluted to about 50 μ g protein/mL (according to than work) among the 0.1mM-EDTA.

Use 1M-Tris-HCl (pH7.0,1mL), 1M-MgCl ₂(0.16mL), 1M-dithiothreitol (DTT) (0.05mL), 5M-NaCl (0.4mL) and water (8.4mL) (amounting to 10mL), preparation 5 * spissated buffer solution mixture.

Use 5 * spissated buffer solution mixture (12 μ L), [ ³H]-UTP (1 μ Ci/ μ L; 21.7 μ M, 1 μ L), 22 μ M-UTP (100 μ M, 13.2 μ L), 10 μ g/mL polyadenylic acid-few U (100 μ g/mL, 6 μ L) and water (12.8 μ L) (amounting to 45 μ L), the preparation substrate mixture.

This mensuration uses enzyme (adding at last to begin reaction) (5 μ L) (amounting to 60 μ L) of substrate mixture (45 μ L), compound (10 μ L) and dilution to carry out.

This reaction is to carry out in the clarifying 96-orifice plate at the bottom of the U-shape.After adding enzyme, reactant is mixed on plate-shaking table, and in 22 ℃ of insulations 2 hours.After this, stop this reaction by the 100mM-EDTA that adds 25 μ L.

With DEAE Filtermat (Part No.1205-405 is available from Pharmacia) pre-wash in water and alcohol, drying.With the Stopped Assay Mix point of 2 * 20 μ L on the grid (square) of DEAE Filtermat.DEAE Filtermat was washed 2 * 15 minutes in SSC damping fluid (0.3M-NaCl, 30mM-Na Citrate), in water, washed 2 * 2 minutes, in alcohol, washed 1 * 1 minute.Dry Filtermat, and be sealed in the sack with the OptiScint HiSafe scintillation solution of 10mL.Measuring the shown radioactivity that goes out on the filtermat on the Wallac 1205Betaplate counter by scintillation counting technique.After deducting the background level that does not have enzyme, the radioactivity when not having compound is compared, and any minimizing of the radioactivity amount of mixing when having compound is considered to the mensuration to the inhibition level.In the diluent of two or three times, measure ten kinds of concentration of compound.For these countings, use Grafit3 or Grafit4 software package to calculate the inhibition per-cent when the maximum concentration of being surveyed or the IC of this compound ₅₀

The vitro detection (B) of the inhibitor of HCV RNA-RNA-dependent polymerase activity

Will [ ³³P]-GMP mixes among the RNA, makes the RNA polymkeric substance of the plain mark of streptavidin organism-absorbing that contains the SPA pearl subsequently.The synthetic template of being made up of the biotinylated 13 polymers-few G with polyrC hybridization is used as the homopolymer substrate.

Reaction conditions is 0.5 μ M[ ³³P]-GTP (0.2Ci/mMol), 1mM dithiothreitol (DTT), 20mMMgCl ₂, 5mM MnCl ₂, 20mM Tris-HCl, pH7.5, the biotinylated few G13 of 1.6 μ g/mL PolyC/0.256 μ M, 10% glycerine, 0.01%NP-40,0.2u/ μ L Rnasin and 50mM NaCl.

With the HCV RNA polymerase (with recombinant chou full-length NS5B (people such as Lohmann, J.Virol.71 (11), 1997,8416 ' Biochemical properties of hepatitis C virus NS5BRNA-dependent RNA polymerase and identification of amino acid sequencemotifs essential for enzymatic activity ') in baculovirus, express and be purified to evenly) to increase to ultimate density be 10nM.

Use 1M MnCl ₂(0.25mL), glycerine (4mL), 10%NP-40 (0.025mL) and water (7.225mL) (amounting to 10mL) prepare 5 * spissated mensuration buffer solution mixture.

2 * spissated enzyme buffer liquid comprises 1M-Tris-HCl, pH7.5 (0.4mL), 5M NaCl (0.2mL), 1M-MgCl ₂(0.4mL), glycerine (1mL), 10%NP-40 (10 μ L), 1M DTT (20 μ L) and water (7.97mL) amount to 10mL.

Use 5 * spissated mensuration buffer solution mixture (4 μ L), [ ³³P]-GTP (10 μ Ci/ μ L, 0.02 μ L), 25 μ M GTP (0.4 μ L), 0.4u/ μ L RNasin (0.04 μ L), 20 μ g/mL polyrC/ are biotinylated-and oligorG (1.6 μ L) and water (3.94 μ L) (amounting to 10 μ L) prepares substrate mixture.

By 1mg/ml total length NS5B polysaccharase (1.5 μ L) is joined 2.811mL 2 *-prepare enzyme mixture in the spissated enzyme buffer liquid.

This mensuration uses compound (1 μ L), substrate mixture (10 μ L) and enzyme mixture (adding at last to begin reaction) (10 μ L) (amounting to 21 μ L) to carry out.

This reaction is to carry out in the white 96-orifice plate at the bottom of the U-shape.After adding enzyme, reactant is mixed on plate-shaking table, and in 22 ℃ of insulations 1 hour.After this, stop this reaction by the 0.1M EDTA solution that adds 40 μ L 1.875mg/ml streptavidin (streptavidin) SPA pearls.After adding the PBS solution of 120 μ L 0.1M EDTA, described pearl and reaction mixture are incubated 1 hour in 22 ℃.Seal this plate, mixing, centrifugal, and determine the radioactivity of mixing by in Trilux (Wallac) or Topcount (Packard) scintillometer, counting.

After deducting the background concentration that does not have enzyme, the radioactivity when not having compound is compared, and any minimizing of the radioactivity amount of mixing when having this compound is considered to the mensuration to the inhibition level.In three or five times diluent, measure ten kinds of concentration of compound.For these countings, use Grafit3 or Grafit4 software package to calculate the inhibition per-cent when the survey maximum concentration or the IC of this compound ₅₀

In one of said determination method, cited compound all has＜IC of 50 μ M ₅₀Therefore, The compounds of this invention has potential treatment benefit in treatment and prevention HCV.Preferred compound has＜IC of 5 μ M ₅₀

Also can unite use according to pharmaceutical composition of the present invention, described other for example immunotherapy of healing potion (for example Interferon, rabbit such as Intederon Alpha-2a (Roferon-A with other healing potion; Hoffmann-LaRoche), Interferon, rabbit (inteferon) α-2b (Intron-A; Schering-Plough), Interferon alfacon-1 (interferon alfacon)-1 (Infergen; Intermune), Peg-Intron (peginterferonalpha) α-2b (Peg-Intron; Schering-Plough) or glycol interferon alpha-2a (Pegasys; Hoffmann-La Roche)); therapeutic vaccine; antifibrotic agents; anti-inflammatory agent such as cortin or NSAID; bronchodilator such as beta-2 adrenergic agonist and xanthine (as theophylline (theophylline)); mucolytic agent (mucolytic agent); muscarine antagonist (anti-muscarinics); anti-leukotriene antagonist; the inhibitor of cell adhesion (as the ICAM antagonist); antioxidant (as the N-acetylcysteine); the cytokine agonist; cytokine antagonist; pulmonary surfactant and/or antiseptic-germicide and antiviral agent (are used in combination as virazole (ribavirin) with Amantidine).Also can treat coupling according to composition of the present invention with gene substitution.

Thereby on the other hand, the invention provides a kind of composition (combination), it comprises formula (I) compound or pharmaceutically acceptable salt thereof or solvate, and and other therapeutic activity medicine specifically be Interferon, rabbit and/or virazole.

Composition mentioned above can be easily uses with the form of medicinal preparations, and therefore this medicinal preparations comprises as defined above composition and represents the present invention's pharmaceutically acceptable carrier of described this medicinal preparations on the other hand.

Also can be with single composition continuous or administration simultaneously in the pharmaceutical preparation that separates or make up of this composition.Persons skilled in the art are readily appreciated that the suitable dose of known pharmaceutical agents.

All publications comprise but the various patents that are not restricted to quote in this specification sheets and the content of patent application all are included in herein as a reference, are equivalent to these publications by concrete and proved absolutely separately.

Claims

1. the compound of formula (Ia):

Wherein:

The A representation hydroxy;

D represents aryl or heteroaryl;

E represents hydrogen, C _1-6Alkyl, aryl, heteroaryl or heterocyclic radical;

R ¹Represent hydrogen, C _1-6Alkyl, arylalkyl or heteroarylalkyl;

J represents C _1-6Alkyl, heterocyclic radical alkyl, arylalkyl or heteroarylalkyl; Condition is

I) E and G not all are hydrogen; And

Ii) this compound is not

With its salt, solvate and ester; Condition is as esterification A formation-OR, and when wherein R was selected from the alkyl, aralkyl, aryloxy alkyl of straight or branched or aryl, R was not the tertiary butyl.

2. according to the compound of claim 1, it is selected from:

With its salt, solvate and ester and if suitable each enantiomer.

3. according to formula (Ia) compound of claim 1, wherein the phenyl that replaces is chosen in the D representative wantonly.

4. according to formula (Ia) compound of claim 3, wherein the D representative is optional further by halogen, C _1-3Alkyl or C _1-3Right-tert-butyl-phenyl that alkoxyl group replaces.

5. according to formula (Ia) compound of claim 1, wherein the heteroaryl that replaces is chosen in the E representative wantonly.

6. according to formula (Ia) compound of claim 5, wherein thiazolyl, pyridyl, pyrazinyl, isoxazolyl and the thienyl that replaces chosen in the E representative wantonly.

7. according to formula (Ia) compound of claim 1, wherein the G representative is optional by halogen, OR ¹, SR ¹, SO ₂R ⁴C with the cyano group replacement _1-6Alkyl.

8. according to formula (Ia) compound of claim 7, wherein the G representative is optional by OR ¹The C that replaces _1-6Alkyl.

9. according to formula (Ia) compound of claim 7 or 8, R wherein ¹Represent hydrogen or C _1-3Alkyl.

10. according to formula (Ia) compound of claim 7, R wherein ⁴Represent C _1-3Alkyl.

11. according to formula (Ia) compound of claim 1, wherein J represents C _1-6Alkyl, arylalkyl or heteroarylalkyl.

12. formula (Ia) compound and its pharmacologically acceptable salt and solvate according to claim 1.

13. the treatment or the method for prophylaxis of viral infections, described method comprise the formula of significant quantity (I) compound and its salt, solvate and ester are delivered medicine to the patient who needs this treatment,

Wherein:

The A representation hydroxy;

D represents aryl or heteroaryl;

E represents hydrogen, C _1-6Alkyl, aryl, heteroaryl or heterocyclic radical;

R ¹Represent hydrogen, C _1-6Alkyl, arylalkyl or heteroarylalkyl;

14. according to the method for claim 13, it comprises inhibition HCV.

15. according to the method for claim 13, wherein this compound is with the oral dosage form administration.

16. formula (I) compound and its salt, solvate and ester are used for medical treatment:

Wherein:

The A representation hydroxy;

D represents aryl or heteroaryl;

E represents hydrogen, C _1-6Alkyl, aryl, heteroaryl or heterocyclic radical;

R ¹Represent hydrogen, C _1-6Alkyl, arylalkyl or heteroarylalkyl;

17. the compound of claim 16, wherein this medical treatment is the treatment of virus infection.

18. the compound of claim 17, wherein this virus infection is HCV.

19. formula (I) compound and its salt, solvate and ester are used for the treatment of purposes in the medicine for treating viral infections in preparation:

Wherein:

The A representation hydroxy;

D represents aryl or heteroaryl;

E represents hydrogen, C _1-6Alkyl, aryl, heteroaryl or heterocyclic radical;

R ¹Represent hydrogen, C _1-6Alkyl, arylalkyl or heteroarylalkyl;

20. the purposes of claim 19, wherein this virus infection is HCV.

21. a pharmaceutical preparation, it comprises as the defined formula of claim 1 (Ia) compound and combining with pharmaceutically acceptable diluent or carrier.

22. comprising, a method that is used for preparation as the defined formula of claim 13 (I) compound, described method use acid treatment formula (II) compound,

Wherein A is an alkoxyl group, and D, E, G and J define suc as formula (I).

23. according to the method for claim 22, wherein A is a tert.-butoxy.