CN101404999A

CN101404999A - Process for the preparation of 3,4-disubstituted-thiazolidin-2-ones

Info

Publication number: CN101404999A
Application number: CNA2007800099636A
Authority: CN
Inventors: J·B·德坎普; P·S·沃森; 佘劲
Original assignee: Inspire Pharmaceuticals Inc
Current assignee: Inspire Pharmaceuticals Inc
Priority date: 2006-03-23
Filing date: 2007-03-23
Publication date: 2009-04-08

Abstract

The present invention is directed to practical high-yielding synthetic processes for preparing 3,4-disubstituted-thiazolidin-2-ones, which do not compromise the absolute stereochemical integrity of the compounds. The present invention is also directed to novel compounds of 3,4-disubstituted-thiazolidin-2-ones. The compounds prepared by the present invention are useful in the synthesis and manufacture of compounds (such as latrunculins and/or their analogs) for treating diseases or conditions associated with inhibiting actin polymerization.

Description

3, the preparation method of 4-two replacement-thiazolidine-2s-ketone

Technical field

The present invention relates generally to 3,4-two replacement-thiazolidine-2s-ketone such as 3-(4-methoxyl group-benzyl)-2-oxo-Thiazolidine-4-carboxylic acid methoxyl group-methyl-amide and intermediate thereof synthetic.The chemical compound of the present invention preparation can be used for syntheticly being used for the treatment of the disease relevant with the inhibition actin polymerization or the chemical compound of disease with preparation.

Background of invention

Glaucoma is that a kind of meeting causes irreversible VI ophthalmic diseases.In the U.S., glaucoma is to cause the 4th the modal reason of losing one's sight and cause VI second modal reason, and is irreversible VI modal reason in Africa-America crowd.Generally speaking, the feature of this disease is a kind of progressive type neuropathy, is to be raise by intraocular pressure to cause the illeffects to optic nerve to cause to small part.In normal individuality, intraocular pressure is in 12-20mm Hg scope, on average about 16mm Hg.Yet in suffering from glaucomatous individuality, intraocular pressure generally rises to and is higher than 25-30mm Hg, reaches 70mm Hg sometimes.Importantly, Lve Gao or even in time several years, can cause vision impairment in the highstrung eye only to pressure in the intraocular pressure within statistical normal range.In addition, extremely high pressure (as, 70mm Hg) may only in several days, will cause losing one's sight.

Glaucomatous conventional therapy is comprised the various pharmaceutical methods of various reduction intraocular pressure (IOP) to normal value.Beta-Blocking agent and carbonic anhydrase inhibitors only can reduce the generation aqueous humor, and aqueous humor is to provide nutrition necessary to no blood vessel crystalline lens and endothelial cell, prostaglandin acts on uvea sclera (uvealscleral) outflow channel, only accounts for 10% of total effect (facility).Also do not check and approve and directly act on the therapeutic agent of trabecular reticulum at present through commerce, trabecular reticulum is to strengthen the inhibition of aqueous humor outflow and the site that IOP is raise and is responsible for.Therefore, the Drug therapy that medically still need descend at the improved IOP-of this structure.Medicament at trabecular reticulum can not alleviated misery for many Drug therapys that present IOP-is descended have the patient who enough reacts and/or can not tolerate the side effect relevant with these medicaments.Therefore, need effectively and the rational Cytoskeletal active compounds for treating of cost glaucoma, regulate the wound healing of trabecular resection postoperative, and treatment is subjected to complete sex other disease of actin cytoskeleton and disease.

United States Patent (USP) the 6th, 586,425,6,110,912 and 5,798, No. 380 the glaucomatous method of a kind of treatment is disclosed, the chemical compound that the actin filament integrity that this method is used can influence eye outflows with the raising aqueous humor.These patents also specifically disclose inhibitors of kinases and several natural product (latrunculin (latrunculin) A, latrunculin B, swinholide A and jasplakinolide), and they can cause the actin cytoskeleton interference in the trabecular reticulum or regulate it and the interaction of lower film.The interference of cytoskeleton and relevant adhesion have reduced the resistance of trabecular reticulum fluid flow, thereby have reduced intraocular pressure.

Natural latrunculin, be from ocean spongia such as Latrunculia magnifica, Negombata magnifica and Spongia mycofijiensis, and from nudibranch (nudibranches) as Chromodoris lochi results and the active Macrolide of isolated cells skeleton, its is difficult to a large amount of the acquisition.Natural latrunculin analog and derivant can only adopt time-consuming low-yield and unpractical synthesizing to prepare (A.B.Smith III etc., J.Am.Chem.Soc.1992,114,2995-3007 at present; J.D.White and M.Kawasaki, J.Org.Chem. (organic chemistry) 1992,57,5292-5300; A.F ü rstner etc., Angew.Chem.Int.Ed.2003,42,5358-5360).In addition, usually key intermediate is as 3,4-two replacement-thiazolidine-2s-ketone synthetic is not enough to solve following problem: (1) use may be fatal reagent, (2) the raceme level of final intermediate, (3) low-yield of each independent process and total process is (referring to Synthesis such as above-mentioned document and M.E.F.Braibante, 1999, the 6 phases, 943-946; J.D.Park etc., J.Med.Chem.2002,45,911-918; A.Furstner, PNAS, 2005, the 102 volumes, the 23rd phase, 8103-8108).

Still need simple and practical synthetic method to prepare and be used to prepare the novel Cytoskeletal active chemical compound such as the intermediate of latrunculin and/or their analog.

Summary of the invention

The present invention relates to practical high yield synthetic method, this method can not sacrifice 3, the absolute stereo chemical integrity of 4-two replacement-thiazolidine-2s-ketone (general formula I), and avoid using unsettled alkylating reagent.This method may further comprise the steps:

(a) sulfo-aminal (thioaminal) annulation carries out the reductive ring open reaction then, obtains the chemical compound of general formula I I;

General formula I I

(b) ring formation and amide are synthetic, obtain the chemical compound of general formula V;

General formula V

(c) organometallic reagent is added the chemical compound of general formula V, obtains the chemical compound of general formula I,

General formula I

R is alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl or heteroaryl in the formula;

A be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl, heteroaryl ,-CO ₂H ,-CO ₂R ₄,-(CH ₂) _nOR ₅, CHO or CN, they have or do not have substituent group;

R ₁And R ₂Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl or heteroaryl independently, they have or do not have substituent group; Perhaps

R ₁And R ₂Be connected to form ring;

R ₃Be H, alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl, heteroaryl ,-CH ₂PXR ₈R ₉Or-CH=PR ₁₀R ₁₁R ₁₂, they have or do not have substituent group;

R ₄Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl or heteroaryl, they have or do not have substituent group;

R ₅Be H, alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl, heteroaryl or Si (R ₆) ₃, they have or do not have substituent group;

R ₆Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl, heteroaryl or OR ₇, they have or do not have substituent group;

R ₇Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl or heteroaryl, they have or do not have substituent group;

X is O, S, does not perhaps exist;

R ₈And R ₉Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl, heteroaryl, alkoxyl, cycloalkyloxy, (heterocycle) oxygen base, aryloxy group, heteroaryloxy, alkyl amino, arylamino, cycloalkyl amino, (heterocycle) amino or heteroaryl amino independently, they have or do not have substituent group;

R ₁₀, R ₁₁And R ₁₂Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl or heteroaryl independently, they have or do not have substituent group; With

N is the integer of 1-5.

Method of the present invention can be used for preparing the chemical compound of general formula I, II and V.This compounds can be used as end product, and perhaps as intermediate, further modification is to prepare other required product.For example, this compounds is as the Cytoskeletal active chemical compound of preparation novelty such as the intermediate of latrunculin and/or their analog.

The chemical compound of general formula I and V has the thiazolidine-2-ketone part identical with the basic chemical structure of latrunculin and/or their analog.Latrunculin and/or their analog can be directly made by the chemical compound of general formula I or V, and from wherein isolating small amount of intermediate, these intermediate all contain the thiazolidine-2-ketone as identical basic structural element.

The invention still further relates to the compounds of general formula I and V.

Detailed Description Of The Invention

Definition

Unless otherwise noted, following term is normally defined following when existing, but is not limited to following:

" alkyl " refers to comprise the group of 1-25 carbon atom, is straight or branched, preferably comprises 1-12 carbon atom, more preferably comprises 1-6 carbon atom, has degree of unsaturation (thiazolinyl and alkynyl) or do not have degree of unsaturation, and be optional substituted.

" alkoxyl " refers to alkyl-O-, and wherein alkyl comprises the optional as defined above alkyl that replaces as defined above.

" aryl " refers to have the aromatic carbocyclyl groups of 6-14 carbon atom, and they have or do not have substituent group, has monocycle (for example phenyl) or a plurality of fused rings (for example naphthyl or anthryl).Preferred aryl groups comprises phenyl, naphthyl etc.

" aryloxy group " refers to aryl-O-, and wherein aryl comprises the optional as defined above aryl that replaces as defined above.

" aryl alkyl " refer to aryl-alkyl-, preferably comprise 1-8 carbon atom at moieties, comprise 6-10 carbon atom at aryl moiety.The moieties of aralkyl can comprise one or more unsaturated sites, for example two keys or the triple bond in the chain when chain comprises two or more carbon atoms; The moieties of aralkyl also can comprise one or more substituent groups; The aryl moiety of aralkyl can be monocycle or multi-ring part, and each ring of aryl moiety comprises 3-8 carbon atom, and more preferably each ring comprises 4-6 carbon atom, and most preferably each ring comprises 5-6 carbon atom; The aryl moiety of aralkyl also can comprise one or more substituent groups.The example of this class aryl alkyl is benzyl, phenethyl etc.

" cycloalkyl " refers to have the cycloalkyl of 3-12 carbon atom, and it has monocycle or a plurality of fused rings, has or do not have degree of unsaturation, has or do not have substituent group.This class cycloalkyl comprises for example single ring architecture, such as cyclopropyl, cyclobutyl, cyclopenta, ring octyl group, 1-methyl cyclopropyl, 2-methylcyclopentyl, 2-methyl ring octyl group etc., or multiring structure, such as adamantyl, or the like.

" cycloalkyl-alkyl " refer to preferably moieties comprise 1-6 carbon atom, cycloalkyl moiety comprise the cycloalkyl-alkyl of 3-10 carbon atom-.The example of this class cycloalkyl-alkyl is cyclopropyl methyl, cyclohexyl ethyl etc.

" cycloalkyloxy " finger ring alkyl-O-, wherein cycloalkyl comprises the optional as defined above cycloalkyl that replaces as defined above.

Heteroarylalkyl comprises 1-8 carbon atom at moieties, more preferably comprises 1-6 carbon atom at moieties, most preferably comprises 1-4 carbon atom at moieties; As indicated above included in the alkyl definition, the moieties of heteroarylalkyl can comprise one or more unsaturated sites, for example two keys or the triple bond in the chain when chain comprises two or more carbon atoms; The moieties of heteroarylalkyl also can comprise one or more hetero atoms and/or substituent group; The heteroaryl moieties of heteroarylalkyl can be monocycle or multi-ring part, and each ring of heteroaryl moieties comprises 3-8 carbon atom, and each ring comprises 1-4 hetero atom, and more preferably each ring comprises 4-6 carbon atom, and most preferably each ring comprises 5-6 carbon atom; The heteroaryl moieties of heteroarylalkyl also can comprise one or more substituent groups.

Heteroaryl can be a monocycle or multi-ring, and each ring contains 1-4 hetero atom.Heteroaryl also can comprise substituent group.

Heterocycle refers to stable 5 yuan or 6 yuan of monocyclic heterocycles, its can be saturated, part is undersaturated or undersaturated (aromatics), form by carbon atom and 1-3 hetero atom that is selected from N, O and S independently of one another.Nitrogen and sulfur heteroatom are randomly oxidized.Heterocycle can any hetero atom or the carbon atom place be connected with its side chain, obtain stable structure.Heterocycle described in the literary composition can be substituted at carbon or nitrogen-atoms place, as long as the chemical compound that obtains is stable.Preferably when the total number of S in the heterocycle and O atom surpassed 1, these hetero atoms were non-conterminous each other.The S in the preferred heterocycle and the total number of O atom are no more than 1.

Heterocyclic example includes but not limited to the 2-Pyrrolidone base, the 2H-pyrrole radicals, the 4-piperidone base, 6H-1,2,5-thiadiazine base, 2H, 6H-1,5,2-dithiazine base, furyl, furazan base (furazanyl), imidazolidinyl, imidazolinyl, imidazole radicals isoxazolyl, morpholinyl oxadiazole base, 1,2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,2,5-oxadiazole base, 1,3,4-oxadiazole base oxazolidinyl oxazolyl, piperazinyl, piperidyl, pteridyl, piperidone base, the 4-piperidone base, pteridyl, purine radicals, pyranose, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridine radicals (pyridinyl), pyridine radicals (pyridyl), pyrimidine radicals, pyrrolidinyl, pyrrolinyl (pyrrolinyl), pyrrole radicals (pyrrolyl), tetrahydrofuran base, 6H-1,2,5-thiadiazine base, 1,2, the 3-thiadiazolyl group, 1,2, the 4-thiadiazolyl group, 1,2, the 5-thiadiazolyl group, 1,3, the 4-thiadiazolyl group, thiazolyl, thienyl, the thieno thiazolyl, thiophene Bing oxazolyl, the Thienoimidazole base, thiophenyl, triazine radical, 1,2, the 3-triazolyl, 1,2, the 4-triazolyl, 1,2,5-triazolyl and 1,3, the 4-triazolyl.Preferred heterocycle includes but not limited to pyridine radicals, furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals He oxazolidinyl.Also comprise and contain for example above-mentioned heterocyclic fused rings and spiro-compounds.

" (heterocycle) oxygen base " refers to heterocycle-O-, and wherein heterocyclic radical comprises the optional heterocyclic radical that replaces as defined above.

The site that is occupied by hydrogen in above-mentioned group can further be substituted base and replace, and described substituent group is such as but not limited to following: hydroxyl, oxo, nitro, methoxyl group, ethyoxyl, alkoxyl, the alkoxyl that replaces, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl group, butyl, alkyl, the alkyl that replaces, sulfo-, alkylthio, acyl group, carboxyl, alkoxy carbonyl, formamido group (carboxamido), the formamido group that replaces, alkyl sulphonyl, alkyl sulphinyl, alkyl sulfonyl-amino, sulfonamido, the sulfonamido that replaces, cyano group, amino, the amino that replaces, acyl amino, trifluoromethyl, trifluoromethoxy, phenyl, aryl, the aryl that replaces, pyridine radicals, imidazole radicals, heteroaryl, the heteroaryl that replaces, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cycloalkyl, the cycloalkyl that replaces, pyrrolidinyl, piperidyl, morpholinyl and heterocycle; Preferred hetero atom is oxygen, nitrogen and sulfur.Should understand, when having open valency (open valence) on these substituent groups, they can also be replaced by alkyl, cycloalkyl, aryl, heteroaryl and/or heterocyclic radical, when having a plurality of this open valency, these groups can by direct key of formation or by with new hetero atom, preferred oxygen, nitrogen or sulfur form one or more keys, are connected to form ring.Should also be understood that and to carry out above-mentioned replacement, in molecule of the present invention, do not introduce unacceptable unstability as long as replace hydrogen, otherwise be exactly chemically rational with these substituent groups.

Diastereomer is the stereoisomer (forming isomers identical but that three dimensional structure is different) that does not have mirror image relationship each other.

Enantiomer is to be mirror image but can not eclipsed stereoisomer each other.

Carbonylation agent is the reagent that carbonyl can be transferred to chemical compound.

Reducing agent is by providing electronics or hydrogen to make the reductive reagent of other material in redox reaction.

Organometallic reagent is the reagent that contains organic group and metal, and described organic group directly is connected with metal by σ or π key.

The metal counter ion counterionsl gegenions refer to positively charged ion or complex, and it is as the companion ion of the negative charge of nucleopilic reagent.The example of suitable metal counter ion counterionsl gegenions includes but not limited to following listed positive charge ion or complex: lithium, sodium, potassium; Copper and any type of salt thereof, for example chloride, bromide or iodide; Magnesium and any type of salt thereof, for example chloride, bromide or iodide; Zinc and any type of salt thereof, for example chloride or bromide; Cerium and any type of salt thereof, for example chloride or bromide; Calcium and any type of salt thereof, for example chloride or bromide.The example of positive charge ion or complex comprises Li ⁺, Na ⁺, K ⁺, MgCl ⁺, MgBr ⁺, MgI ⁺, ZnCl ⁺, ZnBr ⁺, CaCl ⁺, CaBr ⁺, CuBr ⁺And CuCl ⁺

The form of pharmaceutically acceptable salt comprises the various polycrystalline and the amorphous form of the different salt that are derived from sour addition or alkali addition.Acid-addition salts can form with inorganic or organic acid.The illustrative of this class acid but nonrestrictive example comprise: hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, citric acid, acetic acid, propanoic acid, benzoic acid, naphthoic acid, oxalic acid, succinic acid, maleic acid, malic acid, adipic acid, lactic acid, tartaric acid, salicylic acid, methanesulfonic acid, 2-ethylenehydrinsulfonic acid, toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid and ethyl sulfonic acid.Pharmaceutically acceptable base addition salts can form with metal or means organic balance ion, includes but not limited to following: alkali metal salt such as sodium or potassium salt; Alkali salt such as magnesium or calcium salt; With ammonium or tetraalkylammonium salt, i.e. NX ₄ ⁺(wherein X is C _1-4).

Solvate is an addition complex, and wherein, chemical compound and pharmaceutically acceptable cosolvent are with specific ratio combination.Cosolvent includes but not limited to: water, methanol, ethanol, 1-propanol, isopropyl alcohol, 1-butanols, isobutanol, the tert-butyl alcohol, acetone, butanone, acetonitrile, ethyl acetate, benzene,toluene,xylene, ethylene glycol, dichloromethane, 1,2-dichloroethanes, N-methylformamide, N, dinethylformamide, N-methylacetamide, pyridine, diox and ether.Hydrate is that wherein cosolvent is the solvate of water.Should be understood that definition to The compounds of this invention has comprised the hydrate and the solvate of all possible any ratio.

Usually inorganic or organic acid or alkali react in suitable solvent or all kinds of solvents make up and prepare acceptable salt form with an amount of or excessive required salify of stoichiometric proportion by free alkali or acid.

Stable chemical compound refers to enough stablize to experience the chemical compound that separates the purity that reaches useful from reactant mixture.

The present inventor has been found that the novel method of the chemical compound of several preparation general formula Is, II and V, and these chemical compounds can be end products, perhaps further is modified as other required product as intermediate.

The method of the chemical compound of preparation general formula I I

The present invention relates to prepare the method for the chemical compound of general formula I I,

General formula I I

This method may further comprise the steps: make the chemical compound and the Reducing agent reaction of general formula III, form the chemical compound of general formula I I;

General formula III

R ₇Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl or heteroaryl, they have or do not have substituent group; With

N is the integer (1,2,3,4 or 5) of 1-5.

The preparation of solution C; The chemical compound and the proper solvent system of general formula (III) are added in the container.Reinforced order can be carried out according to easy principle, and perhaps other technology Considerations of knowing according to the process chemistry those skilled in the art carry out.Reaction can be carried out in many solvents: carbon tetrachloride, chloroform, dichloromethane, 1, the 1-dichloroethanes, oxolane, 1, the 3-diox, 1, the 4-diox, water, methanol, ethanol, normal propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutanol, furan, ether, glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethyl carbitol, the 2,2'-ethylenedioxybis(ethanol). diisopropyl ether, methoxybenzene, dimethyl formamide (DMF), dimethyl acetylamide (DMAC), N-Methyl pyrrolidone (NMP), Methanamide, the N-methylacetamide, the N-methylformamide, acetonitrile (ACN), dimethyl sulfoxine, propionitrile, sulfolane, N, N-dimethyl propylene amide and hexamethyl phosphoramide; Preferred solvent is water, methanol and ethanol.Preferred solvent is a water.Preferably the serosity that forms in suitable solvent by the initial compounds that adds alkali mutual-through type (III) carries out pH regulator, with dissolving fully.Typical alkali is the carbonate solution of sodium, lithium and potassium; The bicarbonate solution of sodium, lithium and potassium; The hydroxide solution of sodium, lithium and potassium.Preferred alkali is potassium carbonate.

The preparation of solution D: appropriate reductant is added in the reaction vessel.Reducing agent is by providing electronics or hydrogen to make the reductive reagent of other material in the redox reaction.Appropriate reductant includes but not limited to hydrogen, alkyl borane and alkyl borane complex, lithium borohydride, sodium borohydride, sodium triacetoxy borohydride, cyano group lithium borohydride, lithium triethylborohydride, boron triethyl sodium hydride, 3-sec-butyl lithium borohydride, three sec-butyl potassium borohydrides, lithium aluminium hydride reduction, alane, diisobutylaluminium hydride, triphenyl borine hydrofining, sodium cyanoborohydride, trimethyl silane and transfer Reducing agent.Preferred Reducing agent is sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride and trimethyl silane.Preferred Reducing agent is a sodium borohydride, because this Reducing agent cost efficiency is higher.The amount of Reducing agent according to the molar equivalent decision of the chemical compound of general formula (III), is preferably the 1.0-5.0 molar equivalent usually.After adding Reducing agent, add the aqueous solution of alkali.Typical solutions is the carbonate of sodium, lithium and potassium; The bicarbonate of sodium, lithium and potassium; And the hydroxide of sodium, lithium and potassium, preferably 1.0M sodium hydroxide.Arbitrary solution can be added in another solution, but preferably solution C be added in the solution D.The formation of the chemical compound of general formula (II) is preferably carried out under-20-50 ℃ temperature.Reaction can be monitored by HPLC.According to initial solvent and temperature, reaction was finished in 1-12 hour usually.Reaction can come quencher by adding aqueous acid.These acid include but not limited to: mineral acid, for example hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, nitric acid, phosphoric acid; Organic acid, for example formic acid, acetic acid, methanesulfonic acid, trifluoroacetic acid, propanoic acid, butanoic acid, valeric acid, caproic acid and oxalic acid.Other acid also can be the aqueous solution of sodium bisulfate, potassium acid sulfate, ammonium chloride, lithium hydrogen sulfate etc.Acetic acid aqueous solution preferably.Quencher is preferably carried out to get off by temperature being remained on 10 ℃.Product by isolated by filtration general formula (II).Solid can water, methanol or washing with alcohol.Product is preferably under vacuum, be dried to constant weight under 30-60 ℃ temperature.

The preparation of the chemical compound of general formula III

The chemical compound of general formula III can prepare by the chemical compound and the aldehyde reaction of general formula X,

General formula X

In the formula;

R ₇Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl, heteroaryl, they have or do not have substituent group; With

N is the integer (1,2,3,4 or 5) of 1-5.

The preparation of solution A: the chemical compound and the proper solvent system of general formula (X) are added in the reaction vessel.Reinforced order can be carried out according to easy principle, and perhaps other technology Considerations of knowing according to the process chemistry those skilled in the art carry out.Reaction can be carried out in many solvents: carbon tetrachloride, chloroform, dichloromethane, 1, the 2-dichloroethanes, oxolane, 1, the 3-diox, 1, the 4-diox, water, methanol, ethanol, normal propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutanol, furan, ether, glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethyl carbitol, the 2,2'-ethylenedioxybis(ethanol). diisopropyl ether, methoxybenzene, dimethyl formamide (DMF), dimethyl acetylamide (DMAC), N-Methyl pyrrolidone (NMP), Methanamide, the N-methylacetamide, the N-methylformamide, acetonitrile (ACN), dimethyl sulfoxine, propionitrile, sulfolane, N, N-dimethyl propylene amide and hexamethyl phosphoramide; Preferred solvent is water, methanol, ethanol, oxolane and acetonitrile.Preferred solvent is a water.Aldehyde can directly add, and perhaps adds with the form in suitable solvent.

The preparation of aldehyde solution B: will add in the container at the aldehyde in the suitable solvent.Reinforced order can be carried out according to easy principle, and perhaps other technology Considerations of knowing according to the process chemistry those skilled in the art carry out.Aldehyde solution can prepare in many solvents: carbon tetrachloride, chloroform, dichloromethane, 1, the 2-dichloroethanes, oxolane, 1, the 3-diox, 1, the 4-diox, water, methanol, ethanol, normal propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutanol, furan, ether, glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethyl carbitol, the 2,2'-ethylenedioxybis(ethanol). diisopropyl ether, methoxybenzene, dimethyl formamide (DMF), dimethyl acetylamide (DMAC), N-Methyl pyrrolidone (NMP), Methanamide, the N-methylacetamide, the N-methylformamide, acetonitrile (ACN), dimethyl sulfoxine, propionitrile, sulfolane, N, N-dimethyl propylene amide and hexamethyl phosphoramide; Preferred solvent is methanol, ethanol and isopropyl alcohol.Preferred solvent is an ethanol.The amount of aldehyde is determined according to the molar equivalent of general formula (A) usually, is preferably the 1.0-5.0 molar equivalent, more preferably the 1.0-1.5 molar equivalent.

Arbitrary solution can be added in another solution, but preferably solution B be added in the solution A.The formation of the chemical compound of general formula (III) is preferably carried out under 0-30 ℃ temperature.The chemical compound of general formula (III) can further precipitate by adding ethanol.Reaction was finished in 1-6 hour usually.Can pass through the isolated by filtration product, use solvent wash.Product is preferably in vacuum, be dried to constant weight under 30-60 ℃ temperature.

The present inventor has found the high yield two-step method of the chemical compound of a kind of compound general formula I I by general formula X unexpectedly.This two-step method at first prepares general formula III by general formula X, prepares general formula I I by general formula III then.This two-step method can make the cysteine derivative alkylation under the situation of not using alkylating reagent, alkylating reagent is 4-methoxybenzyl bromide for example, this reagent operating difficulties.Cysteine (chemical compound of general formula X) is converted into two step processes of the chemical compound of general formula I Ia and finishes with the productive rate of 61-80%, and the report literature value of one step process as a comparison (J.D.Park etc. J.Med.Chem.2002) are 30-50%.In addition, two-step method has avoided using the fatal Reducing agent of possibility: sodium cyanoborohydride.

The method of the chemical compound of preparation general formula V

The present invention relates to prepare the method for the chemical compound of general formula V,

General formula V

This method may further comprise the steps: the chemical compound and the amine HNR that make general formula I V ₁OR ₂Reaction in the presence of suitable reagent, the chemical compound of formation general formula V,

General formula I V

Wherein R is alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl or heteroaryl, and they have or do not have substituent group;

R ₁And R ₂Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl or heteroaryl independently, they have or do not have substituent group; Or

R ₁And R ₂Be connected to form ring.

The chemical compound and the proper solvent system of general formula (IV) are added in the reaction vessel.Reinforced order can be carried out according to easy principle, and perhaps other technology Considerations of knowing according to the process chemistry those skilled in the art carry out.Reaction can be carried out in many solvents: carbon tetrachloride, chloroform, dichloromethane, 1, the 1-dichloroethanes, oxolane, 1, the 3-diox, 1, the 4-diox, furan, ether, glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethyl carbitol, the 2,2'-ethylenedioxybis(ethanol). diisopropyl ether, methoxybenzene, dimethyl formamide (DMF), dimethyl acetylamide (DMAC), N-Methyl pyrrolidone (NMP), Methanamide, the N-methylacetamide, the N-methylformamide, acetonitrile (ACN), dimethyl sulfoxine, propionitrile, sulfolane, N, N-dimethyl propylene amide and hexamethyl phosphoramide, benzene, toluene, ethylbenzene, meta-xylene, o-Dimethylbenzene or xylol, t-butyl methyl ether, 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), methyl acetate, ethyl acetate, isopropyl acetate, tert-butyl acetate, sulfolane, N, N-dimethyl propylene amide; Preferred solvent is an oxolane, 1,4-diox and isopropyl acetate.Preferred solvent is an isopropyl acetate.Perhaps, can directly use solution from the chemical compound of the general formula I V of step 3.The chemical compound of general formula (IV) is added in the suitable solvent, add alkali then.Reaction can be carried out with multiple alkali: morpholine, N-methylmorpholine (NMM), triethylamine (TEA), diisopropylethylamine (DIPEA) and diethylamine; Preferred alkali is N-methylmorpholine (NMM).The amount of alkali is determined according to the molar equivalent of general formula (IV) usually, is preferably the 1.0-5.0 molar equivalent, more preferably the 1.0-1.5 molar equivalent.Alkali preferably adds excessive activating reagent after adding.Suitable activating reagent is methylchloroformate, ethyl chloroformate, chloro-carbonic acid n-propyl, isopropyl chlorocarbonate, isobutyl chlorocarbonate, N, N-carbonyl dimidazoles (CDI), chloroacetic chloride, propionyl chloride, dimethyl chloroacetic chloride, pivalyl chloride, Benzenecarbonyl chloride. and other carboxylic acid halides etc.Preferred activating reagent is a pivalyl chloride.The amount of activating reagent is determined according to the molar equivalent of the chemical compound of general formula (IV) usually, is preferably the 1.0-1.2 molar equivalent.This mixture preferably stirs under-20-20 ℃ temperature.After the suitable time (1-6 hour usually), add suitable nucleopilic reagent.Preferred primary amine and secondary amine; Preferred amine is N-methoxyl group-methylamine (methanamine).The amount of amine is determined according to the molar equivalent of the chemical compound of general formula (IV) usually, is preferably the 1.0-2.0 molar equivalent.The formation of the chemical compound of logical formula V is preferably carried out under-20-20 ℃ temperature.Reaction is preferably monitored by HPLC.Reaction can be by adding the aqueous acid quencher.These acid include but not limited to: mineral acid, for example hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, nitric acid, phosphoric acid; Organic acid, for example formic acid, acetic acid, methanesulfonic acid, trifluoroacetic acid, propanoic acid, butanoic acid, valeric acid, caproic acid, oxalic acid.Other acid also can be the aqueous solution of sodium bisulfate, potassium acid sulfate, ammonium chloride, lithium hydrogen sulfate etc.Aqueous hydrochloric acid solution preferably.Preferably use the solution washing organic layer of alkali.Usually the aqueous solution of alkali is by following listed making: the carbonate of sodium, lithium and potassium; The bicarbonate of sodium, lithium and potassium; And the hydroxide of sodium, lithium and potassium, preferably sodium hydroxide.The aqueous solution of preferred alkali is a sodium bicarbonate.The product of logical formula V can be by adding contrary solvent crystallization; Normal heptane preferably.Chemical compound by the logical formula V of isolated by filtration.This product preferably under vacuum, at 30-60 ℃ temperature range inner drying to constant weight.

The method of the chemical compound of preparation general formula I

The present invention relates to prepare the method for the chemical compound of general formula I,

General formula I

This method may further comprise the steps: the chemical compound and the organometallic reagent R that make general formula V ₃-M reaction, the chemical compound of formation general formula I,

General formula V

R ₁And R ₂Be connected to form ring;

X is O, S, does not perhaps exist;

R ₁₀, R ₁₁And R ₁₂Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl or heteroaryl independently, they have or do not have substituent group.

In said method, organometallic reagent R ₃-M can be raw material (preformed), perhaps can by with the course of reaction of the chemical compound of general formula V in by R ₃-H and alkyl-M or aryl-M react formation.For example, (R)-dimethyl 2-(3-(4-methoxy-benzyl)-2-oxo Thiazolidine-4-yl)-2-oxoethyl phosphonate ester (general formula I) can make by chemical compound and the reaction of dimethyl methyl phosphonate lithium salts of general formula V, and the latter is by dimethyl methyl phosphonate and lithium alkylide such as n-BuLi or lithium methide reaction generation.

Preferably will lead to the chemical compound of formula V and suitable solvent adds in the reaction vessel.Reinforced order can be carried out according to easy principle, and perhaps other technology Considerations of knowing according to the process chemistry those skilled in the art carry out.Reaction can be carried out in many solvents: for example, chloroform, dichloromethane, 1, the 1-dichloroethanes, oxolane, 1, the 3-diox, 1, the 4-diox, furan, ether, glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethyl carbitol, the 2,2'-ethylenedioxybis(ethanol). diisopropyl ether, methoxybenzene, dimethyl formamide (DMF), dimethyl acetylamide (DMAC), N-Methyl pyrrolidone (NMP), Methanamide, the N-methylacetamide, the N-methylformamide, dimethyl sulfoxine, propionitrile, sulfolane, N, N-dimethyl propylene amide and hexamethyl phosphoramide, preferred solvent is an ether, 1,4-diox and oxolane; Preferred solvent is an oxolane.After adding the chemical compound of logical formula V, add suitable organometallic reagent.Suitable organometallic reagent includes but not limited to organic-magnesium or organolithium reagent.The simple case of this class reagent includes but not limited to: lithium, sodium and the magnesium salt of methylmagnesium-bromide, ethyl-magnesium-bromide, bromination propyl group magnesium, phenyl-magnesium-bromide, bromination benzyl magnesium, dimethyl methyl phosphonate.The amount of organometallic reagent is determined according to the molar equivalent of the chemical compound that leads to formula V usually, is preferably the 1.0-5.0 molar equivalent, more preferably the 2.0-3.0 molar equivalent.The formation of the chemical compound of general formula (I) preferably-60-50 ℃, more preferably under-60-0 ℃ temperature, carry out.Reaction is preferably monitored by HPLC.Reaction can be-20 ℃-20 ℃ and keep internal reaction temperature simultaneously by it is added quencher in the aqueous acid.Aqueous acid includes but not limited to: mineral acid, for example hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, nitric acid, phosphoric acid; Organic acid, for example formic acid, acetic acid, methanesulfonic acid, trifluoroacetic acid, propanoic acid, butanoic acid, valeric acid, caproic acid, oxalic acid.Other acid also can be the aqueous solution of citric acid, sodium bisulfate, potassium acid sulfate, ammonium chloride, lithium hydrogen sulfate etc.Fructus Citri Limoniae aqueous acid preferably.After removing the organic reaction solvent, with an organic solvent extract the product of general formula (I) as methyl acetate, ethyl acetate or isopropyl acetate by distillation.Preferred extractant is an isopropyl acetate.Can come crystallized product by adding the doubly excessive contrary solvent of 1-5, preferably normal heptane.By the isolated by filtration product.This product preferably under vacuum, at 25-50 ℃ temperature range inner drying to constant weight.

The present inventor finds above-mentioned novel method unexpectedly, and this method can prepare chirality 3,4-two replacement-thiazolidine-2s-ketone (chemical compound of general formula I) under the situation of not sacrificing the absolute stereo chemical integrity.The method of Miao Shuing depends on and uses raceme tendency intermediate (for example acyl chlorides) before, and providing needs recrystallization to obtain the material of high level enantiomer excessive (enantiomeric excess).The method advocated uses stable separable intermediate to provide enantiomer excessive in 98% general formula I and the chemical compound of V.Find that according to these the present inventor has been found that the practicality and the effective method of the chemical compound of preparation general formula I.

Chemical compound by the compound general formula I of general formula III

The invention provides method by the novelty of the chemical compound of the compound general formula I of general formula III.

In one embodiment, general formula III is a carboxylic acid.This method may further comprise the steps:

(a) chemical compound of general formula III a and Reducing agent are reacted, form the chemical compound of general formula I Ia,

General formula III a general formula I Ia

(b) chemical compound of general formula I Ia and carbonylation agent are reacted, form the chemical compound of general formula I V;

General formula I V

(c) make chemical compound and the amine HNR of general formula I V ₁OR ₂Reaction, the chemical compound of formation general formula V, wherein R ₁And R ₂Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl or heteroaryl independently, they have or do not have substituent group; Perhaps R ₁And R ₂Be connected to form ring;

General formula V

(d) make chemical compound and the organometallic reagent (R of general formula V ₃-M) reaction, the chemical compound of formation general formula I, wherein R ₃Be H, alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl, heteroaryl or-CH ₂PXR ₈R ₉, they have or do not have substituent group; X is O, S, does not perhaps exist; R ₈And R ₉Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl, heteroaryl, alkoxyl, cycloalkyloxy, (heterocycle) oxygen base, aryloxy group, heteroaryloxy, alkyl amino, arylamino, cycloalkyl amino, (heterocycle) amino or heteroaryl amino independently; M is a metal.

In another embodiment, general formula III is an ester.This method may further comprise the steps:

(a) chemical compound of general formula III b and Reducing agent are reacted, form the chemical compound of general formula I Ib,

General formula III b general formula I Ib

Wherein R is alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl or heteroaryl, and they have or do not have substituent group; R ₄Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl or heteroaryl, they have or do not have substituent group;

(b) chemical compound of general formula I Ib and carbonylation agent are reacted, form the chemical compound of general formula VII,

General formula VII

(c) make the compound hydrolysis of general formula VII, form the chemical compound of general formula I V,

General formula I V

(d) make chemical compound and the amine HNR of general formula I V ₁OR ₂Reaction, the chemical compound of formation general formula V, wherein R ₁And R ₂Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl or heteroaryl independently, they have or do not have substituent group; Perhaps R ₁And R ₂Be connected to form ring;

General formula V

(e) make chemical compound and the organometallic reagent R of general formula V ₃-M reaction, the chemical compound of formation general formula I,

R wherein ₃Be H, alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl, heteroaryl or-CH ₂PXR ₈R ₉, they have or do not have substituent group; X is O, S, or does not exist; R ₈And R ₉Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl, heteroaryl, alkoxyl, cycloalkyloxy, (heterocycle) oxygen base, aryloxy group, heteroaryloxy, alkyl amino, arylamino, cycloalkyl amino, (heterocycle) amino or heteroaryl amino independently, they have or do not have substituent group; M is a metal.

In another embodiment, general formula III is an alcohol.This method may further comprise the steps:

(a) chemical compound of general formula III c and Reducing agent are reacted, form the chemical compound of general formula I Ic;

General formula III c general formula I Ic

Wherein R is alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, aryloxy group, heteroarylalkyl or heteroaryl, and they have or do not have substituent group; R ₅Be H, alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl, heteroaryl or Si (R ₆) ₃, they have or do not have substituent group;

R ₆Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl, heteroaryl or OR ₇, they have or do not have substituent group; R ₇Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl or heteroaryl, they have or do not have substituent group;

(b) chemical compound of general formula I Ic and carbonylation agent are reacted, form the chemical compound of general formula VIII;

General formula VIII

(c) make the chemical compound deprotection of general formula VII, form the chemical compound of general formula I X,

General formula I X

(d) make the compound oxidation of general formula I X, form the chemical compound of general formula I V,

General formula I V

(e) make chemical compound and the amine HNR of general formula I V ₁OR ₂Reaction, the chemical compound of formation general formula V,

R wherein ₁And R ₂Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl or heteroaryl independently, they have or do not have substituent group; Perhaps R ₁And R ₂Be connected to form ring;

General formula V

(f) make chemical compound and the organometallic reagent R of general formula V ₃-M reaction, the chemical compound of formation general formula I, wherein R ₃Be H, alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl, heteroaryl or-CH ₂PXR ₈R ₉, they have or do not have substituent group; X is O, S, does not perhaps exist; R ₈And R ₉Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl, heteroaryl, alkoxyl, cycloalkyloxy, (heterocycle) oxygen base, aryloxy group, heteroaryloxy, alkyl amino, arylamino, cycloalkyl amino, (heterocycle) amino or heteroaryl amino independently, they have or do not have substituent group; M is a metal.

Scheme 1a-c provides the chemical compound 3 of general formula I, the general route of synthesis of 4-two replacement-thiazolidine-2s-ketone.In scheme 1a, make the chemical compound of general formula III a by cysteine, reductive ring open is the chemical compound of general formula I Ia then.The chemical compound cyclisation of general formula I Ia is the chemical compound of general formula I V.Make the compound activating of general formula I V, be converted into the chemical compound of general formula V.Make chemical compound and the organometallic reagent reaction of general formula V, obtain the chemical compound of general formula I.

In scheme 1b, make the chemical compound of general formula III b by the ester (chemical compound of general formula X) of cysteine, reductive ring open is the chemical compound of general formula I Ib then.Make the chemical compound of the chemical compound cyclisation formation general formula VII of general formula I Ib.Make the compound hydrolysis of general formula VII then, the alkali with Lithium hydrate or potassium hydroxide and so on carries out in suitable solvent usually, obtains the chemical compound of general formula I V.

In scheme 1c, make the chemical compound of general formula III c by the protected 01 derivatives (chemical compound of general formula X) of cysteine, reductive ring open is the chemical compound of general formula I Ic then.The chemical compound cyclisation that makes general formula I Ic is the chemical compound of general formula VIII.The chemical compound of mutual-through type VIII carries out deprotection, uses fluoride source to carry out deprotection when using suitable silicon blocking group usually, obtains the chemical compound of general formula I X.Make the compound oxidation of general formula I X, use activatory DMSO step to obtain aldehyde usually, adopt bleach-media reaction (bleach-mediated reaction) to obtain carboxylic acid, thereby obtain the chemical compound of general formula I V.

Scheme 2 provides the object lesson of scheme 1a, is used for preparation (R)-(-)-3-(4-methoxyl group-benzyl)-2-oxo-Thiazolidine-4-carboxylic acid methoxyl group-methyl-amide (chemical compound of general formula V); (R)-(-) (4-acetyl group-3-(4-methoxyl group-benzyl)-thiazolidine-2-ketone (chemical compound of general formula I); (R)-and dimethyl 2-(3-(4-methoxy-benzyl)-2-oxo Thiazolidine-4-yl)-2-oxoethyl phosphonate ester (chemical compound of general formula I) and (R)-4-((R)-9-(benzyloxy)-5-hydroxyl ninth of the ten Heavenly Stems-2-alkynes acyl group (hydroxynon-2-ynoyl)-3-(4-methoxy-benzyl) thiazolidine-2-ketone (chemical compound of general formula I).

The present invention can be used for synthetic these chemical compounds of the form of its enantiomeric pure (enantio pure), and these chemical compounds have preferred spatial chemistry, are used to prepare latrunculin and/or their analog; But method of the present invention also can be used for preparing other enantiomer/epimer or racemic mixture.

Scheme 1 and 2 is used for illustrating the present invention, should not be construed as restriction the present invention.Those skilled in the art will recognize that and to use other raw material and other step to come the interior chemical compound of the production scope of the invention.In some cases, must protect, to realize some conversions in above-mentioned some active function groups.Usually, whether need this class blocking group and to apply and remove the necessary condition of this class blocking group be conspicuous to the technical staff of technical field of organic synthesis.

Scheme 1a

Scheme 1b

Scheme 1c

Scheme 2

Step 3 method

The preparation of solution E: preferably chemical compound and the proper solvent system with general formula (IIa) adds in the reaction vessel.Reinforced order can be carried out according to easy principle, and perhaps other technology Considerations of knowing according to the process chemistry those skilled in the art carry out.Reaction can be carried out in many solvents: carbon tetrachloride, chloroform, dichloromethane, 1, the 1-dichloroethanes, oxolane, 1, the 3-diox, 1, the 4-diox, water, methanol, ethanol, normal propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutanol, furan, ether, glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethyl carbitol, the 2,2'-ethylenedioxybis(ethanol). diisopropyl ether, methoxybenzene, dimethyl formamide (DMF), dimethyl acetylamide (DMAC), N-Methyl pyrrolidone (NMP), Methanamide, the N-methylacetamide, the N-methylformamide, acetonitrile (ACN), dimethyl sulfoxine, propionitrile, sulfolane, N, N-dimethyl propylene amide and hexamethyl phosphoramide; Preferred solvent is acetonitrile, oxolane and water.Preferred solvent is a water.Behind chemical compound that adds general formula (IIa) and suitable solvent, preferably add excessive alkali.Typical alkali is following listed solution: the carbonate of sodium, lithium and potassium; The bicarbonate of sodium, lithium and potassium; And the hydroxide of sodium, lithium and potassium, preferably sodium hydroxide.Preferred alkali is potassium carbonate.Can heat solution E, to promote course of dissolution.

The preparation of solution F: suitable carbonylation agent is added in the container.Reinforced order can be carried out according to easy principle, and perhaps other technology Considerations of knowing according to the process chemistry those skilled in the art carry out.Carbonylation agent is carbonyl can be transferred on the chemical compound of general formula I I to obtain 3, the reagent of 4-two replacement-thiazolidine-2s-ketonic compound.Typical carbonylation agent is DMC dimethyl carbonate, diethyl carbonate, diphenyl carbonate, methylchloroformate, ethyl chloroformate, chloro-carbonic acid n-propyl, isopropyl chlorocarbonate, isobutyl chlorocarbonate, phosgene, triphosgene and N, N-carbonyl dimidazoles (CDI).Preferred reagent is N, N-carbonyl dimidazoles (CDI).Add after this reagent, add suitable solvent, for example: carbon tetrachloride, chloroform, dichloromethane, 1, the 1-dichloroethanes, oxolane, 1, the 3-diox, 1, the 4-diox, water, methanol, ethanol, normal propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutanol, furan, ether, glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethyl carbitol, the 2,2'-ethylenedioxybis(ethanol). diisopropyl ether, methoxybenzene, dimethyl formamide (DMF), dimethyl acetylamide (DMAC), N-Methyl pyrrolidone (NMP), Methanamide, the N-methylacetamide, the N-methylformamide, acetonitrile (ACN), dimethyl sulfoxine, propionitrile, sulfolane, N, N-dimethyl propylene amide and hexamethyl phosphoramide; Preferred solvent is acetonitrile, oxolane and water.Preferred solvent is an acetonitrile.Can will add in another solution in arbitrary solution, but preferably solution F be added in the solution E.

The formation of the chemical compound of general formula (IV) is preferably carried out under-20-40 ℃ temperature.The amount of carbonylation agent is determined according to the molar equivalent of the chemical compound of general formula I I usually, is preferably the 1.0-2.4 molar equivalent.Reaction is preferably monitored by HPLC.According to initial solvent and temperature, reaction was finished in 1-8 hour usually.Remove cosolvent by distillation.Arrive less than 5 with the pH regulator of aqueous acid, be preferably 1-3 gained solution.These acid include but not limited to: mineral acid, for example hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, nitric acid, phosphoric acid; Organic acid, for example formic acid, acetic acid, methanesulfonic acid, trifluoroacetic acid, propanoic acid, butanoic acid, valeric acid, caproic acid, oxalic acid.Other acid also can be the aqueous solution of sodium bisulfate, potassium acid sulfate, ammonium chloride, lithium hydrogen sulfate etc.Aqueous sulfuric acid preferably.Chemical compound with organic solvent such as methyl acetate, ethyl acetate and isopropyl acetate extraction general formula (IV).Preferred solvent is an isopropyl acetate.Can carry out crystallization to product, the reaction after perhaps the solution of the chemical compound of the logical formula V that will obtain is used for.Preferably with the solution drying, less than 0.1%, and then carry out above-mentioned arbitrary operation up to the water content of measuring

Compounds

The present invention also provides the chemical compound of general formula V:

Wherein R is alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, aryloxy group, heteroarylalkyl or heteroaryl, and they have or do not have substituent group;

R ₁And R ₂Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl, heteroaryl independently, they have or do not have substituent group; Perhaps R ₁And R ₂Be connected to form ring.

In one embodiment, the R of the chemical compound of general formula V is the aryl (for example p-methoxyphenyl) that replaces, R ₁And R ₂Be alkyl (for example methyl) independently.

The present invention also provides the chemical compound of general formula I,

R is alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl or heteroaryl in the formula, and they have or do not have substituent group; R ₃Be H, alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl, heteroaryl, they have or do not have substituent group; Prerequisite is R ₃Be not Me or-CH ₂PO (OMe) ₂

In an enforcement side, R ₃Be the alkyl of alkyl or replacement, wherein the hydrogen of alkyl can be by-OR ₅Replace, wherein R ₅Be H, alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl, heteroaryl or Si (R ₆) ₃, they have or do not have substituent group; R ₆Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl, heteroaryl or OR ₇, they have or do not have substituent group; R ₇Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl or heteroaryl, they have or do not have substituent group.

Above-claimed cpd is stable, and they can be final products, perhaps can be used as the process intermediate and is used to prepare other required product.

Further specify the present invention by the following examples, but these embodiment can not be limited to described detailed process with scope of the present invention.

Embodiment

Embodiment 1

(R)-and the preparation of 2-(4-methoxyl group-phenyl)-Thiazolidine-4-carboxylic acid (chemical compound of general formula III a): in the 22 liter of three neck round-bottomed flask that is equipped with internal temperature probe and mechanical agitator, add a hydration L-cysteine hydrochloride (500.0 grams, 2.85 mole), sodium acetate (260.0 grams, 3.17 moles) and 4.00 premium on currency.Stir this mixture, up to all L-cysteine dissolvings.The solution of preparation P-methoxybenzal-dehyde (426.0 grams, 3.13 moles) in 3.50 liters of ethanol adds in the reaction, and internal reaction temperature is remained on below 30 ℃.In the process that adds P-methoxybenzal-dehyde solution, reactant becomes dense condensed white serosity.After 30 minutes, in reaction, add 3.50 liters of ethanol.Continue to stir 1 hour, then by the isolated by filtration solid.Use 1.50 liters of these solids of washing with alcohol.This solid in 50 ℃ vacuum drying oven dry 48 hours.Obtain about 610 gram 2-(4-methoxyl group-phenyl)-Thiazolidine-4-carboxylic acids (productive rate is 90%). ¹H?NMR(300MHz，DMSO)δ7.41-7.31(m，4H)，6.93-6.83(m，4H)，5.56(s，1H)，5.42(s，1H)，4.23(dd，J＝6.7，4.4Hz，1H)，3.84(dd，J＝7.6，7.1Hz，1H)，3.73(s，3H)，3.71(s，3H)，3.37-3.23(m，2H)，3.16-3.00(m，2H)。

Embodiment 2

(R)-and the preparation of 3-sulfydryl-2-(4-methoxyl group-benzylamino)-propanoic acid (chemical compound of general formula I Ia): in the 22 liter of three neck round-bottomed flask that is equipped with internal temperature probe and mechanical agitator, add sodium borohydride (221.3 grams, 5.85 moles).The sodium hydroxide that adds 1.75 liters of 0.25M stirs mixture, up to evenly.Make solution be cooled to 0-5 ℃.2-(4-methoxyl group-phenyl)-Thiazolidine-4-carboxylic acid (350.0 grams, 1.46 moles) is dissolved in the K of 2.1 liter of 0.62 M ₂CO ₃In the aqueous solution.Gained solution is added in the sodium borohydride solution, simultaneously internal temperature is remained on below 30 ℃.Reaction stirred, analyzing demonstration up to HPLC does not have residual raw material (about 1 hour).Make reaction be cooled to 0 ℃, under agitation add 700 milliliters of glacial acetic acids.The final pH of reactant mixture is about 5.The white solid that filtration obtains, with 3 premium on currency and 2.5 liters of washing with alcohol, drying is 12 hours in 50 ℃ vacuum drying oven.Obtain about 240 gram 3-sulfydryl-2-(4-methoxyl group-benzylamino)-propanoic acid (productive rate is 68%). ¹H?NMR(300MHz，DMSO)δ7.32(d，8.9Hz，2H)，6.91(d，8.9Hz，2H)，3.87(AB，J _AB＝13.1Hz，Δv _AB＝18.5Hz，2H)，3.72(s，3H)，3.24(dd，J＝5.3，5.3Hz，1H)，2.76(d，J＝5.7Hz，2H)。

Embodiment 3

(R)-and the preparation of 3-(4-methoxyl group-benzyl)-2-oxo-Thiazolidine-4-carboxylic acid (chemical compound of general formula I V): in the 22 liter of three neck round-bottomed flask that is equipped with internal temperature probe and mechanical agitator, add 3-sulfydryl-2-(4-methoxyl group-benzylamino)-propanoic acid (400.0 grams, 1.66 mole), potassium carbonate (480.0 grams, 3.47 moles) and 2.80 premium on currency.Under agitation, this mixture 40 ℃ of heating, is become evenly up to mixture, be cooled to 20-25 ℃ then.Add N, acetonitrile (2.8 liters) solution of N-carbonyl dimidazoles (400.0 grams, 222.47 moles) remains below internal reaction temperature 30 ℃ simultaneously.React by the HPLC monitoring, show to react up to the raw material disappearance and finish.By removing acetonitrile with 80-100 holder distillation at 40 ℃.Add isopropyl acetate (200 milliliters), with the H of 150 milliliters of 3M ₂SO ₄PH regulator to 2 with mixture.Filter, separate two-phase mixture, azeotropic drying organic layer by distillation under atmospheric pressure.The final water content of measuring is less than 0.5%.Gained solution further dilutes with 1.8 liters of isopropyl acetates, the embodiment after being used for. ¹H?NMR(300MHz，DMSO)δ7.15(d，8.3Hz，2H)，6.88(d，8.3Hz，2H)，4.52(AB，J _AB＝15.5Hz，Δv _AB＝238.4Hz，2H)，4.31-4.24(m，1H)，3.71(s，3H)，3.67-3.59(m，1H)，3.36-3.28(m，1H)。

Embodiment 4

(R)-(-)-and the preparation of 3-(4-methoxyl group-benzyl)-2-oxo-Thiazolidine-4-carboxylic acid methoxyl group-methyl-amide (chemical compound of general formula V): isopropyl acetate solution (310.0 grams that in the 22 liter of three neck round-bottomed flask that is equipped with internal temperature probe and mechanical agitator, add 3-(4-methoxyl group-benzyl)-2-oxo-Thiazolidine-4-carboxylic acid, 1.16 mole, about 3 liters).Use nitrogen purging container, be cooled to 0 ℃.Add 4-methyl-morpholine (130.0 grams, 1.29 moles), simultaneously internal reaction temperature is remained on below 5 ℃.Drip pivalyl chloride (150.0 grams, 1.24 moles), make internal reaction temperature remain on below 5 ℃.Reactant was stirred 45 minutes at 0 ℃.Add N-methoxyl group-methylamine (78.0 grams, 1.28 moles), simultaneously internal reaction temperature is remained on below 5 ℃.By HPLC monitoring reaction, when being 4: 1, the ratio of product and raw material thinks that reaction finishes (behind the adding amine about 30 minutes).Use the HCl of 2.4 liters of 0.1M, 2.4 liters of saturated NaHCO then successively ₃Purging compound.Separate organic facies, be concentrated to 1.0 liters of final volumes by distillation.Begin to form post precipitation, adding 250 milliliters of normal heptane.With the mixture vigorous stirring.Cross filter solid, dry in 40 ℃ vacuum drying oven.Obtain about 250 gram 3-(4-methoxyl group-benzyl)-2-oxo-Thiazolidine-4-carboxylic acid methoxyl group-methyl-amide (productive rate is 70%). ¹H?NMR(300MHz，DMSO)δ7.15(d，8.9Hz，2H)，6.86(d，8.9Hz，2H)，4.49(AB，J _AB＝14.4Hz，Δv _AB＝387.9Hz，2H)，4.40(dd，J＝8.8，5.2Hz，1H)，3.79(s，3H)，3.46(dd，J＝11.0，8.5Hz，1H)，3.38(s，3H)，3.21(s，3H)，3.15(dd，J＝11.0，5.5Hz，1H)。 ¹³C?NMR(75MHz，DMSO)δ28.4，32.9，47.2，55.8，57.9，61.9，114.7，128.5，130.3，159.5，169.4，172.3；[α] ^26.5 _D-93.5? ⁰(c＝1.0 EtOH)。Can use described HPLC method to measure the enantiomeric purity of (R)-(-)-3-(4-methoxyl group-benzyl)-2-oxo-Thiazolidine-4-carboxylic acid methoxyl group-methyl-amide.

The chirality HPLC method that is used for (R)-(-)-N-(to methoxy-benzyl)-2-oxo-Thiazolidine-4-carboxylic acid methoxyl group-methyl-amide

Preparation mobile phase (ethanol/normal heptane, 1: 4)

In suitable containers, shift 200 milliliters of dehydrated alcohol and 800 milliliters of normal heptane.Fully mix.The volume of mobile phase that can regulate preparation is to adapt to the requirement of analyzing and testing.

Sample preparation

About 2 milligrams of INS-115751 are dissolved in 2 milliliters of dehydrated alcohol.

Instrument condition:

Instrument: the suitable gradient HPLC system that disposes UV-detector

Post: chiral technology company (Chiral Technologies Inc.)

25 centimetres of 0.46 centimetre of x of Chiralcel OD-H

Mobile phase A: ethanol/normal heptane (1: 4)

Detect: UV, 254 nanometers

30 ℃ of column temperatures

Volume injected: 10.0 microlitres

Flow velocity: 1.0 ml/min

Running time: 20 minutes

Acquisition time: 20 minutes

Relative retention value (RR): Chemical compound RT (minute) RR

(R)-(-)-amide 10.56 1.00

(S)-(+)-amide 9.64 0.91

Embodiment 5

(R)-and the preparation of 4-acetyl group-3-(4-methoxyl group-benzyl)-thiazolidine-2-ketone (chemical compound of general formula I): the THF solution that in the exsiccant three neck round-bottomed flasks that are equipped with internal temperature probe and mechanical agitator, adds the methylmagnesium-chloride of 0.805 liter of 3M.With this solution of nitrogen purging, be cooled to 0 ℃.In an independent flask, 3-(4-methoxyl group-benzyl)-2-oxo-Thiazolidine-4-carboxylic acid methoxyl group-methyl-amide (250.0 grams, 0.805 mole) is dissolved in 1.00 liters of dry THF.Gained solution is added in the solution of methylmagnesium-chloride, feed rate should make internal reaction temperature remain below 5 ℃.By HPLC monitoring reaction, when raw material disappears, think to react and finish.In the citric acid solution with 1.00 liter 10% of the slow adding of reactant mixture, feed rate should make temperature remain below 25 ℃.Dilute this mixture with 0.90 premium on currency.THF is removed in distillation under atmospheric pressure.With 2.5 liters of ethyl acetate extraction products.Separate organic facies, be concentrated into final volume and be about 800 milliliters, cool to room temperature.Add 16 liters of normal heptane and form suspension.Suspension was stirred 30 minutes.By isolated by filtration gained solid, drying is 12 hours in 40 ℃ vacuum drying oven.Obtain about 170 gram 4-acetyl group-3-(4-methoxyl group-benzyl)-thiazolidine-2-ketone (productive rate is 80%). ¹H?NMR(300MHz，DMSO)δ7.14(d，8.9Hz，2H)，6.88(d，8.9Hz，2H)，4.48(dd，J＝9.4，2.6Hz，1H)，4.27(AB，J _AB＝15.2Hz，Δv _AB＝267.3Hz，2H)，3.72(s，3H)，3.62(dd，J＝11.9，10.0Hz，1H)，3.37(dd，J＝11.8，2.6Hz，1H)，2.19(s，3H)。 ¹³C?NMR(75MHz，DMSO)δ26.9，27.9，47.2，55.8，66.0，114.7，129.1，130.0，159.4，171.7，205.1；[α] ^26.5 _D-56.0 ⁰(c＝1.39，EtOH)。

Embodiment 6

(R)-and dimethyl 2-(3-(4-methoxy-benzyl)-2-oxo Thiazolidine-4-yl)-2-oxoethyl phosphonate ester (chemical compound of general formula I): in the exsiccant three neck round-bottomed flasks that are equipped with internal temperature probe and mechanical agitator, add dimethyl methyl phosphonate (36.7 milliliters, 0.338 mole) and 0.5 liter of THF.Use nitrogen purging solution, be cooled to-70 ℃.Drip the solution of the n-BuLi of 126 milliliters of 2.55M, simultaneously internal reaction temperature is remained below-60 ℃.In an independent flask, 3-(4-methoxyl group-benzyl)-2-oxo-Thiazolidine-4-carboxylic acid methoxyl group-methyl-amide (50.0 grams, 0.161 mole) is dissolved in 300 milliliters of dry THF.Gained solution is added in the anionic solution of dimethyl methyl phosphonate, and feed rate should make internal reaction temperature remain below-60 ℃.By HPLC monitoring reaction, when raw material disappears, think to react and finish.In the citric acid solution with 50 milliliter 10% of the slow adding of reactant mixture, feed rate should make temperature remain below 5 ℃.Dilute this mixture with 0.35 premium on currency.THF is removed in distillation under atmospheric pressure.With 300 milliliters of ethyl acetate extraction products.Separate organic facies, add 250 milliliters of normal heptane and form suspension.Suspension was stirred 30 minutes.By isolated by filtration gained solid, drying is 12 hours in 40 ℃ vacuum drying oven.Obtain about 57 gram (R)-dimethyl 2-(3-(4-methoxy-benzyl)-2-oxo Thiazolidine-4-yl)-2-oxoethyl phosphonate esters (productive rate is 94%). ¹H?NMR(300MHz，DMSO)δ7.16(d，8.5Hz，2H)，6.89(d，8.5Hz，2H)，4.78(d，J＝15.2Hz，1H)，4.69-4.61(m，1H)，3.79-3.55(m，11H)，3.51-3.27(m，3H)。 ¹³CNMR(75MHz，DMSO)δ36.3，38.0，46.9，53.5，55.08，66.1，114.7，129.0，129.9，159.4，171.9，199.0；[α] ^25.0 _D-29.6 ⁰(c＝1.00，EtOH)。

Embodiment 7

(R)-4-((R)-9-(benzyloxy-5-hydroxyl ninth of the ten Heavenly Stems the-2-alkynes acyl group)-3-(4-methoxy-benzyl) thiazolidine-2-ketone (chemical compound of general formula I)

In round-bottomed flask, add the solution of the 16.8 milliliter 1.0Ms of MeMgBr (16.8 mM) in THF, this solution is cooled to 0 ℃.With 5.0 milliliters of THF dilution alkynes coupling material (R)-8-(benzyloxy) suffering-1-alkynes-4-alcohol (2.00 grams, 8.50 mMs), drip then.Make this solution be warming up to room temperature, kept 1 hour, and then be cooled to 0 ℃.The solution of preparation (R)-N-methoxyl group-3-(4-methoxy-benzyl)-N-methyl-2-oxo Thiazolidine-4-Methanamide (0.900 gram, 3.00 mMs) in 5 milliliters of THF is then 0 ℃ of dropping.Make solution be warmed up to room temperature, kept 2 hours, use 10% citric acid quencher then.After stirring 10 minutes, add EtOAc, separate organic layer.With the further aqueous layer extracted of EtOAc, the organic extract that merges with the salt water washing is used Na then ₂SO ₄Drying concentrates.Reactant is carried out chromatography---0-25%EtOAc/DCM, obtains light yellow oil matter---1.1 grams (2.23 mMs, 77%). ¹H?NMR(300MHz)δ： ¹H?NMR(300MHz，CDCl ₃)δ：7.35-7.26(m，5H)7.15(d，J＝8.5Hz，2H)，6.85(d，J＝8.5Hz，2H)，5.12(d，J＝15Hz，1H)，4.50(s，2H)，4.09(dd，J＝2.5，8.8Hz，1H)3.96(d，J＝15Hz，1H)，3.84(m，1H)，3.79(s，3H)，3.50(m，3H)，3.32(dd，J＝2.5，11.5Hz，1H)，2.66(dd，J＝4.5，17.7Hz，1H)，2.55(dd，J＝6.3，17.5Hz，1H)，2.34(d，J＝5.8Hz，1H)，1.7-1.4(m，6H)。

Embodiment 8

(R)-and the preparation of 2-benzylamino-3-sulfydryl-propanoic acid (chemical compound of general formula I Ia): use embodiment 1 and 2 described two-step methods, make 2-benzylamino-3-sulfydryl-propanoic acid, productive rate is 67%. ¹H?NMR(300MHz，DMSO)δ7.42-7.21(m，5H)，3.81(AB，J _AB＝13.5Hz，Δv _AB＝29.6Hz，2H)，3.17(dd，J＝5.6，5.6Hz，1H)，2.8-2.67(m，2H)。

Embodiment 9

(R)-and the preparation of 2-(3,4-dimethoxy-benzylamino)-3-sulfydryl-propanoic acid (chemical compound of general formula I Ia): use embodiment 1 and 2 described two-step methods, make 2,2-(3,4-dimethoxy-benzylamino)-3-sulfydryl-propanoic acid, productive rate is 80%. ¹H?NMR(300MHz，DMSO)δ7.01(s，1H)，6.86(s，2H)，3.84-3.66(m，2H)，3.72(s，3H)，3.70(s，3H)，3.05(dd，J＝5.5，5.5Hz，1H)，2.72-2.66(m，2H)。

Embodiment 10

(R)-and the preparation of 2-(4-fluoro-benzylamino)-3-sulfydryl-propanoic acid (chemical compound of general formula I Ia): use embodiment 1 and 2 described two-step methods, make 2,2-(4-fluoro-benzylamino)-3-sulfydryl-propanoic acid, productive rate is 66%. ¹H?NMR(300MHz，DMSO)δ7.46-7.37(m，2H)，7.20-7.08(m，2H)，3.83(AB，J _AB＝13.6Hz，Δv _AB＝27.5Hz，2H)，3.23(dd，J＝5.7，5.7Hz，1H)，2.77-2.73(m，2H)。

With complete, clear, simple and clear and definite term description the present invention and carry out and use mode of the present invention and method so that those skilled in the art in the invention can implement and use the present invention.Should be understood that the front described preferred implementation of the present invention, and, can change not departing under the scope of the invention that claims propose.Require to be construed to theme of the present invention in order to specifically note and to know, following claims are drawn a conclusion to this description.

Claims

1. method for preparing the chemical compound of general formula I I,

General formula I I

General formula III

R is alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl or heteroaryl in the formula, and they have or do not have substituent group;

N is the integer of 1-5.

2. method for preparing the chemical compound of general formula V,

General formula V

General formula I V

R ₁And R ₂Be connected to form ring.

3. method for preparing the chemical compound of general formula I,

General formula I

General formula V

R ₁And R ₂Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl or heteroaryl independently, they have or do not have substituent group; Or R ₁And R ₂Be connected to form ring;

R ₃Be H, alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl, heteroaryl ,-CH ₂PXR ₈R ₉Or-CH=PR ₁₀R ₁₁R ₁₂

X is O, S, does not perhaps exist;

4. method as claimed in claim 3 is characterized in that, described R ₃Be-CH ₂PXR ₈R ₉

5. method for preparing the chemical compound of general formula I,

General formula I

This method may further comprise the steps:

General formula III a general formula I Ia

General formula I V

(c) make chemical compound and the amine HNR of general formula I V ₁OR ₂Reaction, the chemical compound of formation general formula V, wherein R ₁And R ₂Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl or heteroaryl independently; Perhaps R ₁And R ₂Be connected to form ring;

General formula V

(d) make chemical compound and the organometallic reagent (R of general formula V ₃-M) reaction, the chemical compound of formation general formula I, wherein R ₃Be H, alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl, heteroaryl or-CH ₂PXR ₈R ₉, they have or do not have substituent group;

X is O, S, does not perhaps exist;

M is a metal.

6. method for preparing the chemical compound of general formula I,

General formula I

This method may further comprise the steps:

General formula III b general formula I Ib

R is alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl or heteroaryl in the formula; R ₄Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl or heteroaryl, they have or do not have substituent group;

General formula VII

General formula I V

General formula V

R in the formula ₃Be H, alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl, heteroaryl or-CH ₂PXR ₈R ₉, they have or do not have substituent group;

X is O, S, or does not exist;

R ₈And R ₉Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl, heteroaryl, alkoxyl, cycloalkyloxy, (heterocycle) oxygen base, aryloxy group, heteroaryloxy, alkyl amino, arylamino, cycloalkyl amino, (heterocycle) amino or heteroaryl amino independently, they have or do not have substituent group; M is a metal.

7. method for preparing the chemical compound of general formula I, it may further comprise the steps:

General formula I

General formula III c general formula I Ic

R ₆Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl, heteroaryl or OR ₇, they have or do not have substituent group; R ₇Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl or heteroaryl;

General formula VIII

(c) make the chemical compound deprotection of general formula VIII, form the chemical compound of general formula I X,

General formula I X

General formula I V

(e) make chemical compound and the amine HNR of general formula I V ₁OR ₂Reaction, the chemical compound of formation general formula V, R in the formula ₁And R ₂Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl or heteroaryl independently, they have or do not have substituent group; Perhaps R ₁And R ₂Be connected to form ring;

General formula V

(f) make chemical compound and the organometallic reagent R of general formula V ₃-M reaction, the chemical compound of formation general formula I,

General formula I

X is O, S, does not perhaps exist;

8. the chemical compound of a general formula V:

R ₁And R ₂Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl, heteroaryl independently, they have or do not have substituent group;

Perhaps R ₁And R ₂Be connected to form ring.

9. chemical compound as claimed in claim 8 is characterized in that, R is the aryl that replaces, R ₁And R ₂Be alkyl independently.

10. chemical compound as claimed in claim 9 is characterized in that, described chemical compound is (R)-(-)-3-(4-methoxyl group-benzyl)-2-oxo-Thiazolidine-4-carboxylic acid methoxyl group-methyl-amide.

11. the chemical compound of a general formula I:

X is O, S, does not perhaps exist;

R ₈And R ₉Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl, heteroaryl, alkoxyl, cycloalkyloxy, (heterocycle) oxygen base, aryloxy group, heteroaryloxy independently, alkyl amino, arylamino, cycloalkyl amino, (heterocycle) amino or heteroaryl amino, they have or do not have substituent group;

R ₁₀, R ₁₁And R ₁₂Be alkyl, cycloalkyl, cycloalkyl-alkyl, aralkyl, aryl, heteroarylalkyl or heteroaryl independently, they have or do not have substituent group;

Prerequisite is R ₃Be not Me or-CH ₂PO (OMe) ₂

12. chemical compound as claimed in claim 11 is characterized in that, described chemical compound is (R)-4-((R)-9-(benzyloxy)-5-hydroxyl ninth of the ten Heavenly Stems the-2-alkynes acyl group)-3-(4-methoxy-benzyl) thiazolidine-2-ketone.