CN101282924A

CN101282924A - Chiral 3-carbamoylmethyl-5-methyl hexanoic acids, key intermediates for the new synthesis of (S)-pregabalin

Info

Publication number: CN101282924A
Application number: CNA2006800340308A
Authority: CN
Inventors: V·K·坎萨尔; B·P·乔拉西亚; A·P·蒂瓦里
Original assignee: Teva Pharmaceutical Industries Ltd
Current assignee: Teva Pharmaceutical Industries Ltd
Priority date: 2005-09-19
Filing date: 2006-09-19
Publication date: 2008-10-08
Also published as: CN101268037A

Abstract

The invention encompasses the synthesis of (S)-(+)-3-(aminomethyl)-5- methylhexanoic acid, (S)-Pregabalin, via the intermediate, (3R)-5-methyl-3-(2-oxo-2{[(lR)- l-phenylethyl]amino} ethyl)hexanoic acid.

Description

Chirality 3-carbamyl ylmethyl-5-methylhexanoic acid is used to synthesize the key intermediate of (S)-Pu Ruijia Belling

The cross reference of related application

This application requires U.S. provisional application series Nos.60/718,689 (on September 19th, 2005 submitted); 60/754,392 (on December 27th, 2005 submitted); 60/763,593 (on January 30th, 2006 submitted); 60/752,434 (on December 20th, 2005 submitted); 60/753,220 (on December 21st, 2005 submitted); 60/763,696 (on January 30th, 2006 submitted); With the benefit of priority of 60/839,947 (on August 23rd, 2006 submitted), incorporate the present invention as a reference at this.

Technical field

The present invention includes, by intermediate, (3R)-5-methyl-3-(the 2-oxo-2{[(1R)-the 1-phenylethyl] amino } ethyl) synthetic (S)-(+) of caproic acid-3-(amino methyl)-5-methylhexanoic acid, (S)-Pu Ruijia Belling (Pregabalin).

Background of the present invention

(S)-the Pu Ruijia Belling, (S)-(+)-3-(amino methyl)-5-methylhexanoic acid is a kind of compound with following chemical structure,

Be also referred to as γ-An Jidingsuan or (S)-3-isobutyl-GABA.With trade(brand)name LYRICA

(S)-Pu Ruijia Belling of selling has been found and can have activated GAD (L-L-Glutamic decarboxylase).(S)-the Pu Ruijia Belling has the dose-dependently provide protection of epileptic seizures and is the CNS-active compound.(S)-and the Pu Ruijia Belling can be used for anticonvulsive agent treats, because it can activate GAD, promotes to produce GABA, and the latter is that a kind of main inhibitory nerve of brain transmits matter, discharges under 30% brain cynapse.(S)-the Pu Ruijia Belling has pain relieving, anticonvulsion and anxiety activity.

The several method that is used to synthesize (S)-Pu Ruijia Belling is known.For example, referring to future drugs, 24 (8), 862-870 (1999).A kind of in these methods provides in scheme 1.

Scheme 1

In scheme 1,3-isobutyl-pentanedioic acid, compound 2 handles to be converted to corresponding acid anhydrides, compound 3 by the backflow diacetyl oxide.Acid anhydrides and NH ₄The OH reaction obtains glutaryl amine, and compound 4 splits with (R)-1-phenyl ethyl amine, obtains (R)-phenylethyl amine salt of (R)-3-(formamyl ethyl)-5-methylhexanoic acid, compound 5.This salt combines with sour, discharges the R enantiomer, compound 6.At last, use Br ₂/ NaOH Hoffmann degraded provides (S)-Pu Ruijia Belling.The shortcoming of this method is need to separate two kinds of enantiomers, causes like this losing half product, makes technology cost height.

Several Stereoselective methods that are used to synthesize (S)-Pu Ruijia Belling are disclosed.For example, U.S. patent No.5,599,973 public uses stoichiometric (+)-4-methyl-5-phenyl-2-oxazolidone is as chirality aid preparation (the S)-Pu Ruijia Belling that can be recovered.But in general, restricted when this path is used to amplify, as long as because the required low temperature of reaction, the reagent of igniting, as, the use of butyllithium, side reaction and because low overall yield.Other method is disclosed in U.S. patent application publication No.2003/0212290, wherein discloses the alkene of cyano group-replacement, the asymmetric hydrogenation of compound 7, and to generate the cyano group precursor of (S)-3-(amino methyl)-5-methylhexanoic acid, compound 8 is as scheme 2.

Scheme 2

By the nitrile in the catalytic hydrogenation reducing compound 8, obtain (S)-Pu Ruijia Belling subsequently.Cyano group hexene acid esters starting raw material, compound 7 is by the preparation of 2 methyl propanal and vinyl cyanide people such as (, Bull.Chem.Soc.Jap., 58,3397 (1985)) Yamamoto.But disclosed method need be under high pressure carbon monoxide, when this scheme is applicable to scale production technology, produce serious problems.

G.M.Sammis waits the people at J.Am.Chem.Soc, and 125 (15), disclosed method is utilized the asymmetric catalysis of cyanide complex addition reaction among the 4442-43 (2003).This method is open to be applied to hydrocyanide at α with aluminium salen catalyzer, and the conjugate addition on the beta-unsaturated acyl amine is shown in scheme 3.TMSCN be it is said a kind of useful cyanide source that can be used for substituting HCN.This method is owing to using highly deleterious reagent not to be suitable for scale operation.In addition, last reduction step needs High Pressure Hydrogen, the difficulty when this only increases this scheme and is applicable to scale production technology.

Scheme 3

Silverman has reported a kind of easy to be synthetic of 3-alkyl-4-amino-acid compound in synthetic (1989,955) in 1989.Use 2-alkane olefin(e) acid ester as substrate, at α, the Michael addition on β-unsaturated compound is hydrogenated to amine moiety and makes a series of GABA analogues subsequently under the nitro-compound atmosphere pressures, shown in scheme 4 by Nitromethane 99Min..

Scheme 4

The further splitting step of compound 14 can be used for splitting the Pu Ruijia Belling.

Certainly, this causes losing 50% product.

Current research shows that cinchona alkaloid is extensively effective in the chirality organic chemistry.Many nitroolefins are reported in the tetrahydrofuran (THF) in the presence of cinchona alkaloid with propanedioic acid dimethyl or diethyl ester and handle so that optionally compound 15 of high enantiomer to be provided,

With its analogue.For example,, wait the people, J.Am.Chem.Soc, 126 (32), 9906-07 (2004) referring to H.Li.These catalyzer are obtained by quinine or Quinidine easily and the C-C key that allegedly is used for highly effectively on the synthetic meaning forms asymmetric title complex addition, shown in scheme 5.

Scheme 5

R ₃Represent several alkyl and aromatic yl group.Reaction range has extended to other nitroolefin and has adopted two (oxazoline) Mg (OTf) ₂Be used to prepare ABT-546.Referring to, for example, D.M.Barnes waits the people, J.Am.Chem.Soc, 124 (44), 13097-13105 (2002).

Other group has studied the new dual functional catalyst that has thiocarbamide part and amino group on the chirality skeleton of a class.Referring to T.Okino, wait the people, J.Am.Chem.Soc, 127 (1), 119-125 (2005).Based on the optionally catalysis Michael addition of nitroolefin of enantiomer, they can prepare a series of analogues of compound 15.

Therefore, this area need not have the novel method that is used for preparation (S)-Pu Ruijia Belling of above-mentioned shortcoming.

Summary of the present invention

In one embodiment, the present invention includes compound with structural formula 24

Wherein Ar is selected from naphthyl, the C of the phenyl of phenyl and replacement _6-10Aromatic group and R are straight or side chain C _1-4Alkyl, ester or carboxylic acid.

Wherein Ar is that phenyl and R are methyl, and the compound with structural formula 24 is corresponding to (the 3R)-5-methyl-3-with structural formula 24A (2-oxo-2{[(1R)-1-phenyl methyl] amino } ethyl) caproic acid.

In another embodiment, the present invention includes the compound with structural formula 24A of crystallized form.

In another embodiment, the present invention includes a kind of method that is used to prepare compound, comprising with structural formula 24: will have the Chiral Amine of structural formula 23,

Be selected from least a aromatic hydrocarbon, ether, halon, alcohol, ester, the organic solvent of alkane and ketone and alkali merge to obtain mixture; This mixture is cooled to about 10 degrees centigrade to-70 degrees centigrade approximately of temperature; In this mixture, add 3-isobutyl-Pyroglutaric acid with structural formula 22,

To obtain having the compound of structural formula 24; With from mixture, reclaim compound with structural formula 24, wherein Ar is selected from naphthyl, the C of phenyl and the phenyl that replaces _6-10Aromatic group and R are straight or side chain C _1-4Alkyl, ester or carboxylic acid.

In another embodiment, the present invention includes a kind of method that is used for preparation (S)-Pu Ruijia Belling, comprising: will have the Chiral Amine of structural formula 23,

Be selected from least a aromatic hydrocarbon, ether, halon, alcohol, ester, the organic solvent of alkane and ketone and alkali merge to obtain mixture; This mixture is cooled to about 10 degrees centigrade to-70 degrees centigrade approximately of temperature; In this mixture, add 3-isobutyl-Pyroglutaric acid with structural formula 22;

To obtain having the compound of structural formula 24; From mixture, reclaim compound with structural formula 24; The recovery compound that will have structural formula 24, water, ether, ammonia and basic metal merge down to obtain mixture for about 10 degrees centigrade to about-78 degrees centigrade in temperature; From this mixture, reclaim compound with structural formula 25;

The recovery compound and the bromine that will have structural formula 25, water and alkaline hydrated oxide merge to obtain alkaline mixt; Alkaline mixt is heated to about 60 degrees centigrade to about 85 degrees centigrade of temperature; Add strong inorganic acid in the alkalitropism mixture to obtain acidic mixture; Make acidic mixture and alkali reaction with obtain (S)-Pu Ruijia Belling and

S-Pu Ruijia Belling

Reclaim (S)-Pu Ruijia Belling; Wherein Ar is selected from naphthyl, the C of the phenyl of phenyl and replacement _6-10Aromatic group and R are straight or side chain C _1-4Alkyl, ester or carboxylic acid.

To obtain having the compound of structural formula 24; From mixture, reclaim compound with structural formula 24; The compound and the vitriol oil that will have structural formula 24 merge to obtain mixture; Mixture is remained on temperature to be descended about 10 hours to about 30 hours for about 0 degree centigrade to about 50 degrees centigrade; From this mixture, reclaim compound with structural formula 25;

S-Pu Ruijia Belling

Brief description of the drawings

Fig. 1 explanation (3R)-5-methyl-3-(the 2-oxo-2{[(1R)-the 1-phenylethyl] amino } ethyl) caproic acid ¹H-NMR spectrum.

Fig. 2 explanation (3R)-5-methyl-3-(the 2-oxo-2{[(1R)-the 1-phenylethyl] amino } ethyl) caproic acid ¹³C-NMR spectrum.

The IR spectrum of Fig. 3 explanation (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-phenylethyl] amino } ethyl) caproic acid.

The powder x-ray diffraction pattern of Fig. 4 explanation (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-phenylethyl] amino } ethyl) caproic acid.

Detailed description of the present invention

The invention provides according to the stereoselectivity of (S)-Pu Ruijia Belling of following scheme synthetic:

Scheme 6

(S)-the Pu Ruijia Belling

The present invention includes (3R)-5-methyl-3-with structural formula 24 (2-oxo-2{[(1R)-1-aryl-alkyl] amino } ethyl) caproic acid,

Wherein Ar is selected from naphthyl, the C of the phenyl of phenyl and replacement_6-10Aromatic group and R are straight or side chain C_1-4Alkyl, ester, or carboxylic acid.

Preferably, Ar is phenyl. Preferably, R is straight or side chain C_1-4Alkyl, more preferably, methyl.

Preferably, the phenyl of replacement is to use at least one alkoxyl, halogen, alkyl, carboxylic acid, or ester The phenyl group that replaces. Preferred alkoxyl phenyl is methoxyphenyl. Preferred halogenated phenyl is Chlorobenzene, bromobenzene, and fluorobenzene. Preferred alkylation phenyl is toluene or ethylo benzene.

Preferably, C_1-4Alkyl is methyl, ethyl, isopropyl, n-butyl, isobutyl group or t-butyl. More preferably, C_1-4Alkyl is methyl or ethyl, most preferably, and methyl.

Preferably, carboxylic acid substituent is-COOH-CH₂COOH，-CH(CH ₃) COOH or-C (CH₃) ₂COOH. Preferred ester is the methyl ester of more than one carboxylic acid substituents of enumerating, ethyl Ester, isopropyl esters, n-butyl ester, isobutyl group or t-butyl derivative.

If Ar is phenyl and R is methyl, the compound with structural formula 24 is (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-phenyl methyl] amino } ethyl) caproic acid 24A

Can be characterized by and be selected from following data:¹³C-NMR spectrum (CDCl₃, 75MHz), about 21.74, 22.15,22.61,24.12,24.87,30.85,38.1,40.47,43.38,48.88,126.0, 127.2,128.49,143.00,172.02 and the 176.66ppm place have the carbon geochemistry displacement;¹H-NMR spectrum (CDCl₃, 300MHz), about 0.84,1.19,1.44-1.46,1.63,2.27,5.09, 6.89-6.91,7.28 and the 11.65ppm place have the Hydrochemistry displacement; IR spectrum, about 3323, 3318.8,2955,1691.98,1638,1617,1566 and 761cm^-1The place has the peak. Have The compd A of structural formula 24 can further be characterized by and be selected from following data: basically as shown in Figure 2 ¹³C-NMR spectrum; Basically as shown in Figure 1¹H-NMR spectrum; Basically such as Fig. 3 institute The IR spectrum that shows.

The present invention also comprise separation (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-phenyl methyl] ammonia Base } ethyl) caproic acid 24A, be preferably crystal form. The crystal form of 24A can be characterized by to have about 4.3 °, 6.2 °, 6.8 °, 7.3 °, the peak at 10.3 ° and ° 2 θ places, 17.4 ° of 2 θ ± 0.2 Powder x-ray diffraction (" PXRD ") pattern. The crystal form of 24A can further be characterized by about 7.7 °, 8.2 °, 9.7 °, 11.3 °, 12.8 °, 13.9 °, 15.1 °, 15.7 °, 18.6 °, 19.1 °, 19.6 °, 20.9 °, 21.8 °, 22.4 ° and ° 2 θ places, 23.3 ° of 2 θ ± 0.2 X-ray powder diffraction peak. The crystal form of 24A can even further be characterized by basically such as Fig. 4 The powder x-ray diffraction pattern. In addition, the crystal form of 24A can have melting range about 95 and takes the photograph Family name's degree is to about 97 degrees centigrade.

The present invention also comprises having optical purity at least about 80% area (HPLC), preferably at least about 93 % area (HPLC), more preferably from about 99% (the 3R)-5-methyl-3-(2-to about 100% area (HPLC) Oxo-2{[(1R)-the 1-phenyl methyl] amino } ethyl) caproic acid 24A.

Compound with structural formula 24 can be by will having the Chiral Amine of structural formula 23,

Wherein Ar is selected from naphthyl, the C of the phenyl of phenyl and replacement_6-10Aromatic group and R are straight or side chain C_1-4Alkyl, ester, or carboxylic acid are selected from least a aromatic hydrocarbon, ether, halogenated hydrocarbon, alcohol, Ester, the organic solvent of alkane and ketone and alkali merge, to obtain mixture; This mixture is cold But to temperature about 0 degree centigrade to-70 degrees centigrade approximately; Has structural formula 22 with in mixture, adding 3-isobutylglutaric acid acid anhydride

Obtaining having the compound of structural formula 24,

From mixture, reclaim subsequently and prepare.

3-isobutylglutaric acid acid anhydride with structural formula 22 can be according to being disclosed in U.S. patent No.5, 616,793 method and making.

Chiral Amine with structural formula 23 is commercially available and preferably, primary amine. Preferably, primary amine choosing From 1R, the 2S-ephedrine, naphthyl-Alpha-Methyl ethylamine, the glycine methyl ester, methyl-benzyl amine or Chiral amino acid derivative. Preferably, primary amine is methyl-benzyl amine and more preferably (R)-methyl-benzyl Amine.

Preferably, aromatic hydrocarbon is C_6-8Aromatic hydrocarbon. Preferably, C_6-8The aromatics aromatic hydrocarbon is toluene, dimethylbenzene, Ethylo benzene, or cumene, more preferably, toluene. Preferably, ether is C_3-6Ether. Preferably, C_3-6Ether is uncle Butyl methyl ether, oxolane, Di Iso Propyl Ether, or Anaesthetie Ether, more preferably, oxolane. Preferably, halohydrocarbon is C_1-2Halogenated hydrocarbon. Preferably, C_1-2Halogenated hydrocarbon is dichloroethanes, carbon tetrachloride, Or chloroform, more preferably, carrene. Preferably, alcohol is C_1-4Alcohol. Preferably, C_1-4Alcohol is isopropyl Alcohol, ethanol, methyl alcohol or n-butanols, more preferably, the n-butanols. Preferably, ester is C_3-6Ester. Preferably, C_3-6Ester is ethyl acetate, isopropyl acetate, or isobutyl acetate, more preferably, ethyl acetate. Preferably, alkane is straight, side chain or ring-type C_5-7Alkane, more preferably, hexane, heptane, or hexamethylene Alkane, most preferably, heptane. Preferably, ketone is C_3-6Ketone. Preferably, C_3-6Ketone is acetone, the methyl isobutyl Base ketone, or methyl ethyl ketone, most preferably, acetone. Preferred organic solvent is toluene.

Preferably, alkali is organic base. Preferably, organic base is C_1-12Amine. Preferably, C_1-12Amine is selected from diethylamide, triethylamine, and two n-propyl group amine, diisopropylamine, tert-butylamine, three-n-butylamine, morpholine, piperidines, pyridine, and 4-dimethylaminopyridine, more preferably, C_1-12Amine is the 4-dimethyl Aminopyridine.

Preferably, before adding has the 3-isobutylglutaric acid acid anhydride of structural formula 22, mixture is cooled off To temperature about 0 degree centigrade to-60 degrees centigrade approximately. Preferably, the 3-isobutyl that has structural formula 22 in adding Before the base glutaric anhydride with mixture temperature about 0 degree centigrade to approximately-60 degrees centigrade lower keep at least about 1 hour, more preferably from about 1 hour to about 2 hours.

The order that merges reactive material when preparation has the compound of structural formula 24 can affect finally The purity of product and productive rate. Preferably, adding have structural formula 22 3-isobutylglutaric acid acid anhydride it Front Chiral Amine and the alkali that will have structural formula 23 merges.

Compound with structural formula 24 can pass through the known any side of those skilled in the art Method and reclaiming. These methods include, but not limited to extract organic phase so that acidity with aqueous alkali Product transforms salify and is acidified to such an extent that get back to acid product with inorganic acid water.

The compound with structural formula 24 that obtains by above-mentioned technology has optical purity at least About 80% area (HPLC), preferably at least about 93% area (HPLC), more preferably from about 99% to 100 % area (HPLC).

Have the compound of structural formula 24 can be optionally further by from being selected from least a ester, nitrile, ether, C _4-6Directly, side chain, or cyclic hydrocarbon, and C _6-10Crystallization in the organic solvent of aromatic hydrocarbon and purifying.Preferably, ester is C _3-6Ester.Preferably, C _3-6Ester is ethyl acetate or isopropyl acetate.Preferably, nitrile is C ₂Nitrile.Preferably, C ₂Nitrile is an acetonitrile.Preferably, ether is C _3-6Ether.Preferably, C _3-6Ether is methyl t-butyl ether.Preferably, C _6-10Aromatic hydrocarbon is C _7-9Aromatic hydrocarbon.Preferably, C _7-9Aromatic hydrocarbon is toluene or dimethylbenzene.Preferably, C _4-6Directly, side chain or cyclic hydrocarbon are hexanaphthene or hexane, more preferably, and hexanaphthene.Preferred mixture is dimethylbenzene and ethyl acetate, hexane and ethyl acetate, the mixture of one of hexanaphthene and ethyl acetate and toluene and ethyl acetate combination.Most preferred mixture is the mixture of toluene and ethyl acetate.Most preferably, solvent is a toluene.

The present invention further comprises a kind of method that is used for preparation (S)-Pu Ruijia Belling by following scheme:

(S)-the Pu Ruijia Belling

This method comprises that preparation has the compound of structural formula 24, and the compound that will have structural formula 24 changes into the compound with following structural formula 25;

The compound that will have structural formula 25 changes into (S)-Pregablin; And recovery (S)-Pu Ruijia Belling.

Preferably, the compound with structural formula 24 prepares by aforesaid method.

Compound with structural formula 24 can change into the compound with structural formula 25 by following steps: will have the compound of structural formula 24, and water, ether, ammonia and basic metal merge down to obtain mixture for about 10 degrees centigrade to about-78 degrees centigrade in temperature; With recovery compound 25 from this mixture.

Preferably, will have the compound of structural formula 24, water and ether merge to form first mixture, subsequently to wherein adding ammonia and basic metal.Preferably, will have the compound of structural formula 24, water and ether merge so that first mixture to be provided.Preferably, ammonia and basic metal add subsequently by first mixture.Preferably, have the compound of structural formula 24, water and ether merge down for about 10 degrees centigrade to about-78 degrees centigrade in temperature.

Preferably, will comprise the compound with structural formula 24, the mixture of water and ether and ammonia and basic metal are in temperature-40 degrees centigrade of extremely about 5 degrees centigrade of merging down approximately.

Preferably, ether is C _3-6Ether.Preferably, C _3-6Ether is tetrahydrofuran (THF) or dioxan.

Preferably, ammonia provides at the aqueous solution, that is, and and ammonium hydroxide.

Preferred basic metal is lithium or sodium.

Preferably, reaction mixture kept about 2 to about 10 hours, more preferably from about 6 to about 10 hours.

In addition, the compound with structural formula 24 can change into the compound with structural formula 25 by following steps: the compound and the vitriol oil that will have structural formula 24 merge to obtain mixture; Mixture is remained on temperature descended about 10 hours to about 30 hours and from this mixture, reclaimed compound for about 0 degree centigrade to about 50 degrees centigrade with structural formula 25.

Preferably, the vitriol oil comprise about 96% to about 100% volume sulfuric acid and about 0% to about 4% volume water, more preferably, about 100% volume sulfuric acid.

The preferred amounts of the vitriol oil is about 2 to about 70 molar equivalents, and more preferably, about 15 to about 25 molar equivalents and most preferably, and about 15 molar equivalents/molar equivalent has the compound of structural formula 24.

Preferably, if the amount of the vitriol oil is about 2 to have the compound of structural formula 24 to about 70 molar equivalents/molar equivalent, reaction remains under about 0 degree centigrade to about 50 degrees centigrade of the temperature.More preferably, if the amount of the vitriol oil is about 15 to have the compound of structural formula 24 to about 25 molar equivalents/molar equivalent, reaction remains on the about 250G of temperature under about 45 degrees centigrade, most preferably, if the amount of the vitriol oil is the compound that about 15 molar equivalents/molar equivalent has structural formula 24, reaction remains under about 35 degrees centigrade to about 40 degrees centigrade of the temperature.

Compound with structural formula 25 can reclaim by the known any method of those skilled in the art.These methods include, but are not limited to extraction, and are dry on the anhydrous sodium sulphate subsequently.

Have the compound of structural formula 25 can be optionally by from being selected from ester, direct sum branching C _1-4Crystallization in the polar organic solvent of alcohol and ether and purifying.Preferably, ester is C _3-6Ester.Preferably, C _3-6Ester is an ethyl acetate.Preferably, straight or side chain C _1-4Alcohol is ethanol, methyl alcohol, and Virahol, or butanols, more preferably, Virahol, or n-butanols and most preferably, n-butanols.Preferably, ether is C _3-6Ether.Preferably, C _3-6Ether is tetrahydrofuran (THF) or dioxan.Most preferred polar organic solvent is an ethyl acetate.

(R)-3-(carbamyl the ylmethyl)-5-methylhexanoic acid 25 that obtains by above crystallization processes has optical purity at least about 80% area (HPLC), preferably at least about 93% area (HPLC) and more preferably from about about 99% to about 100% area (HPLC).

(R)-and 3-(carbamyl ylmethyl)-5-methylhexanoic acid 25 can change into (S)-Pu Ruijia Belling by following steps: with (R)-3-(carbamyl ylmethyl)-5-methylhexanoic acid 25 and bromine, water and alkali hydroxide merge to form alkaline mixt; Alkaline mixt is heated to about 60 degrees centigrade to about 85 degrees centigrade of temperature; Strong inorganic acid is added alkaline mixt to obtain acidic mixture; Alkali is added acidic mixture; And recovery (S)-Pu Ruijia Belling.

Preferably, alkali hydroxide is selected from sodium hydroxide, potassium hydroxide, and lithium hydroxide and cesium hydroxide, more preferably, sodium hydroxide.

Preferably, alkali hydroxide and water are at first merged, and to obtain solution, add compound 25 and bromine subsequently.

Preferably, compound 25 is added in the solution under about 5 degrees centigrade to about 10 degrees centigrade of temperature.After adding compound 25, bromine is preferred, adds down for about 5 degrees centigrade to about 10 degrees centigrade in temperature.

Preferably, before adding strong inorganic acid, with C _4-8Alcohol adds alkaline mixt.Preferably, C _4-8Alcohol is selected from butanols, isopropylcarbinol, and the 2-butanols, amylalcohol and primary isoamyl alcohol, more preferably, isopropylcarbinol.Preferably, strong inorganic acid is selected from H ₂SO ₄, HCl, HBr and H ₃PO ₄, more preferably, HCl.Preferably, the adding of strong inorganic acid provides the two-phase system that comprises organic phase and water.

Preferably, alkali is added into organic phase.Alkali can be organic bases.Preferred organic bases is the second month in a season or tertiary amine.Preferably, secondary amine is diisopropylamine or dipropylamine, more preferably, and diisopropylamine.Preferably, tertiary amine is tributylamine or triethylamine, more preferably, and tributylamine.Alkali can be mineral alkali.Preferably, mineral alkali is alkali hydroxide or basic carbonate.Preferred alkali hydroxide includes, but not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide, and cesium hydroxide.More preferably, alkali hydroxide is a sodium hydroxide.Preferred basic carbonate includes, but not limited to yellow soda ash, sodium bicarbonate, and salt of wormwood.More preferably, basic carbonate is a yellow soda ash.Preferred mineral alkali is a basic carbonate, most preferably, and yellow soda ash.

The adding of alkali causes the precipitation of S-Pu Ruijia Belling.The throw out of S-Pu Ruijia Belling can reclaim by the known any method of those skilled in the art.These methods include, but not limited to filter this throw out, subsequent drying.

(the S)-Pu Ruijia Belling that obtains by above technology has optical purity about 93% to about 100% area (HPLC), and preferred about 99% to about 100% area (HPLC).

In addition, 3-isobutyl-Pyroglutaric acid 22 can be regenerated by following steps: will reclaim filtrate and acid merging that (S)-Pu Ruijia Belling obtains, to obtain first mixture; Heat first mixture to obtain having the 3-isobutyl-pentanedioic acid of following structural formula;

3-isobutyl-pentanedioic acid

3-isobutyl-pentanedioic acid and diacetyl oxide are merged to obtain second mixture; Heat second mixture to obtain 3-isobutyl-Pyroglutaric acid 22; With recovery 3-isobutyl-Pyroglutaric acid 22.

Preferably, acid is strong inorganic acid, more preferably 6N to 12N spirit of salt or 20% to 80% sulfuric acid.

Preferably, first mixture heats down for about 100 degrees centigrade to about 125 degrees centigrade in temperature.Preferably, if mineral acid is a spirit of salt, first mixture remains under about 100 degrees centigrade to about 105 degrees centigrade of the temperature.Preferably, if mineral acid is a sulfuric acid, first mixture remains under about 120 degrees centigrade to about 125 degrees centigrade of the temperature.

Preferably, second mixture of 3-isobutyl-pentanedioic acid and diacetyl oxide more preferably heats down for about 135 degrees centigrade to about 145 degrees centigrade in temperature under about 135 degrees centigrade to about 155 degrees centigrade of temperature.

3-isobutyl-Pyroglutaric acid with structural formula 22 can reclaim by the known any method of those skilled in the art.These methods include, but not limited to two further excessive acetic anhydride via and coolings.

Following indefiniteness example only is used to embodiment preferred of the present invention is described, and is not understood that to limit the present invention, and scope of the present invention is determined by appended claims.

Embodiment

Chirality HPLC analyzes

Instrument: Waters-2487

Post: chirality PACK AD-H, 250x4.6mm, 5 μ m

Mobile phase: the 2%TFA in n-hexane/ethanol-95/5

Flow velocity: 0.5ml/ minute

Temperature: 30 degrees centigrade

Wavelength: 210nm/UV visible spectrophotometer

¹H-NMR analyzes

F2-obtains parameter F 2-processing parameter

Instrument dpx 300

Probhd 5mm?Dual?Z5 SI 32768

Pulprog zg SF 300.1300069MHz

TD 16384 WDW EM

Solvent C DCl ₃SSB 0

NS 8 LB 0.01Hz

DS 0 GB 0

SWH 8992.806Hz PC 1.4

FIDRES 0.548877Hz

AQ 0.9110004sec

RG 16

DW 55.600μsec

DE 4.50μsec

TE 300.0K

D1 5 seconds

P1 11.35μsec

SFO1 300.1342018MHz

NUC1 1H

PL1 0dB

¹³C-NMR analyzes

F2-obtains parameter F 2-processing parameter

Instrument dpx 300

Probhd 5mm?Dual?Z5 SI 16384

Pulprog zgdc SF 75.4677595MHz

TD 16384 WDW EM

Solvent C DCl ₃SSB 0

NS 4959 LB 10.00Hz

DS 0 GB 0

SWH 18832.393Hz PC 1.4

FIDRES 1.149438Hz

AQ 0.4350452sec

RG 9195.2

DW 26.550μsec

DE 4.50μsec

TE 300.0K

D11 0.03 second

PL12 17.8Db

Cpdprg2 waltz?16

PCPD2 90.00μsec

SFO2 300.1330013MHz

NUC2 1H

PL2 0dB

D1 1 second

P1 9.4μsec

DE 4.5μsec

SFO1 75.4767751MHz

NUC1 13C

PL1 0dB

IR analyzes

The KBr pellet

Number of sample scans 16

Background scans several 16

Sweep parameter 4000-500cm ^-1

Resolving power 4

Sample increases by 8

Mirror speed 0.6329

Hole 100

X-ray analysis

Instrument SIEMENS model: D-5000

Copper ray 1.5406A

Sweep parameter 2-50 ° of 2 θ

0.03 ° of step scanning

0.5 second step time

Embodiment 1: and preparation (3R)-5-methyl-3-(the 2-oxo-2{[(1R)-the 1-phenylethyl] amino } ethyl) caproic acid compound (24)

Be furnished with feed hopper, thermometer pocket, the three-necked flask of drying tube and the mechanical stirrer toluene (400ml) of packing into, (R)-(+)-phenyl ethyl amine (38.59g, 0.0.319 mole) and 4-dimethylaminopyridine (0.358g, 0.0029 mole).Mixture is cooled to temperature-50 degree centigrade to-60 degrees centigrade, in 45-60 minute, add 3-isobutyl-Pyroglutaric acid (50g subsequently, 0.294 the solution in toluene (100ml) and stirred other 1.5-2 hour down to-60 degrees centigrade mole) in temperature-50 degree centigrade.Use the 3.5-4.0%NaOH aqueous solution (1000ml) to extract subsequently and water toluene (1x250ml) washing in mixture.The pH of water is adjusted to 2-2.5 by adding hydrochloric acid solution (1-12N).Water further uses ethyl acetate (1x300ml and 1x100ml) to extract, subsequently on anhydrous sodium sulphate with the ethyl acetate extract drying that merges with strip solvent to obtain resistates.Resistates crystallization from ethyl acetate and toluene mixture obtains 66g (77.2% productive rate) white solid (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl] amino } ethyl) caproic acid, and optical purity 99.91% is measured by chirality HPLC.

Embodiment 2: and preparation (3R)-5-methyl-3-(the 2-oxo-2{[(1R)-phenylethyl] amino } ethyl) caproic acid compound (24)

Be furnished with feed hopper, thermometer pocket, the three-necked flask of drying tube and the mechanical stirrer ethyl acetate (100ml) of packing into, (R)-(+)-phenyl ethyl amine (26.69g, 0.0.22 mole) and 4-dimethylaminopyridine (2.69g, 0.15. mole).Mixture is cooled to temperature-50 degree centigrade to-60 degrees centigrade, in 25-30 minute, add 3-isobutyl-Pyroglutaric acid (25g subsequently, 0.147 the solution in ethyl acetate (50ml) and stirred other 1.5-2 hour down to-60 degrees centigrade mole) in temperature-50 degree centigrade.Mixture uses the 5-4%NaOH aqueous solution (500ml) to extract subsequently, and water phase separated.The pH of water is adjusted to 2-2.5 by adding hydrochloric acid solution (1-12N).Water further uses ethyl acetate (1x150ml and 1x100ml) to extract, subsequently on anhydrous sodium sulphate with the ethyl acetate extract drying that merges with strip solvent to obtain resistates.Resistates crystallization from ethyl acetate and toluene mixture, obtain 35.43g (82.87% productive rate) white solid (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl] amino } ethyl) caproic acid, optical purity 99.4% is measured by chirality HPLC.

Embodiment 3: and preparation (3R)-5-methyl-3-(the 2-oxo-2{[(1R)-the 1-phenylethyl] amino } ethyl) caproic acid compound (24)

Be furnished with feed hopper, thermometer pocket, the three-necked flask of drying tube and the mechanical stirrer toluene (100ml) of packing into, (R)-(H-)-phenyl ethyl amine (35.58g, 0.294 mole) and 4-dimethylaminopyridine (0.18g, 0.00147 mole).Mixture is cooled to temperature 0-50 degree centigrade, in 15-20 minute, add subsequently 3-isobutyl-Pyroglutaric acid (25g, 0.147 mole) in toluene (25ml) solution and stirred other 1.5-2 hour down at temperature 0-5 degree centigrade.Mixture is used 2.5-3.0%NaHCO subsequently ₃The aqueous solution (500ml) extracts and water washs with toluene (1x100ml).The pH of water is adjusted to 2-2.5 by adding hydrochloric acid solution (1-12N).Water further uses ethyl acetate (1x150ml and 1x50ml) to extract, subsequently on anhydrous sodium sulphate with the ethyl acetate extract drying that merges with strip solvent to obtain resistates.Resistates crystallization from ethyl acetate and toluene mixture obtains 28.4g (66.4% productive rate) white solid (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl] amino } ethyl) caproic acid, and optical purity 99.6% is measured by chirality HPLC.

Embodiment 4: and preparation (3R)-5-methyl-3-(the 2-oxo-2{[(1R)-the 1-phenylethyl] amino } ethyl) caproic acid compound (24)

Be furnished with feed hopper, thermometer pocket, drying tube and mechanical stirrer) the three-necked flask t-butyl methyl ether (100ml) of packing into, (R)-(+)-phenyl ethyl amine (43.05g, 0.355 mole) and 4-dimethylaminopyridine (0.258g, 0.0021 mole).Mixture is cooled to temperature 0-5 degree centigrade, in 15-20 minute, add subsequently 3-isobutyl-Pyroglutaric acid (40g, 0.235 mole) in t-butyl methyl ether (100ml) solution and stirred other 1.5-2 hour down at temperature 0-5 degree centigrade.Mixture is used 5%NaHCO subsequently ₃The aqueous solution (700ml) extracts and water washs with t-butyl methyl ether (1x100ml).The pH of water is adjusted to 2-2.5 by adding hydrochloric acid solution (1-12N).Water further uses ethyl acetate (1x200ml) to extract, subsequently on anhydrous sodium sulphate with the ethyl acetate extract drying that merges with strip solvent to obtain resistates.Resistates crystallization from ethyl acetate and toluene mixture obtains 44.5g (70% productive rate) white solid (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl] amino } ethyl) caproic acid, and optical purity 99.19% is measured by chirality HPLC.

Embodiment 5: and preparation (3R)-5-methyl-3-(the 2-oxo-2{[(1R)-the 1-phenylethyl] amino } ethyl) caproic acid compound (24)

Be furnished with feed hopper, thermometer pocket, the three-necked flask of drying tube and the mechanical stirrer methylene dichloride (100ml) of packing into, (R)-(+)-phenyl ethyl amine (53.38g, 0.44 mole) and 4-dimethylaminopyridine (0.18g, 0.00147 mole).Mixture is cooled to temperature 0-5 degree centigrade, in 15-20 minute, add subsequently 3-isobutyl-Pyroglutaric acid (25g, 0.147 mole) in methylene dichloride (25ml) solution and stirred other 1.5-2 hour down at temperature 0-5 degree centigrade.Mixture is used 2.5-3%NaHCO subsequently ₃The aqueous solution (500ml) extracts, and water (1000ml) dilution, uses toluene (1x100ml and 1x50ml) washing water subsequently.The pH of water is adjusted to 2-2.5 by adding hydrochloric acid solution (1-12N).Water further uses ethyl acetate (1x150ml and 1x50ml) to extract, subsequently on anhydrous sodium sulphate with the ethyl acetate extract drying that merges with strip solvent to obtain resistates.Resistates crystallization from ethyl acetate and toluene mixture obtains 26.2g (61.3% productive rate) white solid (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl] amino } ethyl) caproic acid, and optical purity 99.41% is measured by chirality HPLC.

Embodiment 6: and preparation (3R)-5-methyl-3-(the 2-oxo-2{[(1R)-the 1-phenylethyl] amino } ethyl) caproic acid compound (24)

Be furnished with feed hopper, thermometer pocket, the three-necked flask of drying tube and the mechanical stirrer IPA (100ml) that packs into, (R)-(+)-phenyl ethyl amine (35.58g, 0.147 mole) and 4-dimethylaminopyridine (0.18g, 0.00147 mole).Mixture is cooled to temperature 0-5 degree centigrade, in 15-20 minute, add subsequently 3-isobutyl-Pyroglutaric acid (25g, 0.147 mole) in IPA (25ml) solution and stirred other 1.5-2 hour down at temperature 0-5 degree centigrade.Solvent is stripped and with resistates 2.5-3%NaHCO ₃The aqueous solution (500ml) extracts, and water (1000ml) dilution, uses toluene (1x100ml and 1x50ml) washing water subsequently.The pH of water is adjusted to 2-2.5 by adding hydrochloric acid solution (1-12N).Water further uses ethyl acetate (1x150ml and 1x50ml) to extract, subsequently on anhydrous sodium sulphate with the ethyl acetate extract drying that merges with strip solvent to obtain resistates.Resistates crystallization from ethyl acetate and toluene mixture obtains 25.2g (58.9% productive rate) white solid (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl] amino } ethyl) caproic acid, and optical purity 99.34% is measured by chirality HPLC.

Embodiment 7: and preparation (3R)-5-methyl-3-(the 2-oxo-2{[(1R)-the 1-phenylethyl] amino } ethyl) caproic acid compound (24)

Be furnished with feed hopper, thermometer pocket, the three-necked flask of drying tube and the mechanical stirrer ethyl acetate (100ml) of packing into, (R)-(+)-phenyl ethyl amine (35.58g, 0.147 mole) and 4-dimethylaminopyridine (0.18g, 0.00147 mole).Mixture is cooled to temperature 0-5 degree centigrade, in 15-20 minute, add subsequently 3-isobutyl-Pyroglutaric acid (25g, 0.147 mole) in ethyl acetate (25ml) solution and stirred other 1.5-2 hour down at temperature 0-5 degree centigrade.Solvent is stripped and with resistates 2.5-3%NaHCO ₃The aqueous solution (500ml) extracts, and water (1000ml) dilution, uses toluene (1x100ml and 1x50ml) washing water subsequently.The pH of water is adjusted to 2-2.5 by adding hydrochloric acid solution (1-12N).Water further uses ethyl acetate (1x150ml and 1x50ml) to extract, subsequently on anhydrous sodium sulphate with the ethyl acetate extract drying that merges with strip solvent to obtain resistates.Resistates crystallization from ethyl acetate and toluene mixture obtains 26.6g (61.5% productive rate) white solid (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl] amino } ethyl) caproic acid, and optical purity 99.3% is measured by chirality HPLC.

Embodiment 8: and preparation (3R)-5-methyl-3-(the 2-oxo-2{[(1R)-the 1-phenylethyl] amino } ethyl) caproic acid compound (24)

Be furnished with feed hopper, thermometer pocket, the three-necked flask of drying tube and the mechanical stirrer acetone (100ml) of packing into, (R)-(+)-phenyl ethyl amine (35.58g, 0.147 mole) and 4-dimethylaminopyridine (0.18g, 0.00147 mole).Mixture is cooled to temperature 0-5 degree centigrade, in 15-20 minute, add subsequently 3-isobutyl-Pyroglutaric acid (25g, 0.147 mole) in acetone (25ml) solution and stirred other 1.5-2 hour down at temperature 0-5 degree centigrade.Solvent is stripped and with resistates 2.5-3%NaHCO ₃The aqueous solution (500ml) extracts, and water (1000ml) dilution, uses toluene (1x100ml and 1x50ml) washing water subsequently.The pH of water is adjusted to 2-2.5 by adding hydrochloric acid solution (1-12N).Water further uses ethyl acetate (1x150ml and 1x50ml) to extract, subsequently on anhydrous sodium sulphate with the ethyl acetate extract drying that merges with strip solvent to obtain resistates.Resistates crystallization from ethyl acetate and toluene mixture obtains 24g (56% productive rate) white solid (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl] amino } ethyl) caproic acid, and optical purity 99.32% is measured by chirality HPLC.

Embodiment 9: and preparation (3R)-5-methyl-3-(the 2-oxo-2{[(1R)-the 1-phenylethyl] amino } ethyl) caproic acid compound (24)

Be furnished with feed hopper, thermometer pocket, the three-necked flask of drying tube and the mechanical stirrer hexane (100ml) of packing into, (R)-(+)-phenyl ethyl amine (35.58g, 0.147 mole) and 4-dimethylaminopyridine (0.18g, 0.00147 mole).Mixture is cooled to temperature 0-5 degree centigrade, in 15-20 minute, add subsequently 3-isobutyl-Pyroglutaric acid (25g, 0.147 mole) in hexane (25ml) solution and stirred other 1.5-2 hour down at temperature 0-5 degree centigrade.Mixture is used 2.5-3%NaHCO subsequently ₃The aqueous solution (500ml) extracts, and water (1000ml) dilution, uses toluene (1x100ml and 1x50ml) washing water subsequently.The pH of water is adjusted to 2-2.5 by adding hydrochloric acid solution (1-12N).Water further uses ethyl acetate (1x150ml and 1x50ml) to extract, subsequently on anhydrous sodium sulphate with the ethyl acetate extract drying that merges with strip solvent to obtain resistates.Resistates crystallization from ethyl acetate and toluene mixture obtains 22.2g (51.9% productive rate) white solid (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl] amino } ethyl) caproic acid, and optical purity 99.27% is measured by chirality HPLC.

Embodiment 10: and preparation (3R)-5-methyl-3-(the 2-oxo-2{[(1R)-the 1-phenylethyl] amino } ethyl) caproic acid compound (24)

Is furnished with feed hopper, pack into the mixture of hexanaphthene and toluene (100ml) prorate 1 to 1 of thermometer pocket, the three-necked flask of drying tube and mechanical stirrer, (R)-(+)-phenyl ethyl amine (35.58g, 0.147 mole) and 4-dimethylaminopyridine (0.18g, 0.00147 mole).Mixture is cooled to temperature 0-5 degree centigrade, in 15-20 minute, add 3-isobutyl-Pyroglutaric acid (25g subsequently, 0.147 the solution in hexanaphthene and 1: 1 mixture of toluene prorate (25ml) and stirred other 1.5-2 hour down mole) at temperature 0-5 degree centigrade.Use the 2.5-3.0%NaOH aqueous solution (500ml) to extract subsequently and water toluene (1x50ml) washing in mixture.The pH of water is adjusted to 2-2.5 by adding hydrochloric acid solution (1-12N).Water further uses ethyl acetate (1x150ml and 1x50ml) to extract, subsequently on anhydrous sodium sulphate with the ethyl acetate extract drying that merges with strip solvent to obtain resistates.Resistates crystallization from ethyl acetate and toluene mixture obtains 28.7g (67% productive rate) white solid (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl] amino } ethyl) caproic acid, and optical purity 99.34% is measured by chirality HPLC.

Embodiment 11: and preparation (3R)-5-methyl-3-(the 2-oxo-2{[(1R)-the 1-phenylethyl] amino } ethyl) caproic acid compound (24)

Be furnished with feed hopper, thermometer pocket, the three-necked flask of drying tube and the mechanical stirrer hexone (100ml) of packing into, (R)-(+)-phenyl ethyl amine (35.58g, 0.147 mole) and 4-dimethylaminopyridine (0.18g, 0.00147 mole).Mixture is cooled to temperature 0-5 degree centigrade, in 15-20 minute, add subsequently 3-isobutyl-Pyroglutaric acid (25g, 0.147 mole) in hexone (25ml) solution and stirred other 1.5-2 hour down at temperature 0-5 degree centigrade.Solvent is stripped and with resistates 2.5-3%NaHCO ₃The aqueous solution (500ml) extracts, and uses toluene (1x100ml and 1x50ml) washing water subsequently.The pH of water is adjusted to 2-2.5 by adding hydrochloric acid solution (1-12N).Water further uses ethyl acetate (1x150ml and 1x50ml) to extract, subsequently on anhydrous sodium sulphate with the ethyl acetate extract drying that merges with strip solvent to obtain resistates.Resistates crystallization from ethyl acetate and toluene mixture obtains 25.2g (58.9% productive rate) white solid (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl] amino } ethyl) caproic acid, and optical purity 99.3% is measured by chirality HPLC.

Embodiment 12: and preparation (3R)-5-methyl-3-(the 2-oxo-2{[(1R)-the 1-phenylethyl] amino } ethyl) caproic acid compound (24)

Be furnished with feed hopper, thermometer pocket, the three-necked flask of drying tube and the mechanical stirrer toluene (100ml) of packing into, (R)-(+)-phenyl ethyl amine (35.58g, 0.147 mole) and 4-dimethylaminopyridine (0.18g, 0.00147 mole).Mixture is cooled to temperature 0-5 degree centigrade, in 15-20 minute, add subsequently 3-isobutyl-Pyroglutaric acid (25g, 0.147 mole) in toluene (25ml) solution and stirred other 1.5-2 hour down at temperature 0-5 degree centigrade.Use the 2.5-3.0%NaOH aqueous solution (500ml) to extract subsequently and water toluene (1x50ml) washing in mixture.The pH of water is adjusted to 2-2.5 by adding hydrochloric acid solution (1-12N).Water further uses ethyl acetate (1x150ml and 1x50ml) to extract, subsequently on anhydrous sodium sulphate with the ethyl acetate extract drying that merges with strip solvent to obtain resistates.Resistates crystallization from ethyl acetate and toluene mixture obtains 29.3g (68.5% productive rate) white solid (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl] amino } ethyl) caproic acid, and optical purity 99.34% is measured by chirality HPLC.

Embodiment 13: and preparation (3R)-5-methyl-3-(the 2-oxo-2{[(1R)-the 1-phenylethyl] amino } ethyl) caproic acid compound (24)

Be furnished with feed hopper, thermometer pocket, the three-necked flask of drying tube and the mechanical stirrer methyl alcohol (100ml) of packing into, (R)-(+)-phenyl ethyl amine (35.58g, 0.147 mole) and 4-dimethylaminopyridine (0.18g, 0.00147 mole).Mixture is cooled to temperature 0-5 degree centigrade, in 15-20 minute, add subsequently 3-isobutyl-Pyroglutaric acid (25g, 0.147 mole) in methyl alcohol (25ml) solution and stirred other 1.5-2 hour down at temperature 0-5 degree centigrade.Solvent is stripped and with resistates 2.5-3%NaHCO ₃The aqueous solution (500ml) extracts, and water (1000ml) dilution, uses toluene (1x100ml and 1x50ml) washing water subsequently.The pH of water is adjusted to 2-2.5 by adding hydrochloric acid solution (1-12N).Water further uses ethyl acetate (1x150ml and 1x50ml) to extract, subsequently on anhydrous sodium sulphate with the ethyl acetate extract drying that merges with strip solvent to obtain resistates.Resistates crystallization from the mixture of ethyl acetate and toluene, obtain 22.2g (51.76% productive rate) white solid (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl] amino } ethyl) caproic acid, optical purity 99.1% is measured by chirality HPLC.

Embodiment 14: and preparation (3R)-5-methyl-3-(the 2-oxo-2{[(1R)-the 1-phenylethyl] amino } ethyl) caproic acid compound (24)

Be furnished with feed hopper, thermometer pocket, the three-necked flask of drying tube and the mechanical stirrer ethanol (100ml) of packing into, (R)-(+)-phenyl ethyl amine (35.58g, 0.147 mole) and 4-dimethylaminopyridine (0.18g, 0.00147 mole).Mixture is cooled to temperature 0-5 degree centigrade, in 15-20 minute, add subsequently 3-isobutyl-Pyroglutaric acid (25g, 0.147 mole) in ethanol (25ml) solution and stirred other 1.5-2 hour down at temperature 0-5 degree centigrade.Solvent is stripped and resistates is extracted with the 2.5-3%NaOH aqueous solution (500ml), and water (1000ml) dilution, uses toluene (1x100ml and 1x50ml) washing water subsequently.The pH of water is adjusted to 2-2.5 by adding hydrochloric acid solution (1-12N).Water further uses ethyl acetate (1x150ml and 1x50ml) to extract, subsequently on anhydrous sodium sulphate with the ethyl acetate extract drying that merges with strip solvent to obtain resistates.Resistates crystallization from the mixture of ethyl acetate and toluene, obtain 22.7g (53.09% productive rate) white solid (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl] amino } ethyl) caproic acid, optical purity 99.17% is measured by chirality HPLC.

Embodiment 15: and preparation (3R)-5-methyl-3-(the 2-oxo-2{[(1R)-the 1-phenylethyl] amino } ethyl) caproic acid compound (24)

Be furnished with feed hopper, thermometer pocket, the three-necked flask of drying tube and the mechanical stirrer n-butanols (100ml) of packing into, (R)-(+)-phenyl ethyl amine (35.58g, 0.147 mole) and 4-dimethylaminopyridine (0.18g, 0.00147 mole).Mixture is cooled to temperature 0-5 degree centigrade, in 15-20 minute, add subsequently 3-isobutyl-Pyroglutaric acid (25g, 0.147 mole) in n-butanols (25ml) solution and stirred other 1.5-2 hour down at temperature 0-5 degree centigrade.Solvent is stripped and resistates is extracted with the 2.5-3%NaOH aqueous solution (500ml), and water (1000ml) dilution, uses toluene (1x100ml and 1x50ml) washing water subsequently.The pH of water is adjusted to 2-2.5 by adding hydrochloric acid solution (1-12N).Water further uses ethyl acetate (1x150ml and 1x50ml) to extract, subsequently on anhydrous sodium sulphate with the ethyl acetate extract drying that merges with strip solvent to obtain resistates.

Resistates crystallization from the mixture of ethyl acetate and toluene, obtain 23.1g (54.03% productive rate) white solid (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl] amino } ethyl) caproic acid, optical purity 99.16% is measured by chirality HPLC.

Embodiment 16: preparation (R)-3-carbamyl ylmethyl-5-methylhexanoic acid compound (25)

Be furnished with mechanical stirrer, 2 liter of four neck flask of thermometer pocket and liquefied ammonia inlet packed into from 24 (7.5g, 0.0257 moles) of embodiment 1-13, tetrahydrofuran (THF) (112.5ml) and water (7.5ml).Reaction mixture is cooled to-40 degrees centigrade and adding liquefied ammonia (700ml), adds the sodium Metal 99.5 (2.5g) of small pieces subsequently.With gained reaction mixture vigorous stirring 6-10 hour, be evaporated until ammonia.Water (100ml) is at N ₂Add reaction mass down at 5-10 degree centigrade under the atmosphere, be separated subsequently.The pH of water uses spirit of salt to be adjusted to 1.5-1.7, uses methylene dichloride (2x250ml) to extract subsequently.The dichloromethane layer that merges is dry and solvent stripped on anhydrous sodium sulphate.Resistates is crystallization from ethyl acetate, obtain 1.89g (39.37% productive rate) (R)-3-formamyl ethyl-5-methylhexanoic acid, optical purity 99.81% is measured by chirality HPLC.

Compound 25 is characterized by:

1.IR (KBr): 3436.17,1712.53,1644.29cm ^-1.2. ¹H NMR (CDCl ₃): δ 0.89-0.90 (d, 6H), 1.24-1.26 (t, 2H), 1.63-1.72 (septet, 1H), 2.04-2.11 (d, 2H), 2.26-2.32 (d, 2H),, 6.50 (s, 1H), 6.94 (s, 1H) .3. ¹³C NMR (CDCl ₃): δ 21.79,22.02,22.61,24.27,29.62,37.86,38.82,39.48,42.71,174.39,174.83.

Embodiment 17: preparation (R)-3-carbamyl ylmethyl-5-methylhexanoic acid compound (25)

Be furnished with mechanical stirrer, 2 liter of four neck flask of thermometer pocket and liquefied ammonia inlet packed into from 24 (7.0g, 0.024 moles) of embodiment 1-13, tetrahydrofuran (THF) (70ml) and water (5ml).Reaction mixture is cooled to-40 degrees centigrade and adding liquefied ammonia (400ml), adds the metallic lithium (0.667g, 0.0962 mole) of small pieces subsequently.With gained reaction mixture vigorous stirring 6-10 hour, be evaporated until ammonia.Water (50ml) is at N ₂Add reaction mass down at 5-10 degree centigrade under the atmosphere, be separated subsequently.The pH of water uses spirit of salt to be adjusted to 1.5-1.7, uses ethyl acetate (1x150ml and 1x100ml) to extract subsequently.The ethyl acetate layer that merges is dry and solvent stripped on anhydrous sodium sulphate.Resistates is crystallization from ethyl acetate, obtain 2.66g (59.37% productive rate) (R)-3-carbamyl ylmethyl-5-methylhexanoic acid, optical purity 99.8% is measured by chirality HPLC.

Embodiment 18: preparation (R)-3-carbamyl ylmethyl-5-methylhexanoic acid compound (25)

The 250ml four neck flasks of being furnished with thermometer pocket and drying tube pack into the vitriol oil (36.4g, 0.37 mole) and 24 (2.0g, 0.0068 moles).Reaction mixture stirs down at 25-30 degree centigrade and spends the night, and use trash ice subsequently (150g) cancellation and stirring.Water extracts with ethyl acetate (1x150ml and 1x150ml), washes ethyl acetate layer and dry on anhydrous sodium sulphate at last subsequently with water.Solvent is stripped, and with product crystallization from ethyl acetate, obtain 0.5g (39% productive rate) (R)-3-carbamyl ylmethyl-5-methylhexanoic acid, optical purity 99.5% is measured by chirality HPLC.

Embodiment 19: regeneration 3-isobutyl-pentanedioic acid

Be furnished with mechanical stirrer, 0.5 liter of four neck flask of thermometer pocket and condenser packed into from secondary amide resistates (5g) after crystallization and the dense spirit of salt (100ml) of embodiment 1-13.Reaction mixture is at 100-105 degree centigrade of following backflow 20-24 hour, and is cooled to 20-25 degree centigrade subsequently.The pH of mixture is adjusted to 20% sodium hydroxide solution that the 10-11. water layer extracts with toluene (2x50ml) and the pH of water layer is adjusted to 1.5-2 with dense spirit of salt, uses methylene dichloride (2x50ml) extraction subsequently.The dichloromethane layer that merges is dry and solvent stripped on anhydrous sodium sulphate, obtain 3-isobutyl-pentanedioic acid (3.39g), purity 88.48% is measured by GC.

3-isobutyl-pentanedioic acid is characterized by:

1.IR (KBr): 1713.27cm ^-1.2. ¹HNMR (CDCl ₃): δ 0.89-0.92 (d, 6H), 1.25 (t, 2H), 1.6-1.69 (septet, 1H), 2.42 (s, 4H), 11.96 (s, 2H) .3. ¹³C NMR (CDCl ₃): δ 22.39,25.06,28.11,29.50,38.45,43.38,179.17.

Embodiment 20: regeneration 3-isobutyl-pentanedioic acid

Be furnished with mechanical stirrer, 0.5 liter of four neck flask of thermometer pocket and condenser packed into from secondary amide resistates (5g) after crystallization and 70% sulfuric acid (100ml) of embodiment 1-13.Reaction mixture is at 120-125 degree centigrade of following backflow 1-2 hour, and it is cooled to 20-25 degree centigrade subsequently, regulates pH to 10-11 with 20% sodium hydroxide solution subsequently.Water layer extracts with toluene (2x50ml) and the pH of water layer is adjusted to 1.5-2 with dense spirit of salt, and (2x50ml) extracts to use methylene dichloride subsequently.The dichloromethane layer that merges is dry and solvent stripped to obtain 3-isobutyl-pentanedioic acid (3.3g) on anhydrous sodium sulphate.

Embodiment 21: 3-isobutyl-pentanedioic acid is changed into 3-isobutyl-Pyroglutaric acid, compound 22

With mechanical stirrer, 1 liter of four neck flask of thermometer pocket and condenser pack into 3-isobutyl-pentanedioic acid (250g) and diacetyl oxide (62.7g).Reaction mixture distilled unreacted diacetyl oxide subsequently at 135-145 degree centigrade of following backflow 2.5-3 hour under 147-155 degree centigrade, and continued distillation subsequently to guarantee to remove the unreacted diacetyl oxide of trace under vacuum.Resistates is cooled to 25-30 degree centigrade to obtain 220-225g 3-isobutyl-Pyroglutaric acid.

Embodiment 22: preparation (S)-Pu Ruijia Belling

0.2 rise reactor pack into 60ml water and 17.65g NaOH.Solution is cooled to 10 to 15 degrees centigrade and adding 15g 25.Then, 15g Br ₂In 15 minutes, drip, keep temperature to be lower than 20 degrees centigrade simultaneously.Mixture heated 15 minutes down at 80 degrees centigrade, and was cooled to room temperature subsequently, that is, and and about 20 to about 25 degrees centigrade.32% the HCl aqueous solution that adds q.s is to provide pH 1.Solution is divided into two parts subsequently.

Part I extracts with the 37ml isopropylcarbinol, separates organic layer, and adds the Bu of q.s ₃N is to provide pH 4.(S)-and Pu Ruijia Belling precipitation, filter and wash with the 10ml isopropylcarbinol.Under vacuum, after the drying, obtain (S)-Pu Ruijia Belling at 55 degrees centigrade, white crystal, 71% productive rate.Optical purity: 97.2% area, HPLC.

Part II 37ml pentanol extraction separates organic layer, and adds the Bu of q.s ₃N is to provide pH 4.(S)-and Pu Ruijia Belling precipitation, filter and wash with the 10ml amylalcohol.Under vacuum, after the drying, obtain (S)-Pu Ruijia Belling at 55 degrees centigrade, white crystal, 73% productive rate.Optical purity: 93.1% area, HPLC.

Embodiment 23: preparation (S)-Pu Ruijia Belling

0.1 rise reactor pack into 60ml water and 17.6g NaOH.Solution is cooled to 10 to 15 degrees centigrade and adding 15g 25.Mixture is stirred and 15g Br ₂In 45 minutes, drip, keep temperature to be lower than 20 degrees centigrade simultaneously.Mixture heated 15 minutes down at 85 degrees centigrade, and was cooled to about 20 to about 25 degrees centigrade subsequently.Then, 12.4ml H ₂SO ₄With q.s add with pH is reduced to 1 and gained solution be divided into two parts.

Part I extracts with the 37ml isopropylcarbinol.Separate organic layer, and add the Bu of q.s ₃N is settled out (S)-Pu Ruijia Belling so that pH 4 to be provided, and filters and washs with the 10ml isopropylcarbinol.Under vacuum, after the drying, obtain (S)-Pu Ruijia Belling at 55 degrees centigrade, white crystal, 63% productive rate.Optical purity: 99.1% area, HPLC.

Part II 37ml pentanol extraction separates organic layer, and adds the Bu of q.s ₃N is to provide pH 4.(S)-and Pu Ruijia Belling precipitation, filter and wash with the 10ml amylalcohol.Under vacuum, after the drying, obtain (S)-Pu Ruijia Belling at 55 degrees centigrade, white crystal, 61% productive rate.Optical purity: 96.6% area, HPLC.

Embodiment 24: preparation (S)-Pu Ruijia Belling

0.2 rise reactor pack into 60ml water and 17.65g NaOH.Gained solution is cooled to 10 to 15 degrees centigrade and adding 15g 25.Then, 15g Br ₂In 15 minutes, drip, keep temperature to be lower than 20 degrees centigrade simultaneously.Mixture heated 15 minutes down at 80 degrees centigrade, and was cooled to room temperature subsequently, that is, and and about 20 to about 25 degrees centigrade.Then, add the 75ml isopropylcarbinol, and the 32%HCl aqueous solution of adding q.s is to provide pH 2.Separate organic phase and (S)-Pu Ruijia Belling and adding 14mlBu ₃Precipitation after the N.Mixture is cooled to 2 degrees centigrade, and with solid filtering, washing and 55 degrees centigrade dry under vacuum, 61% productive rate is provided.Optical purity: 98.7% area, HPLC.

Embodiment 25: preparation (S)-Pu Ruijia Belling

0.2 rise reactor pack into 60ml water and 17.65g NaOH.Solution is cooled to 10 to 15 degrees centigrade and adding 15g 25.Then, 15g Br ₂In 15 minutes, drip, keep temperature to be lower than 20 degrees centigrade simultaneously.Mixture heated 15 minutes down at 80 degrees centigrade, and was cooled to room temperature subsequently, that is, and and about 20 to about 25 degrees centigrade.Add the 75ml amylalcohol subsequently, the 32%HCl aqueous solution that adds q.s subsequently is to provide pH 2.Separate organic phase and (S)-Pu Ruijia Belling and adding 14ml Bu ₃Precipitation after the N.Mixture is cooled to 2 degrees centigrade subsequently, and with solid filtering, washing and 55 degrees centigrade dry under vacuum, 52% productive rate is provided.Optical purity: 96.9% area, HPLC.

Embodiment 26: preparation (S)-Pu Ruijia Belling

0.2 rise reactor pack into 110ml water and 27.65g NaOH.Solution is cooled to 10 to 15 degrees centigrade and adding 23.5g 25.Then, 23.5g Br ₂In 15 minutes, drip, keep temperature to be lower than 20 degrees centigrade simultaneously.Mixture heated 15 minutes down at 80 degrees centigrade, and was cooled to room temperature subsequently, that is, and and about 20 to about 25 degrees centigrade.32% the HCl aqueous solution that adds q.s is to provide pH 2.Mixture extracts with the 138ml isopropylcarbinol subsequently, and separates organic phase.(S)-the Pu Ruijia Belling at the diisopropyl ethyl amine that adds q.s to precipitate pH 4 is provided after.Mixture is cooled to 2 degrees centigrade, and with solid filtering, washing and 55 degrees centigrade dry under vacuum, 43% productive rate is provided.Optical purity: 98.4% area, HPLC.

Embodiment 27: preparation (S)-Pu Ruijia Belling

Reactor (0.2 liter) water of packing into (50ml), NaOH (14.7g).Solution is cooled to 10-15 degree centigrade and adding 25 (12.5g).When keeping temperature to be lower than 20 degrees centigrade, drip Br ₂(12.5g) (15min).Mixture heated under 80C 15 minutes and was cooled to room temperature subsequently.Add isopropylcarbinol (75ml), add 66%H subsequently ₂SO ₄Solution is to obtain pH 2.Separate organic phase, distillation (to volume 50ml), (S)-the Pu Ruijia Belling adding Bu ₃N (11.6ml) precipitates afterwards.Mixture is cooled to 2 degrees centigrade, and subsequently with solid filtering, washing and 55 degrees centigrade dry under vacuum, 81% productive rate is provided.Optical purity: 98.9% area, HPLC.

Realize above-described purpose although the present invention disclosed herein obviously is applicable to fully, be appreciated that those skilled in the art can design many modifications and embodiment.Therefore, claims mean that covering falls into all such modifications and the embodiment in true spirit of the present invention and the scope.

Claims

1. the compound that has structural formula 24

Wherein Ar is C _6-10Aromatic hydrocarbon radical is preferably selected from naphthyl, phenyl and the phenyl that replaces; With R be straight or side chain C _1-4Alkyl, ester or carboxylic acid.

2. according to the compound of claim 1, wherein Ar represents unsubstituted phenyl.

3. according to the compound of claim 1 or 2, wherein R is straight or side chain C _1-4Alkyl.

4. according to the compound of claim 3, wherein R represents methyl, ethyl, sec.-propyl, n-butyl, isobutyl-or t-butyl.

5. according to the compound of claim 4, wherein R represents methyl or ethyl.

6. according to the compound of claim 5, wherein R represents methyl.

7. according to the compound of the compound of any aforementioned claim, wherein Ar represents at least a alkoxyl group of phenyl, halogen, alkyl, carboxylic acid, and ester.

8. according to the compound of claim 7, wherein Ar represents p-methoxy-phenyl.

9. according to the compound of claim 7, wherein Ar represents chloro-phenyl-, bromophenyl or fluorophenyl.

10. according to the compound of claim 7, wherein Ar represents toluene or ethylbenzene.

11. according to the compound of claim 7, wherein Ar represent with at least one-COOH ₅-CH ₂COOH ,-CH (CH ₃) COOH and-C (CH ₃) ₂The phenyl that COOH replaces.

12. according to the compound of claim 7, wherein Ar represents usefulness-COOH ₅-CH ₂COOH ₅-CH (CH ₃) COOH or-C (CH ₃) ₂At least a methyl ester of COOH, ethyl ester, isopropyl esters, n-butyl ester, the phenyl that isobutyl and t-butyl ester derivative replace.

13., have optical purity at least about 93% area, in HPLC according to the compound of any aforementioned claim.

14., have about 99% to 100% area of optical purity, in HPLC according to the compound of claim 13.

15. according to the compound of claim 13, wherein Ar is that phenyl and R are methyl (structural formula 24A).

16., be characterized by and be selected from following data according to the compound of claim 15: ¹³C-NMR spectrum (CDCl ₃, 75MHz), about 21.74,22.15,22.61,24.12,24.87,30.85,38.1,40.47,43.38,48.88,126.0,127.2,128.49,143.00,172.02 and the 176.66ppm place have the carbon geochemistry displacement; ¹³C-NMR spectrum, basically as shown in Figure 2; ¹H-NMR spectrum (CDCl ₃, 300MHz), about 0.84,1.19,1.44-1.46,1.63,2.27,5.09,6.89-6.91,7.28 and the 11.65ppm place have the hydrogenation displacement study; ¹H-NMR spectrum, basically as shown in Figure 1; IR spectrum is about 3323,3318.8,2955,1691.98,1638,1617,1566 and 761cm ^-1The place has peak and as shown in Figure 3 IR spectrum basically.

17. the compound according to claim 15 or 16 of crystallized form.

18. according to the compound of arbitrary claim 15 to 17, be characterized by and have at about 4.3 °, 6.2 °, 6.8 °, 7.3 °, the PXRD pattern at the peak at 10.3 ° and ° 2 θ places, 17.4 ° of 2 θ ± 0.2.

19., further be characterized by and be selected from following data according to the compound of claim 18: at about 7.7 °, 8.2 °, 9.7 °, 11.3 °, 12.8 °, 13.9 °, 15.1 °, 15.7 °, 18.6 °, 19.1 °, 19.6 °, 20.9 °, 21.8 °, the X-ray powder diffraction peak at 22.4 ° and ° 2 θ places, 23.3 ° of 2 θ ± 0.2; The PXRD pattern, basically as shown in Figure 4; Melting range, about 95 degrees centigrade to about 97 degrees centigrade.

20. a method that is used to prepare the compound with structural formula 24 comprises:

(a) will have the Chiral Amine of structural formula 23,

Be selected from least a aromatic hydrocarbon, ether, halon, alcohol, ester, the organic solvent of alkane and ketone and alkali merge to obtain mixture;

(b) this mixture is cooled to about 10 degrees centigrade to-70 degrees centigrade approximately of temperature;

(c) in this mixture, add 3-isobutyl-Pyroglutaric acid with structural formula 22,

Obtain having the compound of structural formula 24,

(d) from mixture, reclaim compound with structural formula 24; Wherein Ar is selected from naphthyl, the C of the phenyl of phenyl and replacement _6-10Aromatic group and R are straight or side chain C _1-4Alkyl, ester or carboxylic acid.

21. according to the method for claim 20, wherein Ar represents phenyl.

22. according to the method for arbitrary claim 20 to 21, wherein R represents straight or side chain C _1-4Alkyl.

23. according to the method for claim 22, wherein R represents methyl, ethyl, sec.-propyl, n-butyl, isobutyl-or t-butyl.

24. according to the method for claim 23, wherein R represents methyl or ethyl.

25. according to the method for claim 24, wherein R represents methyl.

26. according to the method for arbitrary claim 20 to 25, wherein Ar represents at least a alkoxyl group of phenyl, halogen, alkyl, carboxylic acid, and ester.

27. according to the method for claim 26, wherein Ar represents p-methoxy-phenyl.

28. according to the method for claim 26, wherein Ar represents chloro-phenyl-, bromophenyl or fluorophenyl.

29. according to the method for claim 26, wherein Ar represents toluene or ethylbenzene.

30. according to the method for claim 26, wherein Ar represent with at least one-COOH ,-CH ₂COOH ,-CH (CH ₃) COOH and-C (CH ₃) ₂The phenyl that COOH replaces.

31. according to the method for claim 26, wherein Ar represents to use COOH ,-CH ₂COOH ,-CH (CH ₃) COOH or-C (CH ₃) ₂At least a methyl ester of COOH, ethyl ester, isopropyl esters, n-butyl ester, the phenyl of isobutyl and t-butyl ester derivative-replacement.

32. according to the method for arbitrary claim 20 to 31, wherein Chiral Amine is a primary amine.

33. according to the method for arbitrary claim 20 to 32, wherein Chiral Amine is selected from: 1R, 2S-ephedrine, naphthyl-Alpha-Methyl ethamine, glycine methyl ester, methylbenzylamine and chiral amino acid derivative.

34. according to the method for claim 33, wherein Chiral Amine is a methyl-benzyl amine.

35. according to the method for claim 34, wherein Chiral Amine is (R)-methyl-benzyl amine.

36. according to the method for arbitrary claim 20 to 35, wherein organic solvent is C _6-8Aromatic hydrocarbon.

37. according to the method for claim 36, wherein organic solvent is toluene or dimethylbenzene.

38. according to the method for arbitrary claim 20 to 35, wherein organic solvent is C _3-6Ether.

39. according to the method for claim 38, wherein organic solvent is selected from t-butyl methyl ether, THF, Di Iso Propyl Ether, and Anaesthetie Ether.

40. according to the method for arbitrary claim 20 to 35, wherein organic solvent is C _1-2Halon.

41. according to the method for claim 40, wherein organic solvent is a methylene dichloride.

42. according to the method for arbitrary claim 21 to 35, wherein organic solvent is to be selected from isopropyl alcohol, ethanol, the C of methyl alcohol and n-butanols _1-4Alcohol.

43. according to the method for arbitrary claim 21 to 35, wherein organic solvent is C _3-6Ester.

44. according to the method for claim 43, wherein organic solvent is selected from ethyl acetate, isopropyl acetate, and isobutyl acetate.

45. according to the method for arbitrary claim 21 to 35, wherein organic solvent is straight, side chain, or ring-type C ₅-C ₇Alkane.

46. according to the method for claim 45, wherein organic solvent is hexane or hexanaphthene.

47. according to the method for arbitrary claim 21 to 35, wherein organic solvent is C _3-6Ketone.

48. according to the method for claim 47, wherein organic solvent is selected from acetone, methyl iso-butyl ketone (MIBK), and methyl ethyl ketone.

49. according to the method for claim 48, wherein organic solvent is an acetone.

50. according to the method for arbitrary claim 20 to 49, wherein alkali is organic bases.

51. according to the method for claim 50, wherein alkali is C _1-12Amine.

52. according to the method for claim 51, wherein C _1-12Amine is selected from diethylamide, triethylamine, two n-propyl group amine, diisopropylamine, tert-butylamine morpholine, piperidines, pyridine, and 4-dimethylaminopyridine.

53. according to the method for claim 52, wherein organic bases is a 4-dimethylaminopyridine.

54. according to the method for arbitrary claim 20 to 53, wherein mixture is cooled to about 0 degree centigrade to-60 degrees centigrade approximately of temperature.

55. according to the method for claim 54, wherein before adding 3-isobutyl-Pyroglutaric acid, mixture kept about 1 hour to about 2 hours down for about 0 degree centigrade to about-60 degrees centigrade in temperature.

56. according to the method for arbitrary claim 20 to 55, the recovery compound that wherein has structural formula 24 has optical purity at least about 93%.

57. according to the method for claim 56, the recovery compound that wherein has structural formula 24 has optical purity about 99% to about 100% area, in HPLC.

58., further comprise by crystallization processes from being selected from ester, nitrile, ether, C according to the method for arbitrary claim 20 to 57 _4-6Directly, side chain or cyclic hydrocarbon, C _6-10The described recovery compound 24 of purifying in the organic solvent of aromatic hydrocarbon and its mixture.

59. according to the method for claim 58, wherein organic solvent is C _3-6Ester.

60. according to the method for claim 59, wherein C _3-6Ester is an ethyl acetate.

61. according to the method for claim 58, wherein organic solvent is an acetonitrile.

62. according to the method for claim 58, wherein organic solvent is C _2-6Ether.

63. according to the method for claim 62, wherein C _2-6Ether is methyl t-butyl ether.

64. according to the method for claim 61, wherein organic solvent is C _7-9Aromatic hydrocarbon.

65. the method for claim 64, wherein C _7-9Aromatic hydrocarbon is toluene or dimethylbenzene.

66. according to the method for claim 58, wherein mixture is dimethylbenzene and ethyl acetate, hexane and ethyl acetate, the mixture of one of hexanaphthene and ethyl acetate and toluene and ethyl acetate.

67. according to the method for claim 66, wherein mixture is the mixture of toluene and ethyl acetate.

68., comprise that further the compound that will have structural formula 24 changes into (S)-Pu Ruijia Belling according to the method for arbitrary claim 20 to 67.

69. according to the method for claim 71, the compound that wherein has structural formula 24 is converted to the compound with structural formula 25,

Be subsequently converted to (S)-Pu Ruijia Belling with the compound that will have structural formula 25.

70. method according to claim 69, the compound that wherein has structural formula 24 is converted to the compound with structural formula 25 by following steps: the method that will have structural formula 24, water, ether, ammonia and basic metal merge down to obtain mixture for about 10 degrees centigrade to about-78 degrees centigrade in temperature; With from this mixture, reclaim compound with structural formula 25.

71. according to the method for claim 70, wherein before adding ammonia and basic metal, will have the compound of structural formula 24, water and ether merge.

72. according to the method for claim 72, wherein ammonia and basic metal are added into the compound with structural formula 24, water, and ether for about 5 degrees centigrade in temperature under making an appointment with-40 degrees centigrade.

73. according to the method for arbitrary claim 70 to 72, wherein ether is C _2-6Ether.

74. according to the method for claim 73, wherein ether is tetrahydrofuran (THF) or dioxan.

75. according to the method for arbitrary claim 70 to 74, wherein ammonia is ammonia soln.

76. according to the method for arbitrary claim 70 to 75, wherein basic metal is lithium or sodium.

77. according to the method for claim 69, the compound that wherein has structural formula 24 is converted to the compound with structural formula 25 by following steps: the compound and the vitriol oil that a) will have structural formula 24 merge to obtain mixture; B) mixture is remained on temperature about 0 degree centigrade to about 50 degrees centigrade about 10 hours to about 30 hours down, and c) from this mixture recovery have the compound of structural formula 25.

78. according to the method for arbitrary claim 69 to 77, the compound that wherein has a structural formula 25 comprises having the compound and the bromine of structural formula 25 to the conversion of (S)-Pu Ruijia Belling, water and alkaline hydrated oxide merge to obtain alkaline mixt; Alkaline mixt is heated to about 60 degrees centigrade to about 85 degrees centigrade of temperature; Add strong inorganic acid in the alkalitropism mixture to obtain acidic mixture; Make acidic mixture and alkali reaction with obtain (S)-Pu Ruijia Belling and

S-Pu Ruijia Belling

Reclaim (S)-Pu Ruijia Belling;

79. 3 method according to Claim 8 is wherein before adding has the compound and bromine of structural formula 25, with alkaline hydrated oxide and hydration and to obtain solution.

80. according to the method for arbitrary claim 78 to 79, wherein alkaline hydrated oxide is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide and cesium hydroxide.

81. 0 method according to Claim 8, wherein alkaline hydrated oxide is a sodium hydroxide.

82. according to the method for arbitrary claim 78 to 81, the compound that wherein has a structural formula 25 is added into solution under about 5 degrees centigrade to about 10 degrees centigrade of temperature.

83. 2 method according to Claim 8, wherein after adding had the compound of structural formula 25, bromine was added into the solution of alkaline hydrated oxide and water.

84. 3 method according to Claim 8, the compound that wherein has a structural formula 25 are added into the solution of alkaline hydrated oxide and water under about 5 degrees centigrade to about 10 degrees centigrade of temperature.

85., wherein before adding strong inorganic acid, add C according to the method for arbitrary claim 78 to 84 _4-8Alcohol.

86. 5 method, wherein C according to Claim 8 _4-8Alcohol is selected from butanols, isopropylcarbinol, 2-butanols, amylalcohol and primary isoamyl alcohol.

87. 6 method, wherein C according to Claim 8 _4-8Alcohol is isopropylcarbinol.

88. according to the method for arbitrary claim 78 to 87, wherein strong inorganic acid is selected from H ₂SO ₄, HCl, HBr and H ₃PO ₄

89. 8 method according to Claim 8, wherein strong inorganic acid is HCl.

90. according to the method for arbitrary claim 78 to 89, wherein the adding of strong inorganic acid provides the two-phase system that comprises organic phase and water.

91. according to the method for claim 90, wherein alkali is added into organic phase.

92. according to the method for arbitrary claim 78 to 91, wherein alkali is organic bases.

93. according to the method for claim 92, wherein organic bases is the second month in a season or tertiary amine.

94. according to the method for claim 93, wherein secondary amine is diisopropylamine or dipropylamine.

95. according to the method for claim 94, wherein secondary amine is diisopropylamine.

96. according to the method for claim 93, wherein tertiary amine is tributylamine or triethylamine.

97. according to the method for claim 96, wherein tertiary amine is a tributylamine.

98. according to the method for arbitrary claim 78 to 91, wherein alkali is mineral alkali.

99. according to the method for claim 98, wherein mineral alkali is alkali hydroxide or basic carbonate.

100. according to the method for claim 99, wherein alkali hydroxide is a sodium hydroxide, potassium hydroxide, lithium hydroxide, or cesium hydroxide.

101. according to the method for claim 10,0 method, wherein alkali hydroxide is a sodium hydroxide.

102. according to the method for claim 99, wherein mineral alkali is a basic carbonate.

103. according to the method for claim 10,2 method, wherein basic carbonate is a yellow soda ash, sodium bicarbonate, or salt of wormwood.

104. according to the method for claim 10,3 method, wherein basic carbonate is a yellow soda ash.

105. the purposes of the described method of arbitrary claim 20 to 67 in making (S)-Pu Ruijia Belling.

106. the purposes of the described intermediate of arbitrary claim 1 to 19 in making (S)-Pu Ruijia Belling.