CN101198594A - Process for the production of intermadiates for the preparation of tricyclic benzimidazoles - Google Patents

Abstract

The invention relates to a process for the synthesis of compounds of the formula 1-a and compounds of the formula 1-b. The compounds of the formula 1-a and the compounds of the formula 1-b, in which the substituents R1, R2, R3, and Ar have the meanings indicated in the description, are valuable intermediates for the preparation of pharmaceutically active compounds.

Description

Be used to prepare the method for the intermediate of producing three ring benzimidazoless

Technical field

The present invention relates to intermediates preparation, this intermediate can be used for pharmaceutical industry with the preparation active compound, relates to some Application of Catalyst in described method, relates to the intermediate of described method preparation and relates to the active compound that can be used for medicine.

Background technology

(a) be used for the treatment of the application of the benzimidizole derivatives of gastrointestinal tract disorder: (it is corresponding to United States Patent (USP) 5 in European patent application EP 0266326,106,862) in, disclose the substituent benzimidizole derivatives with wide variations, it is considered to as anti-ulcerative drug is effective.In International Patent Application WO 97/47603 (it is corresponding to United States Patent (USP) 6,465,505), disclose and had specific substitution pattern benzimidizole derivatives, it is considered suitable for the gastric acid inhibitory secretion and can be used for prevention thus and the treatment inflammatory diseases of gastro-intestinal tract.

In International Patent Application WO 04/054984, the benzimidizole derivatives with different substituents is disclosed, it is considered to as anti-ulcerative drug is effective.

International Patent Application WO 04/087701 has been described the ring-type benzoglyoxaline, and its gastric acid inhibitory secretion also has good stomach and intestine protective value.The pharmaceutical active compounds of this type of enantiomer-pure is from the precursor preparation of enantiomer-pure, and this precursor can be obtained through asymmetric hydrogenation by the prochirality initial substance by using chiral hydrogenation catalyst.

International Patent Application WO 05/058893, WO05/103057, WO05/121139, WO06/037748 and WO06/037759 have described the three ring benzimidizole derivatives that have different substitution patterns on the heteronucleus structure, and the same gastric acid inhibitory secretion of this compounds also has good stomach and intestine protective value.

International Patent Application WO 05,/05 8325 has been described the tricyclic imidazopyridines derivative, and its gastric acid inhibitory secretion also has good stomach and intestine protective value.

This type of enantiopure compound is from the precursor preparation of enantiomer-pure, and this precursor can be obtained through asymmetric hydrogenation by the prochirality initial substance by using chiral hydrogenation catalyst.

International Patent Application WO 05/058894 has been described the synthetic of enantiomer-pure hydroxy intermediate, this intermediate can further be transformed into the pharmaceutical activity imidazopyridine derivatives, for example described in the WO05/058325.This enantiomer-pure hydroxy intermediate is to use chiral hydrogenation catalyst to be obtained through the asymmetric catalytic hydrogenation reaction by the prochiral ketones precursor.

(b) in the presence of homogeneous phase (homogenous) hydrogenation catalyst carbonyl compound to the asymmetric reduction of alcohols:

European patent application EP 0718265 discloses in the presence of homogeneous hydrogenation catalyst, alkali and organic compounds containing nitrogen carbonyl compound to the method for the asymmetric reduction of alcohols.More particularly, the system that is used for this conversion comprises the transition metal complex of VIII family metal (preferred Rh, Ru, Ir, Pd, Pt), the oxyhydroxide of basic metal or alkaline-earth metal or quaternary ammonium salt, and amine.When using optically-active two (diaryl phosphamide) (bis (diarylphosphane)) and two amine ligands, can carry out the reduction of carbonyl compound in asymmetric mode.The specific examples of the part that is fit to comprises BINAP (2,2 '-two (diphenylphosphino)-1,1 '-binaphthylyl), TolBINAP (2,2 '-two (two-4-tolyl phosphino-s)-1,1 '-binaphthylyl), H ₈BINAP (2,2 '-two (diphenylphosphino)-5,6,7,8,5 ', 6 ', 7 ', 8 '-octahydro-[1,1 ']-binaphthylyl), CHIRAPHOS (2,3-two (diphenylphosphino) butane), DPEN (1,2-diphenylethlene diamines), 1,2-dicyclohexyl ethylene diamine, DAMEN (1,1-two (4-anisyl)-2-methyl isophthalic acid, the 2-ethylene diamine), DAIBEN (1,1-two (4-anisyl)-2-isobutyl--1,2-ethylene diamine) and DAIPEN (1,1-two (4-anisyl)-2-sec.-propyl-1, the 2-ethylene diamine).In following specification sheets, the interior respectively general formula PP of part and the NN that belong to two (diaryl phosphamides) and two amine structure classes represent.

In typical test operation, carbonyl derivative is dissolved in the Virahol, hydrogenation in the presence of potassium hydroxide and homogeneous hydrogenation catalyst again (4-50atm hydrogen pressure, 28 ℃, 1-16 hour), it can form in position, for example by (S, S)-DPEN and RuCl ₂[(S)-BINAP] (DMF) _nThis method is described in greater detail in J.Am.Chem.Soc.1995, and 117,2675-2676, J.Am.Chem.Soc.1995,117,10417-10418, J.Am.Chem.Soc.1998,120, among 1086-1087 and patent application JP10273456 and the EP901997.

In the variation of this method, above-mentioned three-component system is RuXY[PP by general formula] the pure ruthenium complex of [NN] replaces, and wherein X and Y represent anion ligand, for example halogen or hydride, and [PP]/[NN] represents two (diaryl phosphamide)/two amine ligands.Complex compound RuCl ₂[(S)-BINAP] [(S, S)-DPEN] represent hydrogenation before-specific examples of catalyzer (pre-catalysts).The catalyst complex that use to form provides some advantages, and for example speed of response improves, productive rate is higher, the stability of air and moisture is improved.Synthetic and the application of these complex compounds is described in-especially-Angew.Chem.1998,110, among 1792-1796 and the patent application JP1189600.

Catalyst system RuXY[PP] scope of [NN] done abundant research.On the one hand, these effort cause the discovery of immobilization hydrogenation catalyst, and it can make catalyst recirculation, and make reaction be easier to handle (for example seeing WO02/062809, WO04/084834, US2004192543).On the other hand, find when alkali-free, to allow carbonyl compound (asymmetric) reductive catalyzer.These catalyzer (X=H, Y=BH ₄) can be easily by before corresponding-catalyzer (X=Y=Cl) prepares with sodium borohydride reduction, and is suitable for preparing the alcohols that contains acid labile group such as ester functional group.Synthetic and the application of these complex compounds is described among patent application US6720439, JP2003104993 and the JP2004238306.

RuCl ₂The hydrogenation catalyst of [PP] [NN] structure class, wherein [PP] is optically pure (replacement) BINAP derivative, and [NN] be optically pure 1,2-diamines, this hydrogenation catalyst have been used to have the ketone of a large amount of different functional groups and the asymmetric reduction of imines class.Yet, paid great efforts and differentiated hydrogenation catalyst with the different part of structure [PP] and [NN] (part that the typical case enumerates is for example seen for example Angew.Chem.2001,713,40-75 and WO05/007662).Part [PP] family has been found the asymmetric reduction that is particularly suitable for carbonyl compound, and the synthetic of this part [PP] family has been disclosed in Tetrahedron Lett.2002, and 43, among the 1539-1543.Contain and 1, the new part of 2-diamines combination [P-Phos (2,2 ', 6,6 '-tetramethoxy-4,4 '-two (diphenyl phosphine)-3,3 '-bipyridyl), Tol-P-Phos (2,2 ', 6,6 '-tetramethoxy-4,4 '-two [two (p-methylphenyl) phosphine]-3,3 '-bipyridyl), Xyl-P-Phos (2,2 ', 6,6 '-tetramethoxy-4,4 '-two [two (3, the 5-3,5-dimethylphenyl) phosphines]-3,3 '-bipyridyl)] hydrogenation catalyst RuCl ₂[PP] [NN], its preparation is described in J.Org.Chem.2002, and 67,7908-7910 and Chem.Eur.J.2003,9, among the 2963-2968.In addition, proved the aromatics of wide variations and enantio-selectivity that the heteroaromatic ketone can be good and be hydrogenated.Usually, in the presence of potassium tert.-butoxide, use substrate than the ratio of catalyzer (S/C than) up to 100.000: 1 and hydrogen pressure be 1bar to 400psi, these reactions are carried out in Virahol.New catalyzer, for example trans-RuCl ₂[(R)-Xy1-P-Phos] [(R, R)-DPEN], be considered to have good performance.

Disclosure of the Invention

Technical problem

The technical problem to be solved in the present invention provides the intermediates preparation that is used to prepare three ring benzimidizole derivatives enantiomorphs, and this three rings benzimidizole derivatives can be used for treatment.

Technical solution

Have now found that, (3R)-6-[3-aryl-3-hydroxypropyl]-7-hydroxyl-3H-benzimidizole derivatives can react by asymmetric catalytic hydrogenation, from corresponding prochiral ketones, use RuXY[(S)-Xyl-P-Phos] [(S)-DAIPEN] or RuXY[(S)-Xyl-BINAP] [(S)-and DAIPEN] prepare as hydrogenation catalyst.

Also find, (3S)-6-[3-aryl-3-hydroxypropyl]-7-hydroxyl-3H-benzimidizole derivatives can react by asymmetric catalytic hydrogenation, from corresponding prochiral ketones, use RuXY[(R)-Xyl-P-Phos] [(R)-DAIPEN] or RuXY[(R)-Xyl-BINAP] [(R)-and DAIPEN] prepare as hydrogenation catalyst.

Therefore (aspect a) relates to the method for preparation formula 1-a compound to first aspect present invention, it is included in hydrogenation catalyst and has catalytic hydrogenation formula 2 compounds down, this hydrogenation catalyst is selected from RuXY[(S)-Xyl-P-Phos] [(S)-DAIPEN] and RuXY[(S)-Xyl-BINAP] [(S)-DAIPEN]

Wherein

X and Y are the identical or different following substituting groups that is selected from: hydrogen, halogen, BH ₄And carboxylate,

And wherein

R1 is hydrogen, halogen, hydroxyl, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxyl group, 1-4C-alkoxyl group-1-4C-alkyl, 1-4C-alkoxy carbonyl, 2-4C-thiazolinyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxyl-1-4C-alkyl or single-or two-1-4C-alkylamino

R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxyl group, 1-4C-alkoxyl group-1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy carbonyl, list-or two-1-4C-alkylamino-1-4C-alkyl-carbonyl, hydroxyl-1-4C-alkyl, fluoro-2-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkyl, silyl 1-4C-alkoxyl group-1-4C alkyl, 1-4C-alkyl-carbonyl, aryl-CH of replacing ₂-oxygen carbonyl,

R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxy carbonyl, hydroxyl-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkyl, fluoro-1-4C-alkoxyl group-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkoxyl group, 1-4C-alkyl-carbonyl-amino, 1-4C-alkyl-carbonyl-N-1-4C-alkylamino, 1-4C-alkoxyl group-1-4C-alkyl-carbonyl-amino or group-CO-NR31R32

Wherein

R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl group-1-4C-alkyl, and

R32 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl group-1-4C-alkyl,

Perhaps wherein

R31 and R32 comprise the nitrogen-atoms of the two connection together, are pyrrolidyl, hydroxyl pyrrolidine base, '-aziridino, azetidine base, piperidino-(1-position only), piperazinyl, N-1-4C-alkylpiperazine base or morpholino group,

The list that Ar is replaced by R4, R5, R6 and R7-or the bicyclic aromatic residue, it is selected from phenyl, naphthyl, pyrryl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indyl, benzimidazolyl-, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, different  azoles base, pyridyl, pyrimidyl, quinolyl and isoquinolyl

Wherein

R4 is a hydrogen; the 1-4C-alkyl; hydroxyl-1-4C-alkyl; the 1-4C-alkoxyl group; 2-4C-alkene oxygen base; carboxyl; the 1-4C-alkoxy carbonyl; carboxyl-1-4C-alkyl; 1-4C-alkoxy carbonyl-1-4C-alkyl; 1-4C-alkoxyl group-1-4C-alkyl; aryloxy-1-4C-alkyl; halogen; hydroxyl; aryl; aryl-1-4C-alkyl; aryl-oxygen base; aryl-1-4C-alkoxyl group; trifluoromethyl; nitro; amino; single-or two-1-4C-alkylamino; the 1-4C-alkyl-carbonyl-amino; the 1-4C-alkoxycarbonyl amino; 1-4C-alkoxyl group-1-4C-alkoxycarbonyl amino or alkylsulfonyl

R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxyl group, 1-4C-alkoxy carbonyl, halogen, trifluoromethyl or hydroxyl,

R6 is hydrogen, 1-4C-alkyl or halogen, and

R7 is hydrogen, 1-4C-alkyl or halogen,

And wherein

Aryl be phenyl or by one, two or three identical or different are selected from the phenyl that following substituting group replaces: 1-4C-alkyl, 1-4C-alkoxyl group, carboxyl, 1-4C-alkoxy carbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxyl and cyano group.

The invention still further relates to according to aspect method a), wherein

R4 is a hydrogen; the 1-4C-alkyl; hydroxyl-1-4C-alkyl; the 1-4C-alkoxyl group; 2-4C-alkene oxygen base; carboxyl; the 1-4C-alkoxy carbonyl; carboxyl-1-4C-alkyl; 1-4C-alkoxy carbonyl-1-4C-alkyl; halogen; hydroxyl; aryl; aryl-1-4C-alkyl; aryl-oxygen base; aryl-1-4C-alkoxyl group; trifluoromethyl; nitro; amino; single-or two-1-4C-alkylamino; the 1-4C-alkyl-carbonyl-amino; the 1-4C-alkoxycarbonyl amino; 1-4C-alkoxyl group-1-4C-alkoxycarbonyl amino or alkylsulfonyl

And other substituting group definition as mentioned above.

The invention still further relates to according to aspect method a), wherein

R4 is 1-4C-alkoxyl group-1-4C-alkyl or aryloxy-1-4C-alkyl

And other substituting group definition as mentioned above.

Second aspect present invention (aspect b) further relates to the method for preparation formula 1-b compound, it is included in hydrogenation catalyst and has catalytic hydrogenation formula 2 compounds down, this hydrogenation catalyst is selected from RuXY[(R)-Xyl-P-Phos] [(R)-DAIPEN] and RuXY[(R)-Xyl-BINAP] [(R)-DAIPEN]

Wherein

X and Y are the identical or different following substituting groups that is selected from: hydrogen, halogen, BH ₄And carboxylate,

And wherein

R1 is hydrogen, halogen, hydroxyl, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxyl group, 1-4C-alkoxyl group-1-4C-alkyl, 1-4C-alkoxy carbonyl, 2-4C-thiazolinyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxyl-1-4C-alkyl or single-or two-1-4C-alkylamino

R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxyl group, 1-4C-alkoxyl group-1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy carbonyl, list-or two-1-4C-alkylamino-1-4C-alkyl-carbonyl, hydroxyl-1-4C-alkyl, fluoro-2-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkyl, silyl 1-4C-alkoxyl group-1-4C alkyl, 1-4C-alkyl-carbonyl, aryl-CH of replacing ₂-oxygen carbonyl,

R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxy carbonyl, hydroxyl-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkyl, fluoro-1-4C-alkoxyl group-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkoxyl group, 1-4C-alkyl-carbonyl-amino, 1-4C-alkyl-carbonyl-N-1-4C-alkylamino, 1-4C-alkoxyl group-1-4C-alkyl-carbonyl-amino or group-CO-NR31R32

Wherein

R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl group-1-4C-alkyl, and

R32 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl group-1-4C-alkyl,

Perhaps wherein

R31 and R32 comprise the nitrogen-atoms of the two connection together, are pyrrolidyl, hydroxyl pyrrolidine base, '-aziridino, azetidine base, piperidino-(1-position only), piperazinyl, N-1-4C-alkylpiperazine base or morpholino group,

The list that Ar is replaced by R4, R5, R6 and R7-or the bicyclic aromatic residue, it is selected from phenyl, naphthyl, pyrryl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indyl, benzimidazolyl-, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, different  azoles base, pyridyl, pyrimidyl, quinolyl and isoquinolyl

Wherein

R4 is a hydrogen; the 1-4C-alkyl; hydroxyl-1-4C-alkyl; the 1-4C-alkoxyl group; 2-4C-alkene oxygen base; carboxyl; the 1-4C-alkoxy carbonyl; carboxyl-1-4C-alkyl; 1-4C-alkoxy carbonyl-1-4C-alkyl; 1-4C-alkoxyl group-1-4C-alkyl; aryloxy-1-4C-alkyl; halogen; hydroxyl; aryl; aryl-1-4C-alkyl; aryl-oxygen base; aryl-1-4C-alkoxyl group; trifluoromethyl; nitro; amino; single-or two-1-4C-alkylamino; the 1-4C-alkyl-carbonyl-amino; the 1-4C-alkoxycarbonyl amino; 1-4C-alkoxyl group-1-4C-alkoxycarbonyl amino or alkylsulfonyl

R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxyl group, 1-4C-alkoxy carbonyl, halogen, trifluoromethyl or hydroxyl,

R6 is hydrogen, 1-4C-alkyl or halogen, and

R7 is hydrogen, 1-4C-alkyl or halogen,

And wherein

Aryl be phenyl or by one, two or three identical or different are selected from the phenyl that following substituting group replaces: 1-4C-alkyl, 1-4C-alkoxyl group, carboxyl, 1-4C-alkoxy carbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxyl and cyano group.

The invention still further relates to according to aspect b) method, wherein

R4 is a hydrogen; the 1-4C-alkyl; hydroxyl-1-4C-alkyl; the 1-4C-alkoxyl group; 2-4C-alkene oxygen base; carboxyl; the 1-4C-alkoxy carbonyl; carboxyl-1-4C-alkyl; 1-4C-alkoxy carbonyl-1-4C-alkyl; halogen; hydroxyl; aryl; aryl-1-4C-alkyl; aryl-oxygen base; aryl-1-4C-alkoxyl group; trifluoromethyl; nitro; amino; single-or two-1-4C-alkylamino; the 1-4C-alkyl-carbonyl-amino; the 1-4C-alkoxycarbonyl amino; 1-4C-alkoxyl group-1-4C-alkoxycarbonyl amino or alkylsulfonyl

And other substituting group definition as mentioned above.

The invention still further relates to according to aspect b) method, wherein

R4 is 1-4C-alkoxyl group-1-4C-alkyl or aryloxy-1-4C-alkyl

And other substituting group definition as mentioned above.

Halogen in the implication of the present invention is bromine, chlorine and fluorine.

1-4C-alkyl represent straight chain or ramose alkyl, it has 1 to 4 carbon atom.The example of mentioning is butyl, isobutyl-, sec-butyl, the tertiary butyl, propyl group, sec.-propyl, ethyl and methyl.

The 3-7C-cycloalkyl is represented cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl, and wherein cyclopropyl, cyclobutyl and cyclopentyl are preferred.

A kind of above-mentioned 1-4C-alkyl of 3-7C-cycloalkyl-1-4C-alkyl represent, it is by a kind of above-mentioned 3-7C-cycloalkyl substituted.The example of mentioning is cyclopropyl methyl, cyclohexyl methyl and cyclohexyl ethyl.

The 1-4C-alkoxyl group is represented a group, and it also contains a kind of above-mentioned 1-4C-alkyl except Sauerstoffatom.The example of mentioning is butoxy, isobutoxy, sec-butoxy, tert.-butoxy, propoxy-, isopropoxy, and preferred oxyethyl group and methoxyl group.

A kind of above-mentioned 1-4C-alkyl of 1-4C-alkoxyl group-1-4C-alkyl represent, it is replaced by a kind of above-mentioned 1-4C-alkoxyl group.The example of mentioning is methoxymethyl, methoxy ethyl and butoxyethyl group.

1-4C-alkoxy carbonyl (1-4C-alkoxy-C O-) is represented a carbonyl, connects a kind of above-mentioned 1-4C-alkoxyl group on it.The example of mentioning is methoxycarbonyl (CH ₃O-C (O)-), ethoxy carbonyl (CH ₃CH ₂O-C (O)-) and tert-butoxycarbonyl.

On behalf of straight chain or ramose, the 2-4C-thiazolinyl have the thiazolinyl of 2 to 4 carbon atoms.The example of mentioning is crotyl, 3-butenyl, 1-propenyl and 2-propenyl (allyl group).

On behalf of straight chain or ramose, the 2-4C-alkynyl have the alkynyl of 2 to 4 carbon atoms.The example of mentioning is 2-butyne base, 3-butynyl and preferred 2-propynyl (propargyl).

A kind of above-mentioned 1-4C-alkyl of fluoro-1-4C-alkyl represent, it is replaced by one or more fluorine atoms.The example of mentioning is trifluoromethyl, difluoromethyl, 2-fluoro ethyl, 2,2-two fluoro ethyls or 2,2,2-trifluoroethyl.

A kind of above-mentioned 1-4C-alkyl of hydroxyl-1-4C-alkyl represent, it is replaced by hydroxyl.The example of mentioning is methylol, 2-hydroxyethyl and 3-hydroxypropyl.Hydroxyl-1-4C-alkyl in the scope of the invention is interpreted as and comprises the 1-4C-alkyl that is replaced by one or more hydroxyls.The example of mentioning is 3,4--dihydroxy butyl, and especially 2, the 3-dihydroxypropyl.

Single-or two-1-4C-alkylamino represent an amino, it is identical or different from above-mentioned 1-4C-alkyl replacement by one or two.The example of mentioning is dimethylamino, diethylin and diisopropylaminoethyl.

Single-or two-1-4C-alkylamino-1-4C-alkyl-carbonyl represent a 1-4C-alkyl-carbonyl, its coverlet-or two-1-4C-alkylamino replacement.The example that can mention is dimethylamino-methyl carbonyl and dimethylamino-ethyl carbonyl.

Fluoro-2-4C-alkyl of 2-4C-alkyl represent, it is replaced by one or more fluorine atoms.The example that can mention is 2,2, the 2-trifluoroethyl.

1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkyl of 1-4C alkyl represent that silyl replaces, it is replaced by silyl.Wherein silyl is to have connected three identical or different substituent Siliciumatoms that are selected from the 1-4C-alkyl or aryl.The example of mentioning is 2-(trimethyl silyl)-ethoxyl methyl, (phenyl dimetylsilyl) methoxymethyl or 1-[2-(trimethyl silyl) oxyethyl group] ethyl.

Aryl-CH ₂-oxygen carbonyl is represented a CH ₂-oxygen carbonyl (CH ₂-O-C (O)), it is replaced by above-mentioned aryl.The example that can mention is a carbobenzoxy-(Cbz).

1-4C-alkoxyl group-1-4C-alkoxyl group is represented a kind of above-mentioned 1-4C-alkoxyl group, and it is replaced by other 1-4C-alkoxyl group.The example of mentioning is group 2-(methoxyl group)-oxyethyl group (CH ₃-O-CH ₂-CH ₂-O-) and 2-(oxyethyl group) oxyethyl group (CH ₃-CH ₂-O-CH ₂-CH ₂-O-).

A kind of above-mentioned 1-4C-alkoxyl group of 1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkyl represent-1-4C-alkyl, it is replaced by a kind of above-mentioned 1-4C-alkoxyl group.The example that can mention is group 2-(methoxyl group) ethoxyl methyl (CH ₃-O-CH ₂-CH ₂-O-CH ₂-).

A kind of above-mentioned 1-4C-alkyl of fluoro-1-4C-alkoxyl group-1-4C-alkyl represent, it is replaced by fluoro-1-4C-alkoxyl group.Fluoro-1-4C-alkoxyl group is represented a kind of above-mentioned 1-4C-alkoxyl group at this moment, and it is replaced by one or more fluorine atoms.The example of the 1-4C-alkoxyl group of the fluoro-replacement that can mention is a 2-fluoro-oxyethyl group, 1,1,1,3,3,3-hexafluoro-2-propoxy-, 2-trifluoromethyl-2-propoxy-, 1,1,1-three fluoro-2-propoxy-, perfluoro-tert.-butoxy, 2,2,3,3,4,4,4-seven fluoro-1-butoxy, 4,4,4-three fluoro-1-butoxy, 2,2,3,3,3-five fluorine propoxy-, perfluor oxyethyl group, 1,2, the 2-trifluoro ethoxy, especially 1,1,2,2-tetrafluoro oxyethyl group, 2,2,2-trifluoro ethoxy, trifluoromethoxy, and preferred difluoro-methoxy.The example of the fluoro that can mention-1-4C-alkoxyl group-1-4C-alkyl group is 1,1,2,2-tetrafluoro ethoxyl methyl, 2,2,2-trifluoro ethoxy methyl, trifluoromethoxy methyl, 2-fluorine ethoxyethyl group, 1,1,2,2-tetrafluoro ethoxyethyl group, 2,2,2-trifluoro ethoxy ethyl, trifluoromethoxy ethyl, and preferred difluoro-methoxy methyl and difluoro-methoxy ethyl group.

1-4C-alkyl-carbonyl-N-1-4C-alkylamino is represented a 1-4C-alkylamino, connects the 1-4C-alkyl-carbonyl on it.The example of mentioning is propionyl-N-methylamino-(C ₃H ₇C (O) NCH ₃-) and ethanoyl-N-methylamino-(CH ₃C (O) NCH ₃-).

1-4C-alkoxyl group-1-4C-alkyl-carbonyl-amino is represented a 1-4C-alkyl-carbonyl-amino, connects the 1-4C-alkoxyl group on it.The example of mentioning is methoxyl group-propionamido (CH ₃O-C ₃H ₆C (O) NH-) and methoxyl group-kharophen (CH ₃O-CH ₂C (O) NH-).

The 1-7C-alkyl represent has the straight chain or the ramose alkyl of 1 to 7 carbon atom.The example of mentioning is heptyl, different heptyl (5-methyl hexyl), hexyl, isohexyl (4-methyl amyl), new hexyl (3, the 3-dimethylbutyl), amyl group, isopentyl (3-methyl butyl), neo-pentyl (2, the 2-dimethyl propyl), butyl, isobutyl-, sec-butyl, the tertiary butyl, propyl group, sec.-propyl, ethyl and methyl.

The group Ar that can mention for example is following substituting group: 4-acetoxyl group phenyl; the 4-acetylamino phenyl; the 2-p-methoxy-phenyl; the 3-p-methoxy-phenyl; the 4-p-methoxy-phenyl; 3-benzyloxy phenyl; 4-benzyloxy phenyl; 3-benzyloxy-4-p-methoxy-phenyl; 4-benzyloxy-3-p-methoxy-phenyl; 3; 5-two (trifluoromethyl) phenyl; the 4-butoxy phenyl; the 2-chloro-phenyl-; the 3-chloro-phenyl-; the 4-chloro-phenyl-; 2-chloro-6-fluorophenyl; 3-chloro-4-fluorophenyl; 2-chloro-5-nitrophenyl; 4-chloro-3-nitrophenyl; 3-(4-chlorophenoxy) phenyl; 2; the 4-dichlorophenyl; 3; the 4-difluorophenyl; 2; the 4-dihydroxy phenyl; 2; the 6-Dimethoxyphenyl; 3; 4-dimethoxy-5-hydroxy phenyl; 2; the 5-3,5-dimethylphenyl; 3-oxyethyl group-4-hydroxy phenyl; the 2-fluorophenyl; the 4-fluorophenyl; the 4-hydroxy phenyl; 2-hydroxyl-5-nitrophenyl; 3-methoxyl group-2-nitrophenyl; the 3-nitrophenyl; 2; 3; the 5-trichlorophenyl; 2; 4; 6-trihydroxy-phenyl; 2; 3; the 4-trimethoxyphenyl; 2-hydroxyl-1-naphthyl; 2-methoxyl group-1-naphthyl; 4-methoxyl group-1-naphthyl; 1-methyl-2-pyrryl; the 2-pyrryl; 3-methyl-2-pyrryl; 3; 4-dimethyl-2-pyrryl; 4-(2-methoxycarbonyl ethyl)-3-methyl-2-pyrryl; 5-ethoxy carbonyl-2; 4-dimethyl-3-pyrryl; 3; 4-two bromo-5-methyl-2-pyrryl; 2; 5-dimethyl-1-phenyl-3-pyrryl; 5-carboxyl-3-ethyl-4-methyl-2-pyrryl; 3; 5-dimethyl-2-pyrryl; 2; 5-dimethyl-1-(4-trifluoromethyl)-3-pyrryl; 1-(2; 6-dichlor-4-trifluoromethyl phenyl)-the 2-pyrryl; 1-(2-oil of mirbane methyl)-2-pyrryl; 1-(2-fluorophenyl)-2-pyrryl; 1-(4-Trifluoromethoxyphen-l)-2-pyrryl; 1-(2-oil of mirbane methyl)-2-pyrryl; 1-(4-ethoxy carbonyl)-2; 5-dimethyl-3-pyrryl; 5-chloro-1; 3-dimethyl-4-pyrazolyl; 5-chloro-1-methyl-3-trifluoromethyl-4-pyrazolyl; 1-(4-chlorophenylmethyl)-5-pyrazolyl; 1; 3-dimethyl-5-(4-chlorophenoxy)-4-pyrazolyl; 1-methyl-3-trifluoromethyl-5-(3-4-trifluoromethylphenopendant)-4-pyrazolyl; 4-methoxycarbonyl-1-(2; the 6-dichlorophenyl)-the 5-pyrazolyl; 5-allyl group-Oxy-1-methyl-3-trifluoromethyl-4-pyrazolyl; 5-chloro-1-phenyl-3-trifluoromethyl-4-pyrazolyl; 3; 5-dimethyl-1-phenyl-4-imidazolyl; 4-bromo-1-methyl-5-imidazolyl; 2-butyryl radicals imidazolyl; 1-phenyl-1; 2; 3-triazole-4-base; the 3-indyl; the 4-indyl; the 7-indyl; 5-methoxyl group-3-indyl; 5-benzyloxy-3-indyl; 1-phenmethyl-3-indyl; 2-(4-chloro-phenyl-)-3-indyl; 7-benzyloxy-3-indyl; 6-benzyloxy-3-indyl; 2-methyl-5-nitro-3-indyl; 4; 5; 6; 7-tetrafluoro-3-indyl; 1-(3; 5-difluoro phenmethyl)-the 3-indyl; 1-methyl-2-(4-trifluoromethoxy phenoxy base)-3-indyl; 1-methyl-2-benzimidazolyl-; 5-nitro-2-furyl; 5-methylol-2-furyl; the 2-furyl; the 3-furyl; 5-(2-nitro-4-trifluoromethyl)-2-furyl; 4-ethoxy carbonyl-5-methyl-2-furyl; 5-(2-Trifluoromethoxyphen-l)-2-furyl; 5-(4-methoxyl group-2-nitrophenyl)-2-furyl; 4-bromo-2-furyl; 5-dimethylamino-2-furyl; 5-bromo-2-furyl; 5-sulfo--2-furyl; the 2-benzofuryl; the 2-thienyl; the 3-thienyl; 3-methyl-2-thienyl; 4-bromo-2-thienyl; 5-bromo-2-thienyl; 5-nitro-2-thienyl; 5-methyl-2-thienyl; 5-(4-p-methoxy-phenyl)-2-thienyl; 4-methyl-2-thienyl; 3-phenoxy group-2-thienyl; 5-carboxyl-2-thienyl; 2; 5-two chloro-3-thienyls; 3-methoxyl group-2-thienyl; the 2-benzothienyl; 3-methyl-2-benzothienyl; 2-bromo-5-chloro-3-benzothienyl; the 2-thiazolyl; 2-amino-4-chloro-5-thiazolyl; 2; 4-two chloro-5-thiazolyls; 2-ethylamino-5-thiazolyl; 3-methyl-different  the azoles of 4-nitro-5-base; the 2-pyridyl; the 3-pyridyl; the 4-pyridyl; 6-methyl-2-pyridyl; 3-hydroxyl-5-methylol-2-methyl-4-pyridyl; 2; 6-two chloro-4-pyridyl; 3-chloro-5-trifluoromethyl-2-pyridyl; 4; 6-dimethyl-2-pyridyl; 4-(4-chloro-phenyl-)-3-pyridyl; 2-chloro-5-methoxyl group-carbonyl-6-methyl-4-phenyl-3-pyridyl; 2-chloro-3-pyridyl; 6-(3-4-trifluoromethylphenopendant)-3-pyridyl; 2-(4-chlorophenoxy)-3-pyridyl; 2,4-dimethoxy-5-pyrimidyl; the 2-quinolyl; the 3-quinolyl; the 4-quinolyl; 2-chloro-3-quinolyl; 2-chloro-6-methoxyl group-3-quinolyl; 8-hydroxyl-2-quinolyl and 4-isoquinolyl.

The representative of 2-4C-alkene oxygen base also contains a kind of group of above-mentioned 2-4C-thiazolinyl except that Sauerstoffatom.The example that can mention is crotyl oxygen base, 3-butenyl oxygen base, 1-propenyl oxygen base and 2-propenyl oxygen base (allyloxy).

The 1-4C-alkyl-carbonyl is represented a group, and it also contains a kind of above-mentioned 1-4C-alkyl except carbonyl.The example of mentioning is ethanoyl and pivaloyl group.

Carboxyl-1-4C-alkyl represent is by the 1-4C-alkyl of carboxyl substituted.The example that can mention is carboxymethyl and 2-propyloic.

The 1-4C-alkyl that 1-4C-alkoxy carbonyl-1-4C-alkyl represent is replaced by a kind of above-mentioned 1-4C-alkoxy carbonyl.The example that can mention is methoxyl group-carbonyl methyl and ethoxy carbonyl methyl.

A kind of above-mentioned 1-4C-alkyl of aryl-1-4C-alkyl represent, it is replaced by a kind of above-mentioned aryl.Exemplary preferred aryl-1-4C-alkyl is a phenmethyl.

Aryl-1-4C-alkoxyl group is represented a kind of above-mentioned 1-4C-alkoxyl group, and it is replaced by a kind of above-mentioned aryl.Exemplary preferred aryl-1-4C-alkoxyl group is a benzyloxy.

The 1-4C-alkyl-carbonyl-amino is represented the amino that connects the 1-4C-alkyl-carbonyl on it.The example of mentioning is propionamido (C ₃H ₇C (O) NH-) and kharophen (kharophen) (CH ₃C (O) NH-).

The 1-4C-alkoxycarbonyl amino is represented an amino, and it is replaced by a kind of above-mentioned 1-4C-alkoxy carbonyl.The example that can mention is the amino and methoxycarbonyl amino of ethoxy carbonyl.

1-4C-alkoxyl group-1-4C-alkoxy carbonyl is represented a carbonyl, connects a kind of above-mentioned 1-4C-alkoxyl group-1-4C-alkoxyl group on it.The example of mentioning is 2-(methoxyl group)-ethoxy carbonyl (CH ₃-O-CH ₂CH ₂-O-CO-) and 2-(oxyethyl group) ethoxy carbonyl (CH ₃CH ₂-O-CH ₂CH ₂-O-CO-).

1-4C-alkoxyl group-1-4C-alkoxycarbonyl amino is represented an amino, and it is replaced by a kind of above-mentioned 1-4C-alkoxyl group-1-4C-alkoxy carbonyl.The example of mentioning is amino and 2-(oxyethyl group) the ethoxy carbonyl amino of 2-(methoxyl group) ethoxy carbonyl.

Aryloxy is represented a group, and it also contains a kind of above-mentioned aryl except Sauerstoffatom.The example that can mention is a benzyloxy.

Aryloxy-1-4C-alkyl of 1-4C-alkyl represent, it is replaced by a kind of above-mentioned aryloxy.The example that can mention is the benzyloxy methyl.

Aspect a preferably of the present invention.

In first embodiment of the invention (embodiment 1), RuXY[(S)-Xyl-P-Phos] [(S)-DAIPEN] be used as hydrogenation catalyst with synthetic (3R)-6-[3-aryl-3-hydroxypropyl]-7-hydroxyl-3H-benzimidizole derivatives.

In second embodiment of the invention (embodiment 2), RuXY[(S)-Xyl-BINAP] [(S)-DAIPEN] be used as hydrogenation catalyst with synthetic (3R)-6-[3-aryl-3-hydroxypropyl]-7-hydroxyl-3H-benzimidizole derivatives.

In third embodiment of the invention (embodiment 3), RuXY[(R)-Xyl-P-Phos] [(R)-DAIPEN] be used as hydrogenation catalyst with synthetic (3S)-6-[3-aryl-3-hydroxypropyl]-7-hydroxyl-3H-benzimidizole derivatives.

In four embodiment of the invention (embodiment 4), RuXY[(R)-Xyl-BINAP] [(R)-DAIPEN] be used as hydrogenation catalyst with synthetic (3S)-6-[3-aryl-3-hydroxypropyl]-7-hydroxyl-3H-benzimidizole derivatives.

Ben is embodiment of the present invention 1.

Preferably from formula 2 compound according to the formula 1-a compound of aspect a or according to the method for the formula 1-b compound of aspect b,

Wherein

X and Y are the identical or different following substituting groups that is selected from: hydrogen, halogen, BH ₄And carboxylate,

And wherein

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkyl or hydroxyl-1-4C-alkyl,

R2 is 1-4C-alkoxyl group-1-4C alkyl, 1-4C-alkyl-carbonyl, the aryl-CH of hydrogen, 1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, hydroxyl-1-4C-alkyl, fluoro-2-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkyl, silyl replacement ₂-oxygen carbonyl,

R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxy carbonyl, hydroxyl-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkyl, fluoro-1-4C-alkoxyl group-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkoxyl group, 1-4C-alkyl-carbonyl-amino, 1-4C-alkyl-carbonyl-N-1-4C-alkylamino, 1-4C-alkoxyl group-1-4C-alkyl-carbonyl-amino or group-CO-NR31R32

Wherein

R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl group-1-4C-alkyl, and

R32 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl group-1-4C-alkyl,

Perhaps wherein

R31 and R32 comprise the nitrogen-atoms of the two connection together, are pyrrolidyl, hydroxyl pyrrolidine base, '-aziridino, azetidine base, piperidino-(1-position only), piperazinyl, N-1-4C-alkylpiperazine base or morpholino group,

Phenyl, naphthyl, pyrryl, thienyl, benzothienyl or pyridyl that Ar is replaced by R4, R5, R6 and R7,

Wherein

R4 is a hydrogen; the 1-4C-alkyl; hydroxyl-1-4C-alkyl; the 1-4C-alkoxyl group; 2-4C-alkene oxygen base; carboxyl; the 1-4C-alkoxy carbonyl; carboxyl-1-4C-alkyl; 1-4C-alkoxy carbonyl-1-4C-alkyl; 1-4C-alkoxyl group-1-4C-alkyl; aryloxy-1-4C-alkyl; halogen; hydroxyl; aryl; aryl-1-4C-alkyl; aryl-oxygen base; aryl-1-4C-alkoxyl group; trifluoromethyl; nitro; amino; single-or two-1-4C-alkylamino; the 1-4C-alkyl-carbonyl-amino; the 1-4C-alkoxycarbonyl amino; 1-4C-alkoxyl group-1-4C-alkoxycarbonyl amino or alkylsulfonyl

R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxyl group, 1-4C-alkoxy carbonyl, halogen, trifluoromethyl or hydroxyl,

R6 is hydrogen, 1-4C-alkyl or halogen, and

R7 is hydrogen, 1-4C-alkyl or halogen,

And wherein

Aryl be phenyl or by one, two or three identical or different are selected from the phenyl that following substituting group replaces: 1-4C-alkyl, 1-4C-alkoxyl group, carboxyl, 1-4C-alkoxy carbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxyl and cyano group.

Particularly preferably be from formula 2 compound according to the formula 1-a compound of aspect a or according to the method for the formula 1-b compound of aspect b,

Wherein

X and Y are the identical or different following substituting groups that is selected from: hydrogen, halogen, BH ₄And carboxylate,

And wherein

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or hydroxyl-1-4C-alkyl,

R2 is 1-4C-alkoxyl group-1-4C alkyl, 1-4C-alkyl-carbonyl or the aryl-CH2-oxygen carbonyl of hydrogen, 1-4C-alkyl, hydroxyl-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkyl, silyl replacement,

R3 is carboxyl, 1-4C-alkoxy carbonyl, hydroxyl-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkyl or group-CO-NR31R32,

Wherein

R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl group-1-4C-alkyl, and

R32 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl group-1-4C-alkyl,

Perhaps wherein

R31 and R32 comprise the nitrogen-atoms of the two connection together, are pyrrolidyl, hydroxyl pyrrolidine base, '-aziridino, azetidine base, piperidino-(1-position only), piperazinyl, N-1-4C-alkylpiperazine base or morpholino group,

Phenyl, naphthyl, pyrryl, thienyl, benzothienyl or pyridyl that Ar is replaced by R4, R5, R6 and R7,

Wherein

R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxyl group, halogen, hydroxyl-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkyl or aryloxy-1-4C-alkyl,

R5 is hydrogen, 1-4C-alkyl or halogen,

R6 is hydrogen, 1-4C-alkyl or halogen, and

R7 is hydrogen, 1-4C-alkyl or halogen.

Emphasize be from formula 2 compound according to the formula 1-a compound of aspect a or according to the method for the formula 1-b compound of aspect b,

Wherein

X and Y are the identical or different following substituting groups that is selected from: hydrogen, halogen, BH ₄And carboxylate,

And wherein

R1 is the 1-4C-alkyl,

R2 is 1-4C-alkoxyl group-1-4C alkyl that hydrogen, 1-4C-alkyl or silyl replace,

R3 is 1-4C-alkoxyl group-1-4C-alkyl or group-CO-NR31R32,

Wherein

R31 be hydrogen, 1-7C-alkyl or 3-7C-cycloalkyl and

R32 is hydrogen or 1-7C-alkyl,

Perhaps wherein

R31 and R32 comprise the nitrogen-atoms of the two connection together, are pyrrolidyl or azetidine base group,

Phenyl, naphthyl, thienyl or benzothienyl that Ar is replaced by R4, R5, R6 and R7,

Wherein

R4 is hydrogen, 1-4C-alkyl, halogen, 1-4C-alkoxyl group-1-4C-alkyl, aryloxy-1-4C-alkyl or trifluoromethyl,

R5 is a hydrogen or halogen,

R6 is a hydrogen, and

R7 is a hydrogen.

Also emphasize be from formula 2 compound according to the formula 1-a compound of aspect a or according to the method for the formula 1-b compound of aspect b,

Wherein

X and Y are the identical or different following substituting groups that is selected from: hydrogen, halogen, BH ₄And carboxylate

And wherein

R1 is the 1-4C-alkyl,

R2 is the 1-4C-alkyl,

R3 is group-CO-NR31R32,

Wherein

R31 be hydrogen, 1-7C-alkyl or 3-7C-cycloalkyl and

R32 is hydrogen or 1-7C-alkyl,

Perhaps wherein

R31 and R32 comprise the nitrogen-atoms of the two connection together, are pyrrolidyl or azetidine base group,

Phenyl, naphthyl, pyrryl, thienyl, benzothienyl or pyridyl that Ar is replaced by R4, R5, R6 and R7,

Wherein

R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxyl group, halogen, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl group-1-4C-alkyl,

R5 is hydrogen, 1-4C-alkyl or halogen,

R6 is hydrogen, 1-4C-alkyl or halogen, and

R7 is hydrogen, 1-4C-alkyl or halogen.

The ben RuXY[(S that is to use)-Xyl-P-Phos] [(S)-and DAIPEN] as hydrogenation catalyst, from the method for formula 2 compound according to the formula 1-a compound of aspect a,

Wherein

Each chloro naturally of X and Y,

And wherein

R1 is the 1-4C-alkyl,

R2 is 1-4C-alkoxyl group-1-4C alkyl that hydrogen, 1-4C-alkyl or silyl replace,

R3 is 1-4C-alkoxyl group-1-4C-alkyl or group-CO-NR31R32,

Wherein

R31 be hydrogen, 1-7C-alkyl or 3-7C-cycloalkyl and

R32 is hydrogen or 1-7C-alkyl,

Perhaps wherein

R31 and R32 comprise the nitrogen-atoms of the two connection together, are pyrrolidyl or azetidine base group,

Phenyl, naphthyl, thienyl or benzothienyl that Ar is replaced by R4, R5, R6 and R7,

Wherein

R4 is hydrogen, 1-4C-alkyl, halogen, 1-4C-alkoxyl group-1-4C-alkyl, aryloxy-1-4C-alkyl or trifluoromethyl,

R5 is a hydrogen or halogen,

R6 is a hydrogen, and

R7 is a hydrogen.

The ben RuXY[(S that also is to use)-Xyl-P-Phos] [(S)-and DAIPEN] as hydrogenation catalyst, from the method for formula 2 compound according to the formula 1-a compound of aspect a,

Each chloro naturally of X and Y,

And wherein

R1 is the 1-4C-alkyl,

R2 is 1-4C-alkoxyl group-1-4C alkyl that 1-4C-alkyl or silyl replace,

R3 is group-CO-NR31R32,

Wherein

R31 is hydrogen or 1-7C-alkyl,

R32 is hydrogen or 1-7C-alkyl,

Perhaps wherein

R31 and R32 comprise the nitrogen-atoms of the two connection together, are azetidine base groups,

The phenyl that Ar is replaced by R4

Wherein

R4 is hydrogen, 1-4C-alkyl or halogen.

The hydrogenation catalyst of emphasizing related to the present invention is above-mentioned those hydrogenation catalysts, and wherein each chloro naturally of X and Y is hydrogenation catalyst RuCl ₂[(S)-Xyl-P-Phos] [(S)-DAIPEN], RuCl ₂[(S)-Xyl-BINAP] [(S)-DAIPEN], RuCl ₂[(R)-Xyl-P-Phos] [(R)-DAIPEN] and RuCl ₂[(R)-Xyl-BINAP] [(R)-DAIPEN].

Ben hydrogenation catalyst related to the present invention is hydrogenation catalyst RuCl ₂[(S)-Xyl-P-Phos] [(S)-DAIPEN].

Compound of the present invention can be synthetic from corresponding initial compounds, for example according to the reaction scheme that hereinafter provides.Synthesize in mode known in the art, for example as describing in more detail among the embodiment, it is according to following diagram.

Formula 1-a and 1-b compound are as preparation as described in the following diagram 1.

Diagram 1

Use RuXY[(S)-Xyl-P-Phos] [(S)-DAIPEN] or RuXY[(S)-Xyl-BINAP] [(S)-and DAIPEN], by the optical purity dibasic alcohol of homogeneous hydrogenation catalysis with the prochiral ketones reduction accepted way of doing sth 1-a of formula 2.

Use RuXY[(R)-Xyl-P-Phos] [(R)-DAIPEN] or RuXY[(R)-Xyl-BINAP] [(R)-and DAIPEN], by the optical purity dibasic alcohol of homogeneous hydrogenation catalysis with the prochiral ketones reduction accepted way of doing sth 1-b of formula 2.

Compare with the method for synthesis type 1-a in the prior art or 1-b related compound, for example compare with the method mentioned in the International Patent Application WO 04/087701, the inventive method is being significant especially aspect the multiple advantage:

1, isolated yield and/or enantiomeric excess increase.

Even if 2, because at low catalyst: substrate than the time also transform fully, product is easy to purifying and is easy to remove metal residue.

3, can use high concentration of substrate to have volumetric efficiency owing to allowing water in this solvent systems.

4, allow that substituting group extensively changes, particularly the ortho position of aromatic ring Ar.

Method of the present invention is to carry out with methods known in the art (for example see the document that outset is mentioned and be described in J.Am.Chem.Soc.2003,125, the research among the 13490-13503).More particularly, preferably use the condition of discussed below or experimental section.Yet, should emphasize that the asymmetric reduction of formula 2 of the present invention is not limited to these conditions.Those skilled in the art can determine to be suitable for the best reaction conditions of carrying out asymmetric catalytic hydrogenation reaction of the present invention because of its professional scientific research department.

It is favourable that asymmetric catalytic hydrogenation of the present invention is reflected in the suitable organic solvent.The solvent of mentioning is for example methyl alcohol, ethanol or the preferred Virahol or the trimethyl carbinol of aliphatics alcohols especially.Preferred solvent systems can also be the mixture of aforementioned a kind of, two or three aliphatics alcohols with any ratio of mixture, mention especially thus be Virahol and the trimethyl carbinol with 0: 100vol-% to 100: the mixture of ratio of mixture arbitrarily between the 0vol-%

Solvent or solvent systems consist essentially of a kind of specific solvent or specific solvent mixture, if wherein contain at least 50%, especially at least 70% described specific solvent or described specific solvent mixture.Other component that this solvent or solvent systems further add is other organic solvent or water for example.

Except described alcohol or alcohols mixture, above-mentioned solvent systems can comprise 0 to 50vol-%, preferred 5 to 30vol-% water.

Other additive, for example toluene also is useful for reaction process.These additives and can determine according to its expertise by those skilled in the art with the ratio of solvent or solvent systems.

Asymmetric catalytic hydrogenation reaction of the present invention is preferably carried out under 20 to 80 ℃ temperature advantageously at 0 to 80 ℃.When being lower than 20 ℃, possible speed of response is low, and this can cause long reaction time.When being higher than 80 ℃, during carrying out, reaction may follow the destruction of hydrogenation catalyst.This can cause incomplete circulation and/or enantio-selectivity to reduce.

Reaction times is depended on multiple parameter, and for example the structure of substrate, substrate/catalyst are than the amount of (S/C-than), alkali, temperature, hydrogen pressure, solvent, hydrogenation apparatus etc.Usually, in 1 hour to 7 days time, can reach conversion fully.Those skilled in the art can determine the optimum reacting time under each reaction conditions.

Asymmetric catalytic hydrogenation of the present invention reaction sharply 1 to 200bars, is preferably carried out under 10 to 80bars hydrogen pressure.In general, hydrogen pressure is high more, and speed of response is high more, and the increase of hydrogen pressure can not cause the destruction (erosion) of enantio-selectivity.

Asymmetric catalytic hydrogenation reaction of the present invention is carried out in the presence of alkali, and purpose is to produce the activation hydrogenation catalyst and increase cycle index.

Therefore reaction mixture comprises 1.0 to 50, preferred 1.01 to 10 and particularly 1.1 to 3.0 normal mineral alkalis or organic bases (with respect to formula 2 substrates).

The mineral alkali that is fit to for example is oxyhydroxide, alkoxide or the carbonate of basic metal (caesium, rubidium, potassium, sodium, lithium) or alkaline-earth metal (magnesium, calcium).The organic bases that is fit to for example be tertiary amine (for example triethylamine) and by force nitrogen base (phosphonitrile bases for example, P4-t-Bu for example, CAS111324-04-0).Preferred alkali is mineral alkali, oxyhydroxide, alkoxide or the carbonate of for example above-mentioned basic metal or alkaline-earth metal.Can mention mineral alkali KOMe, KO especially ⁱPr, LiOH, LiOMe, LiO ⁱPr, NaOH, NaOMe or NaO ⁱPr, and particularly KOH, KO ^tBu, K ₂CO ₃And Cs ₂CO ₃Especially preferably use alkali KO ^tBu and KOH.

Preferably, corresponding alkali is used for the solution of the solvent of hydrogenation-rather than solid alkali-be added in this reaction mixture at one or more.Specific embodiment comprises solution or potassium hydroxide the solution in water of potassium tert.-butoxide in the trimethyl carbinol.

Asymmetric catalytic hydrogenation of the present invention reaction be at formula 2 substrates with 0.001 to 10M, preferred 0.01 to 10M and particularly carry out in the solution of concentration in described solvent of 0.1 to 1 M.Yet peak concentration is by in the solubility test of formula 2 ketone of the solvent mixture that is used for the anti-reaction of hydrogen.For speed of response, high concentration of substrate is useful, and those skilled in the art can determine for the optimum concn of every kind of formula 2 substrates in every kind of solvent systems.

Formula 2 substrates especially depend on the structure of formula 2 ketone than the mol ratio (S/C-ratio) of catalyzer.The S/C-ratio that the present invention is suitable for is 5: 1 to 100000: 1, preferred 10: 1 to 50000: 1, and particularly 100: 1 to 1000: 1.Those skilled in the art can determine the best S/C-ratio of every kind of formula 2 substrates.

Specimen preparation of the present invention can be carried out as following examples institute art, but is not limited to these methods: under inert atmosphere, corresponding alkali and the solution that adds solvent added to formula 2 ketone and hydrogenation before-mixture of catalysts in.Fill hydrogen to reaction soln, use hydrogen pressure, and with the extremely corresponding temperature of this mixture heating up.Perhaps, with the suspension alkaline purification of formula 2 ketone in degassing solvent.Subsequently, hydrogenation catalyst is added in this settled solution, then use hydrogen pressure and as above-mentioned heating.

Another may be to use preactivated hydrogenation catalyst { for example to pass through RuCl ₂[(S)-Xyl-PPhos] [(S)-DAIPEN] (or another procatalyst) and the solution of uncle's potassium butyrate (or another alkali) in Virahol are heated to 60 ℃ and reach 1h and prepare }.In the dual mode of specimen preparation, pre-activated catalyst adds (before using hydrogen pressure) at last.

Similarly, the alcohol of formula 1-a or 1-b separates from reaction mixture and depends on methods known in the art.The separation of the formula 1-a of high purity, no ruthenium or 1-b alcohol can for example be used a kind of following method or finish by any method that other is fit to known in the art.

The processing of reaction mixture:The alcohol of formula 1-a or 1-b obtains with its phenates.The neutral form of corresponding product is to obtain by adding suitable acid, and this is well known by persons skilled in the art.Weak acid or strong acid all can be used for the hydrogenated products of production neutral form.For example crude reaction mixture can be dissolved in the biphase mixture of ammonium chloride and methylene dichloride, then randomly adds mineral acid (for example hydrochloric acid, sulfuric acid), extracts the alcohol of formula 1-a or 1-b again.

Purifying:The alcohol of formula 1-a or 1-b can pass through the column chromatography purifying, perhaps preferably by using the organic solvent crystallization process purifying that is fit to, this organic solvent is the mixture of ketone (for example acetone, methyl ethyl ketone, methyl tertbutyl ketone), alcohols (for example methyl alcohol, ethanol, Virahol), ethers (for example ether, methyl tertiary butyl ether) or these solvents for example.By crystallization or by using scavenger resin to remove the ruthenium resistates is effective.Contain the functional group that can form water-soluble ruthenium complex in the scavenger resin that is fit to, it can be removed by extraction step subsequently.

The present invention be more particularly directed to prepare the method for formula 1-a of the present invention or formula 1-b compound, this method is to be selected from KOH, KO ^tBu, K ₂CO ₃And Cs ₂CO ₃Alkali exist and to carry out down, and solvent consists essentially of Virahol or the trimethyl carbinol or Virahol and the trimethyl carbinol with 0: 100vol-% to 100: the mixture of ratio of mixture arbitrarily between the 0vol-%, and this method is to carry out in the homogeneous phase solution of formula 2 ketone that contain 0.1 to 1M concentration.

The present invention be more particularly directed to prepare the method for formula 1-a of the present invention or formula 1-b compound, this method is to be selected from KOH, KO ^tBu, K ₂CO ₃And Cs ₂CO ₃Alkali exist and to carry out down, and solvent consists essentially of Virahol or the trimethyl carbinol or Virahol and the trimethyl carbinol with 0: 100vol-% to 100: the mixture of ratio of mixture arbitrarily between the 0vol-%, and this solvent interpolation property ground comprises 5 to 30vol-% water, and this method is to carry out in the homogeneous phase solution of formula 2 ketone that contain 0.1 to 1M concentration.

The invention still further relates to the formula 1-a compound by the inventive method preparation, wherein R1, R2, R3 and Ar have the implication that beginning is pointed out.

The present invention be more particularly directed to formula 1-a compound, wherein R1, R2, R3 and Ar have table 1a and show the implication that 1b points out, it is listed in hereinafter for formula 3-a and 3-b compound.

The invention further relates to RuXY[(S)-Xyl-P-Phos] [(S)-DAIPEN] or RuXY[(S)-Xyl-BINAP] [(S)-and DAIPEN] in the methods of the invention as hydrogenation catalyst preparation formula 1-a application of compound, wherein R1, R2, R3 and Ar have the implication that beginning is pointed out.

The invention still further relates to the formula 1-b compound by the inventive method preparation, wherein R1, R2, R3 and Ar have the implication that beginning is pointed out.

The present invention be more particularly directed to formula 1-b compound, wherein R1, R2, R3 and Ar have table 1a and show the implication that 1b points out, it is listed in hereinafter for formula 3-a and 3-b compound.

The invention further relates to RuXY[(R)-Xyl-P-Phos] [(R)-DAIPEN] or RuXY[(R)-Xyl-BINAP] [(R)-and DAIPEN] in the methods of the invention as hydrogenation catalyst preparation formula 1-b application of compound, wherein R1, R2, R3 and Ar have the implication that beginning is pointed out.

Formula 1-a derivative changes into enantiomer-pure (8S)-8-aryl-3,6,7 of the formula 3-a of pharmacologically active, and 8-tetrahydrochysene-chromene also [7,8-d] imidazole derivative can pass through at S _NThe method of carrying out under 2 conditions and realizing, for example those disclosed method among the WO04/087701.For this purpose, the hydroxyl of alpha-position can be converted to suitable leavings group LG on the Ar base, for example by the esterification with acid halide or SULPHURYL CHLORIDE class.The preparation of formula 4-a compound can require temporary protection phenol hydroxyl.The blocking group that is fit to for example is described in T.W.Greene, P.G.M.Wuts " Protective Groups in Organic Synthesis " 3 ^RdEdition, J.Wiley﹠amp; Sons, New York is in 1999.Perhaps the cyclisation of the dibasic alcohol of formula 1-a can be finished under the Mitsunobu condition, for example uses azoformic acid diisopropyl ester and triphenyl phosphine.In the same way, the derivative of formula 1-b can transform enantiomer-pure (8R)-8-aryl-3,6,7 of accepted way of doing sth 3-b, and 8-tetrahydrochysene-chromene is [7,8-d] imidazole derivative also.

Diagram 2:

Formula 2 compounds are known, and for example from WO04/087701, perhaps they can prepare similar known compound (diagram 3) by currently known methods.The purifying of formula 2 compounds has considerable influence to the result of reaction conditions and asymmetric catalytic hydrogenation.

Compare with WO04/087701, need further purification step, for example the crystallisation step in the presence of the organic acid that is fit to is described as illustrative methods among the embodiment.The method easily that formula 2 compounds is changed into other formula 2 compounds with different substituents R3 is shown in the diagram 3, and can illustrate: the ester class of formula 7 compounds by following examples, wherein R33 for example is the 1-4C-alkyl, can transform the acetal of an accepted way of doing sth 8, for example pass through the acid existence down with 2, the 2-Propanal dimethyl acetal reacts.Splitting of ester functional group for example by using the sodium hydroxide saponification, produces the carboxylic-acid of corresponding formula 9, then it used for example TBTU processing of coupling reagent that is fit to, and then adds for example amine of coupling part, the derivative of production 10.Perhaps, the ester class of formula 8 can be reduced into corresponding primary alconol, for example uses lithium aluminum hydride, and described hydroxyl can be for example by changing into halogenide or sulphonate is activated, it uses for example thionyl chloride or methylsulfonyl chloride.Then the exchange of substituent R 3 can by nucleophile for example alkoxide finish.At last, the ketone of acquisition formula 2 by the acetal of the formula 10 of splitting is for example in the presence of sour example hydrochloric acid.

Diagram 3

The invention further relates to the compound of formula 3-a and 3-b, wherein R1, R2, R3 and Ar have the implication that following table 1a points out, and the salt of these compounds.

Formula 3-a compound preferably, wherein R1, R2, R3 and Ar have the implication that following table 1a points out, and the salt of these compounds.

Table 1a:

R1	R2	R3	Ar
				-CH 3	-CH 3	-C(O)-N(CH 3) 2	2-methyl-phenyl
-CH 3	-CH 3	-C(O)-N(CH 3) 2	2-ethyl-phenyl
				-CH 3	-CH 3	-C(O)-N(CH 3) 2	2-sec.-propyl-phenyl
-CH 3	-CH 3	-C(O)-N(CH 3) 2	4-fluoro-2-methyl-phenyl

R1	R2	R3	Ar
				-CH 3	-CH 3	-C(O)-N(CH 3) 2	2-trifluoromethyl-phenyl
-CH 3	-CH 3	-C(O)-N(CH 3) 2	2-methylol-phenyl
				-CH 3	-CH 3	-C(O)-N(CH 3) 2	2-chloro-phenyl
-CH 3	-CH 3	-C(O)-N(CH 3) 2	2-(2-hydroxyethyl)-phenyl
				-CH 3	-CH 3	-C(O)-N(CH 3) 2	2-(1-hydroxyethyl)-phenyl
-CH 3	-CH 3	-C(O)-N(CH 3) 2	2-benzyloxy methyl-phenyl
				-CH 3	-CH 3	-C(O)-N(CH 3) 2	2-methoxymethyl-phenyl
-CH 3	-CH 3	-C(O)-N(CH 3) 2	The 2-thienyl
				-CH 3	-CH 3	-C(O)-N(CH 3) 2	3-methyl-2-thienyl
-CH 3	-CH 3	-C(O)-N(CH 3) 2	The 3-thienyl
				-CH 3	-CH 3	-C(O)-N(CH 3) 2	2-methyl-3-thienyl
-CH 3	-CH 3	-C(O)-N(CH 3) 2	4-methyl-3-thienyl
				-CH 3	-CH 3	-C(O)-N(CH 3) 2	1-thionaphthene-3-base
-CH 3	-CH 3	-C(O)-N(CH 3) 2	The 1-naphthyl
				-CH 3	-CH 3	-C(O)-N(CH 3) 2	The 2-naphthyl
-CH 3	-CH 3	-C(O)-N(CH 3) 2	2-N-methyl-pyrryl
				-CH 3	-CH 3	-C(O)-N(CH 3) 2	The 4-pyridyl
-CH 3	-CH 3	-C(O)-N(H)CH 3	2-methyl-phenyl
				-CH 3	-CH 3	-C(O)-N(H)CH 3	2-ethyl-phenyl
-CH 3	-CH 3	-C(O)-N(H)CH 3	2-sec.-propyl-phenyl
				-CH 3	-CH 3	-C(O)-N(H)CH 3	4-fluoro-2-methyl-phenyl
-CH 3	-CH 3	-C(O)-N(H)CH 3	2-trifluoromethyl-phenyl
				-CH 3	-CH 3	-C(O)-N(H)CH 3	2-methylol-phenyl
-CH 3	-CH 3	-C(O)-N(H)CH 3	2-chloro-phenyl
				-CH 3	-CH 3	-C(O)-N(H)CH 3	2-(2-hydroxyethyl)-phenyl
-CH 3	-CH 3	-C(O)-N(H)CH 3	2-(1-hydroxyethyl)-phenyl
				-CH 3	-CH 3	-C(O)-N(H)CH 3	2-benzyloxy methyl-phenyl
-CH 3	-CH 3	-C(O)-N(H)CH 3	2-methoxymethyl-phenyl
				-CH 3	-CH 3	-C(O)-N(H)CH 3	The 2-thienyl
-CH 3	-CH 3	-C(O)-N(H)CH 3	3-methyl-2-thienyl

R1	R2	R3	Ar
				-CH 3	-CH 3	-C(O)-N(H)CH 3	The 3-thienyl
-CH 3	-CH 3	-C(O)-N(H)CH 3	2-methyl-3-thienyl
				-CH 3	-CH 3	-C(O)-N(H)CH 3	4-methyl-3-thienyl
-CH 3	-CH 3	-C(O)-N(H)CH 3	1-thionaphthene-3-base
				-CH 3	-CH 3	-C(O)-N(H)CH 3	The 1-naphthyl
-CH 3	-CH 3	-C(O)-N(H)CH 3	The 2-naphthyl
				-CH 3	-CH 3	-C(O)-N(H)CH 3	2-N-methyl-pyrryl
-CH 3	-CH 3	-C(O)-N(H)CH 3	The 4-pyridyl
				-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	2-methyl-phenyl
-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	2-ethyl-phenyl
				-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	2-sec.-propyl-phenyl
-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	4-fluoro-2-methyl-phenyl
				-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	2-trifluoromethyl-phenyl
-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	2-methylol-phenyl
				-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	2-chloro-phenyl
-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	2-(2-hydroxyethyl)-phenyl
				-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	2-(1-hydroxyethyl)-phenyl
-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	2-benzyloxy methyl-phenyl
				-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	2-methoxymethyl-phenyl
-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	The 2-thienyl
				-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	3-methyl-2-thienyl
-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	The 3-thienyl
				-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	2-methyl-3-thienyl
-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	4-methyl-3-thienyl
				-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	1-thionaphthene-3-base
-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	The 1-naphthyl
				-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	The 2-naphthyl
-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	2-N-methyl-pyrryl
				-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	The 4-pyridyl
-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	2-methyl-phenyl

R1	R2	R3	Ar
				-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	2-ethyl-phenyl
-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	2-sec.-propyl-phenyl
				-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	4-fluoro-2-methyl-phenyl
-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	2-trifluoromethyl-phenyl
				-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	2-methylol-phenyl
-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	2-chloro-phenyl
				-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	2-(2-hydroxyethyl)-phenyl
-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	2-(1-hydroxyethyl)-phenyl
				-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	2-benzyloxy methyl-phenyl
-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	2-methoxymethyl-phenyl
				-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	The 2-thienyl
-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	3-methyl-2-thienyl
				-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	The 3-thienyl
-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	2-methyl-3-thienyl
				-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	4-methyl-3-thienyl
-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	1-thionaphthene-3-base
				-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	The 1-naphthyl
-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	The 2-naphthyl
				-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	2-N-methyl-pyrryl
-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	The 4-pyridyl
				-CH 3	-CH 3	-C (O)-azetidine-1-base	2-methyl-phenyl
-CH 3	-CH 3	-C (O)-azetidine-1-base	2-ethyl-phenyl
				-CH 3	-CH 3	-C (O)-azetidine-1-base	2-sec.-propyl-phenyl
-CH 3	-CH 3	-C (O)-azetidine-1-base	4-fluoro-2-methyl-phenyl
				-CH 3	-CH 3	-C (O)-azetidine-1-base	2-trifluoromethyl-phenyl
-CH 3	-CH 3	-C (O)-azetidine-1-base	2-methylol-phenyl
				-CH 3	-CH 3	-C (O)-azetidine-1-base	2-chloro-phenyl
-CH 3	-CH 3	-C (O)-azetidine-1-base	2-(2-hydroxyethyl)-phenyl
				-CH 3	-CH 3	-C (O)-azetidine-1-base	2-(1-hydroxyethyl)-phenyl
-CH 3	-CH 3	-C (O)-azetidine-1-base	2-benzyloxy methyl-phenyl

R1	R2	R3	Ar
				-CH 3	-CH 3	-C (O)-azetidine-1-base	2-methoxymethyl-phenyl
-CH 3	-CH 3	-C (O)-azetidine-1-base	The 2-thienyl
				-CH 3	-CH 3	-C (O)-azetidine-1-base	3-methyl-2-thienyl
-CH 3	-CH 3	-C (O)-azetidine-1-base	The 3-thienyl
				-CH 3	-CH 3	-C (O)-azetidine-1-base	2-methyl-3-thienyl
-CH 3	-CH 3	-C (O)-azetidine-1-base	4-methyl-3-thienyl
				-CH 3	-CH 3	-C (O)-azetidine-1-base	1-thionaphthene-3-base
-CH 3	-CH 3	-C (O)-azetidine-1-base	The 1-naphthyl
				-CH 3	-CH 3	-C (O)-azetidine-1-base	The 2-naphthyl
-CH 3	-CH 3	-C (O)-azetidine-1-base	2-N-methyl-pyrryl
				-CH 3	-CH 3	-C (O)-azetidine-1-base	The 4-pyridyl
-CH 3	-CH 3	-CH 2-O-CH 3	2-methyl-phenyl
				-CH 3	-CH 3	-CH 2-O-CH 3	2-ethyl-phenyl
-CH 3	-CH 3	-CH 2-O-CH 3	2-sec.-propyl-phenyl
				-CH 3	-CH 3	-CH 2-O-CH 3	4-fluoro-2-methyl-phenyl
-CH 3	-CH 3	-CH 2-O-CH 3	2-trifluoromethyl-phenyl
				-CH 3	-CH 3	-CH 2-O-CH 3	2-methylol-phenyl
-CH 3	-CH 3	-CH 2-O-CH 3	2-chloro-phenyl
				-CH 3	-CH 3	-CH 2-O-CH 3	2-(2-hydroxyethyl)-phenyl
-CH 3	-CH 3	-CH 2-O-CH 3	2-(1-hydroxyethyl)-phenyl
				-CH 3	-CH 3	-CH 2-O-CH 3	2-benzyloxy methyl-phenyl
-CH 3	-CH 3	-CH 2-O-CH 3	2-methoxymethyl-phenyl
				-CH 3	-CH 3	-CH 2-O-CH 3	The 2-thienyl
-CH 3	-CH 3	-CH 2-O-CH 3	3-methyl-2-thienyl
				-CH 3	-CH 3	-CH 2-O-CH 3	The 3-thienyl
-CH 3	-CH 3	-CH 2-O-CH 3	2-methyl-3-thienyl
				-CH 3	-CH 3	-CH 2-O-CH 3	4-methyl-3-thienyl
-CH 3	-CH 3	-CH 2-O-CH 3	1-thionaphthene-3-base
				-CH 3	-CH 3	-CH 2-O-CH 3	The 1-naphthyl
-CH 3	-CH 3	-CH 2-O-CH 3	The 2-naphthyl

R1	R2	R3	Ar
				-CH 3	-CH 3	-CH 2-O-CH 3	2-N-methyl-pyrryl
-CH 3	-CH 3	-CH 2-O-CH 3	The 4-pyridyl
				-CH 3	H	-C(O)-N(CH 3) 2	2-methyl-phenyl
-CH 3	H	-C(O)-N(CH 3) 2	2-ethyl-phenyl
				-CH 3	H	-C(O)-N(CH 3) 2	2-sec.-propyl-phenyl
-CH 3	H	-C(O)-N(CH 3) 2	4-fluoro-2-methyl-phenyl
				-CH 3	H	-C(O)-N(CH 3) 2	2-trifluoromethyl-phenyl
-CH 3	H	-C(O)-N(CH 3) 2	2-methylol-phenyl
				-CH 3	H	-C(O)-N(CH 3) 2	2-chloro-phenyl
-CH 3	H	-C(O)-N(CH 3) 2	2-(2-hydroxyethyl)-phenyl
				-CH 3	H	-C(O)-N(CH 3) 2	2-(1-hydroxyethyl)-phenyl
-CH 3	H	-C(O)-N(CH 3) 2	2-benzyloxy methyl-phenyl
				-CH 3	H	-C(O)-N(CH 3) 2	2-methoxymethyl-phenyl
-CH 3	H	-C(O)-N(CH 3) 2	The 2-thienyl
				-CH 3	H	-C(O)-N(CH 3) 2	3-methyl-2-thienyl
-CH 3	H	-C(O)-N(CH 3) 2	The 3-thienyl
				-CH 3	H	-C(O)-N(CH 3) 2	2-methyl-3-thienyl
-CH 3	H	-C(O)-N(CH 3) 2	4-methyl-3-thienyl
				-CH 3	H	-C(O)-N(CH 3) 2	1-thionaphthene-3-base
-CH 3	H	-C(O)-N(CH 3) 2	The 1-naphthyl
				-CH 3	H	-C(O)-N(CH 3) 2	The 2-naphthyl
-CH 3	-H	-C(O)-N(CH 3) 2	2-N-methyl-pyrryl
				-CH 3	-H	-C(O)-N(CH 3) 2	The 4-pyridyl
-CH 3	H	-C(O)-N(H)CH 3	2-methyl-phenyl
				-CH 3	H	-C(O)-N(H)CH 3	2-ethyl-phenyl
-CH 3	H	-C(O)-N(H)CH 3	2-sec.-propyl-phenyl
				-CH 3	H	-C(O)-N(H)CH 3	4-fluoro-2-methyl-phenyl
-CH 3	H	-C(O)-N(H)CH 3	2-trifluoromethyl-phenyl
				-CH 3	H	-C(O)-N(H)CH 3	2-methylol-phenyl
-CH 3	H	-C(O)-N(H)CH 3	2-chloro-phenyl

R1	R2	R3	Ar
				-CH 3	H	-C(O)-N(H)CH 3	2-(2-hydroxyethyl)-phenyl
-CH 3	H	-C(O)-N(H)CH 3	2-(1-hydroxyethyl)-phenyl
				-CH 3	H	-C(O)-N(H)CH 3	2-benzyloxy methyl-phenyl
-CH 3	H	-C(O)-N(H)CH 3	2-methoxymethyl-phenyl
				-CH 3	H	-C(O)-N(H)CH 3	The 2-thienyl
-CH 3	H	-C(O)-N(H)CH 3	3-methyl-2-thienyl
				-CH 3	H	-C(O)-N(H)CH 3	The 3-thienyl
-CH 3	H	-C(O)-N(H)CH 3	2-methyl-3-thienyl
				-CH 3	H	-C(O)-N(H)CH 3	4-methyl-3-thienyl
-CH 3	H	-C(O)-N(H)CH 3	1-thionaphthene-3-base
				-CH 3	H	-C(O)-N(H)CH 3	The 1-naphthyl
-CH 3	H	-C(O)-N(H)CH 3	The 2-naphthyl
				-CH 3	H	-C(O)-N(H)CH 3	2-N-methyl-pyrryl
-CH 3	H	-C(O)-N(H)CH 3	The 4-pyridyl
				-CH 3	H	-C (O)-N (H)-cyclopropyl	2-methyl-phenyl
-CH 3	H	-C (O)-N (H)-cyclopropyl	2-ethyl-phenyl
				-CH 3	H	-C (O)-N (H)-cyclopropyl	2-sec.-propyl-phenyl
-CH 3	H	-C (O)-N (H)-cyclopropyl	4-fluoro-2-methyl-phenyl
				-CH 3	H	-C (O)-N (H)-cyclopropyl	2-trifluoromethyl-phenyl
-CH 3	H	-C (O)-N (H)-cyclopropyl	2-methylol-phenyl
				-CH 3	H	-C (O)-N (H)-cyclopropyl	2-chloro-phenyl
-CH 3	H	-C (O)-N (H)-cyclopropyl	2-(2-hydroxyethyl)-phenyl
				-CH 3	H	-C (O)-N (H)-cyclopropyl	2-(1-hydroxyethyl)-phenyl
-CH 3	H	-C (O)-N (H)-cyclopropyl	2-benzyloxy methyl-phenyl
				-CH 3	H	-C (O)-N (H)-cyclopropyl	2-methoxymethyl-phenyl
-CH 3	H	-C (O)-N (H)-cyclopropyl	The 2-thienyl
				-CH 3	H	-C (O)-N (H)-cyclopropyl	3-methyl-2-thienyl
-CH 3	H	-C (O)-N (H)-cyclopropyl	The 3-thienyl
				-CH 3	H	-C (O)-N (H)-cyclopropyl	2-methyl-3-thienyl
-CH 3	H	-C (O)-N (H)-cyclopropyl	4-methyl-3-thienyl

R1	R2	R3	Ar
				-CH 3	H	-C (O)-N (H)-cyclopropyl	1-thionaphthene-3-base
-CH 3	H	-C (O)-N (H)-cyclopropyl	The 1-naphthyl
				-CH 3	H	-C (O)-N (H)-cyclopropyl	The 2-naphthyl
-CH 3	H	-C (O)-N (H)-cyclopropyl	2-N-methyl-pyrryl
				-CH 3	H	-C (O)-N (H)-cyclopropyl	The 4-pyridyl
-CH 3	H	-C (O)-tetramethyleneimine-1-base	2-methyl-phenyl
				-CH 3	H	-C (O)-tetramethyleneimine-1-base	2-ethyl-phenyl
-CH 3	H	-C (O)-tetramethyleneimine-1-base	2-sec.-propyl-phenyl
				-CH 3	H	-C (O)-tetramethyleneimine-1-base	4-fluoro-2-methyl-phenyl
-CH 3	H	-C (O)-tetramethyleneimine-1-base	2-trifluoromethyl-phenyl
				-CH 3	H	-C (O)-tetramethyleneimine-1-base	2-methylol-phenyl
-CH 3	H	-C (O)-tetramethyleneimine-1-base	2-chloro-phenyl
				-CH 3	H	-C (O)-tetramethyleneimine-1-base	2-(2-hydroxyethyl)-phenyl
-CH 3	H	-C (O)-tetramethyleneimine-1-base	2-(1-hydroxyethyl)-phenyl
				-CH 3	H	-C (O)-tetramethyleneimine-1-base	2-benzyloxy methyl-phenyl
-CH 3	H	-C (O)-tetramethyleneimine-1-base	2-methoxymethyl-phenyl
				-CH 3	H	-C (O)-tetramethyleneimine-1-base	The 2-thienyl
-CH 3	H	-C (O)-tetramethyleneimine-1-base	3-methyl-2-thienyl
				-CH 3	H	-C (O)-tetramethyleneimine-1-base	The 3-thienyl
-CH 3	H	-C (O)-tetramethyleneimine-1-base	2-methyl-3-thienyl
				-CH 3	H	-C (O)-tetramethyleneimine-1-base	4-methyl-3-thienyl
-CH 3	H	-C (O)-tetramethyleneimine-1-base	1-thionaphthene-3-base
				-CH 3	H	-C (O)-tetramethyleneimine-1-base	The 1-naphthyl
-CH 3	H	-C (O)-tetramethyleneimine-1-base	The 2-naphthyl
				-CH 3	H	-C (O)-tetramethyleneimine-1-base	2-N-methyl-pyrryl
-CH 3	H	-C (O)-tetramethyleneimine-1-base	The 4-pyridyl
				-CH 3	H	-C (O)-azetidine-1-base	2-methyl-phenyl
-CH 3	H	-C (O)-azetidine-1-base	2-ethyl-phenyl
				-CH 3	H	-C (O)-azetidine-1-base	2-sec.-propyl-phenyl
-CH 3	H	-C (O)-azetidine-1-base	4-fluoro-2-methyl-phenyl

R1	R2	R3	Ar
				-CH 3	H	-C (O)-azetidine-1-base	2-trifluoromethyl-phenyl
-CH 3	H	-C (O)-azetidine-1-base	2-methylol-phenyl
				-CH 3	H	-C (O)-azetidine-1-base	2-chloro-phenyl
-CH 3	H	-C (O)-azetidine-1-base	2-(2-hydroxyethyl)-phenyl
				-CH 3	H	-C (O)-azetidine-1-base	2-(1-hydroxyethyl)-phenyl
-CH 3	H	-C (O)-azetidine-1-base	2-benzyloxy methyl-phenyl
				-CH 3	H	-C (O)-azetidine-1-base	2-methoxymethyl-phenyl
-CH 3	H	-C (O)-azetidine-1-base	The 2-thienyl
				-CH 3	H	-C (O)-azetidine-1-base	3-methyl-2-thienyl
-CH 3	H	-C (O)-azetidine-1-base	The 3-thienyl
				-CH 3	H	-C (O)-azetidine-1-base	2-methyl-3-thienyl
-CH 3	H	-C (O)-azetidine-1-base	4-methyl-3-thienyl
				-CH 3	H	-C (O)-azetidine-1-base	1-thionaphthene-3-base
-CH 3	H	-C (O)-azetidine-1-base	The 1-naphthyl
				-CH 3	H	-C (O)-azetidine-1-base	The 2-naphthyl
-CH 3	H	-C (O)-azetidine-1-base	2-N-methyl-pyrryl
				-CH 3	H	-C (O)-azetidine-1-base	The 4-pyridyl
-CH 3	H	-CH 2-O-CH 3	2-methyl-phenyl
				-CH 3	H	-CH 2-O-CH 3	2-ethyl-phenyl
-CH 3	H	-CH 2-O-CH 3	2-sec.-propyl-phenyl
				-CH 3	H	-CH 2-O-CH 3	4-fluoro-2-methyl-phenyl
-CH 3	H	-CH 2-O-CH 3	2-trifluoromethyl-phenyl
				-CH 3	H	-CH 2-O-CH 3	2-methylol-phenyl
-CH 3	H	-CH 2-O-CH 3	2-chloro-phenyl
				-CH 3	H	-CH 2-O-CH 3	2-(2-hydroxyethyl)-phenyl
-CH 3	H	-CH 2-O-CH 3	2-(1-hydroxyethyl)-phenyl
				-CH 3	H	-CH 2-O-CH 3	2-benzyloxy methyl-phenyl
-CH 3	H	-CH 2-O-CH 3	2-methoxymethyl-phenyl
				-CH 3	H	-CH 2-O-CH 3	The 2-thienyl
-CH 3	H	-CH 2-O-CH 3	3-methyl-2-thienyl

R1	R2	R3	Ar
				-CH 3	H	-CH 2-O-CH 3	The 3-thienyl
-CH 3	H	-CH 2-O-CH 3	2-methyl-3-thienyl
				-CH 3	H	-CH 2-O-CH 3	4-methyl-3-thienyl
-CH 3	H	-CH 2-O-CH 3	1-thionaphthene-3-base
				-CH 3	H	-CH 2-O-CH 3	The 1-naphthyl
-CH 3	H	-CH 2-O-CH 3	The 2-naphthyl
				-CH 3	H	-CH 2-O-CH 3	2-N-methyl-pyrryl
-CH 3	H	-CH 2-O-CH 3	The 4-pyridyl

Particularly preferably be formula 3-a compound, wherein R1, R2, R3 and Ar have the implication that following table 1b points out, and the salt of these compounds.

Table 1b

R1	R2	R3	Ar
				-CH 3	-CH 3	-C(O)-N(CH 3) 2	2-methyl-phenyl
-CH 3	-CH 3	-C(O)-N(CH 3) 2	2-ethyl-phenyl
				-CH 3	-CH 3	-C(O)-N(CH 3) 2	2-sec.-propyl-phenyl
-CH 3	-CH 3	-C(O)-N(CH 3) 2	4-fluoro-2-methyl-phenyl
				-CH 3	-CH 3	-C(O)-N(CH 3) 2	2-trifluoromethyl-phenyl
-CH 3	-CH 3	-C(O)-N(CH 3) 2	2-methylol-phenyl
				-CH 3	-CH 3	-C(O)-N(CH 3) 2	2-chloro-phenyl
-CH 3	-CH 3	-C(O)-N(CH 3) 2	2-(2-hydroxyethyl)-phenyl
				-CH 3	-CH 3	-C(O)-N(CH 3) 2	2-(1-hydroxyethyl)-phenyl
-CH 3	-CH 3	-C(O)-N(CH 3) 2	2-methoxymethyl-phenyl
				-CH 3	-CH 3	-C(O)-N(CH 3) 2	The 2-thienyl
-CH 3	-CH 3	-C(O)-N(CH 3) 2	3-methyl-2-thienyl
				-CH 3	-CH 3	-C(O)-N(CH 3) 2	The 3-thienyl
-CH 3	-CH 3	-C(O)-N(CH 3) 2	2-methyl-3-thienyl
				-CH 3	-CH 3	-C(O)-N(CH 3) 2	4-methyl-3-thienyl

R1	R2	R3	Ar
				-CH 3	-CH 3	-C(O)-N(CH 3) 2	1-thionaphthene-3-base
-CH 3	-CH 3	-C(O)-N(CH 3) 2	The 1-naphthyl
				-CH 3	-CH 3	-C(O)-N(CH 3) 2	The 2-naphthyl
-CH 3	-CH 3	-C(O)-N(CH 3) 2	2-N-methyl-pyrryl
				-CH 3	-CH 3	-C(O)-N(CH 3) 2	The 4-pyridyl
-CH 3	-CH 3	-C(O)-N(H)CH 3	2-methyl-phenyl
				-CH 3	-CH 3	-C(O)-N(H)CH 3	2-ethyl-phenyl
-CH 3	-CH 3	-C(O)-N(H)CH 3	2-sec.-propyl-phenyl
				-CH 3	-CH 3	-C(O)-N(H)CH 3	4-fluoro-2-methyl-phenyl
-CH 3	-CH 3	-C(O)-N(H)CH 3	2-trifluoromethyl-phenyl
				-CH 3	-CH 3	-C(O)-N(H)CH 3	2-methylol-phenyl
-CH 3	-CH 3	-C(O)-N(H)CH 3	2-chloro-phenyl
				-CH 3	-CH 3	-C(O)-N(H)CH 3	2-(2-hydroxyethyl)-phenyl
-CH 3	-CH 3	-C(O)-N(H)CH 3	2-(1-hydroxyethyl)-phenyl
				-CH 3	-CH 3	-C(O)-N(H)CH 3	2-methoxymethyl-phenyl
-CH 3	-CH 3	-C(O)-N(H)CH 3	The 2-thienyl
				-CH 3	-CH 3	-C(O)-N(H)CH 3	3-methyl-2-thienyl
-CH 3	-CH 3	-C(O)-N(H)CH 3	The 3-thienyl
				-CH 3	-CH 3	-C(O)-N(H)CH 3	2-methyl-3-thienyl
-CH 3	-CH 3	-C(O)-N(H)CH 3	4-methyl-3-thienyl
				-CH 3	-CH 3	-C(O)-N(H)CH 3	1-thionaphthene-3-base
-CH 3	-CH 3	-C(O)-N(H)CH 3	The 1-naphthyl
				-CH 3	-CH 3	-C(O)-N(H)CH 3	The 2-naphthyl
-CH 3	-CH 3	-C(O)-N(H)CH 3	2-N-methyl-pyrryl
				-CH 3	-CH 3	-C(O)-N(H)CH 3	The 4-pyridyl
-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	2-methyl-phenyl
				-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	2-ethyl-phenyl
-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	2-sec.-propyl-phenyl
				-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	4-fluoro-2-methyl-phenyl
-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	2-trifluoromethyl-phenyl

R1	R2	R3	Ar
				-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	2-methylol-phenyl
-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	2-chloro-phenyl
				-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	2-(2-hydroxyethyl)-phenyl
-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	2-(1-hydroxyethyl)-phenyl
				-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	2-methoxymethyl-phenyl
-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	The 2-thienyl
				-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	3-methyl-2-thienyl
-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	The 3-thienyl
				-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	2-methyl-3-thienyl
-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	4-methyl-3-thienyl
				-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	1-thionaphthene-3-base
-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	The 1-naphthyl
				-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	The 2-naphthyl
-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	2-N-methyl-pyrryl
				-CH 3	-CH 3	-C (O)-N (H)-cyclopropyl	The 4-pyridyl
-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	2-methyl-phenyl
				-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	2-ethyl-phenyl
-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	2-sec.-propyl-phenyl
				-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	4-fluoro-2-methyl-phenyl
-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	2-trifluoromethyl-phenyl
				-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	2-methylol-phenyl
-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	2-chloro-phenyl
				-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	2-(2-hydroxyethyl)-phenyl
-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	2-(1-hydroxyethyl)-phenyl
				-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	2-methoxymethyl-phenyl
-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	The 2-thienyl
				-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	3-methyl-2-thienyl
-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	The 3-thienyl
				-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	2-methyl-3-thienyl
-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	4-methyl-3-thienyl

R1	R2	R3	Ar
				-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	1-thionaphthene-3-base
-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	The 1-naphthyl
				-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	The 2-naphthyl
-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	2-N-methyl-pyrryl
				-CH 3	-CH 3	-C (O)-tetramethyleneimine-1-base	The 4-pyridyl
-CH 3	-CH 3	-C (O)-azetidine-1-base	2-methyl-phenyl
				-CH 3	-CH 3	-C (O)-azetidine-1-base	2-ethyl-phenyl
-CH 3	-CH 3	-C (O)-azetidine-1-base	2-sec.-propyl-phenyl
				-CH 3	-CH 3	-C (O)-azetidine-1-base	4-fluoro-2-methyl-phenyl
-CH 3	-CH 3	-C (O)-azetidine-1-base	2-trifluoromethyl-phenyl
				-CH 3	-CH 3	-C (O)-azetidine-1-base	2-methylol-phenyl
-CH 3	-CH 3	-C (O)-azetidine-1-base	2-chloro-phenyl
				-CH 3	-CH 3	-C (O)-azetidine-1-base	2-(2-hydroxyethyl)-phenyl
-CH 3	-CH 3	-C (O)-azetidine-1-base	2-(1-hydroxyethyl)-phenyl
				-CH 3	-CH 3	-C (O)-azetidine-1-base	2-methoxymethyl-phenyl
-CH 3	-CH 3	-C (O)-azetidine-1-base	The 2-thienyl
				-CH 3	-CH 3	-C (O)-azetidine-1-base	3-methyl-2-thienyl
-CH 3	-CH 3	-C (O)-azetidine-1-base	The 3-thienyl
				-CH 3	-CH 3	-C (O)-azetidine-1-base	2-methyl-3-thienyl
-CH 3	-CH 3	-C (O)-azetidine-1-base	4-methyl-3-thienyl
				-CH 3	-CH 3	-C (O)-azetidine-1-base	1-thionaphthene-3-base
-CH 3	-CH 3	-C (O)-azetidine-1-base	The 1-naphthyl
				-CH 3	-CH 3	-C (O)-azetidine-1-base	The 2-naphthyl
-CH 3	-CH 3	-C (O)-azetidine-1-base	2-N-methyl-pyrryl
				-CH 3	-CH 3	-C (O)-azetidine-1-base	The 4-pyridyl

The salt that is fit to of formula 3-a of the present invention and 3-b compound-depend on substituting group-especially whole acid salt.Can mention the salt that the mineral acid that is usually used in pharmacy and organic acid pharmacology can tolerate especially.What be fit to is the salt of water-soluble or water-insoluble and sour addition, and this acid is hydrochloric acid, Hydrogen bromide, phosphoric acid, nitric acid, sulfuric acid, acetate, Citric Acid, maltonic acid, phenylformic acid, 2-(4-hydroxy benzoyl) phenylformic acid, butyric acid, sulphosalicylic acid, toxilic acid, lauric acid, oxysuccinic acid, propanedioic acid, fumaric acid, succsinic acid, oxalic acid, tartrate, pamoic acid, stearic acid, toluenesulphonic acids, methylsulfonic acid or 3-hydroxyl-2-naphthoic acid for example.

The salt of formula 3-a of the present invention and 3-b compound can be by being dissolved in described free cpds appropriate solvent (for example a kind of ketone such as acetone, methyl ethyl ketone or methyl iso-butyl ketone (MIBK), a kind of ether such as ether, tetrahydrofuran (THF) or two  alkane, a kind of hydrochloric ether such as methylene dichloride or chloroform, perhaps lower molecular weight fatty alcohol such as methyl alcohol, ethanol or Virahol) in, contain the acid of needs or the acid of adding needs in this solvent then in this solvent, heating when needing.For the preparation of salt, described acid can be used for being used for equimolar amount or different amount preparation salt, depend on it whether is monobasic-or polyprotonic acid and depend on and need which kind of salt.Described salt is for example by evaporating solvent or by cooling precipitation, by redeposition, perhaps by with the non-solvent precipitation of described salt, for example the salt by the filtering separation post precipitation obtains again.

The unacceptable salt of pharmacology, it can be in initial acquisition, and for example as the process product in plant-scale formula 3-a of preparation and 3-b compound, these unacceptable salt can be transformed into the acceptable salt of pharmacology by method known to those skilled in the art.

One skilled in the art will appreciate that formula 3-a and 3-b compound and salt thereof, for example work as them, can contain various amounts of solvent with isolated in crystalline form.Therefore the present invention also comprises formula 3-a listed among table 1a and the 1b and whole solvate of 3-b compound, particularly whole hydrates; And whole solvate of showing the salt of formula 3-a listed among 1a and the 1b and 3-b compound, particularly whole hydrates.

Especially, the present invention relates to show formula 3-a compound and/or its salt of 1a and 1b, formula 3-b compound and/or its salt of its essentially no table 1a and 1b.

" essentially no " meaning in the context of the invention is that formula 3-a compound and/or its salt contain formula 3-b compound and/or its salt that is lower than 30% weight.Preferably, " essentially no " meaning is that formula 3-a compound and/or its salt contain formula 3-b compound and/or its salt that is lower than 10% weight.In a more preferred embodiment, " essentially no " meaning is that formula 3-a compound and/or its salt contain formula 3-b compound and/or its salt that is lower than 5% weight.In the most preferred embodiment, " essentially no " meaning is that formula 3-a compound and/or its salt contain formula 3-b compound and/or its salt that is lower than 2% weight.

Particularly preferably be formula 3-a compound and/or its salt that experimental section is hereinafter described by the mode of embodiment.

Beneficial effect

The good stomach provide protection and the gastric acid secretion restraining effect of formula 3-a of the present invention and 3-b compound, particularly formula 3-a compound can confirm in the research of animal test model.The formula 3-a compound of the present invention numbering of studying in following model corresponding with the numbering of these compounds among the embodiment represented.

Test secretion-restraining effect in the perfusion rat stomach

Following Table A has illustrated formula 3-a compound of the present invention behind the body intraduodenal administration, the sour excretory influence that in the stomach of perfusion rat pentagastrin is stimulated.

Table A

Letter	Dosage (μ mol/kg) i.d.	Acid excretory restraining effect (%)
			A	1	＞60
C	1	＞90
			D	1	＞50
E	1	＞80
			F	1	＞70
G	1	100
			H	1	100
I	1	＞70
			L	1	＞70
N	1	100
			O	1	＞60
P	1	100
			Q	1	100
V	1	100
			W	1	100

Methodology

When by behind the middle upper abdominal surgery tracheostomize, open anesthetized rat (the CD mouse, female, 200-250g; 1.5g/kg the belly i.m. urethane) passes the oral cavity and fixes a PVC catheter in esophagus, and fixes another root through pylorus, makes the end of pipe just in time stretch into gastral cavity.The catheter that stretches out from pylorus enters right stomach wall by side opening.

Behind the cleaning down (about 50-100ml), make temperature (37 ℃) physiology NaCl solution continuously by stomach (0.5ml/min, pH 6.8-6.9; Braun-Unita I).Mensuration pH value (pH meter 632, glass electrode EA 147; φ=5mm, Metrohm), and by be titrated to pH value 7 (Dosimat 665 Metrohm) mensuration excretory HCl in the effluent of collecting in 15 minutes with the 0.01NNaOH solution that newly makes.

Behind the EO (promptly after having determined 2 initial level parts), (about 30 minutes of=1.65ml/h) pentagastrin stimulates stomachial secretion to inject 1 μ g/kg by continuous vein (left side femoral vein).At beginning continuous infusion pentagastrin after 60 minutes, with the 2.5ml/kg liquid volume to be tried material in the duodenum.Make animal heat constant by ir radiation and heating cushion (by rectum with automatic, the stepless control of temperature sensor) at 37.8-38 ℃.

Realize the mode of invention

Following examples are used to illustrate in greater detail the present invention and unrestricted the present invention.Other formula 1-a or 1-b compound that its preparation is done clearly to describe can prepare with the method for similar approach, or use the preparation of routine operation technology with the known method of those skilled in the art itself.Abbreviation ee represents enantiomeric excess, and S/C is the ratio of substrate than catalyzer, and v is a volume.For the assignment of NMR signal, use following abbreviation: s (unimodal), d (doublet), t (triplet), q (quartet), m (multiplet), b (broad peak).Use following unit: ml (milliliter), L (liter), nm (nanometer), mm (millimeter), mg (milligram), g (gram), mmol (mmole), N (equivalent), M (mole), min (minute), h (hour), MHz (megahertz).

In addition, below abbreviation is used to represent chemical substance:

(S)-Xyl-P-PhOS (S)-4,4 '-two-[two-(3,5-dimethyl-phenyl)-phosphino-]-2,6,2 ', 6 '-tetramethoxy-[3,3 '] bipyridyl

(R)-Xy1-P-PhOS (R)-4,4 '-two-[two-(3,5-dimethyl-phenyl)-phosphino-]-2,6,2 ', 6 '-tetramethoxy-[3,3 '] bipyridyl

(S)-Xyl-BINAP (S)-(2,2 '-two (two (3, the 5-3,5-dimethylphenyl) phosphino-s)-1,1 '-binaphthylyl)

(R)-Xy1-BINAP (R)-(2,2 '-two (two (3, the 5-3,5-dimethylphenyl) phosphino-s)-1,1 '-binaphthylyl)

(S)-and DAIPEN (2S)-(+)-1,1-two (4-p-methoxy-phenyl)-3-methyl isophthalic acid, 2-butanediamine

(R)-and DAIPEN (2R)-(-)-1,1-two (4-p-methoxy-phenyl)-3-methyl isophthalic acid, 2-butanediamine

The DIAD diisopropyl azodiformate

The DIPEA diisopropylethylamine

DMAP 4-(dimethylamino) pyridine

The DMSO dimethyl sulfoxide (DMSO)

The THF tetrahydrofuran (THF)

DME 1, the 2-glycol dimethyl ether

The DMF dimethyl formamide

TBTU O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea  a tetrafluoro borate

The optical purity of formula 1-a, 1-b and 3-a compound is measured by capillary electrophoresis (CE) and/or high pressure lipuid chromatography (HPLC) (HPLC).Give each embodiment (RT=retention time) of test portion by the test test of HPLC enantiomer separation.The CE separation is to use following testing apparatus (MT=transition time) to carry out:

Instrument: Agilent CE-3D

The silicon-dioxide bubble naked molten silicon-dioxide bubbles of (Agilent, the whole embodiment except that 24) 56/64.5cm * 75 μ m (Agilent, embodiment 24) of kapillary: 56/64.5cm * 50 μ m naked molten (barefused)

Buffered soln: 50mM sodium phosphate, pH2.5 (Agilent)

Chiral selector: 40mM seven (2,3,6-three-O-methyl)-beta-cyclodextrin (the whole embodiment except that H) 40mM seven (2,3-two-O-methyl)-6-sulfo--beta-cyclodextrin (embodiment H)

Voltage: 30kV

Temperature: 20 ℃ (the whole embodiment except that 8), 10 ℃ (embodiment 8)

Detect: diode array 219/226nm

The HPLC post that is used for analysis purposes is purchased:

·CHIRALPAK ^AD-H：DAICEL Chemical Industries Ltd，Tokyo or ChiralTechnologies-Europe SARL，llkirch，France

·LichroCART ^250-4 ChiraDex(5μg) ^：Merck KgaA，Darmstadt，Germany

If the NMR that provides (nucleus magnetic resonance) chemical shift is integration not, observed is the signal of corresponding proton of compound and the signal overlap of solvent, water or impurity.

Catalyzer RuCl ₂The preparation of [(S)-Xyl-P-Phos] [(S)-DAIPEN]:

With (benzene) dichloro ruthenium dimer (CAS37366-09-9,1 equivalent) and (S)-Xyl-P-PhOS (CAS443347-10-2, be purchased 1.03 equivalents from Strem Chemicals and Alfa Aesar) place the Schlenk flask, this flask is through vacuumizing and applying argon gas.Add DMF (2ml/mmol) anhydrous, the degassing, flask is placed be preheated to 105 ℃ oil bath again.To be reflected at 105 ℃ stirred 1.5 hours down.Adding (S)-DAIPEN (CAS148369-91-9 is purchased from StremChemicals, 1.1 equivalents) should react and at room temperature stir 3 hours.At this moment, with the diluted sample of reaction mixture in chloroform-d, warp again ³¹The P-NMR spectroscopic analysis.Two of observing required complex compound+a little excessive free ligand only are bimodal.In a vacuum with DMF evaporation (heating in case of necessity), resistates is dissolved in the methylene dichloride (5-10ml/mmol) of anhydrous, the degassing, under argon gas, be placed on again on the silicagel column in the Schlenk filter.Product dilutes with methylene dichloride/methyl tertiary butyl ether=1: 1 (v/v).Clarifying yellow solution is collected in the Schlenk flask, and evaporating solvent obtains Huang/green solid, its further in a vacuum dried overnight.Isolated yield is 90% (adopt Noyori at Angew.Chem.1998,110, the general approach of describing among the 1792-1796).

The asymmetric reduction synthesis type 1-a compound of formula 2 prochiral ketones

1. (3R)-7-hydroxyl-6-(3-hydroxyl-3-phenyl-propyl group)-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide

In the flask of applying argon gas, with 7-hydroxyl-2, (2.0g 5.5mmol) is suspended in Virahol (2.8ml) and the water (4.1ml) 3-dimethyl-6-(3-oxygen-3-phenyl-propyl group)-3H-benzoglyoxaline-5-formic acid diformamide.(1M is in the trimethyl carbinol, 8.0ml), the trimethyl carbinol (20ml) and 22mg hydrogenation catalyst RuCl to add uncle's potassium butyrate solution ₂[(S)-Xyl-P-Phos] [(S)-and DAIPEN], this mixture is transferred in the autoclave, again at 65 ℃ and 80bar H ₂Hydrogenation 23h under the-pressure.After being cooled to room temperature and release hydrogen pressure, reaction mixture is concentrated in a vacuum.With resistates by flash chromatography with silica gel (methylene chloride=14: 1) purifying.Obtain two batches title compound, it is crystallization from acetone: the beige solid of batch 1:0.5g (25% productive rate, m.p.261-263 ℃), the beige solid of batch 2:0.9g (45% productive rate, 98%ee, m.p.263-265 ℃). ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.80(bs，2H)，2.35(bs)，2.50(s)，2.68(s，bs，4 H)，2.89(s，3H)，3.64(s，3H)，4.48(t，1H)，5.13(bs，1H)，6.70(s，1H)，7.25(m _c，5H)，9.85(bs，1H).

Use RuCl ₂[(S)-Xyl-P-Phos] [(S)-and DAIPEN] asymmetric catalytic hydrogenation, the screening of reaction conditions:

With sample 7-hydroxyl-2, and 3-dimethyl-6-(3-oxygen-3-phenyl-propyl group)-3H-benzoglyoxaline-5-formic acid diformamide (referring to table, 0.37g, 1.0mmol, project 16:0.48g, 1.3mmol) and RuCl ₂[(S)-Xyl-P-Phos] [(S)-DAIPEN] (above-mentioned preparation) is weighed in the glass bushing pipe, is placed on Argonaut Endeavour (8 hole pressure parallel reactors, overhead stirrer and heat block) then.With the seal of tube, by blowing for each hole to 2bar with nitrogen pressure 5 times, relief pressure again.Inject alkali (uncle's potassium butyrate of 1M is at the solution or the potassium hydroxide aqueous solution of the trimethyl carbinol, referring to table) and solvent (referring to table) then.By giving each hole blow (stirring down), relief pressure again to 25bar with pressurized with hydrogen 5 times.Then reaction is heated to design temperature (referring to table), and is forced into the hydrogen pressure (referring to table) of setting.After the time, release hydrogen pressure uses methyl alcohol (10ml) to help reaction mixture is transferred in the round-bottomed flask again described in the table.Evaporating solvent is analyzed (mensuration transformation efficiency) with rough sample by HPLC and/or NMR again.

Project	S/C	Concentration of substrate	Solvent and alkali	Temperature (℃)	Pressure (bar)	Whenabouts	Transformation efficiency (%)
								1	500/1	0.1M	1.1mLt-BuOK 1M 0.5mLwater 8.4mLi-PrOH	65	20	16	86
2	500/1	0.25M	1 mL KOH 10M 2.0mL t-BuOH 1.0mLi-PrOH	70	25	16	100
								3	500/1	0.25M	1.2mLt-BuOK 1M 0.4mL water 2.4mLi-PrOH	70	25	16	100
4	500/1	0.5M	1.1mLt-BuOK 1M 0.2mL water 0.7mLi-PrOH	65	25	16	＞97
								5	750/1	0.25M	1.1mLt-BuOK 1M 0.2mL water 2.7mLi-PrOH	65	20	16	83
6	750/1	0.2M	2.0mLt-BuOK 1M 0.5mL H 2O 2.5mLi-PrOH	70	25	16	91
								7	1000/1	0.33M	1.2mLt-BuOK 1M 0.6mL H 2O 1.2mLi-PrOH	75	25	16	51
8	1000/1	0.33M	1.2mLt-BuOK 1M 0.3mL H 2O	75	25	16	79

			1.5mLi-PrOH
								9	1000/1	0.5M	1.2mLt-BuOK 1M 0.2mL H 2O 0.6mLi-PrOH	75	25	16	83
10	1000/1	0.33M	1.2mLt-BuOK 1M 0.3mL H 2O 1.5mLi-PrOH	70	25	16	94
								11	1000/1	0.33M	1.2mLt-BuOK 1M 0.3mL H 2O 1.5mLi-PrOH	65	25	16	75
12	1000/1	0.2M	1.2mLt-BuOK 1M 0.25mLH 2O(5％) 3.25mLi-PrOH	70	25	16	67
								13	1000/1	0.33M	1.2mLt-BuOK 1M 0.3mL H 2O 1.5mLi-PrOH	70	25	16	62
14	1000/1	0.33M	1.5mLt-BuOK 1M 0.3mL H 2O 1.2mLi-PrOH	70	25	16	86
								15	1000/1	0.33M	0.3mLKOH 10M 1.2mLt-BuOH 1.5mLi-PrOH	70	25	16	89
16	1000/1	0.33M	1.0mL KOH 10M 2.0 mLt-BuOH 1.0mLi-PrOH *	70	25	16	92
								17	1500/1	0.2M	2.0mLt-BuOK 1M 0.5mL H 2O 2.5mLi-PrOH	70	25	16	65

Use RuCl ₂[(S)-Xyl-BINAP] [(S)-DAIPEN] asymmetric catalytic hydrogenation: with 7-hydroxyl-2,3-dimethyl-6-(3-oxygen-3-phenyl-propyl group)-3H-benzoglyoxaline-5-formic acid diethylamine (2 * 470mg, 1.26mmol) and RuCl ₂[(S)-Xyl-BINAP] [(S)-and DAIPEN] (every duplicate samples: two duplicate samples 6mg) are weighed in the glass bushing pipe, are placed on ArgonautEndeavour (8 hole pressure parallel reactors, overhead stirrer and heat block) then.With the seal of tube, by blowing for each hole to 2bar with nitrogen pressure 5 times, relief pressure again.Inject then uncle's potassium butyrate (the solution of 1M at the trimethyl carbinol, every duplicate samples: 1.60ml, 1.6mmol) and Virahol (every duplicate samples: 3.6ml).By giving each hole blow (stirring down), relief pressure again to 25bar with pressurized with hydrogen 5 times.Reaction is heated to 70 ℃ then, is forced into the 25bar hydrogen pressure again.After the 20h, release hydrogen pressure is evaporated to drying with reaction mixture again.Resistates is dissolved in methylene dichloride, washs with saturated ammonium chloride solution again.Water with dichloromethane extraction for several times.With the organic layer dried over sodium sulfate that merges, concentrate in a vacuum again, obtain green solid (760mg).With crude product by flash chromatography with silica gel (methylene chloride=10: 1) purifying.Obtain purifying title compound (the yellow foam of 560mg, 60% productive rate, 25.3%ee).

Measure optical purity through CE: MT[(3 S)-enantiomorph]=19.1min/36.2 area-%; MT[(3R)-enantiomorph]=19.6min/60.7 area-%; 25.3%ee.

2. (3R)-7-hydroxyl-6-(3-hydroxyl-3-phenyl-propyl group)-2-methyl-3-(2-trimethyl silyl-ethoxyl methyl)-3H-benzoglyoxaline-5-formic acid diformamide

In the flask of applying argon gas, with 7-hydroxy-2-methyl-6-(3-oxygen-3-phenyl-propyl group)-3-(2-trimethyl silyl-ethoxyl methyl)-3H-benzoglyoxaline-5-formic acid diformamide (embodiment a, 6.4g, 13.2mmol) be dissolved in Virahol (9.3ml), water (2.7ml), the trimethyl carbinol (10ml) and uncle's potassium butyrate solution (1M, in the trimethyl carbinol, 14.6ml) in.Add 33mg hydrogenation catalyst RuCl ₂[(S)-Xyl-P-Phos] [(S)-DAIPEN] is transferred to this mixture in the autoclave again, and under 65 ℃ and 80bar pressure hydrogenation 20h.After being cooled to room temperature and release hydrogen pressure, reaction mixture is concentrated in a vacuum.With resistates by flash chromatography with silica gel (first post: toluene/1,4-two  alkane, second post: methylene chloride=15: 1) purifying, the title compound that obtains 4.9g (77% productive rate) is a white solid.-analytic sample is crystallization from diisopropyl ether/Virahol: m.p.142-143 ℃.

Enantiomeric excess is to change into (8S)-2-methyl-8-phenyl-3,6,7 at title compound, and 8-tetrahydrochysene-chromene also [7,8-d] imidazoles-5-formic acid diformamide (Embodiment B, C) is measured afterwards. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝-0.10(s，9H)，0.82(t，2H)，1.80(bs，2H)，2.55(s，bs)，2.67(s)，2.89(s，3H)，3.51(t，2H)，4.49(dt，1H)，5.14(d，1H)，5.49(s，2H)，6.82(s，1H)，7.26(m _c，5H)，9.77(bs，1H).

3. (3R)-azetidine-1-base-[7-hydroxyl-6-(3-hydroxyl-3-phenyl-propyl group)-2,3-dimethyl-3H-benzoglyoxaline-5-yl]-ketone

In the flask of applying argon gas, with 3-[6-(azetidine-1-carbonyl)-4-hydroxyl-1,2-dimethyl-1H-benzoglyoxaline-5-yl]-1-phenyl-third-1-ketone (embodiment e, 2.8g, 7.6mmol) be suspended in Virahol (18.2ml), water (3ml) and uncle's potassium butyrate solution (1M, in the trimethyl carbinol, 9.1ml) in.Add 22mg hydrogenation catalyst RuCl ₂[(S)-Xyl-P-Phos] [(S)-DAIPEN] is transferred to this mixture in the autoclave again, and under 65 ℃ and 80bar pressure hydrogenation 2d.After being cooled to room temperature and release hydrogen pressure, reaction mixture is concentrated in a vacuum.Resistates by flash chromatography silica gel (methylene chloride=10: 1) purifying, is obtained 0.93g (32% productive rate; Title compound 85%ee) is the beige solid.-m.p.265-266℃。

Measure optical purity through CE: MT[(3S)-enantiomorph]=23.1min/7.6 area-%; MT[(3R)-enantiomorph]=23.8min/92.4 area-%; 84.8%ee. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.83(m _c，2H)，2.15(m _c，2H)，2.50，2.55(s，m _c)，2.77(m _c，1H)，3.66(s，3H)，3.80(t，2H)，3.93(t，2H)，4.48(t，1H)，5.21(bs，1H)，6.81(s，1H)，7.26(m _c，5H)，9.80(bs，1H).

4. (3R)-7-hydroxyl-6-(3-hydroxyl-3-phenyl-propyl group)-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid methyl nitrosourea

In the flask of applying argon gas, with 7-hydroxyl-2,3-dimethyl-6-(3-oxygen-3-phenyl-propyl group)-3H-benzoglyoxaline-5-formic acid methyl nitrosourea (embodiment g, 4.4g, 12.5mmol) be suspended in Virahol (30ml), water (5ml) and uncle's potassium butyrate solution (1M, in the trimethyl carbinol, 15ml) in.Add 31mg hydrogenation catalyst RuCl ₂[(S)-Xyl-P-Phos] [(S)-DAIPEN] is transferred to this suspension in the autoclave again, and under 65 ℃ and 80bar pressure hydrogenation 3d.After being cooled to room temperature and release hydrogen pressure, reaction mixture is concentrated in a vacuum.By flash chromatography silica gel (methylene chloride=10: 1) purifying, (52% productive rate, title compound 77%ee) is the light green solid to obtain 2.3g with resistates.-m.p.247-249℃。

Measure optical purity through CE: MT[(3S)-enantiomorph]=24.5min/11.7 area-%; MT[(3R)-enantiomorph]=25.3min/87.7 area-%; 76.5%ee. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.85(m _c，2H)，2.50，2.53(s，m _c)，2.71，2.77(d，m _c，4H)，3.66(s，3H)，4.46(bt，1H)，5.25(bs，1H)，6.88(s，1H)，7.25(m _c，5H)，8.00(q，1H)，9.70(bs，1H).

5. (3R)-6-[3-(2-fluoro-phenyl)-3-hydroxyl-propyl group]-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide

In the flask of applying argon gas, with 6-[3-(2-fluoro-phenyl)-3-oxygen-propyl group]-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide (embodiment k, 3.7g, 9.6mmol) be dissolved in Virahol (4.9ml), water (1.2ml) and uncle's potassium butyrate solution (1M, in the trimethyl carbinol, 14.1ml) in.Add 38.6mg hydrogenation catalyst RuCl ₂[(S)-Xyl-P-Phos] [(S)-DAIPEN] is transferred to this mixture in the autoclave again, and under 65 ℃ and 80bar pressure hydrogenation 20h.After being cooled to room temperature and release hydrogen pressure, reaction mixture is concentrated in a vacuum.Resistates is dissolved in methylene dichloride (300ml) and saturated ammonium chloride solution (50ml)., be separated this solution neutralization by careful interpolation 2N HCl.(2 * 50ml) extract water with methylene dichloride.With the organic phase dried over mgso that merges, concentrate in a vacuum again.With resistates by flash chromatography with silica gel (methylene chloride=14: 1) purifying, crystallization from acetone again, the title compound that obtains 1.7g (49%) is the light green solid.-m.p.264-266℃。

Enantiomeric excess is to change into (8S)-8-(2-fluoro-phenyl) 2 at title compound, and 3-dimethyl-3,6,7,8-tetrahydrochysene-chromene also [7,8-d] imidazoles-5-formic acid diformamide (embodiment F) are measured afterwards.

¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.79(m _c，2H)，2.50(s，bs)，2.68(s，bs，4H)，2.88(s，3H)，3.64(s，3H)，4.82(bt，1H)，5.26(bs，1H)，6.70(s，1H)，7.17(m _c，3H)，7.49(dt，1H)，9.80(bs，1H).

6. (3R)-6-[-(4-fluoro-phenyl)-3-hydroxyl-propyl group]-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide

In the flask of inflated with nitrogen, with 6-[3-(4-fluoro-phenyl)-3-oxygen-propyl group]-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide (example I, 5.1g, 13.3mmol) be suspended in Virahol (9.5ml), water (2.7ml), uncle's potassium butyrate solution (1M, in the trimethyl carbinol, 14.6ml) and in the trimethyl carbinol (1.9ml).This suspension is diluted with Virahol (35ml).Add 33mg hydrogenation catalyst RuCl ₂[(S)-Xyl-P-Phos] [(S)-DAIPEN] is transferred to this suspension in the autoclave again, and under 65 ℃ and 80bar pressure hydrogenation 16h.After being cooled to room temperature and release hydrogen pressure, reaction mixture is concentrated in a vacuum.Resistates is dissolved in methylene dichloride, adds saturated ammonium chloride solution.Be separated.With the organic phase dried over mgso, silica gel exists concentrated down in a vacuum again.By flash chromatography silica gel (methylene chloride=20: 1) purifying, crystallization from acetone again obtains 1.8g (35% productive rate with crude product; Title compound 88%ee) is a white solid.-m.p.276-277℃。

Measure optical purity through CE: MT[(3S)-enantiomorph]=21.4min/6.2 area-%; MT[(3R)-enantiomorph]=21.8min/93.3 area-%; 87.6%ee. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.80(bs，2H)，2.40，2.49(bs，s)，2.68(s，bs，4 H)，2.89(s，3H)，3.64(s，3H)，4.50(t，1H)，5.19(bs，1H)；6.70(s，1H)，7.12(t，2H)，7.33(dd，2 H)，9.90(bs，1H).

7. (3R)-7-hydroxyl-6-(3-hydroxyl-3-o-tolyl-propyl group)-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide

Use RuCl ₂[(S)-Xyl-P-Phos] [(S)-and DAIPEN] asymmetric catalytic hydrogenation, pass through purified by flash chromatography: in the flask of applying argon gas, with 7-hydroxyl-2,3-dimethyl-6-(3-oxygen-3-o-tolyl-propyl group)-3H-benzoglyoxaline-5-formic acid diformamide (embodiment m, 6.0g, 15.8mmol) be dissolved in the Virahol (40ml), slowly add uncle's potassium butyrate solution (1M again, in the trimethyl carbinol, 19ml).Add 198mg hydrogenation catalyst RuCl ₂[(S)-Xyl-P-Phos] [(S)-DAIPEN] is transferred to this mixture in the autoclave again, and under 65 ℃ and 80bar pressure hydrogenation 4d.After being cooled to room temperature and release hydrogen pressure, reaction mixture is concentrated in a vacuum.Resistates by flash chromatography silica gel (methylene chloride=10: 1) purifying, is obtained 4.9g (82% productive rate; Title compound 87%ee) is the light green solid.-m.p.139-140℃。

Measure optical purity through CE: MT[(3S)-enantiomorph]=19.6min/6.4 area-%; MT[(3R)-enantiomorph]=20.4min/88.8 area-%; 86.6%ee. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.79(bs，2H)，2.22(s，3H)，2.49(s，bs)，2.70(s，3H)，2.93(s，bs，4H)，3.65(s，3H)，4.69(bt，1H)，5.03(bs，1H)，6.71(s，1H)，7.13(m _c，3H)，7.41(m _c，1H)，9.85(bs，1H).

Use RuCl ₂[(S)-Xyl-P-Phos] [(S)-and DAIPEN] asymmetric catalytic hydrogenation, by crystallization purifying from acetone: in the flask of applying argon gas, with 7-hydroxyl-2,3-dimethyl-6-(3-oxygen-3-o-tolyl-propyl group)-3H-benzoglyoxaline-5-formic acid diformamide (embodiment m, 35.0g, 92mmol) be suspended in the Virahol (340ml) of the degassing, slowly add uncle's potassium butyrate solution (1M again, in the trimethyl carbinol, 101ml).Should at room temperature stir up to obtaining a solution (20min) by the yellow suspension.Add hydrogenation catalyst RuCl ₂[(S)-Xyl-P-Phos] [(S)-DAIPEN] (1.14g, 0.92mmol).Continue stirred for several minute again.Change device (inlay) over to glass brown solution transferred in the 2L autoclave, blow hydrogen (3x), and under 65 ℃ and 80bar pressure hydrogenation 20h.After being cooled to room temperature and release hydrogen pressure, reaction mixture is poured in the mixture of the saturated ammonium chloride solution (400ml) of stirring and methylene dichloride (700ml).Be separated, (2 * 80ml) extract water with methylene dichloride.With organic phase water (400ml) washing that merges, use dried over sodium sulfate, under reduced pressure concentrate again.(green foam of 41g 94.9%ee) is dissolved in the hot acetone (100ml) with resistates.Be cooled to room temperature, the beginning crystallization.3h and after 0 ℃ of following 2h at room temperature, by this throw out of filtering separation, with acetone (20ml) and ether (40ml) washing, drying in a vacuum again.Title compound be with colorless solid isolated in form (26.5g, 76% productive rate, 93.8%ee).-m.p.215-217℃。

Measure optical purity through CE: MT[(3S)-enantiomorph]=19.9min/3.1 area-%; MT[(3R)-enantiomorph]=20.7min/96.9 area-%; 93.8%ee.

Use RuCl ₂[(S)-Xyl-P-Phos] [(S)-and DAIPEN] asymmetric catalytic hydrogenation, by crystallization purifying from methyl iso-butyl ketone (MIBK): in the flask of applying argon gas, with 7-hydroxyl-2,3-dimethyl-6-(3-oxygen-3-o-tolyl-propyl group)-3H-benzoglyoxaline-5-formic acid diformamide (embodiment m, 4.0g, 10.5mmol) be suspended in the Virahol (37ml) of the degassing, slowly add uncle's potassium butyrate solution (1M again, in the trimethyl carbinol, 13ml).Should at room temperature stir up to obtaining solution (20min) by the yellow suspension.Add hydrogenation catalyst RuCl ₂(0.13g 0.10mmol), continues stirred for several minute to [(S)-Xyl-P-Phos] [(S)-DAIPEN] again.This brown solution is transferred to the 100ml autoclave, blows hydrogen (3x), and under 65 ℃ and 80bar pressure hydrogenation 20h.After being cooled to room temperature and release hydrogen pressure, reaction mixture is poured in the mixture of the saturated ammonium chloride solution (80ml) of stirring and methylene dichloride (200ml).Be separated, (2 * 30ml) extract water with methylene dichloride.With organic phase water (80ml) washing that merges, use dried over sodium sulfate, under reduced pressure concentrate again.(green foam of 3.6g 83.8%ee) is dissolved in temperature (50 ℃) methyl iso-butyl ketone (MIBK) (20ml) with resistates.Be cooled to room temperature, the beginning crystallization.At room temperature after the 40h,,, dry in a vacuum again with methyl iso-butyl ketone (MIBK) (4ml) and ether (10ml) washing by this throw out of filtering separation.Title compound be with colorless solid isolated in form (3.2g, 80% productive rate, 83.8%ee).-m.p.200-202℃。

Measure optical purity through CE: MT[(3S)-enantiomorph]=21.1min/8.1 area-%; MT[(3R)-enantiomorph]=21.9min/91.9 area-%; 83.8%ee.

Use RuCl ₂[(S)-Xyl-P-Phos] [(S)-and DAIPEN] asymmetric catalytic hydrogenation, by crystallization purifying from methyl ethyl ketone: in the flask of applying argon gas, with 7-hydroxyl-2,3-dimethyl-6-(3-oxygen-3-o-tolyl-propyl group)-3H-benzoglyoxaline-5-formic acid diformamide (embodiment m, 4.7g, 12.4mmol) be suspended in the Virahol (29ml) of the degassing, slowly add uncle's potassium butyrate solution (1M again, in the trimethyl carbinol, 21ml).Should at room temperature stir up to obtaining solution (20min) by the yellow suspension.Add hydrogenation catalyst RuCl ₂(153mg 0.12mmol), continues stirred for several minute to [(S)-Xyl-P-Phos] [(S)-DAIPEN] again.This brown solution is transferred to the 100ml autoclave, blows hydrogen (3x), and under 65 ℃ and 80bar pressure hydrogenation 20h.After being cooled to room temperature and release hydrogen pressure, reaction mixture is poured in the mixture of the saturated ammonium chloride solution (80ml) of stirring and methylene dichloride (220ml).Be separated, (2 * 30ml) extract water with methylene dichloride.With organic phase water (50ml) washing that merges, use dried over sodium sulfate, under reduced pressure concentrate again.The acquisition green foam (3.5g, 84.2%ee).Part crude product (2.5g) is dissolved in heat (70 ℃) methyl ethyl ketones (20ml).This solution is at room temperature stirred 40h.Form throw out, it is by filtering separation, with hot methyl ethyl ketone (5ml) and ether (10ml) washing, dry in a vacuum again.Obtain title compound (460mg), optical purity 42.8%ee.Mother liquor is concentrated, measure optical purity (92.4%ee) again.Resistates is dissolved in hot Virahol (8ml), adds oxalic acid (0.71g, 7.9mmol) solution in Virahol (4ml) again.Obtain suspension, it with Virahol (4ml) dilution, is at room temperature stirred 3d again.By this throw out of filtering separation,, dry in a vacuum again with Virahol (5ml) and ether (10ml) washing.The salt (2.1g, m.p.158 ℃) of title compound and oxalic acid is added in batches in the mixture of sodium bicarbonate (1.8g), water (30ml) and methylene dichloride (70ml) of stirring.Be separated, (2 * 10ml) extract water with methylene dichloride.With organic phase water (50ml) washing that merges, use dried over sodium sulfate, under reduced pressure concentrate again.Resistates (the yellow foam of 1.8g) is dissolved in temperature (50 ℃) methyl iso-butyl ketone (MIBK) (10ml).Be cooled to room temperature, the beginning crystallization.At room temperature after the 2h,,, dry in a vacuum again with methyl iso-butyl ketone (MIBK) (2ml) and ether (10ml) washing by this throw out of filtering separation.With the isolated in form title compound of colorless solid (1.3g, 28% productive rate, 39% correcting yield, 94.0%ee).-m.p.202-204℃。

Measure optical purity through CE: MT[(3S)-enantiomorph]=21.1min/3.0 area-%; MT[(3R)-enantiomorph]=22.0min/97.0 area-%; 94.0%ee.

Use RuCl ₂[(S)-Xyl-P-Phos] [(S)-and DAIPEN] asymmetric catalytic hydrogenation, there is crystallization purifying down by oxalic acid: in the flask of applying argon gas, with 7-hydroxyl-2,3-dimethyl-6-(3-oxygen-3-o-tolyl-propyl group)-3H-benzoglyoxaline-5-formic acid diformamide (embodiment m, 5.0g, 13.2mmol) be suspended in the Virahol (35.5ml) of the degassing, slowly add uncle's potassium butyrate solution (1M again, in the trimethyl carbinol, 14.5ml).Should at room temperature stir up to obtaining solution (30min) by the yellow suspension.Add hydrogenation catalyst RuCl ₂(165mg 0.13mmol), continues stirred for several minute to [(S)-Xyl-P-Phos] [(S)-DAIPEN] again.This brown solution is transferred to the 100ml autoclave, blows hydrogen (3x), and under 65 ℃ and 80bar pressure hydrogenation 20h.After being cooled to room temperature and release hydrogen pressure, reaction mixture is poured in the mixture of the saturated ammonium chloride solution (100ml) of stirring and methylene dichloride (220ml).Be separated, (2 * 30ml) extract water with methylene dichloride.With organic phase water (100ml) washing that merges, use dried over sodium sulfate, under reduced pressure concentrate again.(green foam of 4.9g 89.0%ee) is dissolved in temperature (60 ℃) Virahols (15ml), adds oxalic acid (1.7g, 18.9mmol) hot solution in Virahol (10ml) again with resistates.Form suspension, it is at room temperature stirred 2h, stir 2h down at 0 ℃ again.By this throw out of filtering separation,, dry in a vacuum again with Virahol (8ml) and ether (15ml) washing.Obtain the salt of title compound and oxalic acid, 90% productive rate (colorless solid of 5.6g, m.p.146 °-148 ℃) adds to it in mixture of sodium bicarbonate (5g), water (80ml) and methylene dichloride (100ml) of stirring in batches.Be separated, (3 * 20ml) extract water with methylene dichloride.With organic phase water (80ml) washing that merges, use dried over sodium sulfate, under reduced pressure concentrate again.Resistates (the light brown foam of 4.45g) is dissolved in temperature (50 ℃) methyl iso-butyl ketone (MIBK) (25ml).Be cooled to room temperature, the beginning crystallization.At room temperature after 3d and the 0 ℃ of following 2h, by this throw out of filtering separation, with methyl iso-butyl ketone (MIBK) (8ml) and ether (30ml) washing, drying in a vacuum again.Title compound be with colorless solid isolated in form (3.95g, 78% productive rate, 89.4%ee).-m.p.203-205℃。

Measure optical purity through CE: MT[(3S)-enantiomorph]=20.1min/5.3 area-%; MT[(3R)-enantiomorph]=20.8min/94.7 area-%; 89.4%ee.

The salt of title compound and oxalic acid ¹H NMR data (DMSO-d ₆, 200MHz): δ=1.81 (m _c, 2H), 2.23 (s, 3H), 2.58 (s, bs, 4H), 2.70 (s, 3H), 2.93 (s, bs, 4H), 3.70 (s, 3H), 4.71 (m _c, 1H), 6.85 (s, 1H), 7.08 (m _c, 3H), 7.41 (m _c, 1H).

Use RuCl ₂[(S)-Xy1-P-Phos] [(S)-and DAIPEN] asymmetric catalytic hydrogenation, passing through crystallization purifying in the presence of the amygdalic acid: in the flask at applying argon gas, with 7-hydroxyl-2,3-dimethyl-6-(3-oxygen-3-o-tolyl-propyl group)-3H-benzoglyoxaline-5-formic acid diethylamine (embodiment m, 70.0g, 184mmol) be suspended in the Virahol (680ml) of the degassing, add uncle's potassium butyrate solution (1M again, in the trimethyl carbinol, 203ml).Should at room temperature stir up to obtaining solution (30min) by the yellow suspension.Add hydrogenation catalyst RuCl ₂[(S)-Xyl-P-Phos] [(S)-and DAIPEN] (2.3g 1.84mmol), continues to stir 30min again.Change device (inlay) over to glass brown solution transferred in the 2L autoclave, blow hydrogen (3x), and under 65 ℃ and 80bar pressure hydrogenation 20h.After being cooled to room temperature and release hydrogen pressure, reaction mixture is poured in the mixture of the saturated ammonium chloride solution (700ml) of stirring and methylene dichloride (1300ml).Be separated, (2 * 100ml) extract water with methylene dichloride.With organic phase water (1L) washing that merges, use dried over sodium sulfate, under reduced pressure concentrate again.(green foam of 80g 90.6%ee) is dissolved in the hot acetone (500ml), adds (S)-amygdalic acid (33.0g, 217mmol) hot solution in acetone (100ml) again with resistates.This dark solution is stirred 10min down at 60 ℃, at room temperature stir 17h again.Form suspension, it is stirred 2h down at 0 ℃.By this throw out of filtering separation,, dry in a vacuum again with acetone (50ml) and ether (80ml) washing.Obtain title compound with (S)-salt of amygdalic acid, 78% productive rate (colorless solid of 77.0g, m.p.178 °-180 ℃) adds to it in mixture of sodium bicarbonate (60g), water (400ml) and methylene dichloride (400ml) of stirring in batches.Be separated, (2 * 80ml) extract water with methylene dichloride.With organic phase water (200ml) washing that merges, use dried over sodium sulfate, under reduced pressure concentrate again.Resistates (green foam of 66.5g) is dissolved in hot acetone (150ml).Be cooled to room temperature, the beginning crystallization.At room temperature 17h is after 0 ℃ of following 2h, by this throw out of filtering separation, with acetone (30ml) and ether (50ml) washing, dry in a vacuum more again.Title compound be with colorless solid isolated in form (50.0g, 71% productive rate, 95.4%ee).-m.p.207-209℃。

Measure optical purity through CE: MT[(3S)-enantiomorph]=19.8min/2.3 area-%; MT[(3R)-enantiomorph]=20.7min/97.7 area-%; 95.4%ee.

Title compound with (S)-salt of amygdalic acid ¹H NMR data (DMSO-d ₆, 200MHz): δ=1.79 (m _c, 2H), 2.22 (s, 3H), 2.51 (s, bs), 2.69 (s, 3H), 2.92 (s, bs, 4H), 3.65 (s, 3H), 4.69 (m _c, 1H), 5.02 (s, bs, 2H), 6.71 (s, 1H), 7.13 (m _c, 3H), 7.34 (m _c, 6H), 9.82 (bs, 1H).

Use RuCl ₂[(S)-Xyl-P-Phos] [(S)-DAIPEN] and S/C ratio are 250: 1 asymmetric catalytic hydrogenation: in the flask of applying argon gas, with 7-hydroxyl-2,3-dimethyl-6-(3-oxygen-3-o-tolyl-propyl group)-3H-benzoglyoxaline-5-formic acid diformamide (embodiment m, 10.0g, 26.3mmol) be suspended in the Virahol (20ml) of the degassing, (1M is in the trimethyl carbinol, 30ml) slowly to add uncle's potassium butyrate solution again.Should at room temperature stir up to obtaining solution (30min) by the yellow suspension.Add hydrogenation catalyst RuCl ₂(130mg 0.10mmol), continues stirred for several minute to [(S)-Xyl-P-Phos] [(S)-DAIPEN] again.This brown solution is transferred to the 100ml autoclave, blows hydrogen (3x), and under 65 ℃ and 80bar pressure hydrogenation 2d.After being cooled to room temperature and release hydrogen pressure, reaction mixture is poured in the mixture of the saturated ammonium chloride solution (120ml) of stirring and methylene dichloride (200ml).Be separated, (2 * 50ml) extract water with methylene dichloride.With organic phase water (150ml) washing that merges, use dried over sodium sulfate, under reduced pressure concentrate again.(green foam of 10g 90.5%ee) is dissolved in the hot acetone (40ml), adds (S)-amygdalic acid (4.6g, 30.2mmol) hot solution in acetone (20ml) again with resistates.Be cooled to room temperature, obtain suspension, it is at room temperature stirred 3h.By this throw out of filtering separation,, dry in a vacuum again with acetone (15ml) and ether (20ml) washing.Obtain title compound with (S)-salt of amygdalic acid, 66% productive rate (little yellow solid of 9.3g, m.p.174 °-176 ℃) adds to it in mixture of sodium bicarbonate (7g), water (40ml) and methylene dichloride (100ml) of stirring in batches.Be separated, (2 * 10ml) extract water with methylene dichloride.With organic phase water (60ml) washing that merges, use dried over sodium sulfate, under reduced pressure concentrate again.Resistates (the yellow foam of 7.5g) is dissolved in hot acetone (25ml).Be cooled to room temperature, the beginning crystallization.At room temperature after the 3h,,, dry in a vacuum again with acetone (15ml) and ether (20ml) washing by this throw out of filtering separation.Title compound be with little yellow solid isolated in form (5.1g, 51% productive rate, 94.9%ee).-m.p.200-202℃。

Measure optical purity through CE: MT[(3S)-enantiomorph]=18.6min/2.55 area-%; MT[(3R)-enantiomorph]=19.3min/97.45 area-%; 94.9%ee.

Use RuCl ₂[(S)-Xyl-P-Phos] [(S)-and DAIPEN] asymmetric catalytic hydrogenation, the screening reaction conditions:

With RuCl ₂[(S)-Xyl-PPhos] [(S)-DAIPEN] and 7-hydroxyl-2,3-dimethyl-6-(3-oxygen-3-o-tolyl-propyl group)-3H-benzoglyoxaline-5-formic acid diformamide is weighed in the glass bushing pipe, place again the Parr microwave reactor (volume: 25ml-300ml), with its nitrogen blowing 5 times, blow hydrogen 5 times.Add uncle's potassium butyrate solution (1M is in the trimethyl carbinol) and Virahol.Then autoclave is not with to stir and is blown hydrogen 5 times, band stirs and blows hydrogen 5 times again.Pressure is set to 30bar, again with this mixture heating up to 65 ℃.To react under these conditions and stir 17-24h.Be cooled to (yellow mercury oxide occurring) after the room temperature evaporating solvent; Resistates is dissolved in methylene dichloride (100ml), uses saturated ammonium chloride solution (100ml) washing again.Water with dichloromethane extraction for several times.With the organic layer dried over sodium sulfate that merges, concentrate in a vacuum again, obtain green solid.Transformation efficiency and enantiomeric excess are measured by HPLC.

Project	S/C	Substrate	Solvent and alkali	Temperature (℃)	Pressure (bar)	Time	Transformation efficiency (%)	θθ(％)
									1	100/1	0.38g (1.0mmol)	2.8mlt-BuOK(1M int-BuOH)，2.2ml iPrOH(0.18M)	65	30	116h	11000	93
2	100/1	0.82g (2.2mmol)	5.9mlt-BuOK(1Min t-BuOH)，6.1ml iPrOH(0.18M)	65	30	72h	100	95
									3	100/1	2.04g (5.4mmol)	14.9mlt-BuOK(1M int-BuOH)，15.1ml iPrOH(0.18M)	65	30	16h	11000	92
4	100/1	5.47g (14.4mmol)	39.7mlt-BuOK(1M int-BuOH)，40.3ml iPrOH(0.18M)	65	30	16h	＞97	95
									5	250/1	2.04g (5.4mmol)	15ml t-BuOK(1Min t-BuOH)，15ml iPrOH(0.18M)	65	30	16h	100	92
6	250/1	0.38g (1.0mmol)	1.7ml t-BuOK(1M int-BuOH)，3.3ml iPrOH(0.18M)	65	30	16h	11000	95
									7	250/1	0.38g (1.0mmol)	2.8mlt-BuOK(1M int-BuOH)，2.2ml iPrOH(0.18M)	65	30	16h	100	89

HPLC analytical procedure: post: Merck LichroCART 250-4, Chiradex (5 μ g)-elutriant: methanol: 20/80,1ml/min-first wash-out enantiomorph: the 12.8min, second wash-out enantiomorph: the 17.2min, starting raw material: 23.0min.

8. (3R)-6-[3-(2-chloro-phenyl)-3-hydroxyl-propyl group]-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide

With catalyzer RuCl ₂[(S)-Xyl-PPhos] [(S)-DAIPEN] (15mg) and 6-[3-(2-chloro-phenyl)-3-oxygen-propyl group]-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide (embodiment n, 479mg, 1.25mmol) be weighed in the glass bushing pipe, place again the Parr microwave reactor (volume: 25ml), with its nitrogen blowing 5 times, blow hydrogen 5 times.(1M is in the trimethyl carbinol, 3.4ml) and Virahol (3ml) to add uncle's potassium butyrate solution.Then autoclave is not with to stir and is blown hydrogen 5 times, band stirs and blows 5 times again.Pressure is set to 25-30bar, again with this mixture heating up to 65 ℃.To react under these conditions and stir 20h.Be cooled to after the room temperature evaporating solvent.Resistates is dissolved in methylene dichloride, washs with saturated ammonium chloride solution again.Water with dichloromethane extraction for several times.With the organic layer dried over sodium sulfate that merges, concentrate in a vacuum again, obtain green solid (440mg).Transformation efficiency (＞95%) and enantiomeric excess (94%ee) are measured by HPLC.Part crude product (400mg) is by flash chromatography silica gel (methylene chloride=100: 3) purifying.Obtain purifying title compound (the spumescence solid of 220mg, 44% productive rate, 48% correcting yield, 88.4%ee).

HPLC analytical procedure: post: Merck LichroCART 250-4, Chiradex (5 μ g)-elutriant: methanol: 25/75,1ml/min-first wash-out enantiomorph: the 19.2min, second wash-out enantiomorph: the 24.8min, starting raw material: 27.6min.

Measure optical purity through CE: MT[(3S)-enantiomorph]=21.9min/5.8 area-%; MT[(3R)-enantiomorph]=23.7min/94.2 area-%; 88.4%ee. ¹H-NMR(DMSO-d ₆，400MHz)：δ＝1.69(bs，1H)，1.81(bs，1H)，2.38，2.50(bs，s)，2.69，2.70(s，bs，4H)，2.89(s，3H)，3.64(s，3H)，4.89(bs，1H)，5.34(bs，1H)，6.70(s，1H)，7.24(m _c，1H)，7.35(m _c，2H)，7.58(d，1H)，9.78(bs，1H).

9. (3R)-7-hydroxyl-6-[3-hydroxyl-3-(2-trifluoromethyl-phenyl)-propyl group]-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide

With sample 7-hydroxyl-2,3-dimethyl-6-[3-oxygen-3-(2-trifluoromethyl-phenyl)-propyl group]-3H-benzoglyoxaline-5-formic acid diformamide (embodiment o is referring to table) and RuCl ₂[(S)-Xyl-P-Phos] [(S)-DAIPEN] (above-mentioned preparation) is weighed in the glass bushing pipe, is placed on ArgonautEndeavour (8 hole pressure parallel reactors, overhead stirrer and heat block) then.With the seal of tube, by blowing for each hole to 2bar with nitrogen pressure 5 times, relief pressure again.Inject alkali (1 uncle's M potassium butyrate solution is in the trimethyl carbinol) and Virahol then.By giving each hole blow (stirring down), relief pressure again to 25bar with pressurized with hydrogen 5 times.Then reaction is heated to design temperature (referring to table), and is forced into the hydrogen pressure (referring to table) of setting.After the time, release hydrogen pressure uses methyl alcohol (10ml) to help reaction mixture is transferred in the round-bottomed flask again described in the table.Evaporating solvent is analyzed (measuring transformation efficiency and optical purity) with rough sample by HPLC again.

Project	S/C	Substrate	Solvent and alkali	Temperature (℃)	Pressure (bar)	Time	Transformation efficiency (%)	ee(％)
									1	100/1	195mg (0.45mmol)	0.9mlt-BuOK(1 M in t-BuOH)，1.6ml iPrOH(0.18 M)	65	25	16 h	＞95	＞80
2-3	100/1	390mg (0.90mmol)	1.8mlt-BuOK(1Min t-BuOH)，3.2ml iPrOH(0.18M)	65	25	16 h	＞95	＞80

The sample dissolution that merges in methylene dichloride, is washed with saturated ammonium chloride solution again.Water with dichloromethane extraction for several times.With the organic layer dried over sodium sulfate that merges, concentrate in a vacuum again, obtain green solid (630mg).Part crude product (590mg) is by flash chromatography silica gel (methylene chloride=50: 1 to 10: 1) purifying.Obtain purifying title compound (150mg, 15% productive rate, 16% correcting yield, 72.6%ee).

HPLC analytical procedure: post: Merek LichroCART 250-4, Chiradex (5 μ g)-elutriant: methanol: 15/85,0.8ml/min-first wash-out enantiomorph: the 12.8min, second wash-out enantiomorph: the 17.2min, starting raw material: 21.0min.

Measure optical purity through CE: MT[(3S)-enantiomorph]=21.0min/13.7 area-%; MT[(3R)-enantiomorph]=21.4min/86.3 area-%; 72.6%ee. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.67(m _c，1H)，1.89(m _c，1H)，2.50(bs，s)，2.69(s，3 H)，2.92(bs，s，4H)，3.64(s，3H)，4.85(bs，1H)，5.43(bs，1H)，6.70(s，1H)，7.43(m _c，1H)，7.66(m _c，2 H)，7.77(m _c，1H)，9.93(bs，1H).

10. (3R)-7-hydroxyl-6-(3-hydroxyl-3-naphthalene-2-base-propyl group)-2,3-dimethyl-3H-benzoglyoxaline-S-formic acid diformamide

With catalyzer RuCl ₂[(S)-Xyl-PPhos] [(S)-DAIPEN] (12mg) and 7-hydroxyl-2,3-dimethyl-6-(3-naphthalene-2-base-3-oxygen-propyl group)-3H-benzoglyoxaline-5-formic acid diformamide (embodiment p, 400mg, 1.0mmol) be weighed in the glass bushing pipe, place again the Parr microwave reactor (volume: 25ml), with its nitrogen blowing 5 times, blow hydrogen 5 times.(1M is in the trimethyl carbinol, 2.75ml) and Virahol (2.5ml) to add uncle's potassium butyrate solution.Then autoclave is not with to stir and is blown hydrogen 5 times, band stirs and blows 5 times again.Pressure is set to 25-30bar, again with this mixture heating up to 65 ℃.To react under these conditions and stir 20h.Be cooled to after the room temperature evaporating solvent.Resistates is dissolved in methylene dichloride, washs with saturated ammonium chloride solution again.Water with dichloromethane extraction for several times.With the organic layer dried over sodium sulfate that merges, concentrate in a vacuum again, obtain green solid (340mg).Transformation efficiency (100%) is measured by HPLC.Part crude product (300mg) is by flash chromatography silica gel (methylene chloride=15: 1) purifying.Obtain the title compound (green solid of 164mg, 39% productive rate, 45% correcting yield) of purifying.-m.p.145-147℃。

Enantiomeric excess is to change into (8S)-2 at title compound, and 3-dimethyl-S-naphthalene-2-base-3,6,7,8-tetrahydrochysene-chromene also [7,8-d] imidazoles-5-formic acid diformamide hydrochloride (embodiment K) are measured afterwards.

¹H-NMR(DMSO-d ₆，400MHz)：δ＝1.81(bs，1H)，2.01(bs，1H)，2.50(s，bs)，2.66(s，3 H)，2.78(s，bs，4H)，3.64(s，3H)，4.66(bs，1H)，5.29(bs，1H)，6.69(s，1H)，7.48(m _c，3H)，7.81(s，1H)，7.88(m _c，3H)，9.73(bs，1H).

11. (3R)-6-[3-(2-ethyl-phenyl)-3-hydroxyl-propyl group]-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide

With catalyzer RuCl ₂[(S)-Xyl-PPhos] [(S)-DAIPEN] (11mg) and 6-[3-(2-ethyl-phenyl)-3-oxygen-propyl group]-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide (embodiment q, 340mg, 0.9mmol) be weighed in the glass bushing pipe, place again the Parr microwave reactor (volume: 25ml), with its nitrogen blowing 5 times, blow hydrogen 5 times.(1 M is in the trimethyl carbinol, 2.47ml) and Virahol (2.53ml) to add uncle's potassium butyrate solution.Then autoclave is not with to stir and is blown hydrogen 5 times, band stirs and blows 5 times again.Pressure is set to 25-30bar, again with this mixture heating up to 65 ℃.To react under these conditions and stir 20h.Be cooled to after the room temperature evaporating solvent.Resistates is dissolved in methylene dichloride, washs with saturated ammonium chloride solution again.Water with dichloromethane extraction for several times.With the organic layer dried over sodium sulfate that merges, concentrate in a vacuum again, obtain green solid (310mg).Transformation efficiency (＞95%) and enantiomeric excess (85%ee) are measured by HPLC.Part crude product (280mg) is by flash chromatography silica gel (methylene chloride=100: 3) purifying.Obtain purifying title compound (pale solid of 150mg, 42% productive rate, 51% correcting yield, 86.4%ee).-m.p.135-137℃。

HPLC analytical procedure: post: Merck LichroCART 250-4, Chiradex (5 μ g)-elutriant: methanol: 20/80,1ml/min-first wash-out enantiomorph: the 13.5min, second wash-out enantiomorph: the 19.4min, starting raw material: 28.1min.

Measure optical purity through CE: MT[(3S)-enantiomorph]=20.5min/6.8 area-%; MT[(3R)-enantiomorph]=21.8min/93.2 area-%; 86.4%ee. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.12(t，3H)，1.75(bs，2H)，2.40(bs)，2.50(s)，2.58(q)，2.70，2.83，2.94(s，bs，s，7H)，3.65(s，3H)，4.74(bs，1H)，5.01(bs，1H)，6.71(s，1H)，7.13(m _c，3H)，7.41(m _c，1H)，9.75(bs，1H).

12. (3R)-and 7-hydroxyl-6-(3-hydroxyl-3-thiophene-2-base-propyl group)-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide

With two sample 7-hydroxyls-2,3-dimethyl-6-(3-oxygen-3-thiophene-2-base-propyl group)-(embodiment r, 400mg 1.08mmol) are weighed in the glass bushing pipe 3H-benzoglyoxaline-5-formic acid diethylamine, place Argonaut Endeavour again, with its nitrogen blowing 5 times, blow hydrogen 5 times.(180mg, 1.61mmol) and Virahol (3.45ml), [2.3ml is by with RuCl then to add the solution that activates hydrogenation catalyst in advance to add uncle's potassium butyrate ₂[(S)-Xyl-PPhos] [(S)-DAIPEN] (12.6mg) and the solution of uncle's potassium butyrate (1M solution, in the trimethyl carbinol, 115 μ l) in Virahol (2.185ml) be heated to 60 ℃ and reach 1h and prepare)].Reaction tubes is blown into hydrogen for 5 times to 25bar (stirring down), relief pressure again by pressurizeing.Reaction is heated to 65 ℃ then, is forced into the 25bar hydrogen pressure again.After the 20h, release hydrogen pressure is evaporated to drying with reaction mixture again.Resistates is dissolved in methylene dichloride, washs with saturated ammonium chloride solution again.Water with dichloromethane extraction for several times.With the organic layer dried over sodium sulfate that merges, concentrate in a vacuum again, obtain green solid (670mg).With crude product by flash chromatography with silica gel (methylene chloride=25: 1) purifying.Obtain purifying title compound (yellow powder of 500mg, 62% productive rate, 79.9%ee).-m.p.264-265℃。

HPLC analytical procedure: post: Daicel Chiralpak AD-H, 250 * 4.6mm, 5 μ m-elutriants: normal heptane/ethanol: 80/20, flow velocity: 1ml/min, detect wavelength: the 218nm-first wash-out enantiomorph: 21.0min/88.8 area-%, the second wash-out enantiomorph: 23.1min/9.9 area-%, 79.9%ee. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.92(bs，2H)，2.50(s)，2.71(s，bs，4H)，2.95(s，3H)，3.65(s，3H)，4.73(bt，1H)，5.48(bs，1H)，6.72(s，1H)，6.95(m _c，2H)，7.37(dd，1H)，9.80(bs，1H).

13. (3R)-6-[3-(4-fluoro-2-methyl-phenyl)-3-hydroxyl-propyl group]-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide

With RuCl ₂[(S)-Xyl-PPhos] [(S)-DAIPEN] (35mg) and 6-[3-(4-fluoro-2-methyl-phenyl)-3-oxygen-propyl group]-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide (embodiment s, 11g, 2.88mmol) be weighed in the glass bushing pipe, place again the Parr microwave reactor (volume: 50ml), with its nitrogen blowing 5 times, blow hydrogen 5 times.(1M is in the trimethyl carbinol, 8.0ml) and Virahol (8.0ml) to add uncle's potassium butyrate solution.Then autoclave is not with to stir and is blown hydrogen 5 times, band stirs and blows 5 times again.Pressure is set to 25-30bar, again with this mixture heating up to 65 ℃.To react under these conditions and stir 2.5d.Be cooled to after the room temperature evaporating solvent.Resistates is dissolved in methylene dichloride, washs with saturated ammonium chloride solution again.Water with dichloromethane extraction for several times.With the organic layer dried over sodium sulfate that merges, concentrate in a vacuum again, obtain green solid (1.0g).Transformation efficiency (＞95%) and enantiomeric excess (86%ee) are measured by HPLC.Part crude product (950mg) is by flash chromatography silica gel (methylene chloride=100: 3) purifying.Obtain purifying title compound (the spumescence solid of 670mg, 58% productive rate, 61% correcting yield, 83.2%ee).

HPLC analytical procedure: post: Merck LichroCART 250-4, Chiradex (5 μ g)-elutriant: methanol: 20/80,1ml/min-first wash-out enantiomorph: the 17.5min, second wash-out enantiomorph: the 23.7min, starting raw material: 19min.

Measure optical purity through CE: MT[(3S)-enantiomorph]=22.5min/8.4 area-%; MT[(3R)-enantiomorph]=23.7min/91.6 area-%; 83.2%ee. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.78(bs，2H)，2.23(s，3H)，2.36(bs)，2.51(s)，2.69(s，3H)，2.93(s，bs，4H)，3.65(s，3H)，4.67(bs，1H)，5.08(bs，1H)，6.71(s，1H)，6.96(m _c，2H)，7.42(m _c，1H)，9.82(bs，1H).

14. (3R)-[7-hydroxyl-6-(3-hydroxyl-3-o-tolyl-propyl group)-2,3-dimethyl-3H-benzoglyoxaline-5-yl]-tetramethyleneimine-1-base-ketone

With two sample 3-[4-hydroxyls-1,2-dimethyl-6-(tetramethyleneimine-1-carbonyl)-1H-benzoglyoxaline-5-yl]-1-o-tolyl-third-1-ketone (embodiment x, sample A and B:450mg, 1.15mmol) and RuCl ₂[(S)-Xyl-P-Phos] [(S)-DAIPEN] (sample A and B:14mg) is weighed in the glass bushing pipe, is placed on Argonaut Endeavour (8 hole pressure parallel reactors, overhead stirrer and heat block) then.With the seal of tube, by blowing for each hole to 2bar with nitrogen pressure 5 times, relief pressure again.Inject uncle's potassium butyrate (1M solution, in the trimethyl carbinol, sample A:3.1ml, sample B:2.3ml) and Virahol (sample A:2.5ml, sample B:3.3ml) then.By giving each hole blow (stirring down), relief pressure again to 25bar with pressurized with hydrogen 5 times.Reaction is heated to 65 ℃ then, is forced into the 25bar hydrogen pressure again.After the 20h, release hydrogen pressure is evaporated to drying with reaction mixture again.Each resistates is dissolved in methylene dichloride, washs with saturated ammonium chloride solution again.Water with dichloromethane extraction for several times.With the organic layer dried over sodium sulfate that merges, concentrate in a vacuum again, obtain green solid.Transformation efficiency (sample A and B:＞95%) and enantiomeric excess (sample A and B:91%ee) measure by HPLC.Merge sample (0.85g).Measure optical purity (90.8%ee) by CE, the title title compound is used for next step (embodiment O) and is not further purified.

HPLC analytical procedure: post: Merck LichroCART 250-4, Chiradex (5 μ g)-elutriant: methanol: 20/80,1ml/min-first wash-out enantiomorph: the 21.8min, second wash-out enantiomorph: the 30.9min, starting raw material: 32.0min.

Measure optical purity through CE: MT[(3S)-enantiomorph]=21.0min/4.6 area-%; MT[(3R)-enantiomorph]=21.7min/95.4 area-%; 90.8%ee. ¹H-NMR(DMSO-d ₆，400MHz)：δ＝1.71(m _c，3H)，1.82(m _c，3H)，2.22(s，3H)，2.50(bs)，2.60(s，3H)，2.78(bs，1H)，3.00(bs，2H)，3.38(m _c，2H)，3.72(s，3H)，4.72(t，1H)，5.17(bs，1H)，6.97(s，1H)，7.13(m _c，3H)，7.40(d，1H)，9.92(bs，1H).

15. (3R)-and 7-hydroxyl-6-(3-hydroxyl-3-o-tolyl-propyl group)-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid methyl nitrosourea

With 7-hydroxyl-2, and 3-dimethyl-6-(3-oxygen-3-o-tolyl-propyl group)-3H-benzoglyoxaline-5-formic acid methyl nitrosourea (embodiment z, 524mg, 1.44mmol) and RuCl ₂[(S)-Xyl-P-Phos] [(S)-and DAIPEN] (18.5mg) be weighed in the glass bushing pipe, be placed on ArgonautEndeavour (8 hole pressure parallel reactors, overhead stirrer and heat block) then.With the seal of tube, by blowing to the hole to 2bar with nitrogen pressure 5 times, relief pressure again.Inject then potassium hydroxide solution (the 10M aqueous solution, 0.9ml) and Virahol (2.1ml).The hole is blown into hydrogen for 5 times to 25bar (stirring down), relief pressure again by pressurizeing.Reaction is heated to 65 ℃ then, is forced into the 25bar hydrogen pressure again.After the 3d, release hydrogen pressure is evaporated to drying with reaction mixture again.Transformation efficiency (＞95%) and enantiomeric excess (90%ee) are measured by HPLC.Crude product and another sample are merged, this another sample is the 7-hydroxyl-2 by 608mg (1.68mmol), 3-dimethyl-6-(3-oxygen-3-o-tolyl-propyl group)-3H-benzoglyoxaline-5-formic acid methyl nitrosourea asymmetric reduction under conditions of similarity obtain (＞95% transformation efficiency,＞90%ee).The sample dissolution that merges in methylene dichloride, is washed with saturated ammonium chloride solution again.Water with dichloromethane extraction for several times.With the organic layer dried over sodium sulfate that merges, concentrate in a vacuum again, obtain green solid (0.5g).Part crude product (422mg) is by flash chromatography silica gel (methylene chloride=20: 1) purifying.Obtain purifying title compound (gray solid of 288mg, 25% productive rate, 30% correcting yield, 94.7%ee).-m.p.238-240℃。

HPLC analytical procedure: post: Merck LichroCART 250-4, Chiradex (5 μ g)-elutriant: methanol: 20/80,1ml/min-first wash-out enantiomorph: the 18.0min, second wash-out enantiomorph: the 25.0min, starting raw material: 27.0min.

Measure optical purity through CE: MT[(3S)-enantiomorph]=20.7min/2.6 area-%; MT[(3R)-enantiomorph]=21.7min/94.7 area-%; 94.7%ee. ¹H-NMR(DMSO-d _s，400MHz)：δ＝1.67(m _c，1H)，1.87(m _c，1H)，2.18(s，3H)，2.50(s)，2.70，2.72(m _c，d，4H)，2.91(m _c，1H)，3.66(s，3H)，4.66(m _c，1H)，5.23(d，1H)，6.89(s，1H)，7.07(m _c，2H)，7.14(m _c，1H)，7.43(d，1H)，8.05(q，1H)，9.69(bs，1H).

16. (3R)-azetidine-1-base-[7-hydroxyl-6-(3-hydroxyl-3-o-tolyl-propyl group)-2,3-dimethyl-3H-benzoglyoxaline-5-yl]-ketone

With sample 3-[6-(azetidine-1-carbonyl)-4-hydroxyl-1,2-dimethyl-1H-benzoglyoxaline-5-yl]-1-o-tolyl-third-1-ketone (embodiment bb is referring to table) and RuCl ₂[(S)-Xyl-P-Phos] [(S)-DAIPEN] (above-mentioned preparation) is weighed in the glass bushing pipe, is placed on ArgonautEndeavour (8 hole pressure parallel reactors, overhead stirrer and heat block) then.With the seal of tube, by blowing for each hole to 2bar with nitrogen pressure 5 times, relief pressure again.Inject alkali (10M potassium hydroxide aqueous solution) and Virahol then.By giving each hole blow (stirring down), relief pressure again to 25bar with pressurized with hydrogen 5 times.Then reaction is heated to design temperature (referring to table), and is forced into the hydrogen pressure (referring to table) of setting.After the time, release hydrogen pressure uses methyl alcohol (10ml) to help reaction mixture is transferred in the round-bottomed flask again described in the table.Evaporating solvent is analyzed (measuring transformation efficiency and optical purity) with rough sample by HPLC again.

Project	S/C	Substrate	Solvent and alkali	Temperature (℃)	Pressure (bar)	Time	Transformation efficiency (%)	ee(％)
									1	100/1	660mg (1.69mmol)	1.0ml KOH (10M is in water), 2.5ml iPrOH (0.5M)	65	25	3d	＞95	80
2	100/1	404mg (1.03mmol)	0.75ml KOH (10M is in water), 1.75ml iPrOH (0.43 M)	65	25	16h	100	80

The sample dissolution that merges in methylene dichloride, is washed with saturated ammonium chloride solution again.Water with dichloromethane extraction for several times.With the organic layer dried over sodium sulfate that merges, concentrate in a vacuum again, obtain green solid (0.8g).Part crude product (700mg) is by flash chromatography silica gel (methylene chloride=100: 3) purifying.Obtain purifying title compound (the spumescence solid of 90mg, 8% productive rate, 10% correcting yield, 95.2%ee).

HPLC analytical procedure: post: Merck LichroCART 250-4, Chiradex (5ug)-elutriant: methanol: 20/80,1ml/min-first wash-out enantiomorph: the 14.9min, second wash-out enantiomorph: the 20.4min, starting raw material: 26.0min.

Measure optical purity through CE: MT[(3S)-enantiomorph]=20.9min/2.4 area-%; MT[(3R)-enantiomorph]=21.7min/97.6 area-%; 95.2%ee. ¹H-NMR(DMSO-d ₆，400MHz)：δ＝1.69(m _c，1H)，1.84(m _c，1H)，2.16(m _c，2H)，2.20(s，3H)，2.51(s)，2.65(m _c，1H)，2.86(m _c，1H)，3.68(s，3H)，3.81(m _c，2H)，3.96(m _c，2H)，4.68(bs，1H)，5.16(bs，1H)，6.83(s，1H)，7.09(m _c，2H)，7.16(m _c，1H)，7.44(m _c，1H)，9.78(bs，1H).

17. (3R)-6-[3-(2-benzyloxy methyl-phenyl)-3-hydroxyl-propyl group]-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide

With sample 6-[3-(2-benzyloxy-phenyl)-3-oxygen-propyl group]-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide (embodiment cc is referring to table) and RuCl ₂[(S)-Xyl-P-Phos] [(S)-DAIPEN] (above-mentioned preparation) is weighed in the glass bushing pipe, is placed on ArgonautEndeavour (8 hole pressure parallel reactors, overhead stirrer and heat block) then.With the seal of tube, by blowing for each hole to 2bar with nitrogen pressure 5 times, relief pressure again.Inject (uncle's 1M potassium butyrate solution is in the trimethyl carbinol) and Virahol then.By giving each hole blow (stirring down), relief pressure again to 25bar with pressurized with hydrogen 5 times.Then reaction is heated to design temperature (referring to table), and is forced into the hydrogen pressure (referring to table) of setting.After the time, release hydrogen pressure uses methyl alcohol (10ml) to help reaction mixture is transferred in the round-bottomed flask again described in the table.Evaporating solvent is analyzed (mensuration transformation efficiency) with rough sample by HPLC again.

Project	S/C	Substrate	Solvent and alkali	Temperature (℃)	Pressure (bar)	Time	Transformation efficiency (%)	ee(％)
									1	100/1	218mg (0.45mmol)	0.5mlt-BuOK(1M int-BuOH)，2.0ml iPrOH(0.18 M)	65	25	16h	＞95	n.d.
2-4	100/1	540mg (1.13mmol)	1.25mlt-BuOK(1M in t-BuOH)，4.4ml iPrOH(0.2 M)	65	25	16h	＞95	n.d.
									5	100/1	540mg (1.13mmol)	1.25ml t-BuOK(1M in t-BuOH)，4.4ml iPrOH(0.2 M)	65	25	16h	＞85	n.d.

The sample dissolution that merges in methylene dichloride, is washed with saturated ammonium chloride solution again.Water with dichloromethane extraction for several times.With the organic layer dried over sodium sulfate that merges, concentrate in a vacuum again, obtain green solid (2.3g).Part crude product (2.2g) is by flash chromatography silica gel (methylene chloride=20: 1) purifying.Obtain purifying title compound (the spumescence solid of 1.47g, 61% productive rate, 64% correcting yield, 96.4%ee).

Measure optical purity through HPLC: post: Daicel Chiralpak AD-H 250 * 4.6mm, 5 μ m-elutriants: normal heptane/ethanol: 70/30,1ml/min-218nm place photodiode array detection-(3R)-enantiomorph: 14.1min/98.2 area-%, (3S)-and enantiomorph: 25.9min/1.8 area-%, 96.4%ee. ¹H-NMR(DMSO-d ₆，400MHz)：δ＝1.60-2.02(bm，2H)，2.20-2.63(bm)，2.50(s)，2.69(s，3H)，2.94(s，3H)，3.63(s，3H)，4.44(m _c，4H)，4.76 (bs，1H)，5.12(bs，1H)，8.72(s，1H)，7.26 (m _c，8H)，7.48(m _c，1H)，9.85(bs，1H).

18. (3R)-and 7-hydroxyl-6-[3-hydroxyl-3-(2-methoxymethyl-phenyl)-propyl group]-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide

With sample 7-hydroxyl-6-[3-(2-methoxyl group-phenyl)-3-oxygen-propyl group]-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide (embodiment dd is referring to table) and RuCl ₂[(S)-Xyl-P-Phos] [(S)-DAIPEN] (above-mentioned preparation) is weighed in the glass bushing pipe, is placed on Argonaut Endeavour (8 hole pressure parallel reactors, overhead stirrer and heat block) then.With the seal of tube, by blowing for each hole to 2bar with nitrogen pressure 5 times, relief pressure again.Inject alkali (uncle's 1M potassium butyrate solution is in the trimethyl carbinol) and Virahol then.By giving each hole blow (stirring down), relief pressure again to 25bar with pressurized with hydrogen 5 times.Then reaction is heated to design temperature (referring to table), and is forced into the hydrogen pressure (referring to table) of setting.After the time, release hydrogen pressure uses methyl alcohol (10ml) to help reaction mixture is transferred in the round-bottomed flask again described in the table.Evaporating solvent is analyzed (measuring transformation efficiency and optical purity) with rough sample by HPLC again.

Project	S/C	Substrate	Solvent and alkali	Temperature (℃)	Pressure (bar)	Time	Transformation efficiency (%)	ee(％)
									1	100/1	184mg (0.45mmol)	0.5m1t-BuOK(1 M in t-BuOH)，2.0ml iPrOH(0.18 M)	65	25	16h	100	＞95

2-4

100/1

410mg (1.00mmol)

1.1mlt-BuOK(1Min t-BuOH)，3.9ml iPrOH(0.2 M)

65

25

16h

100

＞95

The sample dissolution that merges in methylene dichloride, is washed with saturated ammonium chloride solution again.Water with dichloromethane extraction for several times.With the organic layer dried over sodium sulfate that merges, concentrate in a vacuum again, obtain green solid (1.22g).With crude product by flash chromatography with silica gel (methylene chloride=20: 1) purifying.Obtain purifying title compound (the spumescence solid of 940mg, 66% productive rate, 97.4%ee).

HPLC analytical procedure: post: Merck LichroCART 250-4, Chiradex (5 μ g)-elutriant: methanol: 15/85,1ml/min-first wash-out enantiomorph: the 9.0min, second wash-out enantiomorph: the 12.0min, starting raw material: 15.0min.

Measure optical purity through CE: MT[(3S)-enantiomorph]=20.4min/1.3 area-%; MT[(3R)-enantiomorph]=20.6min/98.7 area-%; 97.4%ee. ¹H-NMR(DMSO-d ₆，400MHz)：δ＝1.81(m _c，2H)，2.48(s，bs)，2.70(s，3H)，2.94(s，bs，4H)，3.24(s，3H)，3.65(s，3H)，4.40(s，2H)，4.75(bs，1H)，5.04(bs，1H)，6.71(s，1H)，7.22(m _c，3H)，7.47(m _c，1H)，9.76(bs，1H).

19.7-hydroxyl-6-(3-hydroxyl-3-o-tolyl-propyl group)-2-methyl-3-(2-trimethyl silyl-ethoxyl methyl)-3H-benzoglyoxaline-5-formic acid diformamide

With two sample 7-hydroxy-2-methyl-6-(3-oxygen-3-o-tolyl-propyl group)-3-(2-trimethyl silyl-ethoxyl methyl)-3H-benzoglyoxaline-5-formic acid diformamide (embodiment ee is referring to table) and RuCl ₂[(S)-Xyl-P-Phos] [(S)-DAIPEN] (above-mentioned preparation) is weighed in the glass bushing pipe, is placed on Argonaut Endeavour (8 hole pressure parallel reactors, overhead stirrer and heat block) then.With the seal of tube, by blowing for each hole to 2bar with nitrogen pressure 5 times, relief pressure again.Inject alkali (uncle's 1M potassium butyrate solution is in the trimethyl carbinol) and Virahol then.By giving each hole blow (stirring down), relief pressure again to 25bar with pressurized with hydrogen 5 times.Then reaction is heated to design temperature (referring to table), and is forced into the hydrogen pressure (referring to table) of setting.After the time, release hydrogen pressure uses methyl alcohol (10ml) to help reaction mixture is transferred in the round-bottomed flask again described in the table.Evaporating solvent is analyzed (measuring transformation efficiency and optical purity) with rough sample by HPLC again.

Project	S/C	Substrate	Solvent and alkali	Temperature (℃)	Pressure (bar)	Time	Transformation efficiency (%)	ee(％)
									1	100/1	223mg (0.45mmol)	0.5ml t-BuOK(1 M in t-BuOH)，2.0ml iPrOH(0.18 M)	65	25	16h	100	92
2	100/1	271mg (0.54mmol)	0.6ml t-BuOK(1M in t-BuOH)，2.4ml iPrOH(0.18 M)	65	25	16h	100	91

The sample dissolution that merges in methylene dichloride, is washed with saturated ammonium chloride solution again.Water with dichloromethane extraction for several times.With the organic layer dried over sodium sulfate that merges, concentrate in a vacuum again, obtain green solid (390mg).Part crude product (350mg) is by flash chromatography silica gel (methylene chloride=20: 1) purifying.Obtain purifying title compound (the spumescence solid of 320mg, 64% productive rate, 70% correcting yield, 95.8%ee).

HPLC analytical procedure: post: Merck LichroCART 250-4, Chiradex (5 μ g)-elutriant: methanol: 50/50,0.8ml/min-first wash-out enantiomorph: the 14.5min, second wash-out enantiomorph: the 16.0min, starting raw material: 19.0min.

Measure optical purity through CE: MT[(3S)-enantiomorph]=27.5min/2.1 area-%; MT[(3R)-enantiomorph]=27.9min/97.9 area-%; 95.8%ee. ¹H-NMR(DMSO-d ₆，400MHz)：δ＝-0.10(s，9H)，0.82(t，2H)，1.78(bm，2H)，2.21(s，3H)，2.55(s)，2.69(s，3H)，2.92(s，4H)，3.50(t，2H)，4.69(bs，1H)，5.03(bd，1H)，5.50(s，2H)，6.84(s，1H)，7.13(m _c，3H)，7.41(m _c，1H)，9.77(bs，1H).

20. (3R)-and 6-(3-benzo [b] thiene-3-yl--3-hydroxyl-propyl group)-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide

With 6-(3-benzo [b] thiene-3-yl--3-oxygen-propyl group)-7-hydroxyl-2, and 3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide (embodiment ff, 190mg, 0.45mmol) and RuCl ₂[(S)-Xyl-P-Phos] [(S)-and DAIPEN] (5.5mg) be weighed in the glass bushing pipe, be placed on Argonaut Endeavour (8 hole pressure parallel reactors, overhead stirrer and heat block) then.With the seal of tube, by blowing for each hole to 2bar with nitrogen pressure 5 times, relief pressure again.Inject then uncle's potassium butyrate (1M solution, in the trimethyl carbinol, 1.00ml, 1.0mmol) and Virahol (1.5ml).By giving each hole blow (stirring down), relief pressure again to 25bar with pressurized with hydrogen 5 times.Reaction is heated to 65 ℃ then, is forced into the 25bar hydrogen pressure again.After the 20h, release hydrogen pressure is evaporated to drying with reaction mixture again.Transformation efficiency (＞95%) is measured by HPLC.Resistates is dissolved in methylene dichloride, washs with saturated ammonium chloride solution again.Water with dichloromethane extraction for several times.With the organic layer dried over sodium sulfate that merges, concentrate in a vacuum again, obtain green solid (140mg).Part crude product (120mg) is by flash chromatography silica gel (methylene chloride=100: 3) purifying.Obtain title compound (Huang-green foam of 40mg, 21% productive rate, 24% correcting yield, 82.2%ee).

HPLC analytical procedure: post: Merck LichroCART 250-4, Chiradex (5 μ g)-elutriant: methanol: 50/50,0.8ml/min-title compound (two enantiomorphs): 5.0min, starting raw material: 11.0min.

HPLC analytical procedure: post: Daicel Chiralpak AD-H, 250 * 4.6mm, 5 μ m-elutriants: normal heptane/ethanol: 80/20, flow velocity: 1ml/min, detect wavelength: the 218nm-first wash-out enantiomorph: 33.1min/91.1 area-%, the second wash-out enantiomorph: 39.9min/8.9 area-%, 82.2%ee. ¹H-NMR(DMSO-d ₆，400MHz)：δ＝1.80-2.26(m _c，2H)，2.51(s，bs)，2.63(s，3H)，2.83(bs，4H)，3.65(s，3H)，4.89(bs，1H)，5.34(d，1H)，6.71(s，1H)，7.36(m _c，2H)，7.54(s，1H)，7.90(bs，1H)，7.96(m _c，1H)，9.79(bs，1H).

21. (3R)-and 7-hydroxyl-6-[3-hydroxyl-3-(2-methyl-thiene-3-yl-)-propyl group]-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide

With sample 7-hydroxyl-2,3-dimethyl-6-[3-(2-methyl-thiene-3-yl-)-3-oxygen-propyl group]-3H-benzoglyoxaline-5-formic acid diethylamine (embodiment gg is referring to table) and RuCl ₂[(S)-Xyl-P-Phos] [(S)-DAIPEN] (above-mentioned preparation) is weighed in the glass bushing pipe, is placed on ArgonautEndeavour (8 hole pressure parallel reactors, overhead stirrer and heat block) then.With the seal of tube, by blowing for each hole to 2bar with nitrogen pressure 5 times, relief pressure again.Inject alkali (uncle's 1M potassium butyrate solution is in the trimethyl carbinol) and Virahol then.By giving each hole blow (stirring down), relief pressure again to 25bar with pressurized with hydrogen 5 times.Then reaction is heated to design temperature (referring to table), and is forced into the hydrogen pressure (referring to table) of setting.After the time, release hydrogen pressure uses methyl alcohol (10ml) to help reaction mixture is transferred in the round-bottomed flask again described in the table.Evaporating solvent is analyzed (mensuration transformation efficiency) with rough sample by HPLC again.

Project	S/C	Substrate	Solvent and alkali	Temperature (℃)	Pressure (bar)	Time	Transformation efficiency (%)	ee(％)
									1	100/1	173mg (0.45mmol)	0.5mlt-BuOK(1 M in t-BuOH)，2.0ml iPrOH(0.18 M)	65	25	16h	100	n.d.
2-3	100/1	410mg (1.06mmol)	1.18mlt-BuOK(1M in t-BuOH)，4.74ml iPrOH(0.18 M)	65	25	16h	100	n.d.

The sample dissolution that merges in methylene dichloride, is washed with saturated ammonium chloride solution again.Water with dichloromethane extraction for several times.With the organic layer dried over sodium sulfate that merges, concentrate in a vacuum again, obtain green solid (860mg).Part crude product (820mg) is by flash chromatography silica gel (methylene chloride=100: 3) purifying.Obtain purifying title compound (the light green foam of 600mg, 60% productive rate, 63% correcting yield, 95.8%ee).

HPLC analytical procedure: post: Merck LichroCART 250-4, Chiradex (5 μ g)-elutriant: methanol: 20/80,1ml/min-title compound (two enantiomorphs): 7.0min, starting raw material: 10.0min.

Measure optical purity through CE: MT[(3S)-enantiomorph]=20.0min/2.1 area-%; MT[(3R)-enantiomorph]=21.0min/97.9 area-%; 95.8%ee. ¹H-NMR(CDCl ₃，200MHz)：δ＝2.10，2.24(bs，bs，5H)，2.59，2.63(s，bs，4H)，2.82(s，3H)，3.12，3.14(bs，s，4H)，3.67(s，3H)，4.64(m _c，1H)，6.69(s，1H)，6.96(d，1H)，7.03(d，1H).

22. (3R)-and 7-hydroxyl-6-(3-hydroxyl-3-o-tolyl-propyl group)-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid cyclopropyl amide

With sample 7-hydroxyl-2,3-dimethyl-6-(3-oxygen-3-o-tolyl-propyl group)-3H-benzoglyoxaline-5-formic acid cyclopropyl amide (embodiment ii is referring to table) and RuCl ₂[(S)-Xyl-P-Phos] [(S)-DAIPEN] (above-mentioned preparation) is weighed in the glass bushing pipe, is placed on ArgonautEndeavour (8 hole pressure parallel reactors, overhead stirrer and heat block) then.With the seal of tube, by blowing for each hole to 2bar with nitrogen pressure 5 times, relief pressure again.Inject alkali (uncle's 1M potassium butyrate solution is in the trimethyl carbinol) and Virahol then.By giving each hole blow (stirring down), relief pressure again to 25bar with pressurized with hydrogen 5 times.Then reaction is heated to design temperature (referring to table), and is forced into the hydrogen pressure (referring to table) of setting.After the time, release hydrogen pressure uses methyl alcohol (10ml) to help reaction mixture is transferred in the round-bottomed flask again described in the table.Evaporating solvent is analyzed (mensuration transformation efficiency) with rough sample by HPLC again.

Project	S/C	Substrate	Solvent and alkali	Temperature (℃)	Pressure (bar)	Time	Transformation efficiency (%)	ee(％)
									1	100/1	175mg (0.45mmol)	1.25mlt-BuOK(1M int-BuOH)，1.25ml iPrOH(0.18 M)	65	25	16h	100	＞95
2-3	100/1	350mg (0.90mmol)	2.5ml t-BuOK(1M in t-BuOH)，2.5ml iPrOH(0.18M)	65	25	16h	100	＞95

The sample dissolution that merges in methylene dichloride, is washed with saturated ammonium chloride solution again.Water with dichloromethane extraction for several times.Division header compound (610mg) is to separate between organic phase and water with the form of colorless solid.With the organic layer dried over sodium sulfate that merges, concentrate in a vacuum again.Obtain the rough title compound of other 70mg.Part crude product (610mg) is by flash chromatography silica gel (methylene chloride=100: 3) purifying.Obtain purifying title compound (colorless solid of 350mg, 40% productive rate, 45% correcting yield, 98.4%ee).-m.p.299-300℃。

HPLC analytical procedure: post: Merck LichroCART 250-4, Chiradex (5 μ g)-elutriant: methanol: 20/80,1ml/min-first wash-out enantiomorph: the 11.0min, second wash-out enantiomorph: the 15.0min, starting raw material: 18.0min.

Measure optical purity through CE: MT[(3S)-enantiomorph]=22.0min/0.8 area-%; MT[(3R)-enantiomorph]=23.1min/99.2 area-%; 98.4%ee. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝0.54(m _c，2H)，0.65(m _c，2H)，1.75(m _c，2H)，2.21(s，3H)，2.50(s)，2.80(m _c，3H)，3.66(s，3H)，4.65(1，1H)，5.19(d，1H)，6.85(s，1H)，7.10(m _c，3H)，7.43(m _c，1H)，8.17(d，1H)，9.63(bs，1H).

23. (3R)-and 5-(3-hydroxyl-3-o-tolyl-propyl group)-6-methoxymethyl-1,2-dimethyl-1H-benzoglyoxaline-4-alcohol

In the flask of applying argon gas, with 3-(4-hydroxyl-6-methoxymethyl-1,2-dimethyl-1H-benzoglyoxaline-5-yl)-1-o-tolyl-third-1-ketone (embodiment mm, 1.4g, 4.0mmol) be suspended in Virahol (40ml), (1M is in the trimethyl carbinol, 5.6ml) slowly to add uncle's potassium butyrate solution again.This suspension is at room temperature stirred 1h, add hydrogenation catalyst RuCl again ₂[(S)-Xyl-P-Phos] [(S)-DAIPEN] (50mg).This mixture is transferred in the autoclave, and under 65 ℃ and 80bar pressure hydrogenation 20h.After being cooled to room temperature and release hydrogen pressure, saturated ammonium chloride solution, methylene dichloride and water are added in this brown solution.Be separated.Organic phase water (1 x) washing, water extracts with methylene dichloride (3 x).With the organic phase dried over mgso that merges, reconcentration is to dry.This resistates by column chromatography silica gel (methylene chloride=50: 1) purifying, is obtained 1.0g (71% productive rate; Title compound 98.2%ee) is the light green foam.

HPLC analytical procedure: post: Daicel Chiralpak AD-H, 250 * 4.6mm, 5 μ m-elutriants: normal hexane/Virahol: 80/20, flow velocity: 1ml/min, detect wavelength: the 218nm-first wash-out enantiomorph: 16.9min/99.1 area-%, the second wash-out enantiomorph: 19.2min/0.9 area-%, 98.2%ee. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.76(m _c，2H)，2.21(s，3H)，2.49(s)，2.64(m _c，1H)，2.81(m _c，1H)，3.22(s，3H)，3.64(s，3H)，4.39(s，2H)，4.75(bt，1H)，5.04(bd，1H)，6.84(s，1H)，7.14(m _c，3H)，7.46(d，1H)，9.49(bs，1H).

The asymmetric reduction synthesis type 1-b compound of through type 2 prochiral ketones

24. (3S)-and 7-hydroxyl-6-(3-hydroxyl-3-phenyl-propyl group)-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide

With 7-hydroxyl-2, and 3-dimethyl-6-(3-oxygen-3-phenyl-propyl group)-3H-benzoglyoxaline-5-formic acid diformamide (0.37g, 1.0mmol) and RuCl ₂[(R)-Xyl-P-Phos] [(R)-DAIPEN] (1.7mg is similar to above institute to the method preparation) is weighed in the glass bushing pipe, is placed on Argonaut Endeavour (8 hole pressure parallel reactors, overhead stirrer and heat block) then.With the seal of tube, by blowing to the hole to 2bar with nitrogen pressure 5 times, relief pressure again.(1 M is in the trimethyl carbinol, 1.2ml), the trimethyl carbinol (0.6ml) and (0.2ml) to inject uncle's potassium butyrate solution then.By giving each hole blow (stirring down), relief pressure again to 25bar with pressurized with hydrogen 5 times.Then reaction is heated to 65 ℃ and be forced into hydrogen pressure 25bar.After the 16h, release hydrogen pressure.Methylene dichloride and saturated aqueous ammonium chloride are added in this rough reaction, are adjusted to neutral pH by adding 2NHCl again.Be separated, with the organic phase dried over mgso, revaporization is to dry.The transformation efficiency and the optical purity of crude product are passed through ¹H NMR spectrum (＞95% transformation efficiency) and capillary electrophoresis (99%ee) are measured.

Measure optical purity through CE: MT[(3S)-enantiomorph]=15.2min/99.4 area-%; MT[(3R)-enantiomorph]=15.7min/0.6 area-%; 98.8%ee. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.80(m _c，2H)，2.35(bs)，2.50(s)，2.68(s，bs，4H)，2.89(s，3H)，3.64(s，3H)，4.48(t，1H)，5.14(bs，1H)，6.70(s，1H)，7.25(m _c，5H)，9.80(bs，1H).

25. (3S)-and 7-hydroxyl-6-(3-hydroxyl-3-o-tolyl-propyl group)-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide

With 7-hydroxyl-2, and 3-dimethyl-6-(3-oxygen-3-o-tolyl-propyl group)-3H-benzoglyoxaline-5-formic acid diformamide (embodiment m, 3 * 400mg, 1.05mmol) and RuCl ₂[(R)-Xyl-PPhos] [(R)-and DAIPEN] (every duplicate samples: three duplicate samples 13mg) are weighed in the glass bushing pipe, are placed on Argonaut Endeavour (8 hole pressure parallel reactors, overhead stirrer and heat block) then.With the seal of tube, by blowing for each hole to 2bar with nitrogen pressure 5 times, relief pressure again.Inject then uncle's potassium butyrate (1M solution, in the trimethyl carbinol, every duplicate samples: 1.15ml, 1.2mmol) and Virahol (every duplicate samples: 4.7ml).By giving each hole blow (stirring down), relief pressure again to 25bar with pressurized with hydrogen 5 times.Reaction is heated to 65 ℃ then, is forced into the 25bar hydrogen pressure again.After the 20h, release hydrogen pressure is evaporated to drying with reaction mixture again.60%) and enantio-selectivity (first sample: 93%ee, second sample: 92%ee, the 3rd sample: 90%ee) measures transformation efficiency (first and second samples: 100%, the three sample: by HPLC.Each resistates is dissolved in methylene dichloride, washs with saturated ammonium chloride solution again.Water with dichloromethane extraction for several times.Organic layer dried over sodium sulfate with each reaction merges concentrates in a vacuum again, obtains green solid.To use same reaction conditions hydrogenation again from the crude product that the 3rd sample obtains.Carry out the processing of reaction mixture as mentioned above.The crude product (1.1g) that merges total overall reaction is again by column chromatography silica gel (ethyl acetate/methanol=20: 1) purifying.The corresponding level part of evaporation obtains green foam (950mg), and it is dissolved in hot acetone (2ml).Be cooled to room temperature, obtain suspension, it is at room temperature stirred 1h.By this throw out of filtering separation,, dry in a vacuum again with acetone (1ml) and ether (5ml) washing.Obtain purifying title compound (colorless solid of 680mg, 57% productive rate, 88.4%ee).-m.p.203-205℃。

HPLC analytical procedure: post: Merck LichroCART 250-4, Chiradex (5 μ g)-elutriant: methanol: 20/80,1ml/min-first wash-out enantiomorph: the 12.8min, second wash-out enantiomorph: the 17.2min, starting raw material: 23.0min.

Measure optical purity through CE: MT[(3S)-enantiomorph]=21.7min/94.2 area-%; MT[(3R)-enantiomorph]=22.9min/5.8 area-%; 88.4%ee. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.79(bs，2H)，2.22(s，3H)，2.49(s，bs)，2.70(s，3H)，2.93(s，bs，4H)，3.65(s，3H)，4.69(bt，1H)，5.03(bs，1H)，6.71(s，1H)，7.13(m _c，3H)，7.41(m _c，1H)，9.85(bs，1H).

Formula 1-a compound transforms accepted way of doing sth 3-a three ring benzimidazoless

A. (8S)-2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also

To (3R)-7-hydroxyl-6-(3-hydroxyl-3-phenyl-propyl group)-2,3-dimethyl-3H-benzoglyoxaline-(embodiment 1 for 5-formic acid diformamide, 1.3g, 3.5mmol) and triphenyl phosphine (2.7g, 10.2mmol) add DIAD (2.1ml in the suspension in tetrahydrofuran (THF) (60ml), 10.5mmol), again this mixture is at room temperature stirred 15min.To react concentrated in a vacuum, resistates is handled with saturated ammonium chloride solution (100ml), uses ethyl acetate (2 * 100ml) extractions again.The organic phase that merges is washed with saturated ammonium chloride solution (20ml) and water (20ml), use dried over mgso, concentrate in a vacuum again.Crude product by flash chromatography silica gel (ethyl acetate/methanol=9: 1) purifying, is obtained the 1.03g title compound.Crystallization from diisopropyl ether (20ml) obtains pure title compound (white solid of 0.95g, 77% productive rate; 96%ee).-m.p.226-227℃。

[α] ²⁰ _D=-32 ° (c=0.57, methyl alcohol)

Measure optical purity through CE: MT[(8S)-enantiomorph]=19.7min/97.9 area-%; MT[(8R)-enantiomorph]=21.0min/2.1 area-%; 95.8%ee. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝2.13(m _c，2H)，2.47(s)，2.57(m _c)，2.77，2.80(s，m _c，4H)，3.00(s，3H)，3.68(s，3H)，5.22(dd，1H)，6.91(s，1H)，7.42(m _c，5H).

B. (8S)-2-methyl-8-phenyl-3-(2-trimethyl silyl-ethoxyl methyl)-3,6,7,8-tetrahydrochysene-chromene is [7,8-d] imidazoles-5-formic acid diformamide also

To (3R)-7-hydroxyl-6-(3-hydroxyl-3-phenyl-propyl group)-2-methyl-3-(2-trimethyl silyl-ethoxyl methyl)-3H-benzoglyoxaline-(embodiment 2 for 5-formic acid diformamide, 3.3g, 6.8mmol) add triphenyl phosphine (5.2g in the solution in tetrahydrofuran (THF) (100ml), 19.7mmol) and DIAD (4.0ml, 20.5mmol), again this mixture is at room temperature stirred 90min.To react in a vacuum and concentrate.Resistates is handled with saturated ammonium chloride solution, uses ethyl acetate extraction again twice.Organic phase is used dried over mgso with saturated ammonium chloride solution and water washing, concentrates in a vacuum again.Resistates by flash chromatography silica gel (toluene/ethyl acetate=1: 4) purifying, is obtained title compound and triphenyl phosphine hopcalite (3.3g beige solid). ¹H-NMR(DMSO-d6，200MHz)：δ＝-0.1(s，9H)，0.83(t，2H)，2.13(m _c，2H)，2.50(s，bs)，2.76，2.80(s，bs，4H)，3.01(s，3H)，3.51(t，2H)，5.23(dd，1H)，5.54(s，2H)，7.05(s，1H)，7.31-7.70(m).

C. (8S)-2-methyl-8-phenyl-3,6,7,8-tetrahydrochysene-chromene is [7,8-d] imidazoles-5-formic acid diformamide also

With (8S)-2-methyl-8-phenyl-3-(2-trimethyl silyl-ethoxyl methyl)-3,6,7,8-tetrahydrochysene-chromene also [7,8-d] imidazoles-5-formic acid diformamide (3.3g, the product of Embodiment B) solution in methylene dichloride (40ml) is cooled to 0 ℃, and the dropping boron-trifluoride etherate (3.6ml, 28.5mmol).Reaction mixture is warmed to room temperature, stirs 19h, concentrate in a vacuum again.With resistates by flash chromatography with silica gel (methylene chloride=20: 1) purifying.Separate beige solid (1.0g, the free alkali of title compound), it is dissolved in acetone (10ml), (0.27g 3.0mmol) handles to use oxalic acid again.This suspension is at room temperature stirred 18h, by the filtering separation throw out, dry in a vacuum again.Obtain title compound, and 24% overall yield (colorless solid of 0.70g, 94%ee).-m.p.215-216℃。

[α] ²⁰ _D=-18 ° (c=0.58, methyl alcohol)

Measure optical purity through CE: MT[(8S)-enantiomorph]=21.1min/96.9 area-%; MT[(8R)-enantiomorph]=22.5min/3.1 area-%; 93.8%ee. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝2.18(m _c，2H)，2.51(s)，2.57(m _c)，2.77，2.80(s，m _c，4H)，3.01(s，3H)，5.29(dd，1H)，6.95(s，1H)，7.46(m _c，5H).

D. (8S)-azetidine-1-base-(2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-yl also)-ketone

To (3R)-azetidine-1-base-[7-hydroxyl-6-(3-hydroxyl-3-phenyl-propyl group)-2,3-dimethyl-3H-benzoglyoxaline-5-yl]-(embodiment 3 for ketone, 0.8g, 2.2mmol) and triphenyl phosphine (1.6g, 6.3mmol) add DIAD (1.3ml in the suspension in tetrahydrofuran (THF) (40ml), 6.5mmol), at room temperature this mixture is stirred again and spend the night.Throw out is filtered, more in a vacuum, 40 ℃ dry down, obtain 0.6g (76% productive rate; Title compound 82%ee) is a white solid.-m.p.241-242℃。

Measure optical purity through CE: MT[(8S)-enantiomorph]=21.3min/90.9 area-%; MT[(8R)-enantiomorph]=23.2min/9.1 area-%; 81.8%ee. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝2.15(m _c，4H)，2.47(s)，2.74(m _c，1H)，2.96(m _c，1H)，3.69(s，3H)，3.94(m _c，4H)，5.21(dd，1H)，7.03(s，1H)，7.40(m _c，5H).

E. (8S)-2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid methyl nitrosourea also

To (3R)-7-hydroxyl-6-(3-hydroxyl-3-phenyl-propyl group)-2,3-dimethyl-3H-benzoglyoxaline-(embodiment 4 for 5-formic acid methyl nitrosourea, 1.0g, 2.8mmol) and triphenyl phosphine (2.1g, 8.1mmol) add DIAD (1.6ml in the suspension in tetrahydrofuran (THF) (50ml), 8.4mmol), at room temperature this suspension is stirred again and spend the night.To react concentrated in a vacuum, resistates with silica gel (methylene chloride=10: 1) purifying, obtains 0.79g (75% productive rate by flash chromatography; Title compound 73%ee) is a white solid.-m.p.290-291℃。

[α] ²⁰ _D=-13 ° (c=0.56, methyl alcohol)

Measure optical purity through CE: MT[(8S)-enantiomorph]=22.0min/86.6 area-%; MT[(8R)-enantiomorph]=24.4min/13.4 area-%; 73.2%ee. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝2.02(m _c，1H)，2.22(m _c，1H)，2.48(s)，2.76，2.80(d，m _c，4H)，3.05(m _c，1H)，3.69(s，3H)，5.19(dd，1H)，7.11(s，1H)，7.42(m _c，5H)，8.08(q，1H).

F. (8S)-8-(2-fluoro-phenyl)-2,3-dimethyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also

With (3R)-6-[3-(2-fluoro-phenyl)-3-hydroxyl-propyl group]-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-(embodiment 5 for 5-formic acid diformamide, 1.6g, 4.1mmol) and triphenyl phosphine (3.1g, 12mmol) DIAD (the 2.5g of the solution in tetrahydrofuran (THF) (100ml), 12mmol) handle, again this mixture is at room temperature stirred 1h.To react concentrated in a vacuum, resistates is handled with saturated ammonium chloride solution (100ml), uses ethyl acetate (3 * 100ml) extractions again.With the organic phase dried over mgso that merges, concentrate in a vacuum again.Resistates by flash chromatography with silica gel (methylene chloride=14: 1) purifying, crystallization from acetone again, (62% productive rate, title compound 96%ee) they are white solid to obtain 0.8g.-m.p.199-201℃。

[α] ²⁰ _D=-50 ° (c=0.49, methyl alcohol)

Measure optical purity through HPLC: post: Daicel Chiralpak AD-H 250 * 4.6mm, 5 μ m-elutriants: normal heptane/ethanol: 80/20+0.1% diethylamine, 1ml/min 230nm place photodiode array detection-(8R)-enantiomorph: 12.4min/1.9 area-%, (8S)-and enantiomorph: 13.6min/96.4 area-%, 96.1%ee. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝2.15(m _c，2H)，2.47，2.55(s，m _c)，2.79，2.83(s，m _c，4H)，3.01(s，3H)，3.68(s，3H)，5.44(dd，1H)，6.94(s，1H)，7.27(t，2H)，7.44(m _c，1H)，7.56(t，1H).

G. (8S)-8-(4-fluoro-phenyl) 2,3-dimethyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide hydrochloride also

To (3R)-6-[3-(4-fluoro-phenyl)-3-hydroxyl-propyl group]-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-(embodiment 6 for 5-formic acid diformamide, 1.8g, 4.7mmol) add triphenyl phosphine (3.6g in the suspension in tetrahydrofuran (THF) (60ml), 13.5mmol) and DIAD (2.9ml, 14.5mmol), again this mixture is at room temperature stirred 3h.To react in a vacuum, silica gel exists concentrated down, resistates is by flash chromatography silica gel (methylene chloride=100: 0 to 87: 13) purifying, crystallization from the mixture of acetone and saturated HCl/ diethyl ether solution again, obtain two batches of title compounds (colorless solid of batch 1:0.81g, 43% productive rate; The colorless solid of batch 2:0.36g, 19% productive rate, 82%ee, m.p.290-292 ℃).The free alkali of a collection of title compound obtains by mother liquor purifying (flash chromatography on silica gel method, methylene chloride=20: 1): the colorless solid of 0.50g (30% productive rate).

Measure optical purity through CE: MT[(8S)-enantiomorph]=20.1min/90.1 area-%; MT[(8R)-enantiomorph]=21.0min/9.0 area-%; 81.8%ee. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝2.13(m _c，1H)，2.33(m _c，1H)，2.75，2.77，2.79(m _c，2s，8H)，3.04(s，3H)，3.89(s，3H)，5.42(dd，1H)，7.28(t，2H)，7.41(s，1H)，7.62(dd，2H).

H. (8S)-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also

Method A: to (3R)-7-hydroxyl-6-(3-hydroxyl-3-o-tolyl-propyl group)-2,3-dimethyl-3H-benzoglyoxaline-(embodiment 7 for 5-formic acid diformamide, 4.8g, 12.6mmol) add triphenyl phosphine (6.1g in the solution in tetrahydrofuran (THF) (60ml), 36.5mmol) and DIAD (7.7ml, 39mmol), again this mixture is at room temperature stirred 16.75h.To react in a vacuum, silica gel exists concentrated down, crude product is by flash chromatography (first post: methylene chloride=20: 1, second post: methylene chloride=100: 0 to 88: 12, the 3rd post: toluene/1,4-two  alkane=1: 1) purifying, (50% productive rate, title compound 87%ee) are the beige foam to obtain 2.3g.

[α] ²⁰ _D=-14 ° (c=0.50, methyl alcohol)

Measure optical purity through CE: MT[(8R)-enantiomorph]=38.9min/6.3 area-%; MT[(8S)-enantiomorph]=46.9min/93.7 area-%; 87.4%ee. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.99(m _c，1H)，2.22(m _c，1H)，2.38(s，3H)，2.47(s)，2.65(m _c，1H)，2.81，2.85(s，m _c，4H)，3.02(s，3H)，3.68(s，3H)，5.32(dd，1H)，6.92(s，1H)，7.24(m _c，3H)，7.47(m _c，1H).

Method B: to (3R)-7-hydroxyl-6-(3-hydroxyl-3-o-tolyl-propyl group)-2,3-dimethyl-3H-benzoglyoxaline-(embodiment 7 for 5-formic acid diethylamine, 26.0g, 68.1mmol) and triphenyl phosphine (35.0g, 133mmol) go through 10min in the suspension in dry tetrahydrofuran (600ml) and add DIAD (27.7ml, 27.0g, 134mmol).Obtain yellow solution, it is at room temperature stirred 5min, under reduced pressure concentrate again.Resistates is by column chromatography silica gel (methylene chloride=100: 2) purifying.The corresponding level part of evaporation obtains title compound, and (colourless foam of 23.0g, it contains the ethyl acetate of 10wt-% to 84% correcting yield, 95.6%ee).After the violent drying, obtain amorphous solid: m.p.126-128 ℃ in the-vacuum.

HPLC analytical procedure: post: Daicel Chiralpak AD-H, 250 * 4.6mm, 5 μ m-elutriants: normal heptane/ethanol: 80/20, flow velocity: 1ml/min, detect wavelength: the 218nm-first wash-out enantiomorph: 10.2min/2.2 area-%, the second wash-out enantiomorph: 13.7min/97.8 area-%, 95.6%ee.

Ha. (8S)-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also; Salt with hydrochloric acid

With (8S)-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene also [7,8-d] imidazoles-5-formic acid diformamide (1.00g, 2.75mmol) be dissolved in the solution of 0.1N hydrochloric acid in Virahol (30ml, 3.0mmol).Evaporating solvent separates colourless foam (1.1g) again.A part of foam (500mg) is handled with ether (6ml), and the suspension that will generate at room temperature stirs 30min again.By this throw out of filtering separation,, dry in a vacuum again with ether (4ml) washing.Obtain the colorless solid (99% correcting yield, m.p.145 ℃) of 470mg. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝2.08(m _c，1H)，2.32(m _c，1H)，2.42(s，3H)，2.71，2.78，2.83(m _c，2s，7H)，3.01，3.06(m _c，s，4H)，3.90(s，3H)，5.54(dd，1H)，7.30(m _c，3H)，7.42(s，1H)，7.52(m _c，1H).

Hb. (8S)-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also, with the salt of toxilic acid

With (8S)-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene is [7,8-d] imidazoles-5-formic acid diformamide (1.00g also, 2.75mm0l) be dissolved in the hot acetone (2ml), add toxilic acid (0.35g, 3.01mmol) solution in acetone (5ml) down at 60 ℃ again.Make solution be cooled to room temperature.Evaporating solvent separates colourless foam (1.4g) again.A part of foam (500mg) is handled with ether (6ml), and the suspension that will generate at room temperature stirs 30min again.By this throw out of filtering separation,, dry in a vacuum again with ether (5ml) washing.Obtain the colorless solid (95% correcting yield, m.p.110-112 ℃) of 450mg. ¹H-NMR(DMSO-d _s，200MHz)：δ＝2.08(m _c，1H)，2.32(m _c，1H)，2.42(s，3H)，2.71，2.78，2.83(m _c，2s，7H)，3.01，3.06(m _c，s，4H)，3.90(s，3H)，5.54(dd，1H)，7.30(m _c，3H)，7.42(s，1H)，7.52(m _c，1H).

Hc. (8S)-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also; Salt with fumaric acid

With (8S)-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene is [7,8-d] imidazoles-5-formic acid diformamide (1.00g also, 2.75mmol) be dissolved in the hot acetone (2ml), add fumaric acid (0.35g, 3.01mmol) solution in acetone (3ml) down at 60 ℃ again.Make solution be cooled to room temperature.Evaporating solvent separates colourless foam (1.4g) again.A part of foam (500mg) is handled with ether (5ml), and the suspension that will generate at room temperature stirs 15min again.By this throw out of filtering separation,, dry in a vacuum again with ether (3ml) washing.Obtain the colorless solid (98% correcting yield, m.p.118-120 ℃) of 460mg. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝2.02(m _c，1H)，2.22(m _c，1H)，2.38(s，3H)，2.47(s，3H)，2.64(m _c，1H)，2.81，2.87(s，m _c，4H)，3.02(s，3H)，3.68(s，3H)，5.33(dd，1H)，6.63(s，2H)，6.93(s，1H)，7.26(m _c，3H)，7.47(m _c，1H).

Hd. (8S)-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also; Salt with oxalic acid

With (8S)-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene is [7,8-d] imidazoles-5-formic acid diformamide (1.00g also, 2.75mmol) be dissolved in the hot acetone (2ml), add oxalic acid (0.27g, 3.00mmol) solution in acetone (1ml) down at 60 ℃ again.Make solution be cooled to room temperature.Evaporating solvent separates colourless foam (1.3g) again.A part of foam (500mg) is handled with ether (3ml) and acetone (0.3ml), and the suspension that will generate at room temperature stirs 30min again.By this throw out of filtering separation,, dry in a vacuum again with ether (2ml) washing.Obtain the colorless solid (99% correcting yield, m.p.112 ℃) of 480mg. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝2.02(m _c，1H)，2.25(m _c，1H)，2.38(s，3H)，2.53，2.63(s，m _c)，2.81，2.88(s，m _c，4H)，3.03(s，3H)，3.72(s，3H)，5.37(dd，1H)，7.05(s，1H)，7.27(m _c，3H)，7.47(m _c，1H).

He. (8S)-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also; Salt with Citric Acid

With (8S)-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene is [7,8-d] imidazoles-5-formic acid diformamide (1.00g also, 2.75mmol) be dissolved in the hot acetone (2ml), add Citric Acid (0.58g, 3.02mmol) solution in acetone (4ml) down at 60 ℃ again.Make solution be cooled to room temperature.Evaporating solvent separates colourless foam (1.6g) again.A part of foam (500mg) is handled with ether (5ml), and the suspension that will generate at room temperature stirs 30min again.By this throw out of filtering separation,, dry in a vacuum again with ether (3ml) washing.Obtain the colorless solid (52% correcting yield, m.p.105 ℃) of 250mg. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.98(m _c，1H)，2.22(m _c，1H)，2.38(s，3H)，2.49(s)，2.70，2.80，2.81(dd，m _c，s，9H)，3.02(s，3H)，3.70(s，3H)，5.34(dd，1H)，6.97(s，1H)，7.27(m _c，3H)，7.47(m _c，1H).

Hf. (8S)-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also; Salt with methylsulfonic acid

With (8S)-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene is [7,8-d] imidazoles-5-formic acid diformamide (1.00g also, 2.75mmol) be dissolved in the hot acetone (2ml), again 60 ℃ add down methylsulfonic acids (0.296, the 3.02mmol) solution in acetone (0.5ml).Make solution be cooled to room temperature.Evaporating solvent separates colourless foam (1.3g) again.A part of foam (500mg) is handled with ether (5ml) and acetone (0.5ml), and the suspension that will generate at room temperature stirs 15min again.By this throw out of filtering separation,, dry in a vacuum again with ether (3ml) washing.Obtain the colorless solid (93% correcting yield, m.p.114-116 ℃) of 450mg. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝2.12(m _c，1H)，2.33，2.37(m _c，s，7H)，2.42(s，3H)，2.49(s)，2.75，2.76，2.83(m _c，2 s，7H)，3.00，3.06(m _c，s，4H)，3.90(s，3H)，5.55(dd，1H)，7.31(m _c，3H)，7.43(s，1H)，7.52(m _c，1H).

I. (8S)-8-(2-chloro-phenyl)-2,3-dimethyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also

To (3R)-6-[3-(2-chloro-phenyl)-3-hydroxyl-propyl group]-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-(embodiment 8 for 5-formic acid diformamide, 200mg, 0.50mmol) add triphenyl phosphine (260mg in the solution in tetrahydrofuran (THF) (10ml), 0.99mmol) and DIAD (197 μ l, 202mg 1.00mmol), at room temperature stirs 5min with this green solution again.Reaction mixture is concentrated in a vacuum, and crude product is by flash chromatography (methylene chloride=100: 3) purifying, and (91% productive rate, title compound 89.6%ee) is a colourless foam to obtain 175mg.

[α] ²⁰ _D＝-93°(c＝0.55，MeOH)

HPLC analytical procedure: post: Daicel Chiralpak AD-H, 250 * 4.6mm, 5 μ m-elutriants: normal heptane/ethanol: 90/10, flow velocity: 1ml/min, detect wavelength: the 218nm-first wash-out enantiomorph: 28.5min/5.2 area-%, the second wash-out enantiomorph: 31.3min/94.8 area-%, 89.6%ee. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.99(m _c，1H)，2.30(m _c，1H)，2.52(s)，2.64(bs，1H)，2.80，2.88(s，m _c，4H)，3.01(s，3H)，3.69(s，3H)，5.47(dd，1H)，6.96(s，1H)，7.46(m _c，3H)，7.63(m _c，1H).

J. (8S)-2,3-dimethyl-8-(2-trifluoromethyl-phenyl)-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also

To (3R)-7-hydroxyl-6-[3-hydroxyl-3-(2-trifluoromethyl-phenyl)-propyl group]-2,3-dimethyl-3H-benzoglyoxaline-(embodiment 9 for 5-formic acid diformamide, 110mg, 0.25mmol) add triphenyl phosphine (115mg in the solution in tetrahydrofuran (THF) (10ml), 0.44mmol) and DIAD (88 μ l, 90mg 0.44mmol), at room temperature stirs 30min with this mixture again.(20 μ l, 21mg 0.10mmol), continue to stir 30min again to add another part DIAD.To react concentrated in a vacuum, crude product is by column chromatography silica gel (methylene chloride=40: 1) purifying.(19% productive rate, title compound 85.3%ee) are brown wax to obtain 20mg.

HPLC analytical procedure: post: Daicel Chiralpak AD-H, 250 * 4.6mm, 5 μ m-elutriants: normal heptane/ethanol: 80/20, flow velocity: 1ml/min, detect wavelength: the 218nm-first wash-out enantiomorph: 7.3min/6.6 area-%, the second wash-out enantiomorph: 8.6min/83.1 area-%, 85.3%ee. ¹H-NMR(DMSO-d ₆，400MHz)：δ＝2.07(m _c，1H)，2.20(m _c，1H)，2.46(s，3H)，2.67(m _c，1H)，2.82，2.88(s，m _c，4H)，3.02(s，3H)，3.69(s，3H)，5.34(d，1H)，6.98(s，1H)，7.60(m _c)，7.88(m _c)，

K. (8S)-2,3-dimethyl-8-naphthalene-2-base-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide hydrochloride also

To (3R)-7-hydroxyl-6-(3-hydroxyl-3-naphthalene-2-base-propyl group)-2,3-dimethyl-3H-benzoglyoxaline-(embodiment 10 for 5-formic acid diformamide, 150mg, 0.36mmol) add triphenyl phosphine (277mg in the solution in tetrahydrofuran (THF) (10ml), 1.04mmol) and DIAD (221 μ l, 1.12mmol), again this mixture is at room temperature stirred 4.25h.To react concentrated in a vacuum, crude product is by flash chromatography silica gel (methylene chloride=20: 1) purifying.The corresponding level of an evaporation part resistates that obtains is dissolved in acetone, adds the solution of 2M hydrochloric acid in ether again.By the filtering separation throw out, dry in a vacuum again.(64% productive rate, title compound 38.7%ee) are the beige solid to obtain 101mg.-m.p.262-264℃。

[α] ²⁰ _D=-34 ° (c=0.49, chloroform)

HPLC analytical procedure: post: Daicel Chiralpak AD-H, 250 * 4.6mm, 5 μ m-elutriants: normal heptane/ethanol: 80/20+0.1% diethylamine, flow velocity: 1ml/min, detect wavelength: the 230nm-first wash-out enantiomorph: 25.3min/30.4 area-%, the second wash-out enantiomorph: 31.2min/68.7 area-%, 38.7%ee. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝2.25(m _c，1H)，2.45(m _c)，2.72，2.78，2.81(m _c，s，s，7H)，3.01，3.05(m _c，s，4H)，3.90(s，3H)，5.59(dd，1H)，7.43(s，1H)，7.56(m _c，2H)，7.70(m _c，1H)，7.99(m _c，3H)，8.14(s，1H).

L. (8S)-(2-ethyl-phenyl)-2,3-dimethyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also

To (3R)-6-[3-(2-ethyl-phenyl)-3-hydroxyl-propyl group]-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-(embodiment 11 for 5-formic acid diformamide, 130mg, 0.33mmol) add triphenyl phosphine (172mg in the solution in tetrahydrofuran (THF) (10ml), 0.66mmol) and DIAD (127 μ l, 130mg 0.64mmol), at room temperature stirs 5min with this green solution again.Reaction mixture is concentrated in a vacuum, and crude product is by flash chromatography (methylene chloride=100: 3) purifying, and (73% productive rate, title compound 83.4%ee) is a colourless foam to obtain 90mg.

HPLC analytical procedure: post: Daicel Chiralpak AD-H, 250 * 4.6mm, 5 μ m-elutriants: normal heptane/ethanol: 80/20, flow velocity: 1ml/min, detect wavelength: the 218nm-first wash-out enantiomorph: 8.3min/8.3 area-%, the second wash-out enantiomorph: 9.5min/91.7 area-%, 83.4%ee. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.21(t，3H)，1.90-2.30(m _c，2H)，2.46(s，3H)，2.55-2.95，2.73，2.82(m _c，dq，s，7H)，3.02(s，3H)，3.67(s，3H)，5.34(dd，1H)，6.92(s，1H)，7.29(m _c，3H)，7.48(m _c，1H).

M. (8S)-2,3-dimethyl-8-thiophene-2-base-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also

To (3R)-7-hydroxyl-6-(3-hydroxyl-3-thiophene-2-base-propyl group)-2,3-dimethyl-3H-benzoglyoxaline-(embodiment 12 for 5-formic acid diformamide, 450mg, 1.20mmol) add triphenyl phosphine (600mg in the solution in tetrahydrofuran (THF) (30ml), 2.25mmol) and DIAD (470 μ l, 483mg 2.38mmol), at room temperature stirs 45min with this red tan solution again.Evaporating solvent in the presence of silica gel is loaded into resistates on the post of filling gel.(colourless foam of 260mg, 61% productive rate is 77.2%ee) with methylene dichloride and methanol mixture [30: 1 (v/v)] wash-out for title compound.

HPLC analytical procedure: post: Daicel Chiralpak AD-H, 250 * 4.6mm, 5 μ m-elutriants: normal hexane/Virahol: 80/20, flow velocity: 1ml/min, detect wavelength: the 218nm-first wash-out enantiomorph: 12.3min/81.5 area-%, the second wash-out enantiomorph: 16.9min/10.5 area-%, 77.2%ee. ¹H-NMR(DMSO-d ₆，400MHz)：δ＝2.16m _c，1H)，2.35m _c，1H)，2.47(s，3H)，2.65m _c，1H)，2.76，2.79(s，m _c，4H)，3.01(s，3H)，3.67(s，3H)，5.50(dd，1H)，6.92(s，1H)，7.07(m _c，1H)，7.20(m _c，1H)，7.55(m _c，1H).

N. (8S)-8-(4-fluoro-2-methyl-phenyl)-2,3-dimethyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also

To (3R)-6-[3-(4-fluoro-2-methyl-phenyl)-3-hydroxyl-propyl group]-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-(embodiment 13 for 5-formic acid diformamide, 630mg, 1.58mmol) add triphenyl phosphine (415mg in the solution in tetrahydrofuran (THF) (20ml), 1.58mmol) and DIAD (633 μ l, 650mg 3.20mmol), at room temperature stirs 30min with this green solution again.Reaction mixture is concentrated in a vacuum, again crude product is passed through flash chromatography (methylene chloride=100: 3) purifying, (48% productive rate, title compound 83.0%ee) is a colourless foam to obtain 290mg.

[α] ²⁰ _D＝-15°(c＝0.41，MeOH)

HPLC analytical procedure: post: Daicel Chiralpak AD-H, 250 * 4.6mm, 5 μ m-elutriants: normal heptane/ethanol: 80/20, flow velocity: 1ml/min, detect wavelength: the 218nm-first wash-out enantiomorph: 12.4min/8.5 area-%, the second wash-out enantiomorph: 17.5min/91.5 area-%, 83.0%ee. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.99(m _c，1H)，2.21(m _c，1H)，2.40(s，3H)，2.47(s，3H)，2.57-2.74(m，1H)，2.74-2.96，2.80(m，s，4H)，3.02(s，3H)，3.68(s，3H)，5.30(dd，1H)，6.93(s，1H)，7.09(m _c，2H)，7.49(m _c，1H).

O. (8S)-(2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-yl also)-tetramethyleneimine-1-base-ketone

To (3R)-[7-hydroxyl-6-(3-hydroxyl-3-o-tolyl-propyl group)-2,3-dimethyl-3H-benzoglyoxaline-5-yl]-(embodiment 14 for tetramethyleneimine-1-base-ketone, 750mg, 1.8mmol) add triphenyl phosphine (1.40g in the solution in tetrahydrofuran (THF) (50ml), 5.3mmol) and DIAD (1.10ml, 1.13g, 5.6mmol), again this mixture is at room temperature stirred 5h.To react concentrated in a vacuum, crude product is by flash chromatography silica gel (methylene chloride=20: 1) purifying.The corresponding level of an evaporation part resistates that obtains is dissolved in acetone, adds the solution of hydrochloric acid in ether of 2M again.This solution is at room temperature stirred 17h, concentrate in a vacuum again.Separate the beige solid, it is dissolved in acetone.Add after the ether, form precipitation, it is by filtering separation, dry in a vacuum again.Obtain the beige solid (hydrochloride of title compound, 51% productive rate) of 401mg.

Annotate: title compound can further pass through the preparation HPLC purifying, uses GROMSaphire C8 post, 125 * 20mm, 65  apertures, 5 μ m granularities.-beige solid, m.p.127-128 ℃, 79.8%ee.

[α] ²⁰ _D=-19 ° (c=0.50, chloroform)

HPLC analytical procedure: post: Daicel Chiralpak AD-H, 250 * 4.6mm, 5 μ m-elutriants: normal heptane/ethanol: 80/20, flow velocity: 1ml/min, detect wavelength: the 218nm-first wash-out enantiomorph: 12.7min/10.1 area-%, the second wash-out enantiomorph: 20.0min/89.9 area-%, 79.8%ee. ¹H-NMR(DMSO-d ₆，400MHz)：δ＝1.92(m _c，5H)，2.21(m _c，1H)，2.38(s，3H)，2.47(s，3H)，2.66(m _c，1H)，2.93(m _c，1H)，3.07(m _c，1H)，3.21(m _c，1H)，3.48(m _c，2H)，3.68(s，3H)，5.32(dd，1H)，6.98(s，1H)，7.26(m _c，3H)，7.47(m _c，1H).

P. (8S)-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-S-formic acid methyl nitrosourea also

To (3R)-7-hydroxyl-6-(3-hydroxyl-3-o-tolyl-propyl group)-2,3-dimethyl-3H-benzoglyoxaline-(embodiment 15 for 5-formic acid methyl nitrosourea, 270mg, 0.73mmol) add triphenyl phosphine (564mg in the suspension in tetrahydrofuran (THF) (10ml), 2.12mmol) and DIAD (446 μ l, 2.26mmol), at room temperature stir the solution that obtains again.During 18h, form throw out, it is passed through filtering separation.Obtain title compound, and 35% productive rate (colorless solid of 89mg, 97.5%ee).-m.p.259-260℃。

[α] ²⁰ _D=-4 ° (c=0.40, chloroform)

HPLC analytical procedure: post: Daicel Chiralpak AD-H, 250 * 4.6mm, 5 μ m-elutriants: normal heptane/ethanol: 80/20+0.1% diethylamine, flow velocity: 1ml/min, detect wavelength: the 218nm-first wash-out enantiomorph: 6.0min/1.3 area-%, the second wash-out enantiomorph: 7.9min/98.7 area-%, 97.5%ee. ¹H-NMR(DMSO-d ₆，400MHz)：δ＝1.94(m _c，1H)，2.22(m _c，1H)，2.38(s，3H)， 2.47(s，3H)，2.77，2.83(d，m _c，4 H)，3.12(m _c，1 H)，3.69(s，3H)，5.29(dd，1H)，7.12(s，1H)，7.27(m _c，3H)，7.45(m _c，1H)，8.09(q，1H).

Q. (8S)-azetidine-1-base-(2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-yl also)-ketone

To (3R)-azetidine-1-base-[7-hydroxyl-6-(3-hydroxyl-3-o-tolyl-propyl group)-2,3-dimethyl-3H-benzoglyoxaline-5-yl]-(embodiment 16 for ketone, 65mg, 0.17mmol) add triphenyl phosphine (105mg in the solution in tetrahydrofuran (THF) (5ml), 0.40mmol) and DIAD (79 μ l, 81mg 0.40mmol), at room temperature stirs 5min with this green solution again.Reaction mixture is concentrated in a vacuum, again crude product is passed through flash chromatography (methylene chloride=100: 3) purifying, (86% productive rate, title compound 94.8%ee) is a colourless foam to obtain 55mg.

HPLC analytical procedure: post: Daicel Chiralpak AD-H, 250 * 4.6mm, 5 μ m-elutriants: normal heptane/ethanol: 80/20, flow velocity: 1ml/min, detect wavelength: the 218nm-first wash-out enantiomorph: 13.0min/2.6 area-%, the second wash-out enantiomorph: 21.7min/97.4 area-%, 94.8%ee. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.95(m _c，1H)，2.22(m _c，3H)，2.38(s，3H)，2.47(s，3H)，2.82(m _c，1H)，3.04(m _c，1H)，3.69(s，3H)，3.88(m _c，1H)，4.05(m _c，3H)，5.31(dd，1H)，7.05(s，1H)，7.26(m _c，3H)，7.47(m _c，1H).

R. (8S)-8-(2-benzyloxy methyl-phenyl)-2,3-dimethyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also

To (3R)-6-[3-(2-benzyloxy methyl-phenyl)-3-hydroxyl-propyl group]-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-(embodiment 17 for 5-formic acid diformamide, 50mg, 0.10mmol) add triphenyl phosphine (50mg in the solution in tetrahydrofuran (THF) (4ml), 0.19mmol) and DIAD (40 μ l, 41mg 0.20mmol), at room temperature stirs 30min with this solution again.(20 μ l, 21mg 0.10mmol), continue to stir 1h again to add another part DIAD.Reaction mixture concentrates under silica gel exists in a vacuum, resistates is loaded on the post of filling gel.(colourless foam of 25mg, 53% productive rate is 95.9%ee) with methylene dichloride and methanol mixture (50: 1 30: 1 then) wash-out with title compound.

HPLC analytical procedure: post: Daicel Chiralpak AD-H, 250 * 4.6mm, 5 μ m-elutriants: normal hexane/Virahol 80/20:, flow velocity: 1ml/min, detect wavelength: the 218nm-first wash-out enantiomorph: 11.4min/96.1 area-%, the second wash-out enantiomorph: 13.6min/2.0 area-%, 95.9%ee. ¹H-NMR(DMSO-d ₆，400MHz)：δ＝1.98(m _c，1H)，221(m _c，1H)，2.46(s，3H)，2.55(m _c)，2.80(s，bs，4H)，3.02(s，3H)，3.68(s，3H)，4.55(s，2H)，4.63(d，1H)，4.72(d，1H)，5.36(d，1H)，6.93(s，1H)，7.36(m _c，8H)，7.56(d，1H).

S. (8S)-8-(2-methoxymethyl-phenyl)-2,3-dimethyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also

To (3R)-7-hydroxyl-6-[3-hydroxyl-3-(2-methoxymethyl-phenyl)-propyl group]-2,3-dimethyl-3H-benzoglyoxaline-(embodiment 18 for 5-formic acid diformamide, 900mg, 2.19mmol) add triphenyl phosphine (1.14g in the solution in tetrahydrofuran (THF) (40ml), 4.3mmol) and DIAD (885 μ l, 903mg 4.46mmol), at room temperature stirs 10min with this brown solution again.Reaction mixture is concentrated in a vacuum, and crude product is by flash chromatography (methylene chloride=20: 1) purifying.Evaporate corresponding fraction, handle resistates (700mg) with ether again, obtain the light brown foam, with its pulp in diisopropyl ether.By the filtering separation title compound (colorless solid of 430mg, 50% productive rate, 97.9%ee).-m.p.200℃。

[α] ²⁰ _D＝-9°(c＝0.51，CH ₂Cl ₂/MeOH＝1∶1)

HPLC analytical procedure: post: Daicel Chiralpak AD-H, 250 * 4.6mm, 5 μ m-elutriants: normal hexane/Virahol: 90/10, flow velocity: 1ml/min, detect wavelength: the 218nm-first wash-out enantiomorph: 46.1min/1.0 area-%, the second wash-out enantiomorph: 48.8min/97.6 area-%, 97.9%ee. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.99(m _c，1H)，2.23(m _c，1H)，2.46(s，3H)，2.64(m _c，1H)，2.81，2.85(s，m _c，4H)，3.02(s，3H)，3.30(s)，3.68(s，3H)，4.56(dd，2H)，5.36(dd，1H)，6.93(s，1H)，7.38(m _c，3H)，7.65(m _c，1H).

T. (8S)-2-methyl-8-o-tolyl-3-(2-trimethyl silyl-ethoxyl methyl)-3,6,7,8-tetrahydrochysene-chromene is [7,8-d] imidazoles-5-formic acid diformamide also

To (3R)-7-hydroxyl-6-(3-hydroxyl-3-o-tolyl-propyl group)-2-methyl-3-(2-trimethyl silyl-ethoxyl methyl)-3H-benzoglyoxaline-(embodiment 19 for 5-formic acid diformamide, 300mg, 0.60mmol) add triphenyl phosphine (300mg in the solution in tetrahydrofuran (THF) (10ml), 1.14mmol) and DIAD (240 μ l, 245mg, 1.21mmol), again this solution is at room temperature stirred 10min.Reaction mixture is concentrated in a vacuum, and crude product is by flash chromatography (first post: methylene chloride=40: 1, second post: gasoline/ethyl acetate=1: 1 to 1: 3) purifying.The corresponding level part of evaporation obtains the title compound (30wt-%, 45% correcting yield) of 430mg and the mixture of triphenyl phosphine oxide compound (70wt-%). ¹H-NMR (DMSO-d ₆, 400 MHz): δ=-0.08 (s, 9H), 0.83 (t, 2H), 1.99 (m _c), 2.24 (m _c, 1H), 2.39 (s, 3H), 2.50 (s), 2.67 (bs, 1H), 2.80 (s, 3H), 2.90 (bs, 1H), 3.02 (s, 3H), 3.52 (t, 2H), 5.35 (dd, 1H), 5.54 (s, 2H), 7.06 (s, 1H), 7.27 (m _c, 3H), 7.48 (m _c, 1H), triphenyl phosphine oxide compound: 7.59 (m _c).

U. (8S)-2-methyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene is [7,8-d] imidazoles-5-formic acid diformamide also

Under 0 ℃, with boron-trifluoride etherate (290 μ l, 325mg 2.3mmol) is added drop-wise to (8S)-2-methyl-8-o-tolyl-3-(2-trimethyl silyl-ethoxyl methyl)-3,6,7,8-tetrahydrochysene-chromene is [7,8-d] imidazoles-5-formic acid diformamide (embodiment T, 400mg also, 30wt-% is 0.25mmol) in the solution in methylene dichloride (10ml).This reaction mixture is at room temperature stirred 3h, again evaporating solvent in the presence of silica gel.Resistates is loaded on the post of filling gel, uses methylene chloride=50: 1 wash-out title compounds again.The corresponding level of evaporation part, obtain title compound (110mg, quantitative yield, 96.1%ee).-m.D.219℃。

[α] ²⁰ _D＝-9°(c＝0.44，CH ₂Cl ₂/MeOH＝1∶1)

HPLC analytical procedure: post: Daicel Chiralpak AD-H, 250 * 4.6mm, 5 μ m-elutriants: normal hexane/Virahol: 90/10, flow velocity: 1ml/min, detect wavelength: the 218nm-first wash-out enantiomorph: 21.9min/97.7 area-%, the second wash-out enantiomorph: 32.5min/1.9 area-%, 96.1%ee. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝2.04(m _c，1H)，2.26(m _c，1H)，2.40(s，3H)，2.53，2.63(s，m _c)，2.81(s，3H)，2.90，3.02(m _c，s，4H)，5.43(dd，1H)，6.99(s，1H)，7.28(m _c，3H)，7.50(m _c，1H).

V. (8S)-2,3-dimethyl-8-(2-methyl-thiene-3-yl-)-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also

To (3R)-7-hydroxyl-6-[3-hydroxyl-3-(2-methyl-thiene-3-yl-)-propyl group]-2,3-dimethyl-3H-benzoglyoxaline-(embodiment 21 for 5-formic acid diformamide, 0.54g, 1.4mmol) add triphenyl phosphine (0.70g in the suspension in tetrahydrofuran (THF) (20ml), 2.7mmol) and DIAD (564mg, 2.8mmol), again this solution is at room temperature stirred 10min.Reaction mixture is concentrated in a vacuum, and crude product (brown oil of 2.5g) is by column chromatography (ethyl acetate is used ethyl acetate/methanol=9: 1 then) purifying.The corresponding level part of evaporation obtains yellow solid, with its pulp in ether (5ml).After at room temperature 10 minutes,,, dry in a vacuum again with ether (2ml) washing by this throw out of filtering separation.Title compound is separated 39% productive rate (colorless solid of 200mg).-m.p.233℃。 ¹H-NMR(DMSO-d ₆，200MHz)：δ＝2.20(m _c，2H)，2.47(s，3H)，2.57(s，3H)，2.88(s，bs，5H)，3.15(s，3H)，3.67(s，3H)，5.27(dd，1H)，6.76(s，1H)，7.03(m _c，2H).

W. (8S)-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid cyclopropyl amide also

To (3R)-7-hydroxyl-6-(3-hydroxyl-3-o-tolyl-propyl group)-2,3-dimethyl-3H-benzoglyoxaline-(embodiment 22 for 5-formic acid cyclopropyl amide, 0.32g, 0.81mmol) add triphenyl phosphine (0.41g in the suspension in tetrahydrofuran (THF) (20ml), 1.6mmol) and DIAD (328mg, 1.62mmol), again this solution is at room temperature stirred 10min.Reaction mixture is concentrated in a vacuum, crude product (brown solid of 1.6g) by column chromatography with silica gel (ethyl acetate is used ethyl acetate/methanol=9: 1 then) purifying.The corresponding level part of evaporation obtains yellow solid (0.26g), with its pulp in ether (3ml).After at room temperature 10 minutes,,, dry in a vacuum again with ether (2ml) washing by this throw out of filtering separation.Title compound is separated, and 66% productive rate (colorless solid of 200mg, 97.5%ee).-m.p.289℃。

HPLC analytical procedure: post: Daicel Chiralpak AD-H, 250 * 4.6mm, 5 μ m-elutriants: normal heptane/ethanol: 80/20, flow velocity: 1ml/min, detect wavelength: the 218nm-first wash-out enantiomorph: 6.0min/12 area-%, the second wash-out enantiomorph: 7.9min/97.5 area-%, 97.5%ee. ¹H-NMR(CDCl ₃，200MHz)：δ＝0.64(m _c，2H)，0.90(m _c，2H)，2.08(m _c，1H)，2.26(m _c，1H)，2.37(s，3H)，2.56(s，3H)，2.98(m _c，2H)，3.22(m _c，1H)，3.68(s，3H)，5.39(dd，1H)，6.02(bs，1H)，6.94(s，1H)，7.19(m _c，3H)，7.56(m _c，1H).

X.5-methoxymethyl-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles also

To (3R)-5-(3-hydroxyl-3-o-tolyl-propyl group)-6-methoxymethyl-1, the 2-dimethyl-(embodiment 23 for 1H-benzoglyoxaline-4-alcohol, 800mg, 2.26mmol) add triphenyl phosphine (1.20g in the solution in tetrahydrofuran (THF) (40ml), 4.6mmol) and DIAD (900 μ l, 918mg 4.5mmol), at room temperature stirs 30min with this solution again.Concentrate under silica gel exists in a vacuum with reaction mixture.Unmodified packed column is written into this resistates, again with title compound and triphenyl phosphine hopcalite eluent ethyl acetate.Further by column chromatography with after silica gel (ethyl acetate/gasoline=3: 2 the is used ethyl acetate then) purifying, obtain the colorless solid form title compound (600mg, it contains the triphenyl phosphine oxide compound of 11mol-%, 79% productive rate, 95.4%ee).

HPLC analytical procedure: post: Daicel Chiralpak AD-H, 250 * 4.6mm, 5 μ m-elutriants: normal hexane/Virahol: 95/5, flow velocity: 1ml/min, detect wavelength: the 218nm-first wash-out enantiomorph: 30.0min/2.3 area-%, the second wash-out enantiomorph: 37.7min/97.7 area-%, 95.4%ee. ¹H-NMR (DMSO, 200MHz): δ=1.99 (m _c, 1H), 2.26 (m _c, 1H), 2.38 (s, 3H), 2.45 (s, 3H), 2.94 (m _c, 2H), 3.33 (s, 3H), 3.67 (s, 3H), 4.48 (s, 2H), 5.24 (dd, 1H), 7.02 (s, 1H), 7.27 (m _c, 3H), 7.49 (m _c, 1H), 7.62 (m _c, the triphenyl phosphine oxide compound).

Synthesizing of formula 2 prochiral ketones

A.7-hydroxy-2-methyl-6-(3-oxygen-3-phenyl-propyl group)-3-(2-trimethyl silyl-ethoxyl methyl)-3H-benzoglyoxaline-5-formic acid diformamide

With 7-hydroxy-2-methyl-3-(2-trimethyl silyl-ethoxyl methyl)-3H-benzoglyoxaline-5-formic acid diformamide (embodiment b, 10.0g, 28.6mmol) solution iodate N in methylene dichloride (600ml), N-dimethyl-methylene radical imonium (6.4g, 34.3mmol) handle, should react again and at room temperature stir 3h.Reaction mixture is poured in the saturated sodium bicarbonate solution, uses dichloromethane extraction again twice.The organic layer dried over mgso concentrates in a vacuum again.Resistates (11.3g, 98%) is suspended in the toluene (250ml), add again 1-(1-phenyl-vinyl)-tetramethyleneimine (CAS3433-56-5,7.2g, 41.6mmol).With the suspension 3h that refluxes, be cooled to after the room temperature, in a vacuum evaporating solvent.Resistates by flash chromatography silica gel (ethyl acetate/petroleum ether=5: 1) purifying, is obtained the beige solid of 10.6g, it is dissolved in acetone, handle with fumaric acid again.Throw out is filtered, be dissolved in the methylene chloride-methanol, again this solution is neutralized with 1M NaOH solution.Layer separates, and the organic layer dried over mgso concentrates in a vacuum again.The title compound that obtains 9.7g (73% productive rate) is a brown solid.-m.p.192-194℃。

B.7-hydroxy-2-methyl-3-(2-trimethyl silyl-ethoxyl methyl)-3H-benzoglyoxaline-5-formic acid diformamide

(31.1mmol) solution in ethanol (1.2L) uses 10%Pd/C (1.4g) at autoclave (5bar H for embodiment c, 13.7g with 7-benzyloxy-2-methyl-3-(2-trimethyl silyl-ethoxyl methyl)-3H-benzoglyoxaline-5-formic acid diformamide ₂) in and room temperature under hydrogenation 16h.Leach catalyzer, again filtrate is concentrated in a vacuum.Resistates is crystallization from diisopropyl ether, and the title compound that obtains 10.1g (93% productive rate) is a white solid.-m.p.154-156℃。

C.7-benzyloxy-2-methyl-3-(2-trimethyl silyl-ethoxyl methyl)-3H-benzoglyoxaline-5-formic acid diformamide

With 4-benzyloxy-6-bromo-2-methyl isophthalic acid-(2-trimethyl silyl-ethoxyl methyl)-1H-benzoglyoxaline (embodiment d, 19.5g, 43.6mmol), triphenyl phosphine (4.6g, 17.9mmol), acid chloride (II) (1.5g, 6.5mmol) and dimethylamine solution (2M, in THF, 218ml, 436mmol) be transferred in the autoclave, and carboxylated (6bar CO) reaches 60h under 120 ℃.Leach catalyzer, again filtrate is concentrated in a vacuum.By flash chromatography silica gel (toluene/two  alkane=2: 1) purifying, the title compound that obtains 13.8g (72% productive rate) is a white solid with resistates.-m.p.118-120℃。

D.4-benzyloxy-6-bromo-2-methyl isophthalic acid-(2-trimethyl silyl-ethoxyl methyl)-1H-benzoglyoxaline

To 4-benzyloxy-6-bromo-2-methyl isophthalic acid H-benzoglyoxaline (36.5g, 115mmol) and triethylamine (17.7ml, 13 8mmol) drip (2-chlorine methoxyl group-ethyl)-trimethyl silyl (24.5ml in the suspension in dimethyl formamide-dichloromethane mixture (10: 1), 138mmol), again this suspension is at room temperature stirred 5h.Reaction is poured in the water, uses methylene dichloride (3x) extraction again.With the organic layer dried over mgso that merges, concentrate in a vacuum again.By flash chromatography silica gel (toluene/two  alkane=9: 1) purifying, the title compound that obtains 19.5g (39% productive rate) is a white solid with resistates.-m.p.94-95℃。

E.3-[6-(azetidine-1-carbonyl)-4-hydroxyl-1,2-dimethyl-1H-benzoglyoxaline-5-yl]-1-phenyl-third-1-ketone

With azetidine-1-base-(8-methoxyl group-2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydrochysene-chromene is [7,8-d] imidazoles-5-yl also)-ketone (embodiment f, 4.7g 12mmol) suspension in THF (75ml) is handled with 1N hydrochloric acid (30ml), this mixture heating up to 50 ℃ is reached 2h again.Be cooled to after the room temperature, this reaction mixture is poured in the water (100ml) carefully, neutralize with 2MNaOH again.Throw out is filtered, and dry in a vacuum again, the title compound that obtains 2.9g (65% productive rate) is a white solid.-m.p.242-243℃。

F. azetidine-1-base-(8-methoxyl group 2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-yl also)-ketone

With 8-methoxyl group-2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydrochysene-chromene also [7,8-d] imidazoles-5-formic acid (embodiment i, 6g, 17mmol) suspension in dimethyl formamide (60ml) with TBTU (6.5g, 20.4mmol), DIPEA (7.3ml, 42.6mmol) handle, at room temperature stir 1h again.(2ml 29mmol), at room temperature stirs 2h with this reaction mixture again to add azetidine.This mixture is poured in the water (400ml), filtering precipitate, dry in a vacuum again, the title compound that obtains 4.8g (72% productive rate) is the beige solid.-m.p.147-150℃。

G.7-hydroxyl-2,3-dimethyl-6-(3-oxygen-3-phenyl-propyl group)-3H-benzoglyoxaline-5-formic acid methyl nitrosourea

With 8-methoxyl group-2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydrochysene-chromene is [7,8-d] imidazoles-5-formic acid methyl nitrosourea (embodiment h also, 5.1g 14mmol) suspension in THF (75ml) is handled with 1N hydrochloric acid (30ml), this mixture heating up to 50 ℃ is reached 3h again.Be cooled to after 5 ℃, this reaction mixture is poured in the water (100ml) carefully, again with 2M NaOH neutralization.Throw out is filtered, and dry in a vacuum again, the title compound that obtains 4.4g (90% productive rate) is a white solid.-m.p.284-285℃。

H.8-methoxyl group-2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid methyl nitrosourea also

With 8-methoxyl group-2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydrochysene-chromene also [7,8-d] imidazoles-5-formic acid (embodiment i, 6.0g, 17mmol) solution in dimethyl formamide (60ml) with TBTU (6.5g, 20.4mmol), DIPEA (7.3ml, 42.6mmol) handle, at room temperature stir 1h again.(2M, in THF, 11.5ml 29mmol), at room temperature stirs 2h with this reaction mixture again to add methylamine solution.This mixture is poured in the water (400ml), throw out is filtered, dry in a vacuum again, the title compound that obtains 5.2g (84% productive rate) is a white solid.-m.p.237-239℃。

I.8-methoxyl group-2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid also

To 8-methoxyl group-2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydrochysene-chromene is [7,8-d] imidazoles-5-ethyl formate (embodiment j also, 13.1g, 34.4mmol) add 2M potassium hydroxide aqueous solution (35ml) in the suspension in methyl alcohol (290ml), again this mixture heating up to 55 ℃ is reached 16h.Be cooled to after the room temperature, under vacuum, remove and desolvate, resistates is suspended in the water (300ml) again.Regulate this suspension to pH 5-6 by adding the 2M HCl aqueous solution, this solution at room temperature stirs 1h again.By the filtering separation throw out, dry in a vacuum again, the title compound that obtains 12g (99% productive rate) is the beige solid.-m.p.288-289℃。

J.8-methoxyl group-2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-ethyl formate also

With 2, (70ml 570mmol) adds to 7-hydroxyl-2 to the 2-Propanal dimethyl acetal, 3-dimethyl-6-(3-oxygen-3-phenyl-propyl group)-3H-benzoglyoxaline-5-ethyl formate (13.9g, 37.9mmol) solution in methylene dichloride (170ml).Slowly add methylsulfonic acid (3.2ml, 49.3mmol) afterwards, with the red solution backflow 16h that obtains.Be cooled to after the room temperature, reaction mixture be poured in the mixture of 170ml saturated sodium bicarbonate solution (170ml) and methylene dichloride (140ml).Be separated, (2 * 50ml) extract water layer with methylene dichloride.With the organic layer dried over mgso of collecting, concentrate in a vacuum again.Resistates is crystallization from diisopropyl ether, and the title compound that obtains 13.2g (92% productive rate) is the beige solid.-m.p.176-178℃。

K.6-[3-(2-fluoro-phenyl)-3-oxygen-propyl group]-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide

With 6-dimethylamino methyl-7-hydroxyl-2, (8.5g 29.2mmol) is suspended in the toluene (130ml) 3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide, again this suspension is heated to 50 ℃.Slowly add 1-[1-(2-fluorophenyl)-vinyl]-(43.9mmol) solution in 20ml toluene ℃ reaches this mixture heating up to 100 1h to tetramethyleneimine again for CAS237436-15-6,8.3g.Be cooled to after the room temperature, in a vacuum evaporating solvent.Resistates is dissolved in methyl alcohol (100ml), handles with fumaric acid again.Stir after the 1h,, be dissolved in methylene dichloride-water (1: 1) again sedimentation and filtration.Regulate this solution to pH 8 by adding the 2N NaOH aqueous solution.Layer separates, and the organic layer dried over mgso concentrates in a vacuum again.Resistates is crystallization from ether, and the title compound that obtains 3.8g (36% productive rate) is a white solid.-m.p.218-221℃。

(1.6-[3-4-fluoro-phenyl)-3-oxygen-propyl group]-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide

With 6-dimethylamino methyl-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide (8.9g 30.6mmol) is suspended in the toluene (200ml), uses 1-[1-(4-fluorophenyl)-vinyl again]-tetramethyleneimine (CAS237436-54-3,8.8g, 46mmol) handle.With this reaction mixture refluxed 6h.Be cooled to after the room temperature, in a vacuum evaporating solvent.With resistates by flash chromatography with silica gel (methylene chloride=20: 1) purifying, crystallization from acetone again, the title compound that obtains 5.2g (44% productive rate) is a white solid.-m.p.248-249℃。

M.7-hydroxyl-2,3-dimethyl-6-(3-oxygen-3-o-tolyl-propyl group)-3H-benzoglyoxaline-5-formic acid diformamide

With 6-dimethylamino methyl-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide (11.3g 32.8mmol) is suspended in the toluene (350ml), uses 1-[1-(2-aminomethyl phenyl)-vinyl again]-tetramethyleneimine (CAS156004-72-7,11.4g, 60.8mmol) handle.With this reaction mixture refluxed 4h.Be cooled to after the room temperature, in a vacuum evaporating solvent.Resistates by flash chromatography silica gel (methylene chloride=10: 1) purifying, is dissolved in the acetone (70ml) then, adds fumaric acid (3g), at room temperature this solution stirring is spent the night again.By the filtering separation throw out, be dissolved in methylene dichloride, wash with saturated sodium bicarbonate aqueous solution again.Be separated, the organic layer dried over mgso concentrates in a vacuum again.The title compound that obtains 6.7g (55% productive rate) is brown foam. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝2.42(s，3H)，2.48(s)，2.77，2.80，3.00，3.05(s，bm _c，s，bm _c，10H)，3.67(s，3H)，6.78(s，1H)，7.30(m _c，2H)，7.42(m _c，1H)，7.70(m _c，1H)，10.00(bs，1H).

N.6-[3-(2-chloro-phenyl)-3-oxygen-propyl group]-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide

With 6-dimethylamino methyl-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide (2.5g, 8.6mmol) 1, suspension in the 2-glycol dimethyl ether (80ml) is heated to 80 ℃, add 1-[1-(2-chloro-phenyl-)-vinyl in time at 15min again]-tetramethyleneimine (CAS237436-24-7,2.9g, 14.0mmol).Keep reaction mixture to reach 3.5h at 80 ℃.Be cooled to after the room temperature, in a vacuum evaporating solvent.Resistates is dissolved in acetone, adds fumaric acid (1.0g), at room temperature this solution stirring is spent the night again.By the filtering separation throw out, the reusable heat washed with isopropyl alcohol.The salt of title compound and fumaric acid is dissolved in methylene dichloride and the saturated sodium bicarbonate aqueous solution.Be separated, the organic layer dried over mgso concentrates in a vacuum again.With resistates by flash chromatography with silica gel (methylene chloride=20: 1) purifying.The title compound that obtains 1.55g (45% productive rate) is a colourless foam. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝2.50(s)，2.76，2.81(s，m _c，5H)，2.98，3.08(s，m _c，5H)，3.66(s，3H)，6.77(s，1H)，7.51(m _c，4H)，9.99(bs，1H).

O.7-hydroxyl-2,3-dimethyl-6-[3-oxygen-3-(2-trifluoromethyl-phenyl)-propyl group]-3H-benzoglyoxaline-5-formic acid diformamide

With 6-dimethylamino methyl-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide (4.3g, 14.8mmol) and 1-[1-(2-trifluoromethyl-phenyl)-vinyl]-tetramethyleneimine (CAS237436-26-9,5.7g 23.6mmol) suspension in toluene (200ml) is heated to reflux and reaches 3h.Be cooled to after the room temperature, in a vacuum evaporating solvent.Resistates is dissolved in acetone, adds fumaric acid (1.7g), at room temperature this solution stirring is spent the night again.Sediment-free forms.Solution is concentrated in a vacuum, again with resistates by flash chromatography with silica gel (methylene chloride=20: 1) purifying, then crystallization from Virahol.Obtain title compound, 54% productive rate (the beige solid of 3.49g).-m.p.204-206℃。

P.7-hydroxyl-2,3-dimethyl-6-(3-naphthalene-2-base-3-oxygen-propyl group)-3H-benzoglyoxaline-5-formic acid diformamide

With 6-dimethylamino methyl-7-hydroxyl-2, (2.6g, 9.0mmol) suspension in toluene (80ml) is heated to 40 ℃ to 3-dimethyl-3H-benzoglyoxaline-5-formic acid diethylamine.(15.4mmol) solution in toluene (40ml) is heated to reaction mixture 93 ℃ again for CAS156004-71-6,3.45g to add 1-(1-naphthalene-2-base-vinyl)-tetramethyleneimine.2.5h afterwards, solution is cooled to room temperature, concentrates in a vacuum again.Resistates is dissolved in acetone (100ml), adds fumaric acid (1.2g), at room temperature this solution stirring is spent the night again.By the filtering separation throw out, use acetone (2 * 20ml) washings again.The salt of title compound and fumaric acid is dissolved in the methylene dichloride (100ml), and adding ammonia soln again is 9 until reaching the pH-value.Be separated, (3 * 50ml) extract water with methylene dichloride.With the organic phase dried over mgso that merges, concentrate in a vacuum again.With resistates by flash chromatography with silica gel (methylene chloride=15: 1) purifying, crystallization from acetone again.The title compound that obtains 0.48g (13% productive rate) is a colorless solid.-m.p.221-225℃。

Q.6-[3-(2-ethyl-phenyl)-3-oxygen-propyl group]-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide

With 6-dimethylamino methyl-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide (3.0g, 10.3mmol) 1, suspension in the 2-glycol dimethyl ether (100ml) is heated to 80 ℃, add 1-[1-(2-ethylphenyl)-vinyl in time at 15min again]-tetramethyleneimine is (synthetic as mentioned below, 3.3g, the 16.4mmol) solution in DME.Reaction mixture is remained on 80 ℃ reach 3h.Be cooled to after the room temperature, in a vacuum evaporating solvent.Resistates is dissolved in acetone, adds fumaric acid (1.2g), again this solution is at room temperature stirred 3d.

(a) by the filtering separation throw out, the reusable heat washed with isopropyl alcohol.The salt of title compound and fumaric acid is dissolved in methylene dichloride and the saturated sodium bicarbonate aqueous solution.Be separated, the organic layer dried over mgso concentrates in a vacuum again.The title compound that obtains 1.1g (27% productive rate) is a colourless foam.

(b) mother liquor is concentrated, resistates with silica gel (toluene/1,4-two  alkane=1: 1) purifying, is followed (the solvent: acetone) of crystallization in the presence of Citric Acid by flash chromatography.The salt of title compound and Citric Acid is dissolved in methylene dichloride and the saturated sodium bicarbonate aqueous solution.Be separated, the organic layer dried over mgso concentrates in a vacuum again.The title compound that obtains other 0.58g (14% productive rate) is the beige solid.

Annotate: this title compound can further pass through the preparation HPLC purifying: post: GROMSaphire C8125 * 20mm, 65  apertures, 5 μ m granularities, the solvent gradient: ammonium formiate damping fluid (pH 3.75)/acetonitrile=97: 3 (v/v) was to 5: 95 (v/v), flow velocity: 30ml/min, working time: 16min.-m.p.159°-160℃。 ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.14(t，3H)，2.50，2.52(bs，s)，2.75，2.75，2.77(q，bs，s，6H)，2.99，3.04(s，bs，5H)，3.67(s，3H)，6.78(s，1H)，7.30(m _c，2H)，7.44(m _c，1H)，7.62(d，1H)，9.98(bs，1H).

R.7-hydroxyl-2,3-dimethyl-6-(3-oxygen-3-thiophene-2-base-propyl group)-3H-benzoglyoxaline-5-formic acid diformamide

With 6-dimethylamino methyl-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide (2.5g, 8.6mmol) 1, suspension in the 2-glycol dimethyl ether (80ml) is heated to 80 ℃, adding 1-(1-thiophene-2-base-vinyl)-tetramethyleneimine in time at 15min again (synthesizes as mentioned below, 2.5g, the 13.9mmol) solution in DME.Reaction mixture is remained on 80 ℃ reach 3h.Be cooled to after the room temperature, in a vacuum evaporating solvent.Crude product by flash chromatography silica gel (methylene chloride=20: 1) purifying, is followed crystallization from Virahol (2x).Obtain title compound, 12% productive rate (the beige solid of 391mg).Mother liquor is concentrated, and resistates with silica gel (toluene/1,4-two  alkane=1: 1) purifying, is followed crystallization in the presence of Citric Acid by flash chromatography.The salt of title compound and Citric Acid is dissolved in methylene dichloride and the saturated sodium bicarbonate aqueous solution.Be separated, the organic layer dried over mgso concentrates in a vacuum again.Obtain the title compound of the brown form of foam of other 324mg (10% productive rate).

Annotate: this title compound can further pass through the preparation HPLC purifying: post: GROMSaphire C8125 * 20mm, 65  apertures, 5 μ m granularities, the solvent gradient: ammonium formiate damping fluid (pH 3.75)/acetonitrile=97: 3 (v/v) was to 5: 95 (v/v), flow velocity: 30ml/min, working time: 16min.-m.p.233-235℃。 ¹H-NMR(DMSO-d ₆，200MHz)：δ＝2.50，2.53(bs，s)，2.78(bs，s，4H)，3.01，3.09(s，bs，5H)，3.68(s，3H)，6.80(s，1H)，7.25(m _c，1H)，7.93(m _c，1H)，7.99(m _c，1H)，10.10(bs，1H).

S.6-[3-(4-fluoro-2-methyl-phenyl)-3-oxygen-propyl group]-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide

With 6-dimethylamino methyl-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide (2.50g, 8.6mmol) 1, suspension in the 2-glycol dimethyl ether (80ml) is heated to 80 ℃, add 1-[1-(4-fluoro-2-aminomethyl phenyl)-vinyl in time at 15min again]-tetramethyleneimine is (synthetic as mentioned below, 2.8g, the 13.6mmol) solution in DME.Reaction mixture is remained on 80 ℃ reach 3.5h.Be cooled to after the room temperature, in a vacuum evaporating solvent.Resistates is dissolved in acetone, adds fumaric acid (1.0g), again this solution is at room temperature stirred 17h.By the filtering separation throw out, the reusable heat washed with isopropyl alcohol.The salt of title compound and fumaric acid is dissolved in methylene dichloride and the saturated sodium bicarbonate aqueous solution.Be separated, the organic layer dried over mgso concentrates in a vacuum again.Resistates washs with diisopropyl ether, again by flash chromatography silica gel (methylene chloride=20: 1) purifying.The corresponding level part of evaporation obtains colorless solid, with its mixture washing with Virahol and diisopropyl ether.Obtain title compound, 44% productive rate (colorless solid of 1.49g). ¹H-NMR(DMSO-d ₆，200MHz)：δ＝2.45(s，3H)，2.48(s，bs)，2.75，2.77(bs，s，4H)，3.00，3.05(s，bs，5H)，3.67(s，3H)，6.78(s，1H)，7.14(m _c，2H)，7.83(m _c，1H)，9.98(bs，1H).

T.7-hydroxyl-2,3-dimethyl-6-(3-oxygen-3-o-tolyl-propyl group)-3H-benzoglyoxaline-5-ethyl formate

With 6-dimethylamino methyl-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-ethyl formate (45.0g, 0.15mol) suspension in DME (600ml) is heated to 85 ℃, drip 1-[1-(2-aminomethyl phenyl)-vinyl again]-tetramethyleneimine (46.0g, 0.25mol) solution in DME (100ml).Should stir 4h, concentrating under reduced pressure in the presence of silica gel down at 85 ℃ by the redness reaction mixture.The pillar of having filled 1kg silica gel is loaded this solid residue, title compound methylene dichloride and methanol mixture [30: 1 (v/v)] wash-out.The corresponding level part of evaporation obtains two batches of title compounds, with its pulp in hot Virahol.First batch of filtration obtains the colorless solid (pure title compound, 27% productive rate, m.p.183 ℃) of 16.0g.Handle with the hot Virahol of another part by filtering second batch of isolating throw out.After the filtration, obtain pink solid (title compound and 7-hydroxyl-2, the mixture of 3-dimethyl-3H-benzoglyoxaline-5-ethyl formate, (mol ratio 85: 15,23% the correcting yield) of 14.7g.

U.8-methoxyl group-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-ethyl formate also

With 2, (135.7ml 1097mmol) adds to 7-hydroxyl-2 to the 2-Propanal dimethyl acetal, 3-dimethyl-6-(3-oxygen-3-o-tolyl-propyl group)-3H-benzoglyoxaline-5-ethyl formate (embodiment t, 28.0g, 73.6mmol) in the solution in methylene dichloride (350ml).Slowly add methylsulfonic acid (6.2ml, 95.5mmol) afterwards, with this mixture backflow 3d.Be cooled to after the room temperature, reaction mixture is poured in the saturated sodium bicarbonate solution.This biphase mixture is stirred 10min.Be separated, water layer extracts with methylene dichloride (2x).With the organic layer dried over mgso of collecting, concentrate in a vacuum again.Resistates is crystallization from diisopropyl ether, and the title compound that obtains 27.8g (96% productive rate) is the beige solid.-m.p.198℃。

V.8-methoxyl group-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid also

To 8-methoxyl group-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene is [7,8-d] imidazoles-5-ethyl formate (embodiment u also, 27.7g, 70.2mmol) in methyl alcohol (300ml) and 1, add 2M aqueous sodium hydroxide solution (140ml) in the suspension in the 4-two  alkane (300ml), again this mixture heating up is reached 2h to refluxing.Be cooled to after the room temperature, this reaction mixture is poured in the water, be adjusted to pH value 5-6 by adding concentrated hydrochloric acid.Form throw out, by filtering its separation, dry in a vacuum again, the title compound that obtains 22.45g (87% productive rate) is the beige solid.Mother liquor is concentrated, regulate the pH value once more to 5-6.Sediment separate out obtains title compound (the beige solid of 3.2g, 12% productive rate)-m.p.304-309 ℃ of another batch.

W. (8-methoxyl group-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-yl also)-tetramethyleneimine-1-base-ketone

With 8-methoxyl group-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene is [7,8-d] imidazoles-5-formic acid (embodiment v, 2.00g, 5.5mmol) TBTU (2.1g of the suspension in DMF (50ml) also, 6.5mmol) and DIPEA (2.40ml, 1.78g, 12.8mmol) processing.This reaction mixture is at room temperature stirred 30min, add again tetramethyleneimine (767 μ l, 660mg, 9.3mmol).At room temperature continuously stirring 17h is poured into reaction in the saturated ammonium chloride solution again.After the 1h, by the filtering separation throw out, dry in a vacuum (40 ℃) again.Title compound is with beige solid isolated in form (1.57g, 69% productive rate).-m.p.202-204℃。

X.3-[4-hydroxyl-1,2-dimethyl-6-(tetramethyleneimine-1-carbonyl)-1H-benzoglyoxaline-5-yl]-1-o-tolyl-third-1-ketone

(the 1M aqueous solution of 8.40ml 8.4mmol) adds to (8-methoxyl group-2,3-dimethyl-8-o-tolyl-3 with hydrochloric acid, 6,7,8-tetrahydrochysene-chromene also [7,8-d] imidazoles-5-yl)-(embodiment w, 1.40g is 3.3mmol) in the suspension in THF (40ml) for tetramethyleneimine-1-base-ketone.Obtain a solution, it is stirred 1d down at 50 ℃.Make reaction mixture be returned to room temperature, be poured in the frozen water, again by adding aqueous sodium hydroxide solution (2N) neutralization.By the filtering separation throw out, dry in a vacuum (40 ℃) again.Obtain 1.0g title compound (colorless solid, 74% productive rate).The mother liquor dichloromethane extraction.With the organic phase dried over mgso that merges, concentrate in a vacuum again.With resistates by flash chromatography with silica gel (methylene chloride=15: 1) purifying.The corresponding level part of evaporation obtains other 104mg title compound (8% productive rate).-m.p.216-217℃。

Y.8-methoxyl group-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid methyl nitrosourea also

With 8-methoxyl group-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene is [7,8-d] imidazoles-5-formic acid (embodiment v, 2.00g, 5.5mmol) DIPEA (2.45ml of the suspension in DMF (50ml) also, 1.85g, 14.3mmol) and TBTU (2.2g 6.9mmol) handles.This yellow solution is at room temperature stirred 20min, add again methylamine (solution of the 2M of 7.1ml in THF, 14.2mmol).At room temperature stir 5h continuously.Reaction mixture is poured in the saturated ammonium chloride solution (250ml), uses methylene dichloride (3 * 200ml) extractions again.With the organic phase dried over mgso that merges, revaporization is to dry.With the crystallization from acetone (20ml) of Huang-brown solid resistates.Obtain title compound, 82% productive rate (1.7g colourless crystallization).Mother liquor by flash chromatography silica gel (methylene chloride=9: 1) purifying, is followed crystallization from acetone.Obtain other 0.16g title compound (8% productive rate)-m.p.257-261 ℃.

Z.7-hydroxyl-2,3-dimethyl-6-(3-oxygen-3-o-tolyl-propyl group)-3H-benzoglyoxaline-5-formic acid methyl nitrosourea

(the 1 M aqueous solution of 18.0ml 18mmol) adds to 8-methoxyl group-2,3-dimethyl-8-o-tolyl-3 with hydrochloric acid, 6,7,8-tetrahydrochysene-chromene also [7,8-d] (embodiment y, 1.70g is 4.5mmol) in the suspension in THF (40ml) for imidazoles-5-formic acid methyl nitrosourea.Obtain a solution, it is stirred down at 50 ℃.After the 3h, (the 1 M aqueous solution of 10.0ml 10mmol), continues to stir 3h down at 50 ℃ again to add more hydrochloric acid.Make reaction mixture be returned to room temperature, be poured in the frozen water (100ml),, use methylene dichloride (3 * 150ml) extractions again by adding aqueous sodium hydroxide solution (2N) neutralization.With the organic phase dried over mgso that merges, concentrate in a vacuum again.With solid residue crystallization from the mixture of ether (100ml) and acetone (10ml).Obtain title compound, 79% productive rate (crystallization of 1.3g beige).-m.p.224-227℃。

Aa. azetidine-1-base-(8-methoxyl group-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-yl also)-ketone

With 8-methoxyl group-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene is [7,8-d] imidazoles-5-formic acid (embodiment v, 2.00g, 5.5mmol) DIPEA (2.45ml of the suspension in DMF (50ml) also, 1.85g, 14.3mmol) and TBTU (2.2g 6.9mmol) handles.This yellow solution is at room temperature stirred 20min, add again azetidine (700 μ l, 592mg, 10.4mmol).Continuously stirring 1d at room temperature.Reaction mixture is poured in the saturated ammonium chloride solution (200ml), uses methylene dichloride (3 * 200ml) extractions again.With the organic phase dried over mgso that merges, revaporization is to dry.Obtain a yellow oil, it with silica gel (methylene chloride=9: 1) purifying, follows crystallization from ether (50ml) by flash chromatography.Obtain title compound, 72% productive rate (crystallization of 1.6g beige).-m.p.209-211℃。

Bb.3-[6-(azetidine-1-carbonyl)-4-hydroxyl-1,2-dimethyl-1H-benzoglyoxaline-5-yl]-1-o-tolyl-third-1-ketone

(the 1M aqueous solution of 18.0ml 18mmol) adds to azetidine-1-base-(8-methoxyl group-2,3-dimethyl-8-o-tolyl-3 with hydrochloric acid, 6,7,8-tetrahydrochysene-chromene also [7,8-d] imidazoles-5-yl)-(embodiment aa, 1.60g is 3.9mmol) in the suspension in THF (46ml) for ketone.Obtain a yellow solution, it is stirred down at 50 ℃.After the 3h, (the 1M aqueous solution of 10.0ml 10mmol), continues to stir 3h down at 50 ℃ again to add more hydrochloric acid.Make reaction mixture be returned to room temperature, be poured into frozen water (100ml),, use methylene dichloride (3 * 150ml) extractions again by adding aqueous sodium hydroxide solution (2N) neutralization.With the organic phase dried over mgso that merges, concentrate in a vacuum again.With solid residue crystallization from the mixture of ether (100ml) and acetone (10ml).Obtain title compound, 78% productive rate (1.20g colourless crystallization).-m.p.229-232℃。

Cc.6-[3-(2-benzyloxy-phenyl)-3-oxygen-propyl group]-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide

With 6-dimethylamino methyl-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide (9.20g, 31.7mmol) 1, suspension in the 2-glycol dimethyl ether (300ml) is heated to 85 ℃, slowly add 1-[1-(2-benzyloxy methyl-phenyl)-vinyl again]-tetramethyleneimine is (synthetic as mentioned below, 15.0g, the 51mmol) solution in DME (15ml).Reaction mixture is remained on 85 ℃ reach 3h, at room temperature stir 17h again.Evaporating solvent in a vacuum.Resistates is dissolved in Virahol (300ml).Form throw out, it uses washed with isopropyl alcohol again by filtering separation.Title compound is further by flash chromatography silica gel (methylene chloride=20: 1) purifying.The corresponding level part of evaporation obtains beige solid (5.3g, 34% productive rate).-m.p.193-194℃。

Dd.7-hydroxyl-6-[3-(2-methoxyl group-phenyl)-3-oxygen-propyl group]-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide

With 6-dimethylamino methyl-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide (5.40g, 18.6mmol) 1, suspension in the 2-glycol dimethyl ether (100ml) is heated to 85 ℃, slowly add 1-[1-(2-methoxymethyl-phenyl)-vinyl again]-tetramethyleneimine is (synthetic as mentioned below, 6.5g, the 31mmol) solution in DME (20ml).Reaction mixture is remained on 85 ℃ reach 3h, at room temperature stir 17h again.Evaporating solvent in a vacuum.Resistates is dissolved in methylene dichloride and the methanol mixture, adds silica gel, again this suspension is evaporated to drying.The pillar of filling 200g silica gel is loaded this solid, again with title compound methylene dichloride and methanol mixture (20: 1) wash-out.The corresponding level part of evaporation obtains brown solid, and it is handled with hot Virahol (150ml).By this throw out of filtering separation, use washed with isopropyl alcohol, drying.Obtain 3.0g title compound (colorless solid, 39% productive rate).-m.p.165℃。

Ee.7-hydroxy-2-methyl-6-(3-oxygen-3-o-tolyl-propyl group)-3-(2-trimethyl silyl-ethoxyl methyl)-3H-benzoglyoxaline-5-formic acid diformamide

With 7-hydroxy-2-methyl-3-(2-trimethyl silyl-ethoxyl methyl)-3H-benzoglyoxaline-5-formic acid diformamide (embodiment b, 2.4g, 6.9mmol) solution iodate N in methylene dichloride (40ml), N-dimethyl-methylene radical imonium (1.8g, 9.8mmol) handle, should react again and at room temperature stir 7h.Reaction mixture is poured in the saturated sodium bicarbonate solution, at room temperature stirs 30min, uses methylene dichloride (3x) extraction again.The organic layer dried over mgso concentrates in a vacuum again.With resistates (the beige solid of 2.77g, 6.8mmol, 99% productive rate) 1, suspension in the 2-glycol dimethyl ether (1 00ml) is heated to 85 ℃, slowly add 1-[1-(2-aminomethyl phenyl)-vinyl again]-tetramethyleneimine (CAS156004-72-7,2.0g, 10.7mmol).This suspension is heated 3h down at 85 ℃.Reaction mixture is cooled to room temperature, again evaporating solvent in a vacuum.(0.79g, 6.8mmol) solution in acetone at room temperature stirs 17h with crude product and fumaric acid.Sediment-free forms.With solution concentration, add the mixture of methylene dichloride and saturated sodium bicarbonate solution again.With the organic layer dried over sodium sulfate, add silica gel, the revaporization solvent.The pillar of filling gel is loaded this resistates, again with title compound toluene/1,4-two  alkane=2: 1 wash-outs.The corresponding level part of evaporation obtains the beige solid, and it is recrystallization from Virahol.Obtain title compound, 20% productive rate (colorless solid of 0.67g).-m.p.163-164℃。

Ff.6-(3-benzo [b] thiene-3-yl--3-oxygen-propyl group)-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide

Rough title compound is from 6-dimethylamino methyl-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide (5.30g, 18.3mmol) and 1-(1-benzo [b] thiene-3-yl--vinyl)-tetramethyleneimine (synthetic as mentioned below, 4.8g, 21mmol) prepare, and by flash chromatography silica gel (first post: toluene/1,4-two  alkane=4: 1, second post: methylene chloride 100: 0 to 88: 12) purifying.The corresponding level part of evaporation obtains brown solid, and it is dissolved in acetone.Add fumaric acid, again by the filtering separation throw out.The salt of title compound and fumaric acid is dissolved in methylene dichloride and the saturated sodium bicarbonate aqueous solution.Be separated, the organic layer dried over mgso concentrates in a vacuum again.With resistates by flash chromatography with silica gel (methylene chloride=20: 1) purifying.Obtain 709mg title compound (brown solid, 9% productive rate, 12% correcting yield).-m.p.150-151℃。

Gg.7-hydroxyl-2,3-dimethyl-6-[3-(2-methyl-thiene-3-yl-)-3-oxygen-propyl group]-3H-benzoglyoxaline-5-formic acid diformamide

With 6-dimethylamino methyl-7-hydroxyl-2,3-dimethyl-3H-benzoglyoxaline-5-formic acid diformamide (4.0g, 13.8mmol) 1, suspension in the 2-glycol dimethyl ether (100ml) is heated to 85 ℃, slowly add 1-[1-(2-methyl-thiene-3-yl-)-vinyl again]-tetramethyleneimine is (synthetic as mentioned below, 4.0g, the 20.7mmol) solution in DME.Reaction mixture is remained on 85 ℃ reach 3h.Evaporating solvent in a vacuum.With resistates by flash chromatography with silica gel (toluene/1,4-two  alkane=4: 1 are used methylene chloride 10: 1 then) purifying.The corresponding level part of evaporation obtains brown solid, with its pulp in hot Virahol (2 x).By this title compound of filtering separation, more further by column chromatography silica gel (methylene chloride=20: 1) purifying.Obtain the beige solid (24% productive rate) of 1.3g. ¹H-NMR(DMSO-d ₆，400MHz)：δ＝2.53(s)，2.67(s，3H)，2.77(s，3H)，3.01(s，bs，6H)，3.67(s，3H)，6.78(s，1H)，7.33(d，1H)，7.49(d，1H)，10.00(bs，1H).

Hh.8-methoxyl group-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid cyclopropyl amide also

With N-(3-dimethylamino-propyl)-N '-ethyl-carbodiimide hydrochloride (6.67g, 34.8mmol), DMAP (0.03g, 0.25mmol) and cyclopropylamine (1.98g 34.7mmol) adds to 8-methoxyl group-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene is [7,8-d] imidazoles-5-formic acid (embodiment v also, 7.0g, 17.4mmol) in the suspension in methylene dichloride (200ml).This reaction mixture is at room temperature stirred 20h, use sodium hydrogen carbonate solution (100ml) to handle then.Be separated, (2 * 30ml) extract water with methylene dichloride.With the organic phase dried over sodium sulfate that merges, revaporization is to dry.With brown resistates (8.3g) by column chromatography with silica gel (ethyl acetate/methanol=9: 1) purifying.Title compound is separated 95% productive rate (colorless solid of 6.7g).-m.p.271℃。 ¹H-NMR(DMSO-d ₆，200MHz)：δ＝0.64(m _c，2H)，0.89(m _c，2H)，1.95(m _c，1H)，2.44(m _c，1H)，2.53(s，3H)，2.62(s，3H)，2.90(m _c，2H)，3.20，3.23(s，m _c，4H)，3.69(s，3H)，6.01(bs，1H)，7.01(s，1H)，7.21(m _c，3H)，7.87(m _c，1H).

Ii 7-hydroxyl-2,3-dimethyl-6-(3-oxygen-3-o-tolyl-propyl group)-3H-benzoglyoxaline-5-formic acid cyclopropyl amide

With 8-methoxyl group-2, also [7,8-d] imidazoles-5-formic acid cyclopropyl amide (embodiment hh, 6.6g, 16.3mmol) 2N hydrochloric acid (50ml) processing of the suspension in THF (150ml) of 3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene.This reaction mixture is at room temperature stirred 2h, stir 2h down at 50 ℃ again.Add sodium hydrogen carbonate solution (100ml) and methylene dichloride (200ml), being adjusted to the pH-value by the interpolation sodium hydroxide solution is 8.This mixture is diluted with methylene dichloride (200ml) and water (200ml).Be separated, (2 * 200ml) extract water with methylene dichloride.With the organic phase water that merges (2 * 200ml) washings, evaporating solvent in a vacuum again.Obtain title compound, 88% productive rate (colorless solid of 5.6g).-m.p.297-299℃。

Jj. (8-methoxyl group-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-yl also)-methyl alcohol

To 8-methoxyl group-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene also [7,8-d] imidazoles-5-formic acid (embodiment v, 6.0g, add in suspension 15.2mmol) in batches lithium aluminum hydride (1.5g, 39.5mmol).This reaction mixture is at room temperature stirred 1.5h, add again another part lithium aluminum hydride (800mg, 21.1mmol).After the 30min, reaction mixture is poured into carefully in the mixture of saturated ammonium chloride solution and methylene dichloride.This biphase mixture is stirred 30min, be separated, water extracts with methylene dichloride (3x).With organic phase water (2x) washing that merges, use dried over mgso, under reduced pressure concentrate again.Title compound (colorless solid of 4.79g, 90% productive rate) is directly used in next step. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.88(m _c，1H)，2.40，2.49，2.50(m _c，s，s)，2.70(m _c，1H)，2.87(m _c，1H)，2.99(s，3H)，3.69(s，3H)，4.57(m _c，2H)，5.04(t，1H)，7.10(m _c，1H)，7.30(m _c，3H)，7.73(m _c，1H).

Kk.5-chloromethyl-8-methoxyl group-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles also

With (8-methoxyl group-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene is [7,8-d] imidazoles-5-yl also)-(13.3mmol) suspension in methylene dichloride (150ml) is cooled to 0 ℃ to methyl alcohol for embodiment jj, 4.7g, again thionyl chloride (1.20ml, 1.96g, 16.5mmol).This yellow solution is stirred 1.5h down at 0 ℃.Add saturated sodium bicarbonate solution, continue to stir 10min again.Separate organic phase,, use dried over mgso again with saturated ammonium chloride solution and water extraction.Evaporating solvent separates light-brown solid (5.4g, quantitative yield) more in a vacuum, and it promptly is used for next step without being further purified. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.93(m _c，1H)，2.48，2.50(m _c，s)，2.90，3.02，3.13(m _c，s，m _c，5H)，3.77(s，3H)，4.93(2d，2H)，7.34(m _c，4H)，7.75(m _c，1H).

11.8-methoxyl group-5-methoxymethyl-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles also

With 5-chloromethyl-8-methoxyl group-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene also [7,8-d] imidazoles (embodiment kk, 5.0g 13.5mmol) are dissolved in the methyl alcohol (50ml), add again sodium methoxide solution (30wt-%, in methyl alcohol, 2.0g, 11.1mmol).This reaction mixture is stirred 30min down at 50 ℃, at room temperature stir 1h again.With the white suspension concentrating under reduced pressure,, use dichloromethane extraction again with the saturated ammonium chloride solution dilution.Organic phase washes with water, and water extracts with methylene dichloride (2 x).With the organic phase dried over sodium sulfate that merges, evaporating solvent in a vacuum again.Obtain the yellow foam of 4.7g (95% productive rate), it is directly used in next step. ¹H-NMR(DMSO-d _s，200MHz)：δ＝1.91(m _c，1H)，2.46，2.49(m _c，s)，2.62(s，3H)，2.76，2.91，3.02(m _c，m _c，s，5H)，3.36(s，3H)，3.78(s，3H)，4.52(2d，2H)，7.28m _c，4H)，7.75(m _c，1H).

Mm.3-(4-hydroxyl-6-methoxymethyl-1,2-dimethyl-1H-benzoglyoxaline-5-yl)-1-o-tolyl-third-1-ketone

With 8-methoxyl group-5-methoxymethyl-2, also [7,8-d] imidazoles (EXAMPLE l l, 4.6g, 12.6mmol) 2N hydrochloric acid (35ml) processing of the suspension in THF (100ml) of 3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene.This yellow solution is at room temperature stirred 1h, stir 1h down at 50 ℃ again, concentrating under reduced pressure is up to removing most of THF.This reaction mixture is diluted with frozen water, again by adding the neutralization of 2N sodium hydroxide solution.Form the light brown throw out, it is dry in a vacuum again by filtering separation.This title compound is further purified with silica gel (methylene chloride=20: 1) by column chromatography.Obtain the pale solid (70% productive rate) of 3.1g.-m.p.163℃。 ¹H-NMR(DMSO-d ₆，200MHz)：δ＝2.41(s，3H)，2.49(s)，2.96(m _c，2H)，3.07m _c，2H)，3.26(s，3H)，3.66(s，3H)，4.48(s，2H)，6.89(s，1H)，7.35(m _c，3H)，7.72(m _c，1H)，9.77(bs，1H).

1-[1-(aryl)-vinyl]-pyrrolidines synthetic

Eneamines 1-[1-(2-fluorophenyl)-vinyl]-tetramethyleneimine, 1-[1-(4-fluorophenyl)-vinyl]-tetramethyleneimine, 1-[1-(2-aminomethyl phenyl)-vinyl]-tetramethyleneimine, 1-[1-(2-chloro-phenyl-)-vinyl]-tetramethyleneimine, 1-[1-(2-trifluoromethyl-phenyl)-vinyl]-tetramethyleneimine, 1-(1-naphthalene-2-base-vinyl)-tetramethyleneimine) be compound known, and by being similar to Synthesis 2004, the following method of describing among 4,52 1-524 is synthetic.

1-[1-(2-ethylphenyl)-vinyl]-tetramethyleneimine

(a) 1-(2-ethyl-phenyl)-ethyl ketone: in flame-dried flask, charge into nitrogen, under-50 ℃ with ethylmagnesium bromide (1M solution, in THF, 62.1ml) add to Manganous chloride tetrahydrate (II) (7.8g, 62.0mmol) and lithium chloride (5.3g is 125.0mmol) in the suspension in doing THF (140ml).Going through the 15min time adds 1-(2-chloro-phenyl)-ethyl ketone (6.7ml, the 51.5mmol) solution in THF (50ml) down stirs reaction mixture 4 hours at-50 ℃ again.To react quencher by adding 2N HCl (50ml), use methylene dichloride (3 x) extraction again.With organic phase saturated sodium bicarbonate solution and the water washing that merges, use dried over mgso, under reduced pressure concentrate again.By vacuum distilling with residue purified.Obtain the title compound (6.1g, 80% productive rate) of colourless liquid form.

(b) 1-[1-(2-ethylphenyl)-vinyl]-tetramethyleneimine: charge into nitrogen in flame-dried flask, (6.1g, 41.1mmol) (20.4ml 247mmol) handles the solution in normal hexane (70ml) with tetramethyleneimine with 1-(2-ethyl-phenyl)-ethyl ketone.(2.7ml 24.7mmol), at room temperature stirs 15h with reaction mixture again to add titanium tetrachloride down at 0 ℃.Filter this suspension.Evaporated filtrate obtains title compound (yellow oil of 6.3g, 74% productive rate). ¹H-NMR(DMSO-d ₆，400MHz)：δ＝1.13(t，3H)，1.78(m _c，4H)，2.61(q，2H)，2.89(m _c，4H)，3.40(s，1H)，3.69(s，1H)，7.09-7.48(m，4H).

1-(1-thiophene-2-base-vinyl)-tetramethyleneimine

Charge into nitrogen in flame-dried flask, (3.7ml, 34.4mmol) (17.1ml 207mmol) handles the solution in normal hexane (60ml) with tetramethyleneimine with the 2-acetyl thiophene.(2.3ml 20.7mmol), at room temperature stirs 15h with reaction mixture again to add titanium tetrachloride down at 0 ℃.Filter this suspension.Evaporated filtrate obtains title compound (brown oil of 4.2g, 68% productive rate). ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.84(m _c，4H)，3.02(m _c，4H)，3.34(s，1H)，3.95(s，1H)，7.00(m _c，2H)，7.48(m _c，1H).

1-[1-(4-fluoro-2-aminomethyl phenyl)-vinyl]-tetramethyleneimine

Charge into nitrogen in flame-dried flask, (5.2g, 34.2mmol) (17.1ml 207mmol) handles the solution in normal hexane (60ml) with tetramethyleneimine with 4-fluoro-2-methyl acetanilide.(2.3ml 20.7mmol), at room temperature stirs 15.5h with reaction mixture again to add titanium tetrachloride down at 0 ℃.Filter this suspension.Evaporated filtrate obtains title compound (yellow oil of 6.4g, 91% productive rate). ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.80(m _c，4H)，2.24(s，3H)，2.85(m _c，4H)，3.40(s，1H)，3.68(s，1H)，7.05(m _c，3H).

1-[1-(2-benzyloxy methyl-phenyl)-vinyl]-tetramethyleneimine

(a) 2-(2-methyl-[1; 3] dioxolane-2-yl)-ethyl benzoate: with triethyl orthoformate (68.4g; 0.46mol), 1; 2-ethylene glycol (104.2g; 1.68mol) and tosic acid monohydrate (0.8g; 4.2mmol) (80.7g is 0.42mol) in the solution in THF (120ml) to add to 2-ethanoyl-ethyl benzoate.This reaction mixture is heated 17h down at 40 ℃, be poured into again in the solution of sodium bicarbonate (370mg) in water (160ml).This biphase mixture is stirred 15min, be separated, again water is extracted with ethyl acetate (150ml).With the organic phase dried over sodium sulfate that merges, under reduced pressure concentrate again.With resistates (yellow liquid of 121g) by flash chromatography with silica gel (petrol ether/ethyl acetate=9: 1) purifying.The corresponding level part of evaporation obtains title compound (pale solid of 74.8g, 75% productive rate). ¹H-NMR(DMSO-d ₆，400MHz)：δ＝1.26(t，3H)，1.69(s，3H)，3.48(m _c，2H)，3.91(m _c，2 H)，4.24(q，2H)，7.30-7.43(m _c，2H)，7.48(m _c，2H).

(b) [2-(2-methyl-[1,3] dioxolane-2-yl)-phenyl]-methyl alcohol: under 0 ℃, (3.3g 87mmol) adds to 2-(2-methyl-[1 in batches with lithium aluminum hydride, 3] dioxolane-2-yl)-(27.4g is 116mmol) in the solution in doing THF (150ml) for ethyl benzoate.This grey suspension is at room temperature stirred 30min.Reaction mixture is used carefully the mixture quencher of ice (100g) and saturated ammonium chloride solution (100ml).Add methylene dichloride (300ml), again this biphase mixture is stirred 10min.Be separated, (2 * 200ml) extract water with methylene dichloride.With organic phase water (150ml) washing that merges, use dried over sodium sulfate, under reduced pressure concentrate again.(5.7g, 150mmol) 2-(2-methyl-[1,3] dioxolane-2-yl)-ethyl benzoate of reduction 47.3g (200mmol) carries out under conditions of similarity with lithium aluminum hydride.Crude product (21.7g is from first experiment, and 38.7g is from second experiment) is merged, again by flash chromatography silica gel (petrol ether/ethyl acetate=7: 3) purifying.Title compound is separated 88% productive rate (water white oil of 60.6g contains the ethyl acetate of 11wt-%). ¹H-NMR(CDCl ₃，200MHz)：δ＝1.25(t，3H，EtOAc)，1.71(s，3H)，2.03(s，3H，EtOAc)，3.82(m _c，2H)，4.01(m _c，2H)，4.11(q，2H，EtOAc)，4.76(s，2H)，7.33(m _c，3H)，7.56(m _c，1H).

(c) 2-(2-benzyloxy methyl-phenyl)-2-methyl-[1,3] dioxolane: (60wt-% is in oil with several parts of sodium hydrides, total amount: 9.9g, 248mmol) add to [2-(2-methyl-[1,3] dioxolane-2-yl)-phenyl]-(48.0g is 247mmol) in the solution in doing DMF (450ml) for methyl alcohol.This solution is at room temperature stirred 1h, add tetrabutylammonium iodide (9.2g, 249mmol) and bromotoluene (42.3g, 247mmol).At room temperature stir 2h continuously.With reaction mixture saturated ammonium chloride solution (400ml) and methylene dichloride (500ml) quencher.Be separated, water extracts with methylene dichloride (200ml).(dried over sodium sulfate use in 2 * 200ml) washings, and is concentrated with the organic phase water that merges.With resistates (brown oil of 80g) by flash chromatography with silica gel (sherwood oil is used petrol ether/ethyl acetate=9: 1 then) purifying.Title compound is separated 57% productive rate (yellow oil of 40.1g). ¹H-NMR(CDCl ₃，200MHz)：δ＝1.67(s，3H)，3.71(m _c，2H)，4.01(m _c，2H)，4.51(s，2H)；4.84 (s，2H)，7.32(m _c，7H)，7.59(m _c，2H).

(d) 1-(2-benzyloxy methyl-phenyl)-ethyl ketone: hydrochloric acid (the 2N solution of 250ml) is added to 2-(2-benzyloxy methyl-phenyl)-2-methyl-[1,3] dioxolane, and (40.1g is 141mmol) in the solution in THF (500ml).This reaction mixture is heated 2h down at 50 ℃, be poured into again in the mixture of water (400ml) and methylene dichloride (300ml).By adding 6N sodium hydroxide solution adjusting pH value is 8.Be separated, water extracts with methylene dichloride (200ml).The organic phase dried over sodium sulfate that merges concentrates in a vacuum again.With crude product (yellow liquid of 33g) by flash chromatography with silica gel (petrol ether/ethyl acetate=9: 1) purifying.The corresponding level part of evaporation obtains title compound (yellow liquid of 31.9g, 94% productive rate). ¹H-NMR(DMSO-d _s，200MHz)：δ＝2.58(s，3H)，4.63(s，2H)，4.89(s，2H)，7.34(m _c，6H)，7.51(m _c，1H)，7.74(m _c，2H).

(e) 1-[1-(2-benzyloxy methyl-phenyl)-vinyl]-tetramethyleneimine: in flame-dried flask, charge into argon gas, with 1-(2-benzyloxy methyl-phenyl)-ethyl ketone (31.9g, 133mmol) (47.1g 663mmol) handles the solution in normal hexane (450ml) with tetramethyleneimine.(12.6g, the 663mmol) solution in normal hexane (60ml) at room temperature stir 17h with reaction mixture again to add titanium tetrachloride down at 0 ℃.Suspension is filtered, and (3 * 200ml) wash throw out with normal hexane.Evaporated filtrate obtains title compound (orange oil of 36g, 93% productive rate). ¹H-NMR(CDCl ₃，200 MHz)：δ＝1.78(m _c，4H)，2.90(m _c，4H)，3.59(s，1H)，3.75(s，1H)，4.56(s，2H)，4.63(s，2H)，7.31(m _c，8H)，7.55(d，1H).

1-[1-(2-methoxymethyl-phenyl)-vinyl]-tetramethyleneimine

(a) 2-(2-methoxymethyl-phenyl)-2-methyl-[1,3] dioxolane: (60wt-% is in oil with sodium hydride, 2.3g, 57.5mmol) add in the solution of [2-(2-methyl-[1,3] dioxolane-2-yl)-phenyl]-methyl alcohol (10.0g, 51.5mmo]) in THF (100ml) in batches.(3.5ml, 8.0g 56.0mmol) afterwards, at room temperature stir 1.5h with this reaction mixture, and (25wt-% is in water, 2ml), water and ethyl acetate be its quencher by adding ammonia solution again to drip methyl-iodide.Be separated, water extracts with ethyl acetate (2 x).With the organic phase dried over mgso that merges, under reduced pressure concentrate again.With resistates (yellow oil of 12g) by flash chromatography with silica gel (gasoline/ethyl acetate=9: 1) purifying.Title compound is separated 67% productive rate (water white oil of 7.1g). ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.58(s，3H)，3.34(s，3H)，3.62(m _c，2H)，3.97(m _c，2H)，4.63(s，2H)，7.30(m _c，2H)，7.47(m _c，2H).

(b) 1-(2-methoxymethyl-phenyl)-ethyl ketone: under 50 ℃ with 2-(2-methoxymethyl-phenyl)-2-methyl-[1,3] dioxolane (7.0g, 33.7mmol) the solution stirring 1.5h in THF (100ml) and 2N hydrochloric acid (50ml).With methylene dichloride and water dilution, is 7-8 by add 6N sodium hydroxide solution adjusting pH-value again with this reaction mixture.Organic phase washes with water, the water dichloromethane extraction.With the organic phase dried over mgso that merges, under reduced pressure concentrate again.Title compound is the isolated in form (5.5g, 99% productive rate) with yellow oil, and it promptly is used for next step without being further purified. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝2.55(s，3H)，3.33(s，3H)，4.64(s，2H)，7.43(m _c，3H)，7.84(m _c，1H).

(c) 1-[1-(2-methoxymethyl-phenyl)-vinyl]-tetramethyleneimine: in flame-dried flask, charge into argon gas, with 1-(2-methoxy yloxymethyl-phenyl)-ethyl ketone (5.4g, 32.9mmol) (16.3ml, 14.1g 198mmol) handle with tetramethyleneimine for solution in normal hexane (80ml).(20.0mmol) solution in normal hexane (2ml) at room temperature stirs 17h with reaction mixture again for 2.2ml, 3.8g to add titanium tetrachloride down at 0 ℃.Suspension is filtered, and throw out washs with normal hexane.Evaporated filtrate obtains title compound (yellow oil of 6.5g, 90% productive rate). ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.79(m _c，4H)，2.85(m _c，4H)，3.28(s，3H)，3.45(s，1H)，3.72(s，1H)，4.42(s，2H)，7.29(m _c，4H).

1-(1-benzo [b] thiene-3-yl--vinyl)-tetramethyleneimine

Charge into nitrogen in flame-dried flask, (5.0g, 28.4mmol) solution in toluene (10ml) dilutes with normal hexane (50ml) with 1-benzo [b] thiene-3-yl--ethyl ketone.Under 0 ℃, add tetramethyleneimine (14.0ml, 12.0g, 169mmol) and titanium tetrachloride (1.9ml, 3.3g, 17mmol) solution in normal hexane.Reaction mixture is at room temperature stirred 17h.Suspension is filtered, and throw out washs with normal hexane.Evaporated filtrate obtains title compound (Huang-brown oil of 4.8g, 74% productive rate). ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.82(m _c，4H)，2.94(m _c，4H)，3.82(s，1H)，3.88(s，1H)，7.40(m _c，2H)，7.64(s，1H)，7.83(m _c，1H)，7.99(m _c，1H).

1-[1-(2-methyl-thiene-3-yl-)-vinyl]-tetramethyleneimine

(a) 3-bromo-2-methyl-thiophene: with 3 bromo thiophene (25.0g 153mmol) is dissolved among the THF (180ml), again-78 ℃ add down LDAs (2M, in THF/ heptane/ethylbenzene, 88.0ml, 176mmol) solution.At-78 ℃ of following continuously stirring 3h.Reaction mixture is warmed to-30 ℃, adds methyl-iodide (14.3ml, 32.6g, 230mmol) solution in THF (15ml) again.Make reaction mixture be warmed to room temperature, continue to stir 18.5h again.To react the water quencher, use ether (3x) extraction again.The organic phase dried over mgso under reduced pressure concentrates again.Resistates is by vacuum distilling purifying (little yellow oil of 27.8g, it contains the title compound of 80wt-% and the ethylbenzene of 20wt-%, 126mol, 82% productive rate). ¹H-NMR (DMSO-d ₆, 200MHz): δ=2.36 (s, 3H), 7.01 (d, 1H), 7.44 (d, 1H), ethylbenzene: 1.18 (t, 3H), 2.60 (q, 2H), 7.22 (m _c, 5H)

(b) 1-(2-methyl-thiene-3-yl-)-ethyl ketone is via 3-(1-butoxy-vinyl)-2-methyl-thiophene: in autoclave, with 3-bromo-2-methyl-thiophene (mixture that step a obtains, 27.8g, 126mmol), n-butyl vinyl ether (49.6ml, 38.4g, 383mmol), acid chloride (1.70g, 7.6mmol), 1,3-two (diphenyl phosphine) propane (7.60g, 18.4mmol) and salt of wormwood (22.9g, 166mmol) the heating 3d under 100 ℃ of the solution in the degassing mixture of DMF (330ml) and water (40ml).Reaction mixture is cooled to room temperature.Add hydrochloric acid (5%), continue at room temperature to stir 2.75h again.By adding potassium hydroxide solution (10%), use methylene dichloride (3x) extraction again with the reaction mixture neutralization.With the organic phase dried over mgso that merges.There is evaporating solvent down in silica gel, resistates is loaded on the post of filling gel.With mixture [20: 1 (the v/v)] wash-out of title compound (orange oil of 9.7g, 55% productive rate) with gasoline and ethyl acetate. ¹H-NMR(DMSO-d ₆，200MHz)：δ＝2.47(s，3H)，2.65(s，3H)，7.32(d，1H)，7.48(d，1H).

(c) 1-[1-(2-methyl-thiene-3-yl-)-vinyl]-tetramethyleneimine: in flame-dried flask, charge into nitrogen, with 1-(2-methyl-thiene-3-yl-)-ethyl ketone (4.2g, 30mmol) (15.0ml, 12.9g 181mmol) handle the solution in normal hexane (70ml) with tetramethyleneimine.(18mmol) solution in normal hexane at room temperature stirs 17.5h with reaction mixture again for 2.0ml, 3.4g to add titanium tetrachloride down at 0 ℃.Suspension is filtered, and throw out washs with normal hexane.Evaporated filtrate obtains title compound (Huang-brown oil of 4.0g, 69% productive rate). ¹H-NMR(DMSO-d ₆，200MHz)：δ＝1.80(m _c，4H)，2.38(s，3H)，2.90(m _c，4H)，3.54(s，1H)，3.77(s，1H)，6.85(d，1H)，7.23(d，1H).

Industrial application

Formula 1-a and formula 1-b compound be respectively at the 8-aryl-3,6,7 of the enantiomer-pure of preparation formula 3-a or 3-b, and 8-tetrahydrochysene-chromene is valuable intermediate in [7,8-d] imidazole derivative also.

Formula 3-a and 3-b compound and pharmacologically acceptable salt thereof (=active compound of the present invention), preferred formula 3-a compound and pharmacologically acceptable salt thereof, they have useful pharmacology performance, and this makes them can be used for commercial applications.Especially they especially show obvious suppression gastric acid secretion effect and excellent stomach and intestine protection or therapeutic action warm-blooded animal among the mankind.In this application, compound of the present invention with have highly selective effect, onset effect fast, superior dauer effect, effectively dosage control action time, good especially secretion inhibitor effect, do not have significant side effects and wide therapeutic domain and be celebrated.Compare with the prior art compound known, the excellent results that active compound of the present invention suppresses with its gastric acid secretion and/or cause that the possibility possibility low and/or drug-drug interactions of side effect is low and celebrated, the described side effect for example avidity to one or more other enzymes is low, and the restraining effect of these enzymes is relevant with these side effects.

" stomach and intestine protection or treatment " herein; according to general knowledge; be understood to include prevention; treat and keep the treatment gastrointestinal illness; especially gastroenteritis disease and damage are (for example such as reflux esophagitis; gastritis; the functional dyspepsia and the peptic ulcer disease of hyperactivity hyperkinesia or drug-associated [comprise digestive ulcerative bleeding; stomach ulcer; duodenal ulcer]; they can be by such as microorganism (as Hp); bacteriotoxin; medicine (as some anti-inflammatory and antirheumatic thing, as NSAIDs and COX-inhibitor); chemical (as alcohol); hydrochloric acid in gastric juice or Stress cause.

According to general knowledge, term " gastrointestinal illness " is understood to include,

A) gastroesophageal reflux disease (GERD), its symptom include but not limited to pyrosis and/or sour regurgitation and/or anacidity gastric disorder causing nausea.

B) the outer symptom of other oesophagus of GERD includes but not limited to acid-related asthma, bronchitis, laryngitis and somnopathy.

C) may with ND anti-stream and/or air-breathing other relevant disease, include but not limited to thick wind such as asthma, bronchitis, COPD (chronic obstructive pulmonary disease).

D) Helicobacter pylori infection is eradicated it and will be brought into play keying action in the treatment gastrointestinal illness.

E) in addition, " gastrointestinal illness " comprises that other may the gastrointestinal symptoms relevant with acid secretion, for example Zollinger Ellison syndrome (Zollinger-Ellison syndrome), acute upper gastrointestinal bleeding, nauseating, the vomiting owing to chemotherapy or postoperative symptom, stress ulcer, IBD (inflammatory bowel) and particularly IBS (irritable bowel syndrome).

In the various models of determining the former and secretion inhibitor character of antiulcer agent, aspect their excellent properties, active compound of the present invention proves astoundingly and obviously is better than the prior art compound known.Because these character, active compound of the present invention obviously is suitable for people and veterinary drug, and they are used for the treatment of especially and/or prevent stomach and/or intestines and/or upper gastrointestinal obstacle, particularly above-mentioned disease at this.

Therefore the further theme of the present invention is the application of active compound of the present invention in treating and/or preventing above-mentioned disease.

The present invention comprises that equally active compound of the present invention is used for the treatment of and/or prevents application in the medicine of above-mentioned disease in manufacturing.

The present invention also comprises the application of active compound of the present invention in treating and/or preventing above-mentioned disease.

The further theme of the present invention is the medicine that comprises one or more active compounds of the present invention.

As medicine, active compound of the present invention both can so be used, also can be preferably and the synthetic following form of vehicle group that is suitable for of pharmacy: tablet, coated tablet (for example film coating tablet), multiple-unit microparticulate systems tablet, capsule, suppository, granule, pulvis (for example freeze drying mixt), pilule, paster (for example TTS[transdermal therapeutic system]), emulsion, suspensoid or solution.Active compound content is between 0.1～95% (weight percentage of final formulation) valuably, preferably between 1～60%.By the mode of suitable selection vehicle, can obtain a kind of pharmaceutical administration form, it is suitable for active compound and/or required drug effect and/or continuous action (as slowly-releasing form or enteric form).

Active compound of the present invention can per os, parenteral (for example vein), rectum or percutaneous dosing.Per os or intravenously administrable are preferred.

The vehicle or the excipient composition that are suitable for required pharmaceutical preparation are that those skilled in the art know according to its expertise, and have made up one or more ancillary components.Except solvent, oxidation inhibitor, stablizer, tensio-active agent, complexing agent (as cyclodextrin), can mention following vehicle as an example: for oral administration, jelling agent, defoamer, softening agent, sorbent material, wetting agent, tinting material, seasonings, sweeting agent and/or compressing tablet vehicle (for example carrier, weighting agent, tackiness agent, disintegrating agent, lubricant, Drug coating); For intravenously administrable, dispersion agent, emulsifying agent, sanitas, solubilizing agent, buffer substance and/or etc. ooze the adjusting material.For percutaneous dosing, those skilled in the art for example are elected to be vehicle: solvent, jelling agent, polymkeric substance, penetration enhancer, tackiness agent, skeletal substance and/or wetting agent.

In general, aspect the human medicine, under case of oral administration, about 20 with about 0.01-, preferred 0.02-5, it is favourable that the per daily dose of preferred especially 0.02-1.5mg/kg body weight gives active compound, if be fit to, with several, preferred 1-2 single dose reaches required effect.Parenteral treatment, similar or (especially giving under the situation of described active compound) at intravenously generally, can use lower dosage.In addition, administration frequency can be adapted to periodically, weekly, every month even (for example implanting) administration of still less taking place.Those skilled in the art can easily determine to give in all cases required optimal dose of active compound and mode based on its expertise.

Medicine can exist with unit dose shape easily, and can be by the known any method preparation of pharmacy scientific domain.All method comprises the step that active compound of the present invention and vehicle or excipient composition are combined.Usually, described formulation is by the two evenly and closely combines with the solid excipient of active compound of the present invention and liquid excipient or fine dispersion or its, then if desired, this product is mixed with the medicine that needs and prepares.

Active compound of the present invention or its medicament production also can be used for and one or more pharmacological component combinations [combination and compatibility body (combination partner)] from other medicines group (Other groups of drugs)." combination " is interpreted as active compound of the present invention and combination and compatibility body is provided as respectively, uses across one after the other, side by side or in turn.Combination normally be designed to have with add and or super add and meaning increase basic role or elimination or reduce the purpose of the side effect of combination and compatibility body, perhaps have the purpose of faster onset of acquisition and faster relief of symptoms.By selecting to be contained in the appropriate drug formulation in this combination, the drug release pattern of each component can be adjusted to required effect exactly, for example a kind of release of compound and onset thereof be in turn property ground before another compound release.

Combination can be for example, to contain the composition (for example fixed combination) of whole active compounds, or comprise the portions medicine box (kit-of-parts) of whole active compounds of preparation respectively.

" fixed combination " is defined as a kind of combination, and wherein first activeconstituents and second activeconstituents are present in the unit dosage together or are present in the single entities.An example of " fixed combination " is a kind of pharmaceutical composition, wherein said first activeconstituents with become to state the mixture that second activeconstituents is present in administration simultaneously, for example be present in the formulation.Another example of " fixed combination " is a kind of pharmaceutical composition, wherein said first activeconstituents with become to state that second activeconstituents is present in the unit and unmixed.

" portions medicine box " is defined as a kind of combination, and wherein said first activeconstituents and described second activeconstituents are present in the above unit.An example of " portions medicine box " is a kind of combination, wherein said first activeconstituents with become to state second activeconstituents and exist respectively.Each component of portions medicine box administration across respectively, one after the other, side by side or in turn.

" other medicines group " is interpreted as and comprises; for example: tranquilizer is (for example from the group of Benzodiazepines; as stable), spasmolytic (as N-butylscopolammonium bromide [Buscopan ]), anticholinergic (as Tropintran, pirenzepine, tolterodine), the pain sensation alleviates or the normalizing agent (as paracetamol, tetracaine or PROCAINE HCL, PHARMA GRADE; perhaps Oxethazaine particularly), and if suitable can also be enzyme, vitamins, microelement kind or amino acids.

This paper lay special stress on active compound of the present invention and buffering or in and the combination of hydrochloric acid in gastric juice medicine (for example magaldrate, aluminium hydroxide, magnesiumcarbonate, magnesium hydroxide or other antacid), perhaps especially with for example following inhibition or the combination that alleviates sour excretory medicine:

(I) histamine-H2 retarding agent [for example cimitidine, Ranitidine HCL], perhaps

(II) proton pump inhibitor [for example omeprazole, Ai Suomeila azoles (esomeprazole), pantoprazole, lansoprazole, rabeprazole, tenatoprazole (tenatoprazole), according to pula azoles (ilaprazole), leminoprazole, all comprise its salt and enantiomorph], perhaps

(III) the competitive sour retarding agent [for example soraprazan and steric isomer thereof, linaprazan, revaprazan all comprise its salt] of other potassium), perhaps

(IV) so-called periphery anticholinergic (for example pirenzepine), and gastrin antagonists is CCK2 antagonist (cholestocystokinin 2 receptor antagonists) for example.

A kind of important combination of mentioning is and the antibacterial substance combination, and the material that particularly has germicidal action, perhaps its combination.These combination and compatibility bodies are applicable to the control Helicobacter pylori infection especially, eradicate it and will bring into play keying action in the treatment gastrointestinal illness.The anti-microbial activity combination and compatibility style that is fit to that can mention as:

(A) cephalosporins, for example cifuroximaxetil

(B) penicillins, for example amoxycilline Trihydrate bp, Ampicillin Trihydrate

(C) tetracyclines, for example tsiklomitsin itself, Vibravenos

(D) beta-lactamase inhibitor, for example clavulanic acid

(E) macrolide antibiotics, for example erythromycin, clarithromycin, Azythromycin

(F) rifomycins, for example rifomycin itself

(G) glucosides class microbiotic, for example gentamicin, Streptomycin sulphate

(H) helicase inhibitor, for example Ciprofloxacin, Gatifloxacin, Moxifloxacin

(I)  azoles alkanes, for example Linezolid (linezolid)

(J) itrofurans or nitro glyoxaline, for example metronidazole, tinidazole, furadantin

(K) bismuth salt, for example Bismuth Potassium Citrate

(L) other antibacterial substance

And the combination that is selected from material (A) to (L), for example clarithromycin+metronidazole.Two combination and compatibility bodies of preferred use.Preferred two the combination and compatibility bodies that are selected from amoxycilline Trihydrate bp, clarithromycin and metronidazole that use.Preferred examples is to use amoxycilline Trihydrate bp and clarithromycin.

Consider their excellent activity to stomach and intestine protections or treatment, active compound of the present invention is specially adapted to and medicine is free or combination regularly, and described medicine has been notified and caused " drug-induced maldigestion "; Perhaps known have the medicine that some causes the effect of ulcer, for example an acetylsalicylic acid; Some anti-inflammatory agent and rheumatism, for example NSAIDs (NSAID (non-steroidal anti-inflammatory drug), for example etofenamate, diclofenac, indomethacin, Ibuprofen BP/EP, piroxicam, Naproxen Base, meloxicam); Oral steroide; Bis phosphoric acid salt (for example alendronate); Perhaps or even NO discharge NSAIDs, cox 2 inhibitor (for example celecoxib, Luo Mei former times cloth (lumiracoxib)).

In addition, active compound of the present invention be applicable to power-changes or-to regulate medicine (for example medicine for stomach dynamic (gastroprokinetics) is as mosapride, Tegaserod, itopride, metoclopramide) free or make up regularly; And the drug regimen that particularly takes place with the generation reduction that makes transience LESR (TLESR) or normalizing; GABA-B agonist (baclofen for example for example; (2R)-3-amino-2-fluoropropyl phosphonic acids) or isomerism GABA-B agonist (for example 3; 5-two (1; the 1-dimethyl ethyl)-the 4-hydroxy-beta; the beta-dimethyl-phenylpropyl alcohol); GABA-B reuptake inhibithors (for example tiagabine); metabotropic glutamate receptors 5 types (mGluR5) antagonist (for example 2-methyl-6-(phenylacetylene base) pyridine hydrochloride); CB2 (Cannabined receptor) agonist (for example [(3R)-2; 3-dihydro-5-methyl-3-(4-morpholinyl-methyl) pyrrolo-[1; 2; 3; de]-1,4-benzoxazine-6-yl]-1-naphthyl-ketone mesylate).The medicine that is used for the treatment of IBS or IBD also is suitable for the combination and compatibility body, for example: 5-HT4 receptor stimulant such as mosapride, Tegaserod; 5-HT3 receptor antagonist such as Lotronex, cilansetron; NK2 antagonist such as Saredutant, nepadutant (nepadutant); κ-opiate agonist such as fedotozine.

The combination and compatibility body that is fit to also comprises the air flue therapeutical agent, for example therapic acid dependency asthma and bronchitis.In some cases, may be favourable as the application of the hypnosis auxiliary agent (for example zolpidem [Bikalm ]) of combination and compatibility body, for example treat GERD-inductive somnopathy.

Claims (17)

1. the method for preparation formula 1-a compound, it is included in hydrogenation catalyst and has catalytic hydrogenation formula 2 compounds down, this hydrogenation catalyst is selected from RuXY[(S)-Xyl-P-Phos] [(S)-DAIPEN] and RuXY[(S)-Xyl-BINAP] [(S)-DAIPEN],

Wherein

X and Y are the identical or different following substituting groups that is selected from: hydrogen, halogen, BH ₄And carboxylate,

And wherein

R1 is hydrogen, halogen, hydroxyl, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxyl group, 1-4C-alkoxyl group-1-4C-alkyl, 1-4C-alkoxy carbonyl, 2-4C-thiazolinyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxyl-1-4C-alkyl or single-or two-1-4C-alkylamino

R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxyl group, 1-4C-alkoxyl group-1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy carbonyl, list-or two-1-4C-alkylamino-1-4C-alkyl-carbonyl, hydroxyl-1-4C-alkyl, fluoro-2-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkyl, silyl 1-4C-alkoxyl group-1-4C alkyl, 1-4C-alkyl-carbonyl, aryl-CH of replacing ₂-oxygen carbonyl,

R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxy carbonyl, hydroxyl-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkyl, fluoro-1-4C-alkoxyl group-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkoxyl group, 1-4C-alkyl-carbonyl-amino, 1-4C-alkyl-carbonyl-N-1-4C-alkylamino, 1-4C-alkoxyl group-1-4C-alkyl-carbonyl-amino or group-CO-NR31R32

Wherein

R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl group-1-4C-alkyl, and

R32 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl group-1-4C-alkyl,

Perhaps wherein

R31 and R32 comprise the nitrogen-atoms of the two connection together, are pyrrolidyl, hydroxyl pyrrolidine base, '-aziridino, azetidine base, piperidino-(1-position only), piperazinyl, N-1-4C-alkylpiperazine base or morpholino group,

The list that Ar is replaced by R4, R5, R6 and R7-or the bicyclic aromatic residue, it is selected from phenyl, naphthyl, pyrryl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indyl, benzimidazolyl-, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, different  azoles base, pyridyl, pyrimidyl, quinolyl and isoquinolyl

Wherein

R4 is a hydrogen; the 1-4C-alkyl; hydroxyl-1-4C-alkyl; the 1-4C-alkoxyl group; 2-4C-alkene oxygen base; carboxyl; the 1-4C-alkoxy carbonyl; carboxyl-1-4C-alkyl; 1-4C-alkoxy carbonyl-1-4C-alkyl; 1-4C-alkoxyl group-1-4C-alkyl; aryloxy-1-4C-alkyl; halogen; hydroxyl; aryl; aryl-1-4C-alkyl; aryl-oxygen base; aryl-1-4C-alkoxyl group; trifluoromethyl; nitro; amino; single-or two-1-4C-alkylamino; the 1-4C-alkyl-carbonyl-amino; the 1-4C-alkoxycarbonyl amino; 1-4C-alkoxyl group-1-4C-alkoxycarbonyl amino or alkylsulfonyl

R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxyl group, 1-4C-alkoxy carbonyl, halogen, trifluoromethyl or hydroxyl,

R6 is hydrogen, 1-4C-alkyl or halogen, and

R7 is hydrogen, 1-4C-alkyl or halogen,

And wherein

Aryl be phenyl or by one, two or three identical or different are selected from the phenyl that following substituting group replaces: 1-4C-alkyl, 1-4C-alkoxyl group, carboxyl, 1-4C-alkoxy carbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxyl and cyano group.

2. the method for preparation formula 1-b compound, it is included in hydrogenation catalyst and has catalytic hydrogenation formula 2 compounds down, this hydrogenation catalyst is selected from RuXY[(R)-Xyl-P-Phos] [(R)-DAIPEN] and RuXY[(R)-Xy1-BINAP] [(R)-DAIPEN],

Wherein

X and Y are the identical or different following substituting groups that is selected from: hydrogen, halogen, BH ₄And carboxylate,

And wherein

R1 is hydrogen, halogen, hydroxyl, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxyl group, 1-4C-alkoxyl group-1-4C-alkyl, 1-4C-alkoxy carbonyl, 2-4C-thiazolinyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxyl-1-4C-alkyl or single-or two-1-4C-alkylamino

R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxyl group, 1-4C-alkoxyl group-1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy carbonyl, list-or two-1-4C-alkylamino-1-4C-alkyl-carbonyl, hydroxyl-1-4C-alkyl, fluoro-2-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkyl, silyl 1-4C-alkoxyl group-1-4C alkyl, 1-4C-alkyl-carbonyl, aryl-CH of replacing ₂-oxygen carbonyl,

R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxy carbonyl, hydroxyl-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkoxyl group-1-4C-alkyl, fluoro-1-4C-alkoxyl group-1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkoxyl group, 1-4C-alkyl-carbonyl-amino, 1-4C-alkyl-carbonyl-N-1-4C-alkylamino, 1-4C-alkoxyl group-1-4C-alkyl-carbonyl-amino or group-CO-NR31R32

Wherein

R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl group-1-4C-alkyl, and

R32 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl group-1-4C-alkyl,

Perhaps wherein

R31 and R32 comprise the nitrogen-atoms of the two connection together, are pyrrolidyl, hydroxyl pyrrolidine base, '-aziridino, azetidine base, piperidino-(1-position only), piperazinyl, N-1-4C-alkylpiperazine base or morpholino group,

The list that Ar is replaced by R4, R5, R6 and R7-or the bicyclic aromatic residue, it is selected from phenyl, naphthyl, pyrryl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indyl, benzimidazolyl-, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, different  azoles base, pyridyl, pyrimidyl, quinolyl and isoquinolyl

Wherein

R4 is a hydrogen; the 1-4C-alkyl; hydroxyl-1-4C-alkyl; the 1-4C-alkoxyl group; 2-4C-alkene oxygen base; carboxyl; the 1-4C-alkoxy carbonyl; carboxyl-1-4C-alkyl; 1-4C-alkoxy carbonyl-1-4C-alkyl; 1-4C-alkoxyl group-1-4C-alkyl; aryloxy-1-4C-alkyl; halogen; hydroxyl; aryl; aryl-1-4C-alkyl; aryl-oxygen base; aryl-1-4C-alkoxyl group; trifluoromethyl; nitro; amino; single-or two-1-4C-alkylamino; the 1-4C-alkyl-carbonyl-amino; the 1-4C-alkoxycarbonyl amino; 1-4C-alkoxyl group-1-4C-alkoxycarbonyl amino or alkylsulfonyl

R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxyl group, 1-4C-alkoxy carbonyl, halogen, trifluoromethyl or hydroxyl,

R6 is hydrogen, 1-4C-alkyl or halogen, and

R7 is hydrogen, 1-4C-alkyl or halogen,

And wherein

Aryl be phenyl or by one, two or three identical or different are selected from the phenyl that following substituting group replaces: 1-4C-alkyl, 1-4C-alkoxyl group, carboxyl, 1-4C-alkoxy carbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxyl and cyano group.

3. the method for claim 1 is used RuXY[(S)-Xyl-P-Phos] [(S)-and DAIPEN] as hydrogenation catalyst, wherein

X and Y are the identical or different following substituting groups that is selected from: hydrogen, halogen, BH ₄And carboxylate,

And wherein

R1 is the 1-4C-alkyl,

R2 is 1-4C-alkoxyl group-1-4C alkyl that hydrogen, 1-4C-alkyl or silyl replace,

R3 is 1-4C-alkoxyl group-1-4C-alkyl or group-CO-NR31R32,

Wherein

R31 be hydrogen, 1-7C-alkyl or 3-7C-cycloalkyl and

R32 is hydrogen or 1-7C-alkyl,

Perhaps wherein

R31 and R32 comprise the nitrogen-atoms of the two connection together, are pyrrolidyl or azetidine base group,

Phenyl, naphthyl, thienyl or benzothienyl that Ar is replaced by R4, R5, R6 and R7,

Wherein

R4 is hydrogen, 1-4C-alkyl, halogen, 1-4C-alkoxyl group-1-4C-alkyl, aryloxy-1-4C-alkyl or trifluoromethyl,

R5 is a hydrogen or halogen,

R6 is a hydrogen, and

R7 is a hydrogen.

4. the method for claim 1 is used RuXY[(S)-Xyl-P-Phos] [(S)-DAIPEN] as hydrogenation catalyst, each chloro naturally of X and Y wherein,

And wherein

R1 is the 1-4C-alkyl,

R2 is 1-4C-alkoxyl group-1-4C alkyl that 1-4C-alkyl or silyl replace,

R3 is group-CO-NR31R32,

Wherein

R31 is hydrogen or 1-7C-alkyl,

R32 is hydrogen or 1-7C-alkyl,

Perhaps wherein

R31 and R32 comprise the nitrogen-atoms of the two connection together, are azetidine base groups,

The phenyl that Ar is replaced by R4

Wherein

R4 is hydrogen, 1-4C-alkyl or halogen.

5. claim 1,2,3 or 4 method, it carries out in the presence of alkali.

6. the method for claim 5, it carries out in the presence of alkali, and this alkali is selected from KOH, KO ^tBu, K ₂CO ₃And Cs ₂CO ₃

7. claim 1,2,3,4,5 or 6 method, wherein said solvent consist essentially of Virahol or the trimethyl carbinol or Virahol and the trimethyl carbinol with 0: 100vol-% to 100: the mixture of ratio of mixture arbitrarily between the 0vol-%.

8. the method for claim 7 comprises to wherein said solvent interpolation property 5 to 30vol-% water.

9. claim 1,2,3 or 4 method, it is to be selected from KOH, KO ^tBu, K ₂CO ₃And Cs ₂CO ₃Alkali exist and to carry out down, and wherein said solvent consists essentially of Virahol or the trimethyl carbinol or Virahol and the trimethyl carbinol with 0: 100vol-% to 100: the mixture of ratio of mixture arbitrarily between the 0vol-%, and wherein said method is to carry out in the homogeneous phase solution of formula 2 ketone that contain 0.1 to 1M concentration.

10. claim 1,2,3 or 4 method, it is to be selected from KOH, KO ^tBu, K ₂CO ₃And Cs ₂CO ₃Alkali exist and to carry out down, and wherein said solvent consists essentially of Virahol or the trimethyl carbinol or Virahol and the trimethyl carbinol with 0: 100vol-% to 100: the mixture of ratio of mixture arbitrarily between the 0vol-%, and wherein said solvent interpolation property ground comprises 5 to 30vol-% water, and wherein said method is to carry out in the homogeneous phase solution of formula 2 ketone that contain 0.1 to 1M concentration.

11. formula 1-a compound,

Wherein R1, R2, R3 and Arom have the implication that following table is pointed out:

R1 R2 R3 Ar -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 2-methyl-phenyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 2-ethyl-phenyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 2-sec.-propyl-phenyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 4-fluoro-2-methyl-phenyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 2-trifluoromethyl-phenyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 2-methylol-phenyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 2-chloro-phenyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 2-(2-hydroxyethyl)-phenyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 2-(1-hydroxyethyl)-phenyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 2-benzyloxy methyl-phenyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 2-methoxymethyl-phenyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ The 2-thienyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 3-methyl-2-thienyl

R1 R2 R3 Ar -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ The 3-thienyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 2-methyl-3-thienyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 4-methyl-3-thienyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 1-thionaphthene-3-base -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ The 1-naphthyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ The 2-naphthyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 2-N-methyl-pyrryl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ The 4-pyridyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 2-methyl-phenyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 2-ethyl-phenyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 2-sec.-propyl-phenyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 4-fluoro-2-methyl-phenyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 2-trifluoromethyl-phenyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 2-methylol-phenyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 2-chloro-phenyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 2-(2-hydroxyethyl)-phenyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 2-(1-hydroxyethyl)-phenyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 2-benzyloxy methyl-phenyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 2-methoxymethyl-phenyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ The 2-thienyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 3-methyl-2-thienyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ The 3-thienyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 2-methyl-3-thienyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 4-methyl-3-thienyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 1-thionaphthene-3-base -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ The 1-naphthyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ The 2-naphthyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 2-N-methyl-pyrryl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ The 4-pyridyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 2-methyl-phenyl

R1 R2 R3 Ar -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 2-ethyl-phenyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 2-sec.-propyl-phenyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 4-fluoro-2-methyl-phenyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 2-trifluoromethyl-phenyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 2-methylol-phenyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 2-chloro-phenyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 2-(2-hydroxyethyl)-phenyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 2-(1-hydroxyethyl)-phenyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 2-benzyloxy methyl-phenyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 2-methoxymethyl-phenyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl The 2-thienyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 3-methyl-2-thienyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl The 3-thienyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 2-methyl-3-thienyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 4-methyl-3-thienyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 1-thionaphthene-3-base -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl The 1-naphthyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl The 2-naphthyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 2-N-methyl-pyrryl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl The 4-pyridyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 2-methyl-phenyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 2-ethyl-phenyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 2-sec.-propyl-phenyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 4-fluoro-2-methyl-phenyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 2-trifluoromethyl-phenyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 2-methylol-phenyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 2-chloro-phenyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 2-(2-hydroxyethyl)-phenyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 2-(1-hydroxyethyl)-phenyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 2-benzyloxy methyl-phenyl

R1 R2 R3 Ar -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 2-methoxymethyl-phenyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base The 2-thienyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 3-methyl-2-thienyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base The 3-thienyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 2-methyl-3-thienyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 4-methyl-3-thienyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 1-thionaphthene-3-base -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base The 1-naphthyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base The 2-naphthyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 2-N-methyl-pyrryl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base The 4-pyridyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 2-methyl-phenyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 2-ethyl-phenyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 2-sec.-propyl-phenyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 4-fluoro-2-methyl-phenyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 2-trifluoromethyl-phenyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 2-methylol-phenyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 2-chloro-phenyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 2-(2-hydroxyethyl)-phenyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 2-(1-hydroxyethyl)-phenyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 2-benzyloxy methyl-phenyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 2-methoxymethyl-phenyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base The 2-thienyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 3-methyl-2-thienyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base The 3-thienyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 2-methyl-3-thienyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 4-methyl-3-thienyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 1-thionaphthene-3-base -CH ₃ -CH ₃ -C (O)-azetidine-1-base The 1-naphthyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base The 2-naphthyl

R1 R2 R3 Ar -CH ₃ -CH ₃ -C (O)-azetidine-1-base 2-N-methyl-pyrryl -CH ₃ -CH ₃ -C (O)-azetidine-1-base The 4-pyridyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 2-methyl-phenyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 2-ethyl-phenyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 2-sec.-propyl-phenyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 4-fluoro-2-methyl-phenyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 2-trifluoromethyl-phenyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 2-methylol-phenyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 2-chloro-phenyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 2-(2-hydroxyethyl)-phenyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 2-(1-hydroxyethyl)-phenyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 2-benzyloxy methyl-phenyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 2-methoxymethyl-phenyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ The 2-thienyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 3-methyl-2-thienyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ The 3-thienyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 2-methyl-3-thienyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 4-methyl-3-thienyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 1-thionaphthene-3-base -CH ₃ -CH ₃ -CH ₂-O-CH ₃ The 1-naphthyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ The 2-naphthyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 2-N-methyl-pyrryl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ The 4-pyridyl -CH ₃ H -C(O)-N(CH ₃) ₂ 2-methyl-phenyl -CH ₃ H -C(O)-N(CH ₃) ₂ 2-ethyl-phenyl -CH ₃ H -C(O)-N(CH ₃) ₂ 2-sec.-propyl-phenyl -CH ₃ H -C(O)-N(CH ₃) ₂ 4-fluoro-2-methyl-phenyl -CH ₃ H -C(O)-N(CH ₃) ₂ 2-trifluoromethyl-phenyl -CH ₃ H -C(O)-N(CH ₃) ₂ 2-methylol-phenyl -CH ₃ H -C(O)-N(CH ₃) ₂ 2-chloro-phenyl

R1 R2 R3 Ar -CH ₃ H -C(O)-N(CH ₃) ₂ 2-(2-hydroxyethyl)-phenyl -CH ₃ H -C(O)-N(CH ₃) ₂ 2-(1-hydroxyethyl)-phenyl -CH ₃ H -C(O)-N(CH ₃) ₂ 2-benzyloxy methyl-phenyl -CH ₃ H -C(O)-N(CH ₃) ₂ 2-methoxymethyl-phenyl -CH ₃ H -C(O)-N(CH ₃) ₂ The 2-thienyl -CH ₃ H -C(O)-N(CH ₃) ₂ 3-methyl-2-thienyl -CH ₃ H -C(O)-N(CH ₃) ₂ The 3-thienyl -CH ₃ H -C(O)-N(CH ₃) ₂ 2-methyl-3-thienyl -CH ₃ H -C(O)-N(CH ₃) ₂ 4-methyl-3-thienyl -CH ₃ H -C(O)-N(CH ₃) ₂ 1-thionaphthene-3-base -CH ₃ H -C(O)-N(CH ₃) ₂ The 1-naphthyl -CH ₃ H -C(O)-N(CH ₃) ₂ The 2-naphthyl -CH ₃ -H -C(O)-N(CH ₃) ₂ 2-N-methyl-pyrryl -CH ₃ -H -C(O)-N(CH ₃) ₂ The 4-pyridyl -CH ₃ H -C(O)-N(H)CH ₃ 2-methyl-phenyl -CH ₃ H -C(O)-N(H)CH ₃ 2-ethyl-phenyl -CH ₃ H -C(O)-N(H)CH ₃ 2-sec.-propyl-phenyl -CH ₃ H -C(O)-N(H)CH ₃ 4-fluoro-2-methyl-phenyl -CH ₃ H -C(O)-N(H)CH ₃ 2-trifluoromethyl-phenyl -CH ₃ H -C(O)-N(H)CH ₃ 2-methylol-phenyl -CH ₃ H -C(O)-N(H)CH ₃ 2-chloro-phenyl -CH ₃ H -C(O)-N(H)CH ₃ 2-(2-hydroxyethyl)-phenyl -CH ₃ H -C(O)-N(H)CH ₃ 2-(1-hydroxyethyl)-phenyl -CH ₃ H -C(O)-N(H)CH ₃ 2-benzyloxy methyl-phenyl -CH ₃ H -C(O)-N(H)CH ₃ 2-methoxymethyl-phenyl -CH ₃ H -C(O)-N(H)CH ₃ The 2-thienyl -CH ₃ H -C(O)-N(H)CH ₃ 3-methyl-2-thienyl -CH ₃ H -C(O)-N(H)CH ₃ The 3-thienyl -CH ₃ H -C(O)-N(H)CH ₃ 2-methyl-3-thienyl -CH ₃ H -C(O)-N(H)CH ₃ 4-methyl-3-thienyl

R1 R2 R3 Ar -CH ₃ H -C(O)-N(H)CH ₃ 1-thionaphthene-3-base -CH ₃ H -C(O)-N(H)CH ₃ The 1-naphthyl -CH ₃ H -C(O)-N(H)CH ₃ The 2-naphthyl -CH ₃ H -C(O)-N(H)CH ₃ 2-N-methyl-pyrryl -CH ₃ H -C(O)-N(H)CH ₃ The 4-pyridyl -CH ₃ H -C (O)-N (H)-cyclopropyl 2-methyl-phenyl -CH ₃ H -C (O)-N (H)-cyclopropyl 2-ethyl-phenyl -CH ₃ H -C (O)-N (H)-cyclopropyl 2-sec.-propyl-phenyl -CH ₃ H -C (O)-N (H)-cyclopropyl 4-fluoro-2-methyl-phenyl -CH ₃ H -C (O)-N (H)-cyclopropyl 2-trifluoromethyl-phenyl -CH ₃ H -C (O)-N (H)-cyclopropyl 2-methylol-phenyl -CH ₃ H -C (O)-N (H)-cyclopropyl 2-chloro-phenyl -CH ₃ H -C (O)-N (H)-cyclopropyl 2-(2-hydroxyethyl)-phenyl -CH ₃ H -C (O)-N (H)-cyclopropyl 2-(1-hydroxyethyl)-phenyl -CH ₃ H -C (O)-N (H)-cyclopropyl 2-benzyloxy methyl-phenyl -CH ₃ H -C (O)-N (H)-cyclopropyl 2-methoxymethyl-phenyl -CH ₃ H -C (O)-N (H)-cyclopropyl The 2-thienyl -CH ₃ H -C (O)-N (H)-cyclopropyl 3-methyl-2-thienyl -CH ₃ H -C (O)-N (H)-cyclopropyl The 3-thienyl -CH ₃ H -C (O)-N (H)-cyclopropyl 2-methyl-3-thienyl -CH ₃ H -C (O)-N (H)-cyclopropyl 4-methyl-3-thienyl -CH ₃ H -C (O)-N (H)-cyclopropyl 1-thionaphthene-3-base -CH ₃ H -C (O)-N (H)-cyclopropyl The 1-naphthyl -CH ₃ H -C (O)-N (H)-cyclopropyl The 2-naphthyl -CH ₃ H -C (O)-N (H)-cyclopropyl 2-N-methyl-pyrryl -CH ₃ H -C (O)-N (H)-cyclopropyl The 4-pyridyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 2-methyl-phenyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 2-ethyl-phenyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 2-sec.-propyl-phenyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 4-fluoro-2-methyl-phenyl

R1 R2 R3 Ar -CH ₃ H -C (O)-tetramethyleneimine-1-base 2-trifluoromethyl-phenyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 2-methylol-phenyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 2-chloro-phenyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 2-(2-hydroxyethyl)-phenyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 2-(1-hydroxyethyl)-phenyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 2-benzyloxy methyl-phenyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 2-methoxymethyl-phenyl -CH ₃ H -C (O)-tetramethyleneimine-1-base The 2-thienyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 3-methyl-2-thienyl -CH ₃ H -C (O)-tetramethyleneimine-1-base The 3-thienyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 2-methyl-3-thienyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 4-methyl-3-thienyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 1-thionaphthene-3-base -CH ₃ H -C (O)-tetramethyleneimine-1-base The 1-naphthyl -CH ₃ H -C (O)-tetramethyleneimine-1-base The 2-naphthyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 2-N-methyl-pyrryl -CH ₃ H -C (O)-tetramethyleneimine-1-base The 4-pyridyl -CH ₃ H -C (O)-azetidine-1-base 2-methyl-phenyl -CH ₃ H -C (O)-azetidine-1-base 2-ethyl-phenyl -CH ₃ H -C (O)-azetidine-1-base 2-sec.-propyl-phenyl -CH ₃ H -C (O)-azetidine-1-base 4-fluoro-2-methyl-phenyl -CH ₃ H -C (O)-azetidine-1-base 2-trifluoromethyl-phenyl -CH ₃ H -C (O)-azetidine-1-base 2-methylol-phenyl -CH ₃ H -C (O)-Ding pyridine-1-base 2-chloro-phenyl -CH ₃ H -C (O)-azetidine-1-base 2-(2-hydroxyethyl)-phenyl -CH ₃ H -C (O)-azetidine-1-base 2-(1-hydroxyethyl)-phenyl -CH ₃ H -C (O)-azetidine-1-base 2-benzyloxy methyl-phenyl -CH ₃ H -C (O)-azetidine-1-base 2-methoxymethyl-phenyl -CH ₃ H -C (O)-azetidine-1-base The 2-thienyl -CH ₃ H -C (O)-azetidine-1-base 3-methyl-2-thienyl

R1 R2 R3 Ar -CH ₃ H -C (O)-azetidine-1-base The 3-thienyl -CH ₃ H -C (O)-azetidine-1-base 2-methyl-3-thienyl -CH ₃ H -C (O)-azetidine-1-base 4-methyl-3-thienyl -CH ₃ H -C (O)-azetidine-1-base 1-thionaphthene-3-base -CH ₃ H -C (O)-azetidine-1-base The 1-naphthyl -CH ₃ H -C (O)-azetidine-1-base The 2-naphthyl -CH ₃ H -C (O)-azetidine-1-base 2-N-methyl-pyrryl -CH ₃ H -C (O)-azetidine-1-base The 4-pyridyl -CH ₃ H -CH ₂-O-CH ₃ 2-methyl-phenyl -CH ₃ H -CH ₂-O-CH ₃ 2-ethyl-phenyl -CH ₃ H -CH ₂-O-CH ₃ 2-sec.-propyl-phenyl -CH ₃ H -CH ₂-O-CH ₃ 4-fluoro-2-methyl-phenyl -CH ₃ H -CH ₂-O-CH ₃ 2-trifluoromethyl-phenyl -CH ₃ H -CH ₂-O-CH ₃ 2-methylol-phenyl -CH ₃ H -CH ₂-O-CH ₃ 2-chloro-phenyl -CH ₃ H -CH ₂-O-CH ₃ 2-(2-hydroxyethyl)-phenyl -CH ₃ H -CH ₂-O-CH ₃ 2-(1-hydroxyethyl)-phenyl -CH ₃ H -CH ₂-O-CH ₃ 2-benzyloxy methyl-phenyl -CH ₃ H -CH ₂-O-CH ₃ 2-methoxymethyl-phenyl -CH ₃ H -CH ₂-O-CH ₃ The 2-thienyl -CH ₃ H -CH ₂-O-CH ₃ 3-methyl-2-thienyl -CH ₃ H -CH ₂-O-CH ₃ The 3-thienyl -CH ₃ H -CH ₂-O-CH ₃ 2-methyl-3-thienyl -CH ₃ H -CH ₂-O-CH ₃ 4-methyl-3-thienyl -CH ₃ H -CH ₂-O-CH ₃ 1-thionaphthene-3-base -CH ₃ H -CH ₂-O-CH ₃ The 1-naphthyl -CH ₃ H -CH ₂-O-CH ₃ The 2-naphthyl -CH ₃ H -CH ₂-O-CH ₃ 2-N-methyl-pyrryl -CH ₃ H -CH ₂-O-CH ₃ The 4-pyridyl

12.RuXY[(S)-Xyl-P-Phos] [(S)-and DAIPEN] as the application of hydrogenation catalyst in the method for claim 1 preparation formula 1-a compound, wherein R1, R2, R3 and Arom have the implication that claim 1 is pointed out.

13. formula 3-a compound or its salt,

Wherein said substituent R 1, R2, R3 and Ar have the implication that following table provides:

R1 R2 R3 Ar -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 2-methyl-phenyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 2-ethyl-phenyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 2-sec.-propyl-phenyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 4-fluoro-2-methyl-phenyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 2-trifluoromethyl-phenyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 2-methylol-phenyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 2-chloro-phenyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 2-(2-hydroxyethyl)-phenyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 2-(1-hydroxyethyl)-phenyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 2-benzyloxy methyl-phenyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 2-methoxymethyl-phenyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ The 2-thienyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 3-methyl-2-thienyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ The 3-thienyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 2-methyl-3-thienyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 4-methyl-3-thienyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 1-thionaphthene-3-base -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ The 1-naphthyl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ The 2-naphthyl

R1 R2 R3 Ar -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ 2-N-methyl-pyrryl -CH ₃ -CH ₃ -C(O)-N(CH ₃) ₂ The 4-pyridyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 2-methyl-phenyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 2-ethyl-phenyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 2-sec.-propyl-phenyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 4-fluoro-2-methyl-phenyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 2-trifluoromethyl-phenyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 2-methylol-phenyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 2-chloro-phenyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 2-(2-hydroxyethyl)-phenyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 2-(1-hydroxyethyl)-phenyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 2-benzyloxy methyl-phenyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 2-methoxymethyl-phenyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ The 2-thienyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 3-methyl-2-thienyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ The 3-thienyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 2-methyl-3-thienyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 4-methyl-3-thienyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 1-thionaphthene-3-base -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ The 1-naphthyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ The 2-naphthyl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ 2-N-methyl-pyrryl -CH ₃ -CH ₃ -C(O)-N(H)CH ₃ The 4-pyridyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 2-methyl-phenyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 2-ethyl-phenyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 2-sec.-propyl-phenyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 4-fluoro-2-methyl-phenyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 2-trifluoromethyl-phenyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 2-methylol-phenyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 2-chloro-phenyl

R1 R2 R3 Ar -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 2-(2-hydroxyethyl)-phenyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 2-(1-hydroxyethyl)-phenyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 2-benzyloxy methyl-phenyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 2-methoxymethyl-phenyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl The 2-thienyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 3-methyl-2-thienyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl The 3-thienyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 2-methyl-3-thienyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 4-methyl-3-thienyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 1-thionaphthene-3-base -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl The 1-naphthyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl The 2-naphthyl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl 2-N-methyl-pyrryl -CH ₃ -CH ₃ -C (O)-N (H)-cyclopropyl The 4-pyridyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 2-methyl-phenyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 2-ethyl-phenyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 2-sec.-propyl-phenyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 4-fluoro-2-methyl-phenyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 2-trifluoromethyl-phenyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 2-methylol-phenyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 2-chloro-phenyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 2-(2-hydroxyethyl)-phenyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 2-(1-hydroxyethyl)-phenyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 2-benzyloxy methyl-phenyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 2-methoxymethyl-phenyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base The 2-thienyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 3-methyl-2-thienyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base The 3-thienyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 2-methyl-3-thienyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 4-methyl-3-thienyl

R1 R2 R3 Ar -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 1-thionaphthene-3-base -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base The 1-naphthyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base The 2-naphthyl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base 2-N-methyl-pyrryl -CH ₃ -CH ₃ -C (O)-tetramethyleneimine-1-base The 4-pyridyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 2-methyl-phenyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 2-ethyl-phenyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 2-sec.-propyl-phenyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 4-fluoro-2-methyl-phenyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 2-trifluoromethyl-phenyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 2-methylol-phenyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 2-chloro-phenyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 2-(2-hydroxyethyl)-phenyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 2-(1-hydroxyethyl)-phenyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 2-benzyloxy methyl-phenyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 2-methoxymethyl-phenyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base The 2-thienyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 3-methyl-2-thienyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base The 3-thienyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 2-methyl-3-thienyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 4-methyl-3-thienyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 1-thionaphthene-3-base -CH ₃ -CH ₃ -C (O)-azetidine-1-base The 1-naphthyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base The 2-naphthyl -CH ₃ -CH ₃ -C (O)-azetidine-1-base 2-N-methyl-pyrryl -CH ₃ -CH ₃ -C (O)-azetidine-1-base The 4-pyridyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 2-methyl-phenyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 2-ethyl-phenyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 2-sec.-propyl-phenyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 4-fluoro-2-methyl-phenyl

R1 R2 R3 Ar -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 2-trifluoromethyl-phenyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 2-methylol-phenyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 2-chloro-phenyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 2-(2-hydroxyethyl)-phenyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 2-(1-hydroxyethyl)-phenyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 2-benzyloxy methyl-phenyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 2-methoxymethyl-phenyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ The 2-thienyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 3-methyl-2-thienyl -CH ₃ -CH ₃ -CH _2-O-CH ₃ The 3-thienyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 2-methyl-3-thienyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 4-methyl-3-thienyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 1-thionaphthene-3-base -CH ₃ -CH ₃ -CH ₂-O-CH ₃ The 1-naphthyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ The 2-naphthyl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ 2-N-methyl-pyrryl -CH ₃ -CH ₃ -CH ₂-O-CH ₃ The 4-pyridyl -CH ₃ H -C(O)-N(CH ₃) ₂ 2-methyl-phenyl -CH ₃ H -C(O)-N(CH ₃) ₂ 2-ethyl-phenyl -CH ₃ H -C(O)-N(CH ₃) ₂ 2-sec.-propyl-phenyl -CH ₃ H -C(O)-N(CH ₃) ₂ 4-fluoro-2-methyl-phenyl -CH ₃ H -C(O)-N(CH ₃) ₂ 2-trifluoromethyl-phenyl -CH ₃ H -C(O)-N(CH ₃) ₂ 2-methylol-phenyl -CH ₃ H -C(O)-N(CH ₃) ₂ 2-chloro-phenyl -CH ₃ H -C(O)-N(CH ₃) ₂ 2-(2-hydroxyethyl)-phenyl -CH ₃ H -C(O)-N(CH ₃) ₂ 2-(1-hydroxyethyl)-phenyl -CH ₃ H -C(O)-N(CH ₃) ₂ 2-benzyloxy methyl-phenyl -CH ₃ H -C(O)-N(CH ₃) ₂ 2-methoxymethyl-phenyl -CH ₃ H -C(O)-N(CH ₃) ₂ The 2-thienyl -CH ₃ H -C(O)-N(CH ₃) ₂ 3-methyl-2-thienyl

R1 R2 R3 Ar -CH ₃ H -C(O)-N(CH ₃) ₂ The 3-thienyl -CH ₃ H -C(O)-N(CH ₃) ₂ 2-methyl-3-thienyl -CH ₃ H -C(O)-N(CH ₃) ₂ 4-methyl-3-thienyl -CH ₃ H -C(O)-N(CH ₃) ₂ 1-thionaphthene-3-base -CH ₃ H -C(O)-N(CH ₃) ₂ The 1-naphthyl -CH ₃ H -C(O)-N(CH ₃) ₂ The 2-naphthyl -CH ₃ -H -C(O)-N(CH ₃) ₂ 2-N-methyl-pyrryl -CH ₃ -H -C(O)-N(CH ₃) ₂ The 4-pyridyl -CH ₃ H -C(O)-N(H)CH ₃ 2-methyl-phenyl -CH ₃ H -C(O)-N(H)CH ₃ 2-ethyl-phenyl -CH ₃ H -C(O)-N(H)CH ₃ 2-sec.-propyl-phenyl -CH ₃ H -C(O)-N(H)CH ₃ 4-fluoro-2-methyl-phenyl -CH ₃ H -C(O)-N(H)CH ₃ 2-trifluoromethyl-phenyl -CH ₃ H -C(O)-N(H)CH ₃ 2-methylol-phenyl -CH ₃ H -C(O)-N(H)CH ₃ 2-chloro-phenyl -CH ₃ H -C(O)-N(H)CH ₃ 2-(2-hydroxyethyl)-phenyl -CH ₃ H -C(O)-N(H)CH ₃ 2-(1-hydroxyethyl)-phenyl -CH ₃ H -C(O)-N(H)CH ₃ 2-benzyloxy methyl-phenyl -CH ₃ H -C(O)-N(H)CH ₃ 2-methoxymethyl-phenyl -CH ₃ H -C(O)-N(H)CH ₃ The 2-thienyl -CH ₃ H -C(O)-N(H)CH ₃ 3-methyl-2-thienyl -CH ₃ H -C(O)-N(H)CH ₃ The 3-thienyl -CH ₃ H -C(O)-N(H)CH ₃ 2-methyl-3-thienyl -CH ₃ H -C(O)-N(H)CH ₃ 4-methyl-3-thienyl -CH ₃ H -C(O)-N(H)CH ₃ 1-thionaphthene-3-base -CH ₃ H -C(O)-N(H)CH ₃ The 1-naphthyl -CH ₃ H -C(O)-N(H)CH ₃ The 2-naphthyl -CH ₃ H -C(O)-N(H)CH ₃ 2-N-methyl-pyrryl -CH ₃ H -C(O)-N(H)CH ₃ The 4-pyridyl -CH ₃ H -C (O)-N (H)-cyclopropyl 2-methyl-phenyl

R1 R2 R3 Ar -CH ₃ H -C (O)-N (H)-cyclopropyl 2-ethyl-phenyl -CH ₃ H -C (O)-N (H)-cyclopropyl 2-sec.-propyl-phenyl -CH ₃ H -C (O)-N (H)-cyclopropyl 4-fluoro-2-methyl-phenyl -CH ₃ H -C (O)-N (H)-cyclopropyl 2-trifluoromethyl-phenyl -CH ₃ H -C (O)-N (H)-cyclopropyl 2-methylol-phenyl -CH ₃ H -C (O)-N (H)-cyclopropyl 2-chloro-phenyl -CH ₃ H -C (O)-N (H)-cyclopropyl 2-(2-hydroxyethyl)-phenyl -CH ₃ H -C (O)-N (H)-cyclopropyl 2-(1-hydroxyethyl)-phenyl -CH ₃ H -C (O)-N (H)-cyclopropyl 2-benzyloxy methyl-phenyl -CH ₃ H -C (O)-N (H)-cyclopropyl 2-methoxymethyl-phenyl -CH ₃ H -C (O)-N (H)-cyclopropyl The 2-thienyl -CH ₃ H -C (O)-N (H)-cyclopropyl 3-methyl-2-thienyl -CH ₃ H -C (O)-N (H)-cyclopropyl The 3-thienyl -CH ₃ H -C (O)-N (H)-cyclopropyl 2-methyl-3-thienyl -CH ₃ H -C (O)-N (H)-cyclopropyl 4-methyl-3-thienyl -CH ₃ H -C (O)-N (H)-cyclopropyl 1-thionaphthene-3-base -CH ₃ H -C (O)-N (H)-cyclopropyl The 1-naphthyl -CH ₃ H -C (O)-N (H)-cyclopropyl The 2-naphthyl -CH ₃ H -C (O)-N (H)-cyclopropyl 2-N-methyl-pyrryl -CH ₃ H -C (O)-N (H)-cyclopropyl The 4-pyridyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 2-methyl-phenyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 2-ethyl-phenyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 2-sec.-propyl-phenyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 4-fluoro-2-methyl-phenyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 2-trifluoromethyl-phenyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 2-methylol-phenyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 2-chloro-phenyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 2-(2-hydroxyethyl)-phenyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 2-(1-hydroxyethyl)-phenyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 2-benzyloxy methyl-phenyl

R1 R2 R3 Ar -CH ₃ H -C (O)-tetramethyleneimine-1-base 2-methoxymethyl-phenyl -CH ₃ H -C (O)-tetramethyleneimine-1-base The 2-thienyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 3-methyl-2-thienyl -CH ₃ H -C (O)-tetramethyleneimine-1-base The 3-thienyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 2-methyl-3-thienyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 4-methyl-3-thienyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 1-thionaphthene-3-base -CH ₃ H -C (O)-tetramethyleneimine-1-base The 1-naphthyl -CH ₃ H -C (O)-tetramethyleneimine-1-base The 2-naphthyl -CH ₃ H -C (O)-tetramethyleneimine-1-base 2-N-methyl-pyrryl -CH ₃ H -C (O)-tetramethyleneimine-1-base The 4-pyridyl -CH ₃ H -C (O)-azetidine-1-base 2-methyl-phenyl -CH ₃ H -C (O)-azetidine-1-base 2-ethyl-phenyl -CH ₃ H -C (O)-azetidine-1-base 2-sec.-propyl-phenyl -CH ₃ H -C (O)-azetidine-1-base 4-fluoro-2-methyl-phenyl -CH ₃ H -C (O)-azetidine-1-base 2-trifluoromethyl-phenyl -CH ₃ H -C (O)-azetidine-1-base 2-methylol-phenyl -CH ₃ H -C (O)-azetidine-1-base 2-chloro-phenyl -CH ₃ H -C (O)-azetidine-1-base 2-(2-hydroxyethyl)-phenyl -CH ₃ H -C (O)-azetidine-1-base 2-(1-hydroxyethyl)-phenyl -CH ₃ H -C (O)-azetidine-1-base 2-benzyloxy methyl-phenyl -CH ₃ H -C (O)-azetidine-1-base 2-methoxymethyl-phenyl -CH ₃ H -C (O)-azetidine-1-base The 2-thienyl -CH ₃ H -C (O)-azetidine-1-base 3-methyl-2-thienyl -CH ₃ H -C (O)-azetidine-1-base The 3-thienyl -CH ₃ H -C (O)-azetidine-1-base 2-methyl-3-thienyl -CH ₃ H -C (O)-azetidine-1-base 4-methyl-3-thienyl -CH ₃ H -C (O)-azetidine-1-base 1-thionaphthene-3-base -CH ₃ H -C (O)-azetidine-1-base The 1-naphthyl -CH ₃ H -C (O)-azetidine-1-base The 2-naphthyl

R1 R2 R3 Ar -CH ₃ H -C (O)-azetidine-1-base 2-N-methyl-pyrryl -CH ₃ H -C (O)-azetidine-1-base The 4-pyridyl -CH ₃ H -CH ₂-O-CH ₃ 2-methyl-phenyl -CH ₃ H -CH ₂-O-CH ₃ 2-ethyl-phenyl -CH ₃ H -CH ₂-O-CH ₃ 2-sec.-propyl-phenyl -CH ₃ H -CH ₂-O-CH ₃ 4-fluoro-2-methyl-phenyl -CH ₃ H -CH ₂-O-CH ₃ 2-trifluoromethyl-phenyl -CH ₃ H -CH ₂-O-CH ₃ 2-methylol-phenyl -CH ₃ H -CH ₂-O-CH ₃ 2-chloro-phenyl -CH ₃ H -CH ₂-O-CH ₃ 2-(2-hydroxyethyl)-phenyl -CH ₃ H -CH ₂-O-CH ₃ 2-(1-hydroxyethyl)-phenyl -CH ₃ H -CH ₂-O-CH ₃ 2-benzyloxy methyl-phenyl -CH ₃ H -CH ₂-O-CH ₃ 2-methoxymethyl-phenyl -CH ₃ H -CH ₂-O-CH ₃ The 2-thienyl -CH ₃ H -CH ₂-O-CH ₃ 3-methyl-2-thienyl -CH ₃ H -CH ₂-O-CH ₃ The 3-thienyl -CH ₃ H -CH ₂-O-CH ₃ 2-methyl-3-thienyl -CH ₃ H -CH ₂-O-CH ₃ 4-methyl-3-thienyl -CH ₃ H -CH ₂-O-CH ₃ 1-thionaphthene-3-base -CH ₃ H -CH ₂-O-CH ₃ The 1-naphthyl -CH ₃ H -CH ₂-O-CH ₃ The 2-naphthyl -CH ₃ H -CH ₂-O-CH ₃ 2-N-methyl-pyrryl -CH ₃ H -CH ₂-O-CH ₃ The 4-pyridyl

14. formula 3-a compound or its salt

It is selected from:

(8S)-and 2-methyl-8-phenyl-3-(2-trimethyl silyl-ethoxyl methyl)-3,6,7,8-tetrahydrochysene-chromene is [7,8-d] imidazoles-5-formic acid diformamide also,

(8S)-and 8-(2-fluoro-phenyl)-2,3-dimethyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also,

(8S)-and 8-(4-fluoro-phenyl)-2,3-dimethyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also,

(8S)-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also,

(8S)-and 8-(2-chloro-phenyl)-2,3-dimethyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also,

(8S)-2,3-dimethyl-8-(2-trifluoromethyl-phenyl)-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also,

(8S)-2,3-dimethyl-8-naphthalene-2-base-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also,

(8S)-and (2-ethyl-phenyl)-2,3-dimethyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also,

(8S) 2,3-dimethyl-8-thiophene-2-base-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also,

(8S)-and 8-(4-fluoro-2-methyl-phenyl)-2,3-dimethyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also,

(8S)-(2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-yl also)-tetramethyleneimine-1-base-ketone,

(8S)-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid methyl nitrosourea also,

(8S)-azetidine-1-base-((S)-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene are [7,8-d] imidazoles-5-yl also)-ketone,

(8S)-and 8-(2-benzyloxy methyl-phenyl)-2,3-dimethyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also,

(8S)-and 8-(2-methoxymethyl-phenyl)-2,3-dimethyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also,

(8S)-and 2-methyl-8-o-tolyl-3-(2-trimethyl silyl-ethoxyl methyl)-3,6,7,8-tetrahydrochysene-chromene is [7,8-d] imidazoles-5-formic acid diformamide also,

(8S)-and 2-methyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene is [7,8-d] imidazoles-5-formic acid diformamide also,

(8S)-2,3-dimethyl-8-(2-methyl-thiene-3-yl-)-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles-5-formic acid diformamide also,

(8S)-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene also [7,8-d] imidazoles-5-formic acid cyclopropyl amide and

5-methoxymethyl-2,3-dimethyl-8-o-tolyl-3,6,7,8-tetrahydrochysene-chromene be [7,8-d] imidazoles also,

Or its salt.

15. a medicine comprises compound and/or its pharmacologically acceptable salt and the conventional pharmacy auxiliary and/or the vehicle of claim 13 or 14.

16. the compound of claim 13 or 14 and pharmacologically acceptable salt thereof the application in preventing and/or treating gastrointestinal tract disorder.

17. the compound of claim 13 or 14 and pharmacologically acceptable salt thereof are used for the treatment of and/or prevent application in the medicine of gastrointestinal tract disorder in manufacturing.