CN101228142A - Intermediate compound for synthesizing pharmaceutical agent and production method thereof - Google Patents
Intermediate compound for synthesizing pharmaceutical agent and production method thereof Download PDFInfo
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- CN101228142A CN101228142A CNA2006800267798A CN200680026779A CN101228142A CN 101228142 A CN101228142 A CN 101228142A CN A2006800267798 A CNA2006800267798 A CN A2006800267798A CN 200680026779 A CN200680026779 A CN 200680026779A CN 101228142 A CN101228142 A CN 101228142A
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Abstract
The present invention relates to a production method of an optically active morpholine compound represented by the formula 10, which includes the following steps: wherein each symbol is as defined in the specification. The present invention also relates to a production method of an compound represented by the formula 55, which includes the following steps: wherein each symbol is as defined in the specification. According to the production method of the present invention, an optically active 2-aryl-substituted morpholine compound and 3-oxo-3-(pyrimidin-4-yl)propionate, which are important as starting materials for synthesizing 2-(2-arylmorpholin-4-yl)-1-methyl-1H-[4,4']bipyrimidinyl-6-one having a tau protein kinase 1 inhibitory activity and useful as a therapeutic drug for Alzheimer's disease and the like, can be produced in a high yield by an industrially advantageous method.
Description
Technical field
The present invention relates to a kind of usefulness act on synthesizing pharmaceutical agent intermediate, have a preparation method of the morpholinium compound that optically active 2-aryl replaces, and the novel cpd that makes by this preparation method.The invention still further relates to preparation method with 3-oxo-3-(pyrimidine-4-yl) propionic ester of the intermediate that acts on synthesizing pharmaceutical agent.
Background technology
Patent documentation WO 2003/027080 described by following formula 43 expression such as 2-(2-aryl morpholine-4-yl)-1-methyl isophthalic acid H-[4,4 '] compound of connection pyrimidyl-6-ketone and so on etc. has tau protein kinases 1 and suppress active, and described compound can be used as the medicine of Alzheimer etc.It is by the 2-chloro-1-methyl isophthalic acid H-[4 shown in the formula 41 that described patent documentation has also been described the compound shown in the formula 43,4 '] aryl shown in connection pyrimidyl-6-ketone and the formula 42 morpholinium compound that replaces obtains as starting material is synthetic.
Wherein R is for can randomly have substituent aryl, perhaps for can randomly have substituent heteroaryl.
Therefore, the 2-chloro-1-methyl isophthalic acid H-[4 shown in the formula 41,4 '] morpholinium compound that replaces of the aryl shown in connection pyrimidyl-6-ketone and the formula 42 is used as the intermediate that is used for synthesizing pharmaceutical agent.
In addition, according to patent documentation WO 2004/085408, the compound shown in the formula 41 can be by the 3-oxo-3-shown in the formula 44 (pyrimidine-4-yl) ethyl propionate through the 2-sulfydryl shown in the formula 45-1-methyl isophthalic acid H-[4,4 '] connection pyrimidyl-6-ketone is synthetic obtains.
Therefore, the compound shown in the formula 44 be used for synthetic such as 2-(2-aryl morpholine-4-yl)-1-methyl isophthalic acid H-[4,4 '] the important initial compounds of the compound of connection pyrimidyl-6-ketone and so on.
Document Eur.J.Med.Chem.31, having described 2-aryl-4-(2-hydroxyethyl) morpholine among the 909-914 (1996) can pass through chloroacetophenone and N, the N-diethanolamine heats to synthesize in formic acid, wherein said chloroacetophenone is not substituted on 4, perhaps has chlorine atom or methyl on its 4.
Document Chem.Ber.115, having described 2-aryl-4-alkyl morpholine among the 2635-2642 (1982) can be by heating 2-acetoxyl group phenyl methyl ketone and N-alkyl ethanol amine to synthesize in formic acid, wherein said 2-acetoxyl group phenyl methyl ketone is not substituted on 4, perhaps has chlorine atom, bromine atoms or methoxyl group on its 4; Moieties in the described N-alkyl ethanol amine is methyl, ethyl, propyl group, sec.-propyl, butyl or benzyl.
Document Arch.Pharm. (Weinheim), 323,41-42 has described 2-phenyl-3 in (1990), and the 4-thebaine can be by heating 2-brom-acetophenone (2-bromopropiophenone) and N-Mono Methyl Ethanol Amine to synthesize in formic acid.
Document J.Med.Chem, 35, having described 2-aryl-4-propyl group morpholine among the 3045-3049 (1992) can synthesize by the following method: will have the carbonyl reduction of substituent phenacyl bromide on two or three-digit, thereby gained compound and alkali reaction are obtained 2-aryl rings oxidative ethane, thereby gained compound and propylamine reaction are obtained 1-aryl-2-(propyl group amino) ethanol, thereby the gained compound is obtained 2-aryl-4-propyl group morpholine-5-ketone with the bromoacetyl chloride reaction in the presence of potassium hydroxide, and the gained compound is reduced; And described 2-aryl-4-propyl group morpholine can be by heating to come synthetic in formic acid with the acetobrom thiophene or having substituent phenacyl bromide and N-propyl group thanomin on the two or three-digit.
Document J.Med.Chem, 18,573, (1975) having described 2-alkoxy methyl-4-alkyl morpholine in can synthesize by the following method: with 1-alkylamino-3-aryloxy propan-2-ol (its moieties is hydrogen atom, methyl, sec.-propyl, allyl group, cyclopentyl or benzyl) and chloroacetyl chloride reaction, gained compound and sodium methylate are reacted, and the gained compound is reduced.
Document Chem.Pharm.Bull.33, having described 2-aryloxy methyl morpholine in 3766 (1985) can be by synthesizing 2-(aryloxy methyl) oxyethane in the presence of sodium hydroxide with the reaction of hydrogen sulfate 2-ammonia ethyl ester.
Document Heterocycles, 34, described in 1343 (1992) 4 replacements or unsubstituted 2-aryl-morpholine can synthesize by the following method: with 2-bromine alkylaryl ketone and the N position is that replace or unsubstituted phenylmethylamine reaction, with the carbonyl reduction of the 2-keto-amine of gained, and with resultant 1-aryl-2-monoethanolamine and reacting ethylene oxide; 2-monoethanolamine reaction that perhaps 2-bromine alkylaryl ketone and N position are replaced or unsubstituted, with the carbonyl reduction of resultant 2-(2-hydroxyethyl) keto-amine, and with 1-aryl-2-(2-hydroxyethyl) monoethanolamine of gained with the Hydrogen bromide reaction.
In addition, French Patent No.2285886 has described 2-aryl morpholine compound and can synthesize by the following method: for example, and will be by formula: X-CH
2-CH
2-O-CH (Br)-CH
2The represented compound of-Br (wherein X is a halogen) with by the represented compound reaction of formula: Ph-MgBr (wherein Ph is for can randomly having substituent phenyl).Can carry out optical resolution by the racemize 2-aryl morpholine compound that ordinary method will so obtain, thereby obtain the optical isomer of described compound.
Described these methods are described to the synthetic method of the morpholine of racemize 2-aryl-4-replacement, and the efficient synthesis of the morpholine that the 2-of optical activity form aryl-4-replaces is not known.Especially, for the 2-aryl morpholine, can not surpass 50% (this is because the another kind of enantiomorph of 2-aryl morpholine can not be converted into described racemic modification or opposite enantiomorph effectively owing to its chemical structure) in theory owing to obtain the productive rate that method reached of a kind of enantiomorph of 2-aryl morpholine by optical resolution, so this method is totally unfavorable on synthetic.In addition, when by by document Eur.J.Med.Chem.31,909-914 (1996); Chem.Ber.115,2635-2642 (1982); Arch.Pharm. (Weinheim), 323,41-42 (1990); Perhaps J.Med.Chem; 35; when the described method of 3045-3049 (1992) and morpholine that the N-that obtains replaces make the morpholine of the non-replacement of N-; these reference literatures are not provided for making N-benzyl etc. to be easy to the synthetic example of ground deprotection; or the method productive rate that is provided is lower; and under substituent productive rate condition with higher, need harsh deprotection condition.For these reasons, the method that these reference literatures provided is unfavorable for synthesizing.Document J.Med.Chem, 18,573, (1975) and Chem.Pharm.Bull.33,3766 (1985) have described the synthetic method of the morpholine of the non-replacement of N-, but do not describe the synthetic example of 2-aryl morpholine; Document Heterocycles, 34, the problem of 1343 (1992) described methods is: prepared mixture of isomers in building-up process, discriminating to intermediate is comparatively complicated owing to need handle under highly acid condition in final step, the application of functional group has sizable limitation, etc.; French Patent No.2285886 has proposed the concern to the synthetic and processing of reaction intermediate.
Document Tetrahedron Asymmetry, Vol.2, No.2, pp 113-122,1991 have described and can synthesize S-(+)-4-fluorophenethyl olefinic oxide (that is: (2S)-2-(4-fluorophenyl) oxyethane) or R-(-)-4-fluorophenethyl olefinic oxide by the following method, described method is: 4-fluorobenzoyl methyl chloride is reduced, use lipase P that 2-chloro-1-(4-fluorophenyl) ethanol of gained is carried out optical resolution, and optically active 2-chloro-1-(4-fluorophenyl) ethanol that has that is obtained is reacted with sodium hydroxide.
Document Tetrahedron, 58, (2002) 4693-4706 has described and has had optically active beta-alkamine that (for example (1S)-1-phenyl-2-(benzyl amino) ethanol etc.) can optically active O-ethanoyl amygdalic acid is synthetic to be obtained by having.
But above-mentioned document is not described has that optically active beta-alkamine can optically active 2-aryl rings oxidative ethane is synthetic to be obtained through having by aryl Acetyl Chloride 98Min. compound (for example 4-fluorobenzoyl methyl chloride etc.); And above-mentioned document also describe have that optically active 2-aryl replaces morpholinium compound can optically active beta-alkamine is synthetic to be obtained by having.
Some whey acid esters are known, and the part of these whey acid esters is commercially available getting.In addition, as the method that is used for by the synthetic whey acid esters of vitamin B13 or derivatives thereof, known have a following method.
Document Yakugaku Zasshi, 84,1057-1061 has described can be by heating to synthesize the vitamin B13 ethyl ester with vitamin B13 in the mixture that is made of sulfuric acid and ethanol.
Document Scientia Pharmaceutica, 51,374 (1984) have described and can synthesize the vitamin B13 ethyl ester by the following method, described method is: in ethanol with whey base nitrile (orotonitrile) and hcl reaction, thereby generate imido-ester; Subsequently with the imido-ester hydrolysis.
Document J.Org.Chem, 27,3507 (1962) have described and can synthesize the vitamin B13 methyl esters by the following method, and described method is: under the condition that the pyridine of catalytic amount exists with vitamin B13 and thionyl chloride reaction, thereby generation whey acyl chlorides (orotyl chloride); Subsequently the whey acyl chlorides is heated in methyl alcohol.
Document J.Org.Chem, 25,1950 (1960) have described under the condition that can exist by the sulfuric acid at catalytic amount that heating lactic acid synthesizes the vitamin B13 butyl ester in butanols.
Document International Journal of Pharmaceutics, 61,43 (1990) described can by with vitamin B13 in the saturated alcohol of hydrogenchloride or containing in the alcohol of the vitriol oil heating and synthesize corresponding whey acid esters.
Document Bull.Soc.Chim.Belg.1953,611 described can be by synthesizing corresponding whey acid esters with vitamin B13 heating in saturated methyl alcohol of hydrogenchloride or ethanol.
Document Biochimica et Biophysica Acta.23,295 (1957) described can be by synthesizing corresponding whey acid esters with vitamin B13 heating in saturated methyl alcohol of hydrogenchloride or ethanol.The document has also been described can be according to document Ann.Soc.Chim.Milano, II, 18,71 (1905); Chem.Ber.63,1000 (1930); Perhaps Chem.Ber.64, the method described in 2683 (1931) is by reacting vitamin B13 silver and methyl-iodide or iodoethane to synthesize corresponding whey acid esters.
Having described among the patent documentation WO 83/02891 can be by with vitamin B13 and butanols and sulfuric acid heating hydrolysis 12 hours in toluene, thereby obtains 56% vitamin B13 butyl ester.
French Patent No.1525298 has described and can obtain the vitamin B13 butyl ester by the following method: with vitamin B13 and butanols and tosic acid heating hydrolysis 5 hours in toluene, repeat (5 times) in addition and add tosic acid, butanols and toluene and heat their mixture, and the document has also been described and can have been obtained corresponding vitamin B13 pentyl ester or vitamin B13 isopentyl ester by similar method.
Document WO 95/02407 has been described can be by heating to synthesize corresponding whey acid esters with the vitamin B13 methyl esters under the condition that exists at sulfuric acid in 2-ethyl butanol or 1-methylpropanol.
Described these methods have following point.For example, document Yakugaku Zasshi, 84,1057-1061 (1964) needs complicated operations, for example neutralizes, extraction etc.Document ScientiaPharmaceutica, 51,374 (1984) need long reaction scheme, and can not carry out directly synthetic.Document J.Org.Chem, 27,3507 (1962) need long reaction times and a plurality of reactions steps, and have produced the toxic gas such as hydrogenchloride, sulfurous gas, monochloro methane.Document J.Org.Chem, 25,1950 (1960) need the long reaction times, and contain residual starting material.Document International Journal ofPharmaceutics, 61,43 (1990); Bull.Soc.Chim.Belg.1953,611; And Biochimica et Biophysica Acta.23,295 (1957) needs deleterious hydrogenchloride of use and reaction times are longer.Document Ann.Soc.Chim.Milano, II, 18,71 (1905); Chem.Ber.63,1000 (1930); And Chem.Ber.64,2683 (1931) have used silver salt, and its problem is light stability and cost.Patent documentation WO83/02891 needs the long reaction times and obtains lower productive rate.French Patent No.1525298 needs long reaction times and complicated operations.Patent documentation WO95/02407 needs the long reaction times.
As the whey acid esters is converted into 2, the reaction of 6-dichloro pyrimidine-4-carboxylicesters, document Khimiya Seterotsiklicheskikh Soedinenii, 1986,818 have described and can the chlorination of vitamin B13 butyl ester have been come Synthetic 2, the 6-dichloro pyrimidine-positive butyl ester of 4-carboxylic acid by using phosphoryl chloride.Document J.Org.Chem, 27,3507 (1962) have described and can the chlorination of vitamin B13 methyl esters have been come Synthetic 2,6-dichloro pyrimidine-4-carboxylate methyl ester by using phosphoryl chloride.Document J.Org.Chem, 26,2755 (1961) have described and can the chlorination of vitamin B13 methyl esters have been come Synthetic 2,6-dichloro pyrimidine-4-carboxylate methyl ester by using phosphoryl chloride.
As 2, the dechlorination reaction of 6-dichloro pyrimidine-4-carboxylicesters, document Tetrahedron Lett.1976,693 reported use magnesium oxide and triethylamine as alkali in 2 steps to 2,6-two chloro-5-nitro-pyrimidine-4-carboxylic acid, ethyl esters carry out dechlorination reaction, simultaneously with nitroreduction.
Synthetic method as pyrimidine-4-carboxylicesters, except that method mentioned above, document J.Med.Chem, 20,1312 (1977) have reported and can synthesize pyrimidine-4-carboxylate methyl ester by following method, described method is: thus use tin anhydride that the oxidation of 4-methylpyrimidine is obtained pyrimidine-4-carboxylic acid, and with gained compound and diazomethane reaction.Yet the problem of this method is that it has used the higher selenium compound of toxicity.
In addition, document J.Org.Chem.30,2398 (1965) have described and can synthesize pyrimidine-4-carboxylate methyl ester by the following method, described method is: according to document J.Chem.Soc.1953, method described in 3129, thereby use Raney's nickel to handle 5-bromo-2-methyl sulfo-pyrimidine-4-carboxylic acid and obtain pyrimidine-4-carboxylic acid, and under the condition that concentrated hydrochloric acid exists, in methyl alcohol, heat the gained compound.The problem of this method is on the operability of starting material.
About 3-oxo-3-(pyrimidine-4-yl) propionic ester,, describe to some extent in 1981,530 at document KhimiyaSeterotsiklicheskikh Soedinenii; And document Khimiya Seterotsiklicheskikh Soedinenii, 1980,822 and patent documentation JP-A-52-105181 the synthetic example of 3-oxo-3-(pyrimidine-4-yl) ethyl propionate has been described, it is included in following to pyrimidine-4-carboxylate methyl ester and acetic acid ethyl reaction that alkali exists.But, also do not have the example of discovery by the synthetic described compound of step cause vitamin B13 of the present invention.
Summary of the invention
About the method that is used to obtain to have the morpholinium compound that optically active 2-aryl replaces (by carrying out the method that optical resolution prepares) to obtain the morpholinium compound that racemize 2-aryl replaces by the preparation method described in the French Patent No.2285886, because another enantiomorph of the morpholinium compound that the 2-aryl replaces can not be converted into described racemic modification or opposite enantiomorph effectively because of its chemical structure, so unwanted described another enantiomorph can not be used for optical resolution once more and have to be thrown away usually.Therefore, the productive rate that optical resolution reached of the morpholinium compound that the 2-aryl replaces can not surpass 50% in theory, thus this method synthetic and industrial be totally unfavorable.Therefore, the object of the present invention is to provide a kind of usefulness act on synthesizing pharmaceutical agent intermediate, have a novel and effective preparation method of the morpholinium compound that optically active 2-aryl replaces, and the novel cpd that obtains by this method.
The industrial favourable preparation method of 3-oxo-3-(pyrimidine-4-yl) propionic ester of the intermediate that the present invention also aims to provide a kind of usefulness to act on synthesizing pharmaceutical agent.
For attempting to address the above problem, the inventor has carried out a large amount of research, and the inventor has found to synthesize the effective preparation method with morpholinium compound that optically active 2-aryl replaces via having optically active 2-ethanolamine compound, thereby has finished the present invention.
Therefore, the invention provides a kind of preparation method with optically active 2-ethanolamine compound, a kind ofly have optically active 2-ethanolamine compound, a kind ofly have method that optically active 2-ethanolamine compound preparation has the morpholinium compound that optically active 2-aryl replaces and a kind ofly have a morpholinium compound that optically active 2-aryl replaces by what this method obtained by described by what this method obtained.To be described these details below.
The invention provides by the represented preparation method with optically active compound of formula 5, this method may further comprise the steps:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; X
1Be halogen; R
1Be C
1-C
6Alkyl, can randomly have substituent aralkyl or for C
2-C
6Thiazolinyl;
Step 1) is reacted the compound shown in the formula 1 and borine or its complex compound, thereby is obtained the compound shown in the formula 2 under the condition that (S)-2-methyl-CBS- azoles borine (oxazaborolidine) exists in solvent,
Step 2) compound and the alkali shown in the formula 2 is reacted in solvent, thereby obtain the compound of formula 3, and
Step 3) is reacted the amine shown in compound shown in the formula 3 and the formula 4, thereby obtains the compound shown in the formula 5.
The present invention also provides by the represented preparation method with optically active morpholinium compound of formula 10, and this method may further comprise the steps:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; R
1Be C
1-C
6Alkyl, can randomly have substituent aralkyl or for C
2-C
6Thiazolinyl; R
2Be C
1-C
6Alkyl, C
1-C
6Haloalkyl, can randomly have substituent aryl or for can randomly have substituent benzyl; X
2Be halogen;
Step 1) is reacted the compound shown in the formula 5 and activatory Mono Chloro Acetic Acid or bromoacetic acid in solvent, thereby obtains the compound shown in the formula 6,
Step 2) compound and the alkali shown in the formula 6 is reacted, thereby obtain the compound shown in the formula 7, and
Step 3) is reacted compound and the reductive agent shown in the formula 7 in solvent, thereby obtains the compound shown in the formula 8,
Step 4) is reacted compound and the chloro-formic ester shown in the formula 8, thereby obtains the compound shown in the formula 9, and
Step 5) is hydrolyzed the compound shown in the formula 9, thereby obtains the compound shown in the formula 10.
The present invention also provide by formula 11 represented have optically active compound or its salt:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; R
1Be C
1-C
6Alkyl, can randomly have substituent aralkyl or for C
2-C
6Thiazolinyl; R
10For hydrogen atom or be :-CO-CH by formula
2-X
2(X wherein
2Be halogen) represented group.
In addition, the present invention also provide by formula 12 represented have optically active morpholinium compound or its salt:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; R
1aBe hydrogen atom, C
1-C
6Alkyl, can randomly have substituent aralkyl, C
2-C
6Thiazolinyl or be :-COOR by formula
2(R wherein
2Be C
1-C
6Alkyl, C
1-C
6Haloalkyl, can randomly have substituent aryl or for can randomly having substituent benzyl) represented group; Z is O or H
2,
Condition is to work as R
1aFor hydrogen atom, Z are H
2The time, R not should be the 4-fluorophenyl.
The present invention also provides by the represented preparation method with optically active morpholinium compound of formula 10, and this method is included under the condition that transition-metal catalyst exists, and compound and the hydrogen shown in the formula 13 is reacted:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; R
3For can randomly having substituent benzyl, can randomly having substituent 1-styroyl or for can randomly have substituent carbobenzoxy-(Cbz).
The present invention also further provides by the represented preparation method with optically active compound of formula 25, and this method may further comprise the steps:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; X
1Be halogen; R
1Be C
1-C
6Alkyl, can randomly have substituent aralkyl or for C
1-C
6Thiazolinyl;
Step 1) is reacted the compound shown in the formula 21 and borine or its complex compound, thereby is obtained the compound shown in the formula 22 under the condition that (R)-2-methyl-CBS- azoles borine exists in solvent,
Step 2) compound and the alkali shown in the formula 22 is reacted in solvent, thereby obtain the compound shown in the formula 23, and
Step 3) is reacted the amine shown in compound shown in the formula 23 and the formula 24, thereby obtains the compound shown in the formula 25.
In addition, the present invention also provides by the represented preparation method with optically active morpholinium compound of formula 30, and this method may further comprise the steps:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; R
1Be C
1-C
6Alkyl, can randomly have substituent aralkyl or for C
1-C
6Thiazolinyl; R
2Be C
1-C
6Alkyl, C
1-C
6Haloalkyl, can randomly have substituent aryl or for can randomly have substituent benzyl; X
2Be halogen,
Step 1) is reacted the compound shown in the formula 25 and activatory Mono Chloro Acetic Acid or bromoacetic acid in solvent, thereby obtains the compound shown in the formula 26,
Step 2) compound and the alkali shown in the formula 26 is reacted, thereby obtains the compound shown in the formula 27,
Step 3) is reacted compound and the reductive agent shown in the formula 27 in solvent, thereby obtains the compound shown in the formula 28,
Step 4) is reacted compound and the chloro-formic ester shown in the formula 28, from obtaining the compound shown in the formula 29, and
Step 5) is hydrolyzed the compound shown in the formula 29, thereby obtains the compound shown in the formula 30.
The present invention also provide by formula 31 represented have optically active compound or its salt:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; R
1Be C
1-C
6Alkyl, can randomly have substituent aralkyl or for C
2-C
6Thiazolinyl; R
10For hydrogen atom or be :-CO-CH by formula
2-X
2(X wherein
2Be halogen) represented group.
In addition, the present invention also provide by formula 32 represented have optically active morpholinium compound or its salt:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; R
1aBe hydrogen atom, C
1-C
6Alkyl, can randomly have substituent aralkyl, C
2-C
6Thiazolinyl or be :-COOR by formula
2Represented group (R wherein
2Be C
1-C
6Alkyl, C
1-C
6Haloalkyl, can randomly have substituent aryl or can randomly have substituent benzyl); Z is O or H
2,
Condition is to work as R
1aFor hydrogen atom, Z are H
2The time, R not should be the 4-fluorophenyl.
In addition, the present invention also provides by the represented preparation method with optically active morpholinium compound of formula 30, and this method is included under the condition that transition-metal catalyst exists, and compound and the hydrogen shown in the formula 33 is reacted:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; R
3For can randomly having substituent benzyl, can randomly have substituent 1-styroyl or can randomly having substituent carbobenzoxy-(Cbz).
In addition, the present invention also provides by the represented preparation method with optically active compound of formula 35, this method be included in ruthenium catalyst (hereinafter being also referred to as the Ru catalyzer) and have optically active amino alcohol or condition that the amine ligand exists under, the compound shown in the formula 34 and Virahol or formic acid are reacted:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; R
1' be hydrogen atom, C
1-C
6Alkyl, can randomly have substituent aralkyl or for C
2-C
6Thiazolinyl; R
11Be hydrogen atom or tertbutyloxycarbonyl.
The present invention further provides by the represented compound or its salt of formula 34:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; R
1' be hydrogen atom, C
1-C
6Alkyl, can randomly have substituent aralkyl or for C
2-C
6Thiazolinyl; R
11Be hydrogen atom or tertbutyloxycarbonyl.
In addition, the present invention also provides by the represented preparation method with optically active compound of formula 36, this method is included in the Ru catalyzer and has under the condition that optically active amino alcohol or amine ligand exist, and the compound shown in the formula 34 and Virahol or formic acid are reacted:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; R
1' be hydrogen atom, C
1-C
6Alkyl, can randomly have substituent aralkyl or for C
2-C
6Thiazolinyl; R
11Be hydrogen atom or tertbutyloxycarbonyl.
The present invention also provides by the represented preparation method with optically active compound of formula (I), and this method comprises any one method in the method mentioned above:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; And by the * marked carbon atoms is asymmetric carbon atoms.
The present invention further provides by the represented preparation method with optically active compound of formula (I), this method comprises any one compound that uses in the compound mentioned above:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; And by the * marked carbon atoms is asymmetric carbon atoms.
In addition, carried out a large amount of research, and the inventor found the very effectively preparation method of 3-oxo-3-(pyrimidine-4-yl) propionic ester, thereby finished the present invention in order to attempt to address the above problem the inventor.
Therefore, the invention provides a kind of preparation method by the represented compound of formula 55, this method may further comprise the steps:
R wherein
aAnd R
bBe identical or different, and be C
1-C
6Alkyl;
Step 1) is reacted vitamin B13 and the alkylating agent shown in the formula 51, thereby is obtained the compound shown in the formula 52 under the condition that alkali exists in solvent,
Step 2) under refluxad, compound and the chlorizating agent shown in the formula 52 together heated, thereby obtains the compound shown in the formula 53,
Step 3) is carried out dechlorination reaction with the compound shown in the formula 53, thereby is obtained the compound shown in the formula 54 under the condition that alkali exists, and
Step 4) is reacted compound and the acetic ester shown in the formula 54, thereby is obtained the compound shown in the formula 55 under the condition that alkali exists.
The present invention also provides a kind of preparation method by the represented compound of formula 52, and this method is included under the condition that alkali exists, and vitamin B13 and the alkylating agent shown in the formula 51 reacted in solvent:
R wherein
aBe C
1-C
6Alkyl.
The present invention further provides a kind of preparation method by the represented compound of formula 53, this method comprises under refluxad, and compound and the chlorizating agent shown in the formula 52 together heated:
R wherein
aBe C
1-C
6Alkyl.
In addition, the invention provides a kind of preparation method by the represented compound of formula 54, this method is included under the condition that alkali exists, and the compound shown in the formula 53 is carried out dechlorination reaction,
R wherein
aBe C
1-C
6Alkyl.
Preparation in accordance with the present invention, can have morpholinium compound and 3-oxo-3-(pyrimidine-4-yl) propionic ester that optically active 2-aryl replaces with higher productive rate preparation by industrial advantageous method, shown in 2-the aryl morpholinium compound and 3-oxo-3-(pyrimidine-4-yl) propionic ester that replace synthetic as being used for such as 2-(2-aryl morpholine-4-yl)-1-methyl isophthalic acid H-[4,4 '] starting material of the compound of connection pyrimidyl-6-ketone and so on is important, described compound has the medicine that tau protein kinases 1 suppresses active and can be used as Alzheimer etc.
Preferred forms of the present invention
Below with the present invention will be described in detail.
In this manual, aryl is that carbonatoms is 6 to 10 aryl, for example can enumerate phenyl, naphthyl etc.
As heteroaryl, for example can enumerate furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl etc.
Halogen is chlorine, bromine, iodine or fluorine.
C
1-C
6Alkyl is that carbonatoms is 1 to 6 straight or branched alkyl, for example can enumerate methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, the tertiary butyl, amyl group, hexyl etc.
C
1-C
6Haloalkyl for replaced by halogen, carbonatoms is 1 to 6 straight or branched alkyl, for example can enumerate chloromethyl, 1-chloroethyl, 2-chloroethyl, 1-chloropropyl, brooethyl, 1-bromotrifluoromethane, 1-bromopropyl, 1-chlorobutyl etc.
The C of aralkyl for being replaced by aryl
1-C
4Alkyl for example can be enumerated benzyl, 2-styroyl, 1-styroyl, 3-hydrocinnamyl etc.
C
2-C
6Thiazolinyl is that carbonatoms is 2 to 6 straight or branched thiazolinyl, for example can enumerate vinyl, allyl group (2-propenyl), crotyl etc.
In addition, above-mentioned aryl, heteroaryl and aralkyl can randomly have 1 to 5 substituting group on its ring, and described substituting group is selected from: halogen (chlorine, bromine, iodine, fluorine), C
1-C
6Alkyl (for example carbonatoms is 1 to 6 alkyl, as methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, the tertiary butyl etc.), C
1-C
6Alkoxyl group (for example carbonatoms is 1 to 6 alkoxyl group, as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, sec-butoxy, tert.-butoxy etc.), hydroxyl, nitro, amino, cyano group, aminoalkoxy (alkoxyl group that is replaced by primary amine, secondary amine or cyclammonium), the aralkoxy (C that is replaced by aryl for example
1-C
6Alkoxyl group is as benzyloxy, 2-phenyl ethoxy, 1-phenyl ethoxy etc.), C
1-C
6Alkylsulfonyloxy (for example carbonatoms is 1 to 6 alkylsulfonyloxy, as mesyloxy, ethanesulfonyloxy group etc.), aryl-sulfonyl oxygen (for example carbonatoms is 6 to 10 aryl-sulfonyl oxygen, as phenylsulfonyloxy, naphthalene sulfonyl oxygen base etc.) and C
1-C
6The aryl-sulfonyl oxygen that alkyl replaces is (for example by C
1-C
6The aryl-sulfonyl oxygen that alkyl replaces is as tosyloxy etc.).
Substituent C as aryl, heteroaryl and aralkyl
1-C
6Alkyl and C
1-C
6Alkoxyl group can randomly have 1 to 3 substituting group, and this substituting group is selected from: halogen (chlorine, bromine, iodine, fluorine), hydroxyl, nitro, amino and cyano group.
In this manual, salt comprises the salt of mineral acid (hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid etc.) or the salt of organic acid (acetic acid, propionic acid, succsinic acid, oxyacetic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, toxilic acid, fumaric acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid, camphorsulfonic acid, xitix etc.).
In the present invention, having the morpholinium compound that optically active 2-aryl replaces can obtain through having optically active 2-ethanolamine compound.At first, the preparation to the 2-ethanolamine compound describes.
Can prepare according to following scheme 1 (S type) or scheme 2 (R type) and have optically active 2-ethanolamine compound.
Scheme 1
Scheme 2
Wherein the symbol shown in each scheme as hereinbefore defined.
Below scheme 1 is described.
In step 1, under the condition that (S)-2-methyl-CBS- azoles borine exists, by the compound shown in the formula 1 and borine or its complex compound are reacted, thereby obtain the compound shown in the formula 2 in solvent.
As borine and complex compound thereof, for example can enumerate: borine-ammonia complex, borine-TERTIARY BUTYL AMINE complex compound, borine-N, N-diethylbenzene amine complex, borine-N, N-diisopropylethylamine complex compound, borine-dimethylamine complex compound, borine-dimethyl sulphide ether complexes, borine-diphenyl phosphine complex compound, borine-isoamyl sulfide complex compound, borine-4-methylmorpholine complex compound, borine-morpholine complex compound, borine-pyrimidine complex compound, borine-tetrahydrofuran complex, borine-triethylamine complex compound, borine-Trimethylamine 99 complex compound, borine-triphenyl phosphine complex compound, borine-tributylphosphine complex compound, borine 4-ethyl morpholine complex compound, borine-1,4-oxathiane complex compound, borine-di-t-butyl phosphine complex compound, borine-dicyclohexylphosphontetrafluoroborate complex compound, borine-di-t-butyl chloro phosphine complex compound, borine-Phenylphosphine complex compound, borine-methylphosphine complex compound, borine-tert-butyl-phenyl phosphine complex compound, adjacent benzene dioxy borine etc.
Compound shown in the formula 1 with respect to 1 mole, the used borine and the amount of complex compound thereof are generally 0.1 mole to 100 moles, are preferably 1 mole to 2 moles.
Compound shown in the formula 1 with respect to 1 mole, the amount of used (S)-2-methyl-CBS- azoles borine is generally 0.01 mole to 10 moles, is preferably 0.05 mole to 1 mole.
As solvent, for example can enumerate: tetrahydrofuran (THF), toluene, methylene dichloride, diethyl ether and composition thereof etc.
Described reactions steps-80 ℃ to 100 ℃, preferably under-30 ℃ to 0 ℃, carried out 0.1 hour to 10 hours.
In step 2, by compound and the alkali shown in the formula 2 is reacted, thereby obtain the compound shown in the formula 3 in solvent.
As alkali, for example can enumerate: lithium hydroxide, sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide, sodium hydride, triethylamine, 1,8-diazabicyclo [5,4,0] 11 carbon-7-alkene, n-Butyl Lithium etc.
Compound shown in the formula 2 with respect to 1 mole, the amount of used alkali are generally 1 mole to 10 moles, are preferably 1 mole to 3 moles.
As solvent, for example can enumerate: methyl alcohol, ethanol, Virahol, the trimethyl carbinol, hexanol, chloroform, methylene dichloride, methyl-sulphoxide, N, dinethylformamide, acetonitrile, water, tetrahydrofuran (THF), diethyl ether, 1,4-two alkane, acetone, N-N-methyl-2-2-pyrrolidone N-, pentane and mixed solvent thereof etc.
Described reactions steps was carried out under 0 ℃ to 100 ℃ 0.1 hour to 10 hours.
In step 3, by the amine shown in compound shown in the formula 3 and the formula 4 is reacted, thereby obtain the compound shown in the formula 5.
With respect to the compound shown in 1 mole of formula 3, the amount of the amine shown in the used formula 4 is generally 1 mole to 10 moles, is preferably 1 mole to 5 moles.
Shown in reactions steps under 50 ℃ to 150 ℃, carried out 0.1 hour to 50 hours.
By these steps, can make 2-ethanolamine compound (S type), it is the represented compound of formula 5.
Can come embodiment 2 by the step similar to scheme 1, difference is to use in step 1 (R)-2-methyl-CBS- azoles borine to replace (S)-2-methyl-CBS- azoles borine, thereby can make 2-ethanolamine compound (R type), it is the represented compound of formula 25.
Can use the above-mentioned optically active 2-ethanolamine compound (compound shown in compound shown in the formula 5 or the formula 25) that has that makes to prepare morpholinium compound according to following scheme 3 (S type) or scheme 4 (R type) with optically active 2-aryl replacement.
Scheme 3
Scheme 4
Wherein the symbol shown in each scheme as hereinbefore defined.
Below scheme 3 is described.
In step 1, by the compound shown in the formula 5 and activatory Mono Chloro Acetic Acid or bromoacetic acid are reacted, thereby obtain the compound shown in the formula 6 in solvent.
As activatory Mono Chloro Acetic Acid or bromoacetic acid, for example can enumerate: acid anhydrides (for example sym-dichloroacetic anhydride, bromoacetic acid acid anhydride etc.); Acyl halide (for example chloroacetyl chloride, chloro-acetyl bromide, bromoacetyl chloride, bromoacetyl bromide etc.); With sulfonic acid (as methylsulfonic acid, toluenesulphonic acids etc.) blended acid anhydrides; With chloro-formic ester (for example isobutyl chlorocarbonate etc.) blended acid anhydrides; Activatory ester (for example Mono Chloro Acetic Acid 4-nitro phenyl ester, bromoacetic acid 4-nitro phenyl ester, benzotriazole-1-base chloracetate (benzotriazol-1-yl chloroacetate), benzotriazole-1-base bromacetate, 3,5-dioxo-4-aza-tricycle [5.2.1.0
2,6] last of the ten Heavenly stems-8-alkene-4-base chloracetate (3,5-dioxo-4-azatricyclo[5.2.1.0
2,6] dec-8-en-4-yl chloroacetate), 3,5-dioxo-4-aza-tricycle [5.2.1.0
2,6] last of the ten Heavenly stems-8-alkene-4-base bromacetate, 1,3-dioxo-1,3-xylylenimine-2-base chloracetate (1,3-dioxo-1,3-dihydroisoindol-2-ylchloroacetate), 1,3-dioxo-1,3-xylylenimine-2-base bromacetate, 2,5-dioxo tetramethyleneimine-1-base chloracetate (2,5-dioxopyrrolidin-1-yl chloroacetate), 2,5-dioxo tetramethyleneimine-1-base bromacetate, [1,2,3] triazolo [4,5-b] pyridin-3-yl chloracetate ([1,2,3] triazolo[4,5-b] pyridine-3-yl chloroacetate), [1,2,3] triazolo [4,5-b] pyridin-3-yl bromacetate etc.); Activator through being used for carboxylic acid (1H-benzotriazole-1-base oxygen base tripyrrole alkyl phosphorus hexafluorophosphate for example; 1H-benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate; O-(benzotriazole-1-yl)-N; N; N '; N '-tetramethyl-urea hexafluorophosphate; O-(benzotriazole-1-yl)-N; N; N '; N '-tetramethyl-urea a tetrafluoro borate; two (2-oxo-3- oxazolidinyl) phospho acid chlorine; 2-bromo-1-ethylpyridine a tetrafluoro borate; N-carbobenzoxy-(Cbz) maloyl imines; 2-bromobenzyl succinimdyl carbonate (2-bromobenzyl succinimidyl carbonate); carbonic acid two-2-pyridine ester; 2; 2 '-carbonyl two (3; 5-dioxo-4-methyl isophthalic acid; 2; 4- diazole alkane); 1; 1 '-carbonyl is two-the 1H-imidazoles; 2-benzyl chloride base-N-succinimidyl carbonate (N-(2-chlorobenzyloxycarbonyloxy) succinimide); chlorination (4R; 5R)-2-chloro-1; 3-dimethyl-4; 5-phenylbenzene-1-tetrahydroglyoxaline ; chlorination (4S; 5S)-2-chloro-1; 3-dimethyl-4; 5-phenylbenzene-1-tetrahydroglyoxaline ; chlorination 2-chloro-1; 3-methylimidazole quinoline thing; 2-chloro-1; 3-methylimidazole quinoline hexafluorophosphate; 2-chloro-3-ethyl benzoxazol a tetrafluoro borate; iodate 2-chloro-1-picoline ; 2-chloro-1-picoline p-methyl benzenesulfonic acid salt; 1-(chloro-1-pyrrolidyl methylene radical) tetramethyleneimine hexafluorophosphate; 1-(chloro-1-pyrrolidyl methylene radical) tetramethyleneimine a tetrafluoro borate; cyano group methylene tri normal-butyl phosphorane; 1-cyclohexyl-3-(2-morpholine ethyl) carbodiimide p-methyl benzenesulfonic acid salt; N; N '-dicyclohexyl carbodiimide; (2; 3-dihydro-2-sulfo--3-benzoxazol base) phosphonic acid diphenyl ester; N; N '-DIC; two (N-succinimide) carbonic ether; 1-ethoxycarbonyl-2-oxyethyl group-1; the 2-dihydroquinoline; 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride; 2-fluoro-1-picoline p-methyl benzenesulfonic acid salt; 1-(4-oil of mirbane alkylsulfonyl)-1H-1; 2; the 4-triazole; 2-(5-norbornylene-2; 3-di carbonyl imide base)-1; 1; 3; 3-tetramethyl-urea a tetrafluoro borate; mu-oxo-two [three (dimethylamino) phosphorus ] two (a tetrafluoro borates); N-(1; 2; 2,2-tetrachloro ethoxycarbonyl-oxygen base) succinimide; 1-(to the Methyl benzenesulfonyl base) imidazoles; the trichoroacetic acid(TCA) pentachlorophenyl ester; trifluoroacetic acid 4-nitro phenyl ester etc.) activatory Mono Chloro Acetic Acid or bromoacetic acid.
Compound shown in the formula 5 with respect to 1 mole, the used activatory Mono Chloro Acetic Acid or the amount of bromoacetic acid are generally 1 mole to 10 moles, are preferably 1 mole to 2 moles.
As solvent, for example can enumerate: methylene dichloride, 1,2-ethylene dichloride, 1,1,1-trichloroethane, chloroform, tetracol phenixin, 1,2-dichlorobenzene, ethyl acetate, butylacetate, isopropyl acetate, acetonitrile, propionitrile, tetrahydrofuran (THF), 1,4-two alkane, diethyl ether, 1,2-glycol dimethyl ether, isopropyl ether, benzene,toluene,xylene, water, ethanol, methyl alcohol, Virahol, its mixed solvent etc.
Described reactions steps was carried out under-10 ℃ to 60 ℃ 0.1 hour to 10 hours.
In step 2, by compound and the alkali shown in the formula 6 is reacted, thereby obtain the compound shown in the formula 7.
As alkali, for example can list: lithium hydroxide, sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide, sodium hydride etc.
Compound shown in the formula 6 with respect to 1 mole, the amount of used alkali are generally 1 mole to 10 moles, are preferably 1 mole to 3 moles.
Described step can be carried out in solvent, as described solvent, for example can enumerate: Virahol, toluene, its mixed solvent etc.
Described reactions steps was carried out under 0 ℃ to 100 ℃ 0.1 hour to 10 hours.
After step 1 reaction finishes, can be in the reaction that need not to carry out then to carry out under the condition of other operation step 2.
In step 3, by compound and the reductive agent shown in the formula 7 reacted, thereby obtain the compound shown in the formula 8 in solvent.
As reductive agent, for example can enumerate: lithium aluminium hydride, two (2-methoxy ethoxy) sodium alanate (sodium bis (2-methoxyethoxy) aluminum hydride), lithium borohydride, sodium borohydride, POTASSIUM BOROHYDRIDE, borine and complex compound thereof are (for example, borine-ammonia complex, borine-TERTIARY BUTYL AMINE complex compound, borine-N, N-diethylbenzene amine complex, borine-N, N-diisopropylethylamine complex compound, borine-dimethylamine complex compound, borine-dimethyl sulphide ether complexes, borine-diphenyl phosphine complex compound, borine-isoamyl sulfide complex compound, borine-4-methylmorpholine complex compound, borine-morpholine complex compound, borine-pyridine complex, borine-tetrahydrofuran complex, borine-triethylamine complex compound, borine-Trimethylamine 99 complex compound, borine-triphenyl phosphine complex compound, borine-tributylphosphine complex compound, borine-4-ethyl morpholine complex compound, borine-1,4-oxathiane complex compound, borine-di-t-butyl phosphine complex compound, borine-dicyclohexylphosphontetrafluoroborate complex compound, borine-di-t-butyl chlorine phosphine complex compound, borine-Phenylphosphine complex compound, borine-methylphosphine complex compound, borine-tert-butyl-phenyl phosphine complex compound) etc.These reductive agents can together use with the inorganic reagent such as iodine, sulfuric acid, lithium halide, etherate of trifluoroboron, trimethylchlorosilane.
Compound shown in the formula 7 with respect to 1 mole, the amount of used reductive agent are generally 1 mole to 10 moles, are preferably 1 mole to 3 moles.
As solvent, for example can enumerate: ether solvent (for example tetrahydrofuran (THF), methyltetrahydrofuran, dimethoxy ethane, diethylene glycol dimethyl ether etc.), varsol (for example toluene, dimethylbenzene etc.) and mixed solvent thereof.
Described reactions steps was carried out under 0 ℃ to 120 ℃ 0.5 hour to 10 hours.
In step 4, by compound and the chloro-formic ester shown in the formula 8 reacted, thereby obtain the compound shown in the formula 9.
As chloro-formic ester, for example can enumerate: chloroformic acid C
1-C
6Alkanol ester (for example methyl-chloroformate, Vinyl chloroformate etc.), chloroformic acid halo C
1-C
6Alkanol ester (for example chloroformic acid 1-chloroethene ester etc.), chloroformic acid aryl ester (wherein aryl moiety can randomly have substituting group), benzyl chloroformate (wherein benzyl moiety can randomly have substituting group) etc.
Compound shown in the formula 8 with respect to 1 mole, the amount of used chloro-formic ester are generally 1 mole to 10 moles, are preferably 1 mole to 5 moles.
Described step can be carried out in solvent, as described solvent, for example can enumerate: ethylene dichloride, methylene dichloride, benzene,toluene,xylene, chloroform, chlorobenzene, ethyl acetate, acetone, its mixed solvent etc.In addition, described step can be carried out under the condition that the additive such as sodium iodide, potassiumiodide, lithium iodide exists.
Described reactions steps was carried out under 0 ℃ to 180 ℃ 0.5 hour to 100 hours.
In step 5, by the compound shown in the formula 9 is hydrolyzed, thereby obtain the compound shown in the formula 10.
Described hydrolysis is to use acid or alkali to carry out.As acid, for example can enumerate hydrochloric acid etc.As alkali, for example can enumerate sodium hydroxide, potassium hydroxide etc.
Compound shown in the formula 9 with respect to 1 mole, the used acid or the amount of alkali are generally 1 mole to 50 moles, are preferably 1 mole to 10 moles.
Described step can be carried out in solvent, as described solvent, for example can enumerate methyl alcohol, ethanol, its mixed solvent etc.
Described reactions steps was carried out under 20 ℃ to 150 ℃ 0.5 hour to 50 hours.
Work as R
2During for the 1-chloroethyl, can carry out described hydrolysis in 0.1 hour to 10 hours in the alcohol such as methyl alcohol, ethanol under 50 ℃ to 100 ℃ by the compound shown in the formula 9 is heated.
By described these steps, can make the morpholinium compound (S type) that the 2-aryl replaces, it is the represented compound of formula 10.
Can come embodiment 4 by the step similar to scheme 3, difference is that the compound shown in the use formula 25 in step 1 (R type) comes the compound shown in the replacement formula 5 (S type), thereby can make the morpholinium compound (R type) that the 2-aryl replaces, it is the represented compound of formula 30.
In addition, can also prepare morpholinium compound according to following scheme 5 (S type) or scheme 6 (R type) with optically active 2-aryl replacement.
Scheme 5
Scheme 6
Wherein the symbol shown in each scheme as hereinbefore defined.
Below scheme 5 is described.
In described step, under the condition that exists at transition-metal catalyst, compound and the hydrogen shown in the formula 13 is reacted, thereby make the morpholinium compound shown in the formula 10.
As transition-metal catalyst, for example can enumerate: palladium, nickel, platinum, rhodium or ruthenium.As representational example, for example can enumerate: palladium carbon, palladous oxide, palladium black, palladium hydroxide, palladium-silica-alumina, palladium aluminum oxide, Raney's nickel, platinum carbon, platinum black, platinum oxide, platinum oxidation aluminium, rhodium carbon, rhodium aluminum oxide, rhodium oxide, ruthenium oxide, ruthenium carbon, ruthenium black, ruthenium aluminum oxide etc.
Compound shown in the formula 13 with respect to 1 mole, the amount of used transition-metal catalyst are generally 0.001 mole to 10 moles, are preferably 0.01 mole to 0.3 mole.
As described solvent, for example can enumerate: alcoholic solvent (for example methyl alcohol, ethanol, Virahol, propyl alcohol, butanols, the trimethyl carbinol), ether solvent (for example THF, two alkane, 1,2-glycol dimethyl ether, t-butyl methyl ether), esters solvent (for example ethyl acetate, propyl acetate, methyl acetate, butylacetate, isopropyl acetate), water, its mixed solvent etc.
Described reactions steps was carried out under 0 ℃ to 100 ℃ 0.5 hour to 100 hours.
By described step, can make the morpholinium compound (S type) that the 2-aryl replaces, it is the compound shown in the formula 10.
Can come embodiment 6 by the step similar to scheme 5, difference has been to use the compound shown in the formula 33 (R type) to come the compound shown in the replacement formula 13 (S type), thereby can make the morpholinium compound (R type) that the 2-aryl replaces, it is the represented compound of formula 30.
In addition, can be according to the step of having carried out again through preparing hydrochloride by the represented compound of formula 10 and formula 30 with hydrochloric acid reaction.
Compound (it is for being obtained by the compound shown in scheme 3 Chinese styles 5) shown in compound shown in the formula 5 (it has optically active 2-ethanolamine compound (S type) for prepared in the scheme 1) and the formula 6 is novel cpd (these compounds can be expressed as jointly by the represented compound of following formula 11):
Wherein shown each symbol as hereinbefore defined.
In above-claimed cpd, preferred such compound: in this compound, R is for having 1 to 3 substituent phenyl, and wherein said substituting group is selected from halogen, C
1-C
6Alkyl, the C that is substituted
1-C
6Alkyl, C
1-C
6Alkoxyl group, the C that is substituted
1-C
6Alkoxyl group, nitro aralkoxy, C
1-C
6Alkylsulfonyloxy, aryl-sulfonyl oxygen and C
1-C
6The aryl-sulfonyl oxygen that alkyl replaces; More preferably such compound: in this compound, R is for having 1 to 3 substituent phenyl, and wherein said substituting group is selected from fluorine, chlorine, bromine, nitro, benzyloxy, mesyloxy, phenylsulfonyloxy and tosyloxy.Particularly, can mention following compounds:
(1S)-1-(4-fluorophenyl)-2-(benzyl amino) ethanol,
(1S)-1-(4-fluorophenyl)-2-(4-methoxybenzyl amino) ethanol,
(1S)-1-(4-fluorophenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1S)-1-(4-fluorophenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1S)-1-(4-fluorophenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1S)-1-(4-fluorophenyl)-2-(2-benzene ethylamino) ethanol,
(1S)-1-(4-fluorophenyl)-2-(methylamino-) ethanol,
(1S)-1-(4-fluorophenyl)-2-(ethylamino) ethanol,
(1S)-1-(4-fluorophenyl)-2-(uncle's fourth amino) ethanol,
(1S)-1-(4-fluorophenyl)-2-(allyl amino) ethanol,
(1S)-1-(3-fluorophenyl)-2-(benzyl amino) ethanol,
(1S)-1-(3-fluorophenyl)-2-(4-methoxybenzyl amino) ethanol,
(1S)-1-(3-fluorophenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1S)-1-(3-fluorophenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1S)-1-(3-fluorophenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1S)-1-(3-fluorophenyl)-2-(2-benzene ethylamino) ethanol,
(1S)-1-(3-fluorophenyl)-2-(methylamino-) ethanol,
(1S)-1-(3-fluorophenyl)-2-(ethylamino) ethanol,
(1S)-1-(3-fluorophenyl)-2-(uncle's fourth amino) ethanol,
(1S)-1-(3-fluorophenyl)-2-(allyl amino) ethanol,
(1S)-1-(4-chloro-phenyl-)-2-(benzyl amino) ethanol,
(1S)-1-(4-chloro-phenyl-)-2-(4-methoxybenzyl amino) ethanol,
(1S)-1-(4-chloro-phenyl-)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1S)-1-(4-chloro-phenyl-)-2-((1R)-1-benzene ethylamino) ethanol,
(1S)-1-(4-chloro-phenyl-)-2-((1S)-1-benzene ethylamino) ethanol,
(1S)-1-(4-chloro-phenyl-)-2-(2-benzene ethylamino) ethanol,
(1S)-1-(4-chloro-phenyl-)-2-(methylamino-) ethanol,
(1S)-1-(4-chloro-phenyl-)-2-(ethylamino) ethanol,
(1S)-1-(4-chloro-phenyl-)-2-(uncle's fourth amino) ethanol,
(1S)-1-(4-chloro-phenyl-)-2-(allyl amino) ethanol,
(1S)-1-(4-bromophenyl)-2-(benzyl amino) ethanol,
(1S)-1-(4-bromophenyl)-2-(4-methoxybenzyl amino) ethanol,
(1S)-1-(4-bromophenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1S)-1-(4-bromophenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1S)-1-(4-bromophenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1S)-1-(4-bromophenyl)-2-(2-benzene ethylamino) ethanol,
(1S)-1-(4-bromophenyl)-2-(methylamino-) ethanol,
(1S)-1-(4-bromophenyl)-2-(ethylamino) ethanol,
(1S)-1-(4-bromophenyl)-2-(uncle's fourth amino) ethanol,
(1S)-1-(4-bromophenyl)-2-(allyl amino) ethanol,
(1S)-1-(4-nitrophenyl)-2-(benzyl amino) ethanol,
(1S)-1-(4-nitrophenyl)-2-(4-methoxybenzyl amino) ethanol,
(1S)-1-(4-nitrophenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1S)-1-(4-nitrophenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1S)-1-(4-nitrophenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1S)-1-(4-nitrophenyl)-2-(2-benzene ethylamino) ethanol,
(1S)-1-(4-nitrophenyl)-2-(methylamino-) ethanol,
(1S)-1-(4-nitrophenyl)-2-(ethylamino) ethanol,
(1S)-1-(4-nitrophenyl)-2-(uncle's fourth amino) ethanol,
(1S)-1-(4-nitrophenyl)-2-(allyl amino) ethanol,
(1S)-1-(4-fluorophenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-fluorophenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1S)-1-(4-fluorophenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-fluorophenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-fluorophenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol,
(1S)-1-(4-fluorophenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol,
(1S)-1-(4-bromophenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-bromophenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1S)-1-(4-bromophenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-bromophenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-bromophenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol,
(1S)-1-(4-bromophenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol,
(1S)-1-(4-nitrophenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-nitrophenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1S)-1-(4-nitrophenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-nitrophenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-nitrophenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol,
(1S)-1-(4-nitrophenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(benzyl amino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(4-methoxybenzyl amino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(2-benzene ethylamino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(methylamino-) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(ethylamino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(uncle's fourth amino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(allyl amino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(benzyl amino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(4-methoxybenzyl amino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(2-benzene ethylamino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(methylamino-) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(ethylamino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(uncle's fourth amino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(allyl amino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(benzyl amino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(4-methoxybenzyl amino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(2-benzene ethylamino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(methylamino-) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(ethylamino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(uncle's fourth amino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(allyl amino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(benzyl amino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(4-methoxybenzyl amino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(2-benzene ethylamino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(methylamino-) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(ethylamino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(uncle's fourth amino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(allyl amino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol and
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol.
In addition, the compound (it is for being obtained by the compound shown in scheme 4 Chinese styles 25) shown in compound shown in the formula 25 (it has optically active 2-ethanolamine compound (R type) for prepared in the scheme 2) and the formula 26 is novel cpd (these compounds can be expressed as jointly by the represented compound of following formula 11):
Wherein shown each symbol as hereinbefore defined.
In above-claimed cpd, preferred such compound: in this compound, R is for having 1 to 3 substituent phenyl, and wherein said substituting group is selected from halogen, C
1-C
6Alkyl, the C that is substituted
1-C
6Alkyl, C
1-C
6Alkoxyl group, the C that is substituted
1-C
6Alkoxyl group, nitro aralkoxy, C
1-C
6Alkylsulfonyloxy, aryl-sulfonyl oxygen and C
1-C
6The aryl-sulfonyl oxygen that alkyl replaces; More preferably such compound: in this compound, R is for having 1 to 3 substituent phenyl, and wherein said substituting group is selected from fluorine, chlorine, bromine, nitro, benzyloxy, mesyloxy, phenylsulfonyloxy and tosyloxy.Particularly, can mention following compounds:
(1R)-1-(4-fluorophenyl)-2-(benzyl amino) ethanol,
(1R)-1-(4-fluorophenyl)-2-(4-methoxybenzyl amino) ethanol,
(1R)-1-(4-fluorophenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1R)-1-(4-fluorophenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1R)-1-(4-fluorophenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1R)-1-(4-fluorophenyl)-2-(2-benzene ethylamino) ethanol,
(1R)-1-(4-fluorophenyl)-2-(methylamino-) ethanol,
(1R)-1-(4-fluorophenyl)-2-(ethylamino) ethanol,
(1R)-1-(4-fluorophenyl)-2-(uncle's fourth amino) ethanol,
(1R)-1-(4-fluorophenyl)-2-(allyl amino) ethanol,
(1R)-1-(3-fluorophenyl)-2-(benzyl amino) ethanol,
(1R)-1-(3-fluorophenyl)-2-(4-methoxybenzyl amino) ethanol,
(1R)-1-(3-fluorophenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1R)-1-(3-fluorophenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1R)-1-(3-fluorophenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1R)-1-(3-fluorophenyl)-2-(2-benzene ethylamino) ethanol,
(1R)-1-(3-fluorophenyl)-2-(methylamino-) ethanol,
(1R)-1-(3-fluorophenyl)-2-(ethylamino) ethanol,
(1R)-1-(3-fluorophenyl)-2-(uncle's fourth amino) ethanol,
(1R)-1-(3-fluorophenyl)-2-(allyl amino) ethanol,
(1R)-1-(4-chloro-phenyl-)-2-(benzyl amino) ethanol,
(1R)-1-(4-chloro-phenyl-)-2-(4-methoxybenzyl amino) ethanol,
(1R)-1-(4-chloro-phenyl-)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1R)-1-(4-chloro-phenyl-)-2-((1R)-1-benzene ethylamino) ethanol,
(1R)-1-(4-chloro-phenyl-)-2-((1S)-1-benzene ethylamino) ethanol,
(1R)-1-(4-chloro-phenyl-)-2-(2-benzene ethylamino) ethanol,
(1R)-1-(4-chloro-phenyl-)-2-(methylamino-) ethanol,
(1R)-1-(4-chloro-phenyl-)-2-(ethylamino) ethanol,
(1R)-1-(4-chloro-phenyl-)-2-(uncle's fourth amino) ethanol,
(1R)-1-(4-chloro-phenyl-)-2-(allyl amino) ethanol,
(1R)-1-(4-bromophenyl)-2-(benzyl amino) ethanol,
(1R)-1-(4-bromophenyl)-2-(4-methoxybenzyl amino) ethanol,
(1R)-1-(4-bromophenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1R)-1-(4-bromophenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1R)-1-(4-bromophenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1R)-1-(4-bromophenyl)-2-(2-benzene ethylamino) ethanol,
(1R)-1-(4-bromophenyl)-2-(methylamino-) ethanol,
(1R)-1-(4-bromophenyl)-2-(ethylamino) ethanol,
(1R)-1-(4-bromophenyl)-2-(uncle's fourth amino) ethanol,
(1R)-1-(4-bromophenyl)-2-(allyl amino) ethanol,
(1R)-1-(4-nitrophenyl)-2-(benzyl amino) ethanol,
(1R)-1-(4-nitrophenyl)-2-(4-methoxybenzyl amino) ethanol,
(1R)-1-(4-nitrophenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1R)-1-(4-nitrophenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1R)-1-(4-nitrophenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1R)-1-(4-nitrophenyl)-2-(2-benzene ethylamino) ethanol,
(1R)-1-(4-nitrophenyl)-2-(methylamino-) ethanol,
(1R)-1-(4-nitrophenyl)-2-(ethylamino) ethanol,
(1R)-1-(4-nitrophenyl)-2-(uncle's fourth amino) ethanol,
(1R)-1-(4-nitrophenyl)-2-(allyl amino) ethanol,
(1R)-1-(4-fluorophenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-fluorophenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1R)-1-(4-fluorophenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-fluorophenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-fluorophenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol,
(1R)-1-(4-fluorophenyl)-2-(N-(1 S)-1-styroyl-N-acetobrom amino) ethanol,
(1R)-1-(4-bromophenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-bromophenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1R)-1-(4-bromophenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-bromophenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-bromophenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol,
(1R)-1-(4-bromophenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol,
(1R)-1-(4-nitrophenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-nitrophenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1R)-1-(4-nitrophenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-nitrophenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-nitrophenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol,
(1R)-1-(4-nitrophenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(benzyl amino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(4-methoxybenzyl amino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(2-benzene ethylamino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(methylamino-) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(ethylamino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(uncle's fourth amino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(allyl amino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(benzyl amino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(4-methoxybenzyl amino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(2-benzene ethylamino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(methylamino-) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(ethylamino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(uncle's fourth amino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(allyl amino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(benzyl amino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(4-methoxybenzyl amino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(2-benzene ethylamino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(methylamino-) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(ethylamino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(uncle's fourth amino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(allyl amino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(benzyl amino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(4-methoxybenzyl amino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(2-benzene ethylamino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(methylamino-) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(ethylamino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(uncle's fourth amino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(allyl amino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol and
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol.
In addition, the compound shown in the compound shown in scheme 3 Chinese styles 7, the compound shown in the formula 8 and the formula 9 is novel cpd (these compounds can be expressed as jointly by the represented compound of following formula 12).
Wherein shown each symbol as hereinbefore defined.
In above-claimed cpd, preferred such compound: in this compound, R is for having 1 to 3 substituent phenyl, and wherein said substituting group is selected from halogen, C
1-C
6Alkyl, the C that is substituted
1-C
6Alkyl, C
1-C
6Alkoxyl group, the C that is substituted
1-C
6Alkoxyl group, nitro aralkoxy, C
1-C
6Alkylsulfonyloxy, aryl-sulfonyl oxygen and C
1-C
6The aryl-sulfonyl oxygen that alkyl replaces; More preferably such compound: in this compound, R is for having 1 to 3 substituent phenyl, and wherein said substituting group is selected from fluorine, chlorine, bromine, nitro, benzyloxy, mesyloxy, phenylsulfonyloxy and tosyloxy.Particularly, can mention following compounds:
(6S)-6-(4-fluorophenyl)-4-(benzyl) morpholine-3-ketone,
(6S)-6-(4-fluorophenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-fluorophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-fluorophenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-fluorophenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-fluorophenyl)-4-(2-styroyl) morpholine-3-ketone,
(6S)-6-(4-fluorophenyl)-4-(methyl) morpholine-3-ketone,
(6S)-6-(4-fluorophenyl)-4-(ethyl) morpholine-3-ketone,
(6S)-6-(4-fluorophenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6S)-6-(4-fluorophenyl)-4-(allyl group) morpholine-3-ketone,
(6S)-6-(4-fluorophenyl) morpholine-3-ketone,
(6S)-6-(3-fluorophenyl)-4-(benzyl) morpholine-3-ketone,
(6S)-6-(3-fluorophenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6S)-6-(3-fluorophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6S)-6-(3-fluorophenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6S)-6-(3-fluorophenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6S)-6-(3-fluorophenyl)-4-(2-styroyl) morpholine-3-ketone,
(6S)-6-(3-fluorophenyl)-4-(methyl) morpholine-3-ketone,
(6S)-6-(3-fluorophenyl)-4-(ethyl) morpholine-3-ketone,
(6S)-6-(3-fluorophenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6S)-6-(3-fluorophenyl)-4-(allyl group) morpholine-3-ketone,
(6S)-6-(3-fluorophenyl) morpholine-3-ketone,
(6S)-6-(4-chloro-phenyl-)-4-(benzyl) morpholine-3-ketone,
(6S)-6-(4-chloro-phenyl-)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-chloro-phenyl-)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-chloro-phenyl-)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-chloro-phenyl-)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-chloro-phenyl-)-4-(2-styroyl) morpholine-3-ketone,
(6S)-6-(4-chloro-phenyl-)-4-(methyl) morpholine-3-ketone,
(6S)-6-(4-chloro-phenyl-)-4-(ethyl) morpholine-3-ketone,
(6S)-6-(4-chloro-phenyl-)-4-(tertiary butyl) morpholine-3-ketone,
(6S)-6-(4-chloro-phenyl-)-4-(allyl group) morpholine-3-ketone,
(6S)-6-(4-bromophenyl)-4-(benzyl) morpholine-3-ketone,
(6S)-6-(4-bromophenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-bromophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-bromophenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-bromophenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-bromophenyl)-4-(2-styroyl) morpholine-3-ketone,
(6S)-6-(4-bromophenyl)-4-(methyl) morpholine-3-ketone,
(6S)-6-(4-bromophenyl)-4-(ethyl) morpholine-3-ketone,
(6S)-6-(4-bromophenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6S)-6-(4-bromophenyl)-4-(allyl group) morpholine-3-ketone,
(6S)-6-(4-nitrophenyl)-4-(benzyl) morpholine-3-ketone,
(6S)-6-(4-nitrophenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-nitrophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-nitrophenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-nitrophenyl)-4-((1 S)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-nitrophenyl)-4-(2-styroyl) morpholine-3-ketone,
(6S)-6-(4-nitrophenyl)-4-(methyl) morpholine-3-ketone,
(6S)-6-(4-nitrophenyl)-4-(ethyl) morpholine-3-ketone,
(6S)-6-(4-nitrophenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6S)-6-(4-nitrophenyl)-4-(allyl group) morpholine-3-ketone,
(2S)-2-(4-fluorophenyl)-4-(benzyl) morpholine,
(2S)-2-(4-fluorophenyl)-4-(4-methoxy-benzyl) morpholine,
(2S)-2-(4-fluorophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2S)-2-(4-fluorophenyl)-4-((1R)-1-styroyl) morpholine,
(2S)-2-(4-fluorophenyl)-4-((1 S)-1-styroyl) morpholine,
(2S)-2-(4-fluorophenyl)-4-(2-styroyl) morpholine,
(2S)-2-(4-fluorophenyl)-4-(methyl) morpholine,
(2S)-2-(4-fluorophenyl)-4-(ethyl) morpholine,
(2S)-2-(4-fluorophenyl)-4-(tertiary butyl) morpholine,
(2S)-2-(4-fluorophenyl)-4-(allyl group) morpholine,
(2S)-2-(3-fluorophenyl)-4-(benzyl) morpholine,
(2S)-2-(3-fluorophenyl)-4-(4-methoxy-benzyl) morpholine,
(2S)-2-(3-fluorophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2S)-2-(3-fluorophenyl)-4-((1R)-1-styroyl) morpholine,
(2S)-2-(3-fluorophenyl)-4-((1S)-1-styroyl) morpholine,
(2S)-2-(3-fluorophenyl)-4-(2-styroyl) morpholine,
(2S)-2-(3-fluorophenyl)-4-(methyl) morpholine,
(2S)-2-(3-fluorophenyl)-4-(ethyl) morpholine,
(2S)-2-(3-fluorophenyl)-4-(tertiary butyl) morpholine,
(2S)-2-(3-fluorophenyl)-4-(allyl group) morpholine,
(2S)-2-(3-fluorophenyl) morpholine,
(2S)-2-(4-chloro-phenyl-)-4-(benzyl) morpholine,
(2S)-2-(4-chloro-phenyl-)-4-(4-methoxy-benzyl) morpholine,
(2S)-2-(4-chloro-phenyl-)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2S)-2-(4-chloro-phenyl-)-4-((1R)-1-styroyl) morpholine,
(2S)-2-(4-chloro-phenyl-)-4-((1S)-1-styroyl) morpholine,
(2S)-2-(4-chloro-phenyl-)-4-(2-styroyl) morpholine,
(2S)-2-(4-chloro-phenyl-)-4-(methyl) morpholine,
(2S)-2-(4-chloro-phenyl-)-4-(ethyl) morpholine,
(2S)-2-(4-chloro-phenyl-)-4-(tertiary butyl) morpholine,
(2S)-2-(4-chloro-phenyl-)-4-(allyl group) morpholine,
(2S)-2-(4-bromophenyl)-4-(benzyl) morpholine,
(2S)-2-(4-bromophenyl)-4-(4-methoxy-benzyl) morpholine,
(2S)-2-(4-bromophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2S)-2-(4-bromophenyl)-4-((1R)-1-styroyl) morpholine,
(2S)-2-(4-bromophenyl)-4-((1S)-1-styroyl) morpholine,
(2S)-2-(4-bromophenyl)-4-(2-styroyl) morpholine,
(2S)-2-(4-bromophenyl)-4-(methyl) morpholine,
(2S)-2-(4-bromophenyl)-4-(ethyl) morpholine,
(2S)-2-(4-bromophenyl)-4-(tertiary butyl) morpholine,
(2S)-2-(4-bromophenyl)-4-(allyl group) morpholine,
(2S)-2-(4-bromophenyl) morpholine,
(2S)-2-(4-nitrophenyl)-4-(benzyl) morpholine,
(2S)-2-(4-nitrophenyl)-4-(4-methoxy-benzyl) morpholine,
(2S)-2-(4-nitrophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2S)-2-(4-nitrophenyl)-4-((1R)-1-styroyl) morpholine,
(2S)-2-(4-nitrophenyl)-4-((1S)-1-styroyl) morpholine,
(2S)-2-(4-nitrophenyl)-4-(2-styroyl) morpholine,
(2S)-2-(4-nitrophenyl)-4-(methyl) morpholine,
(2S)-2-(4-nitrophenyl)-4-(ethyl) morpholine,
(2S)-2-(4-nitrophenyl)-4-(tertiary butyl) morpholine,
(2S)-2-(4-nitrophenyl)-4-(allyl group) morpholine,
(2S)-2-(4-nitrophenyl) morpholine,
(2S)-2-(4-fluorophenyl) morpholine-4-carboxylate methyl ester,
(2S)-2-(4-fluorophenyl) morpholine-4-carboxylic acid, ethyl ester,
(2S)-2-(4-fluorophenyl) morpholine-4-carboxylic acid phenyl ester,
(2S)-2-(4-fluorophenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(2S)-2-(3-fluorophenyl) morpholine-4-carboxylate methyl ester,
(2S)-2-(3-fluorophenyl) morpholine-4-carboxylic acid, ethyl ester,
(2S)-2-(3-fluorophenyl) morpholine-4-carboxylic acid phenyl ester,
(2S)-2-(3-fluorophenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(2S)-2-(4-chloro-phenyl-) morpholine-4-carboxylate methyl ester,
(2S)-2-(4-chloro-phenyl-) morpholine-4-carboxylic acid, ethyl ester,
(2S)-2-(4-chloro-phenyl-) morpholine-4-carboxylic acid phenyl ester,
(2S)-2-(4-chloro-phenyl-) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(2S)-2-(4-bromophenyl) morpholine-4-carboxylate methyl ester,
(2S)-2-(4-bromophenyl) morpholine-4-carboxylic acid, ethyl ester,
(2S)-2-(4-bromophenyl) morpholine-4-carboxylic acid phenyl ester,
(2S)-2-(4-bromophenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(2S)-2-(4-nitrophenyl) morpholine-4-carboxylate methyl ester,
(2S)-2-(4-nitrophenyl) morpholine-4-carboxylic acid, ethyl ester,
(2S)-2-(4-nitrophenyl) morpholine-4-carboxylic acid phenyl ester,
(2S)-2-(4-nitrophenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(2S)-2-(4-fluorophenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2S)-2-(3-fluorophenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2S)-2-(4-chloro-phenyl-) morpholine-4-carboxylic acid 1-chloroethene ester,
(2S)-2-(4-bromophenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2S)-2-(4-nitrophenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(6S)-6-(4-benzyloxy phenyl)-4-(benzyl) morpholine-3-ketone,
(6S)-6-(4-benzyloxy phenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-benzyloxy phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-benzyloxy phenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-benzyloxy phenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-benzyloxy phenyl)-4-(2-styroyl) morpholine-3-ketone,
(6S)-6-(4-benzyloxy phenyl)-4-(methyl) morpholine-3-ketone,
(6S)-6-(4-benzyloxy phenyl)-4-(ethyl) morpholine-3-ketone,
(6S)-6-(4-benzyloxy phenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6S)-6-(4-benzyloxy phenyl)-4-(allyl group) morpholine-3-ketone,
(6S)-6-(4-benzyloxy phenyl) morpholine-3-ketone,
(2S)-2-(4-benzyloxy phenyl)-4-(benzyl) morpholine,
(2S)-2-(4-benzyloxy phenyl)-4-(4-methoxy-benzyl) morpholine,
(2S)-2-(4-benzyloxy phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2S)-2-(4-benzyloxy phenyl)-4-((1R)-1-styroyl) morpholine,
(2S)-2-(4-benzyloxy phenyl)-4-((1S)-1-styroyl) morpholine,
(2S)-2-(4-benzyloxy phenyl)-4-(2-styroyl) morpholine,
(2S)-2-(4-benzyloxy phenyl)-4-(methyl) morpholine,
(2S)-2-(4-benzyloxy phenyl)-4-(ethyl) morpholine,
(2S)-2-(4-benzyloxy phenyl)-4-(tertiary butyl) morpholine,
(2S)-2-(4-benzyloxy phenyl)-4-(allyl group) morpholine,
(2S)-2-(4-benzyloxy phenyl) morpholine-4-carboxylate methyl ester,
(2S)-2-(4-benzyloxy phenyl) morpholine-4-carboxylic acid, ethyl ester,
(2S)-2-(4-benzyloxy phenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2S)-2-(4-benzyloxy phenyl) morpholine-4-carboxylic acid phenyl ester,
(2S)-2-(4-benzyloxy phenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(6S)-6-(4-mesyloxy phenyl)-4-(benzyl) morpholine-3-ketone,
(6S)-6-(4-mesyloxy phenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-mesyloxy phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-mesyloxy phenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-mesyloxy phenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-mesyloxy phenyl)-4-(2-styroyl) morpholine-3-ketone,
(6S)-6-(4-mesyloxy phenyl)-4-(methyl) morpholine-3-ketone,
(6S)-6-(4-mesyloxy phenyl)-4-(ethyl) morpholine-3-ketone,
(6S)-6-(4-mesyloxy phenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6S)-6-(4-mesyloxy phenyl)-4-(allyl group) morpholine-3-ketone,
(6S)-6-(4-mesyloxy phenyl) morpholine-3-ketone,
(2S)-2-(4-mesyloxy phenyl)-4-(benzyl) morpholine,
(2S)-2-(4-mesyloxy phenyl)-4-(4-methoxy-benzyl) morpholine,
(2S)-2-(4-mesyloxy phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2S)-2-(4-mesyloxy phenyl)-4-((1R)-1-styroyl) morpholine,
(2S)-2-(4-mesyloxy phenyl)-4-((1S)-1-styroyl) morpholine,
(2S)-2-(4-mesyloxy phenyl)-4-(2-styroyl) morpholine,
(2S)-2-(4-mesyloxy phenyl)-4-(methyl) morpholine,
(2S)-2-(4-mesyloxy phenyl)-4-(ethyl) morpholine,
(2S)-2-(4-mesyloxy phenyl)-4-(tertiary butyl) morpholine,
(2S)-2-(4-mesyloxy phenyl)-4-(allyl group) morpholine,
(2S)-2-(4-mesyloxy phenyl) morpholine-4-carboxylate methyl ester,
(2S)-2-(4-mesyloxy phenyl) morpholine-4-carboxylic acid, ethyl ester,
(2S)-2-(4-mesyloxy phenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2S)-2-(4-mesyloxy phenyl) morpholine-4-carboxylic acid phenyl ester,
(2S)-2-(4-mesyloxy phenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(6S)-6-(4-phenylsulfonyloxy phenyl)-4-(benzyl) morpholine-3-ketone,
(6S)-6-(4-phenylsulfonyloxy phenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-phenylsulfonyloxy phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-phenylsulfonyloxy phenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-phenylsulfonyloxy phenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-phenylsulfonyloxy phenyl)-4-(2-styroyl) morpholine-3-ketone,
(6S)-6-(4-phenylsulfonyloxy phenyl)-4-(methyl) morpholine-3-ketone,
(6S)-6-(4-phenylsulfonyloxy phenyl)-4-(ethyl) morpholine-3-ketone,
(6S)-6-(4-phenylsulfonyloxy phenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6S)-6-(4-phenylsulfonyloxy phenyl)-4-(allyl group) morpholine-3-ketone,
(6S)-6-(4-phenylsulfonyloxy phenyl) morpholine-3-ketone,
(2S)-2-(4-phenylsulfonyloxy phenyl)-4-(benzyl) morpholine,
(2S)-2-(4-phenylsulfonyloxy phenyl)-4-(4-methoxy-benzyl) morpholine,
(2S)-2-(4-phenylsulfonyloxy phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2S)-2-(4-phenylsulfonyloxy phenyl)-4-((1R)-1-styroyl) morpholine,
(2S)-2-(4-phenylsulfonyloxy phenyl)-4-((1S)-1-styroyl) morpholine,
(2S)-2-(4-phenylsulfonyloxy phenyl)-4-(2-styroyl) morpholine,
(2S)-2-(4-phenylsulfonyloxy phenyl)-4-(methyl) morpholine,
(2S)-2-(4-phenylsulfonyloxy phenyl)-4-(ethyl) morpholine,
(2S)-2-(4-phenylsulfonyloxy phenyl)-4-(tertiary butyl) morpholine,
(2S)-2-(4-phenylsulfonyloxy phenyl)-4-(allyl group) morpholine,
(2S)-2-(4-phenylsulfonyloxy phenyl) morpholine-4-carboxylate methyl ester,
(2S)-2-(4-phenylsulfonyloxy phenyl) morpholine-4-carboxylic acid, ethyl ester,
(2S)-2-(4-phenylsulfonyloxy phenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2S)-2-(4-phenylsulfonyloxy phenyl) morpholine-4-carboxylic acid phenyl ester,
(2S)-2-(4-phenylsulfonyloxy phenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(6S)-6-(4-(4-tosyloxy) phenyl)-4-(benzyl) morpholine-3-ketone,
(6S)-6-(4-(4-tosyloxy) phenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-(4-tosyloxy) phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-(4-tosyloxy) phenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-(4-tosyloxy) phenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-(4-tosyloxy) phenyl)-4-(2-styroyl) morpholine-3-ketone,
(6S)-6-(4-(4-tosyloxy) phenyl)-4-(methyl) morpholine-3-ketone,
(6S)-6-(4-(4-tosyloxy) phenyl)-4-(ethyl) morpholine-3-ketone,
(6S)-6-(4-(4-tosyloxy) phenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6S)-6-(4-(4-tosyloxy) phenyl)-4-(allyl group) morpholine-3-ketone,
(6S)-6-(4-(4-tosyloxy) phenyl) morpholine-3-ketone,
(2S)-2-(4-(4-tosyloxy) phenyl)-4-(benzyl) morpholine,
(2S)-2-(4-(4-tosyloxy) phenyl)-4-(4-methoxy-benzyl) morpholine,
(2S)-2-(4-(4-tosyloxy) phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2S)-2-(4-(4-tosyloxy) phenyl)-4-((1R)-1-styroyl) morpholine,
(2S)-2-(4-(4-tosyloxy) phenyl)-4-((1S)-1-styroyl) morpholine,
(2S)-2-(4-(4-tosyloxy) phenyl)-4-(2-styroyl) morpholine,
(2S)-2-(4-(4-tosyloxy) phenyl)-4-(methyl) morpholine,
(2S)-2-(4-(4-tosyloxy) phenyl)-4-(ethyl) morpholine,
(2S)-2-(4-(4-tosyloxy) phenyl)-4-(tertiary butyl) morpholine,
(2S)-2-(4-(4-tosyloxy) phenyl)-4-(allyl group) morpholine,
(2S)-2-(4-(4-tosyloxy) phenyl) morpholine-4-carboxylate methyl ester,
(2S)-2-(4-(4-tosyloxy) phenyl) morpholine-4-carboxylic acid, ethyl ester,
(2S)-2-(4-(4-tosyloxy) phenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2S)-2-(4-(4-tosyloxy) phenyl) morpholine-4-carboxylic acid phenyl ester and
(2S)-2-(4-(4-tosyloxy) phenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester.
In addition, the compound shown in scheme 4 Chinese styles 27, the compound shown in the formula 28 and
Compound shown in the formula 29 also is novel cpd (these compounds can be expressed as jointly by the represented compound of following formula 32).
Wherein shown each symbol as hereinbefore defined.
In above-claimed cpd, preferred such compound: in this compound, R is for having 1 to 3 substituent phenyl, and wherein said substituting group is selected from halogen, C
1-C
6Alkyl, the C that is substituted
1-C
6Alkyl, C
1-C
6Alkoxyl group, the C that is substituted
1-C
6Alkoxyl group, nitro aralkoxy, C
1-C
6Alkylsulfonyloxy, aryl-sulfonyl oxygen and C
1-C
6The aryl-sulfonyl oxygen that alkyl replaces; More preferably such compound: in this compound, R is for having 1 to 3 substituent phenyl, and wherein said substituting group is selected from fluorine, chlorine, bromine, nitro, benzyloxy, mesyloxy, phenylsulfonyloxy and tosyloxy.Particularly, can mention following compounds:
(6R)-6-(4-fluorophenyl)-4-(benzyl) morpholine-3-ketone,
(6R)-6-(4-fluorophenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-fluorophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-fluorophenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-fluorophenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-fluorophenyl)-4-(2-styroyl) morpholine-3-ketone,
(6R)-6-(4-fluorophenyl)-4-(methyl) morpholine-3-ketone,
(6R)-6-(4-fluorophenyl)-4-(ethyl) morpholine-3-ketone,
(6R)-6-(4-fluorophenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6R)-6-(4-fluorophenyl)-4-(allyl group) morpholine-3-ketone,
(6R)-6-(4-fluorophenyl) morpholine-3-ketone,
(6R)-6-(3-fluorophenyl)-4-(benzyl) morpholine-3-ketone,
(6R)-6-(3-fluorophenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6R)-6-(3-fluorophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6R)-6-(3-fluorophenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6R)-6-(3-fluorophenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6R)-6-(3-fluorophenyl)-4-(2-styroyl) morpholine-3-ketone,
(6R)-6-(3-fluorophenyl)-4-(methyl) morpholine-3-ketone,
(6R)-6-(3-fluorophenyl)-4-(ethyl) morpholine-3-ketone,
(6R)-6-(3-fluorophenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6R)-6-(3-fluorophenyl)-4-(allyl group) morpholine-3-ketone,
(6R)-6-(3-fluorophenyl) morpholine-3-ketone,
(6R)-6-(4-chloro-phenyl-)-4-(benzyl) morpholine-3-ketone,
(6R)-6-(4-chloro-phenyl-)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-chloro-phenyl-)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-chloro-phenyl-)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-chloro-phenyl-)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-chloro-phenyl-)-4-(2-styroyl) morpholine-3-ketone,
(6R)-6-(4-chloro-phenyl-)-4-(methyl) morpholine-3-ketone,
(6R)-6-(4-chloro-phenyl-)-4-(ethyl) morpholine-3-ketone,
(6R)-6-(4-chloro-phenyl-)-4-(tertiary butyl) morpholine-3-ketone,
(6R)-6-(4-chloro-phenyl-)-4-(allyl group) morpholine-3-ketone,
(6R)-6-(4-bromophenyl)-4-(benzyl) morpholine-3-ketone,
(6R)-6-(4-bromophenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-bromophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-bromophenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-bromophenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-bromophenyl)-4-(2-styroyl) morpholine-3-ketone,
(6R)-6-(4-bromophenyl)-4-(methyl) morpholine-3-ketone,
(6R)-6-(4-bromophenyl)-4-(ethyl) morpholine-3-ketone,
(6R)-6-(4-bromophenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6R)-6-(4-bromophenyl)-4-(allyl group) morpholine-3-ketone,
(6R)-6-(4-nitrophenyl)-4-(benzyl) morpholine-3-ketone,
(6R)-6-(4-nitrophenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-nitrophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-nitrophenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-nitrophenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-nitrophenyl)-4-(2-styroyl) morpholine-3-ketone,
(6R)-6-(4-nitrophenyl)-4-(methyl) morpholine-3-ketone,
(6R)-6-(4-nitrophenyl)-4-(ethyl) morpholine-3-ketone,
(6R)-6-(4-nitrophenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6R)-6-(4-nitrophenyl)-4-(allyl group) morpholine-3-ketone,
(2R)-2-(4-fluorophenyl)-4-(benzyl) morpholine,
(2R)-2-(4-fluorophenyl)-4-(4-methoxy-benzyl) morpholine,
(2R)-2-(4-fluorophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2R)-2-(4-fluorophenyl)-4-((1R)-1-styroyl) morpholine,
(2R)-2-(4-fluorophenyl)-4-((1S)-1-styroyl) morpholine,
(2R)-2-(4-fluorophenyl)-4-(2-styroyl) morpholine,
(2R)-2-(4-fluorophenyl)-4-(methyl) morpholine,
(2R)-2-(4-fluorophenyl)-4-(ethyl) morpholine,
(2R)-2-(4-fluorophenyl)-4-(tertiary butyl) morpholine,
(2R)-2-(4-fluorophenyl)-4-(allyl group) morpholine,
(2R)-2-(3-fluorophenyl)-4-(benzyl) morpholine,
(2R)-2-(3-fluorophenyl)-4-(4-methoxy-benzyl) morpholine,
(2R)-2-(3-fluorophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2R)-2-(3-fluorophenyl)-4-((1R)-1-styroyl) morpholine,
(2R)-2-(3-fluorophenyl)-4-((1S)-1-styroyl) morpholine,
(2R)-2-(3-fluorophenyl)-4-(2-styroyl) morpholine,
(2R)-2-(3-fluorophenyl)-4-(methyl) morpholine,
(2R)-2-(3-fluorophenyl)-4-(ethyl) morpholine,
(2R)-2-(3-fluorophenyl)-4-(tertiary butyl) morpholine,
(2R)-2-(3-fluorophenyl)-4-(allyl group) morpholine,
(2R)-2-(3-fluorophenyl) morpholine,
(2R)-2-(4-chloro-phenyl-)-4-(benzyl) morpholine,
(2R)-2-(4-chloro-phenyl-)-4-(4-methoxy-benzyl) morpholine,
(2R)-2-(4-chloro-phenyl-)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2R)-2-(4-chloro-phenyl-)-4-((1R)-1-styroyl) morpholine,
(2R)-2-(4-chloro-phenyl-)-4-((1S)-1-styroyl) morpholine,
(2R)-2-(4-chloro-phenyl-)-4-(2-styroyl) morpholine,
(2R)-2-(4-chloro-phenyl-)-4-(methyl) morpholine,
(2R)-2-(4-chloro-phenyl-)-4-(ethyl) morpholine,
(2R)-2-(4-chloro-phenyl-)-4-(tertiary butyl) morpholine,
(2R)-2-(4-chloro-phenyl-)-4-(allyl group) morpholine,
(2R)-2-(4-bromophenyl)-4-(benzyl) morpholine,
(2R)-2-(4-bromophenyl)-4-(4-methoxy-benzyl) morpholine,
(2R)-2-(4-bromophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2R)-2-(4-bromophenyl)-4-((1R)-1-styroyl) morpholine,
(2R)-2-(4-bromophenyl)-4-((1S)-1-styroyl) morpholine,
(2R)-2-(4-bromophenyl)-4-(2-styroyl) morpholine,
(2R)-2-(4-bromophenyl)-4-(methyl) morpholine,
(2R)-2-(4-bromophenyl)-4-(ethyl) morpholine,
(2R)-2-(4-bromophenyl)-4-(tertiary butyl) morpholine,
(2R)-2-(4-bromophenyl)-4-(allyl group) morpholine,
(2R)-2-(4-bromophenyl) morpholine,
(2R)-2-(4-nitrophenyl)-4-(benzyl) morpholine,
(2R)-2-(4-nitrophenyl)-4-(4-methoxy-benzyl) morpholine,
(2R)-2-(4-nitrophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2R)-2-(4-nitrophenyl)-4-((1R)-1-styroyl) morpholine,
(2R)-2-(4-nitrophenyl)-4-((1S)-1-styroyl) morpholine,
(2R)-2-(4-nitrophenyl)-4-(2-styroyl) morpholine,
(2R)-2-(4-nitrophenyl)-4-(methyl) morpholine,
(2R)-2-(4-nitrophenyl)-4-(ethyl) morpholine,
(2R)-2-(4-nitrophenyl)-4-(tertiary butyl) morpholine,
(2R)-2-(4-nitrophenyl)-4-(allyl group) morpholine,
(2R)-2-(4-nitrophenyl) morpholine,
(2R)-2-(4-fluorophenyl) morpholine-4-carboxylate methyl ester,
(2R)-2-(4-fluorophenyl) morpholine-4-carboxylic acid, ethyl ester,
(2R)-2-(4-fluorophenyl) morpholine-4-carboxylic acid phenyl ester,
(2R)-2-(4-fluorophenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(2R)-2-(3-fluorophenyl) morpholine-4-carboxylate methyl ester,
(2R)-2-(3-fluorophenyl) morpholine-4-carboxylic acid, ethyl ester,
(2R)-2-(3-fluorophenyl) morpholine-4-carboxylic acid phenyl ester,
(2R)-2-(3-fluorophenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(2R)-2-(4-chloro-phenyl-) morpholine-4-carboxylate methyl ester,
(2R)-2-(4-chloro-phenyl-) morpholine-4-carboxylic acid, ethyl ester,
(2R)-2-(4-chloro-phenyl-) morpholine-4-carboxylic acid phenyl ester,
(2R)-2-(4-chloro-phenyl-) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(2R)-2-(4-bromophenyl) morpholine-4-carboxylate methyl ester,
(2R)-2-(4-bromophenyl) morpholine-4-carboxylic acid, ethyl ester,
(2R)-2-(4-bromophenyl) morpholine-4-carboxylic acid phenyl ester,
(2R)-2-(4-bromophenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(2R)-2-(4-nitrophenyl) morpholine-4-carboxylate methyl ester,
(2R)-2-(4-nitrophenyl) morpholine-4-carboxylic acid, ethyl ester,
(2R)-2-(4-nitrophenyl) morpholine-4-carboxylic acid phenyl ester,
(2R)-2-(4-nitrophenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(2R)-2-(4-fluorophenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2R)-2-(3-fluorophenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2R)-2-(4-chloro-phenyl-) morpholine-4-carboxylic acid 1-chloroethene ester,
(2R)-2-(4-bromophenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2R)-2-(4-nitrophenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(6R)-6-(4-benzyloxy phenyl)-4-(benzyl) morpholine-3-ketone,
(6R)-6-(4-benzyloxy phenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-benzyloxy phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-benzyloxy phenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-benzyloxy phenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-benzyloxy phenyl)-4-(2-styroyl) morpholine-3-ketone,
(6R)-6-(4-benzyloxy phenyl)-4-(methyl) morpholine-3-ketone,
(6R)-6-(4-benzyloxy phenyl)-4-(ethyl) morpholine-3-ketone,
(6R)-6-(4-benzyloxy phenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6R)-6-(4-benzyloxy phenyl)-4-(allyl group) morpholine-3-ketone,
(6R)-6-(4-benzyloxy phenyl) morpholine-3-ketone,
(2R)-2-(4-benzyloxy phenyl)-4-(benzyl) morpholine,
(2R)-2-(4-benzyloxy phenyl)-4-(4-methoxy-benzyl) morpholine,
(2R)-2-(4-benzyloxy phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2R)-2-(4-benzyloxy phenyl)-4-((1R)-1-styroyl) morpholine,
(2R)-2-(4-benzyloxy phenyl)-4-((1S)-1-styroyl) morpholine,
(2R)-2-(4-benzyloxy phenyl)-4-(2-styroyl) morpholine,
(2R)-2-(4-benzyloxy phenyl)-4-(methyl) morpholine,
(2R)-2-(4-benzyloxy phenyl)-4-(ethyl) morpholine,
(2R)-2-(4-benzyloxy phenyl)-4-(tertiary butyl) morpholine,
(2R)-2-(4-benzyloxy phenyl)-4-(allyl group) morpholine,
(2R)-2-(4-benzyloxy phenyl) morpholine-4-carboxylate methyl ester,
(2R)-2-(4-benzyloxy phenyl) morpholine-4-carboxylic acid, ethyl ester,
(2R)-2-(4-benzyloxy phenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2R)-2-(4-benzyloxy phenyl) morpholine-4-carboxylic acid phenyl ester,
(2R)-2-(4-benzyloxy phenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(6R)-6-(4-mesyloxy phenyl)-4-(benzyl) morpholine-3-ketone,
(6R)-6-(4-mesyloxy phenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-mesyloxy phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-mesyloxy phenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-mesyloxy phenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-mesyloxy phenyl)-4-(2-styroyl) morpholine-3-ketone,
(6R)-6-(4-mesyloxy phenyl)-4-(methyl) morpholine-3-ketone,
(6R)-6-(4-mesyloxy phenyl)-4-(ethyl) morpholine-3-ketone,
(6R)-6-(4-mesyloxy phenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6R)-6-(4-mesyloxy phenyl)-4-(allyl group) morpholine-3-ketone,
(6R)-6-(4-mesyloxy phenyl) morpholine-3-ketone,
(2R)-2-(4-mesyloxy phenyl)-4-(benzyl) morpholine,
(2R)-2-(4-mesyloxy phenyl)-4-(4-methoxy-benzyl) morpholine,
(2R)-2-(4-mesyloxy phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2R)-2-(4-mesyloxy phenyl)-4-((1R)-1-styroyl) morpholine,
(2R)-2-(4-mesyloxy phenyl)-4-((1S)-1-styroyl) morpholine,
(2R)-2-(4-mesyloxy phenyl)-4-(2-styroyl) morpholine,
(2R)-2-(4-mesyloxy phenyl)-4-(methyl) morpholine,
(2R)-2-(4-mesyloxy phenyl)-4-(ethyl) morpholine,
(2R)-2-(4-mesyloxy phenyl)-4-(tertiary butyl) morpholine,
(2R)-2-(4-mesyloxy phenyl)-4-(allyl group) morpholine,
(2R)-2-(4-mesyloxy phenyl) morpholine-4-carboxylate methyl ester,
(2R)-2-(4-mesyloxy phenyl) morpholine-4-carboxylic acid, ethyl ester,
(2R)-2-(4-mesyloxy phenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2R)-2-(4-mesyloxy phenyl) morpholine-4-carboxylic acid phenyl ester,
(2R)-2-(4-mesyloxy phenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(6R)-6-(4-phenylsulfonyloxy phenyl)-4-(benzyl) morpholine-3-ketone,
(6R)-6-(4-phenylsulfonyloxy phenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-phenylsulfonyloxy phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-phenylsulfonyloxy phenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-phenylsulfonyloxy phenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-phenylsulfonyloxy phenyl)-4-(2-styroyl) morpholine-3-ketone,
(6R)-6-(4-phenylsulfonyloxy phenyl)-4-(methyl) morpholine-3-ketone,
(6R)-6-(4-phenylsulfonyloxy phenyl)-4-(ethyl) morpholine-3-ketone,
(6R)-6-(4-phenylsulfonyloxy phenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6R)-6-(4-phenylsulfonyloxy phenyl)-4-(allyl group) morpholine-3-ketone,
(6R)-6-(4-phenylsulfonyloxy phenyl) morpholine-3-ketone,
(2R)-2-(4-phenylsulfonyloxy phenyl)-4-(benzyl) morpholine,
(2R)-2-(4-phenylsulfonyloxy phenyl)-4-(4-methoxy-benzyl) morpholine,
(2R)-2-(4-phenylsulfonyloxy phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2R)-2-(4-phenylsulfonyloxy phenyl)-4-((1R)-1-styroyl) morpholine,
(2R)-2-(4-phenylsulfonyloxy phenyl)-4-((1S)-1-styroyl) morpholine,
(2R)-2-(4-phenylsulfonyloxy phenyl)-4-(2-styroyl) morpholine,
(2R)-2-(4-phenylsulfonyloxy phenyl)-4-(methyl) morpholine,
(2R)-2-(4-phenylsulfonyloxy phenyl)-4-(ethyl) morpholine,
(2R)-2-(4-phenylsulfonyloxy phenyl)-4-(tertiary butyl) morpholine,
(2R)-2-(4-phenylsulfonyloxy phenyl)-4-(allyl group) morpholine,
(2R)-2-(4-phenylsulfonyloxy phenyl) morpholine-4-carboxylate methyl ester,
(2R)-2-(4-phenylsulfonyloxy phenyl) morpholine-4-carboxylic acid, ethyl ester,
(2R)-2-(4-phenylsulfonyloxy phenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2R)-2-(4-phenylsulfonyloxy phenyl) morpholine-4-carboxylic acid phenyl ester,
(2R)-2-(4-phenylsulfonyloxy phenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(6R)-6-(4-(4-tosyloxy) phenyl)-4-(benzyl) morpholine-3-ketone,
(6R)-6-(4-(4-tosyloxy) phenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-(4-tosyloxy) phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-(4-tosyloxy) phenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-(4-tosyloxy) phenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-(4-tosyloxy) phenyl)-4-(2-styroyl) morpholine-3-ketone,
(6R)-6-(4-(4-tosyloxy) phenyl)-4-(methyl) morpholine-3-ketone,
(6R)-6-(4-(4-tosyloxy) phenyl)-4-(ethyl) morpholine-3-ketone,
(6R)-6-(4-(4-tosyloxy) phenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6R)-6-(4-(4-tosyloxy) phenyl)-4-(allyl group) morpholine-3-ketone,
(6R)-6-(4-(4-tosyloxy) phenyl) morpholine-3-ketone,
(2R)-2-(4-(4-tosyloxy) phenyl)-4-(benzyl) morpholine,
(2R)-2-(4-(4-tosyloxy) phenyl)-4-(4-methoxy-benzyl) morpholine,
(2R)-2-(4-(4-tosyloxy) phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2R)-2-(4-(4-tosyloxy) phenyl)-4-((1R)-1-styroyl) morpholine,
(2R)-2-(4-(4-tosyloxy) phenyl)-4-((1S)-1-styroyl) morpholine,
(2R)-2-(4-(4-tosyloxy) phenyl)-4-(2-styroyl) morpholine,
(2R)-2-(4-(4-tosyloxy) phenyl)-4-(methyl) morpholine,
(2R)-2-(4-(4-tosyloxy) phenyl)-4-(ethyl) morpholine,
(2R)-2-(4-(4-tosyloxy) phenyl)-4-(tertiary butyl) morpholine,
(2R)-2-(4-(4-tosyloxy) phenyl)-4-(allyl group) morpholine,
(2R)-2-(4-(4-tosyloxy) phenyl) morpholine-4-carboxylate methyl ester,
(2R)-2-(4-(4-tosyloxy) phenyl) morpholine-4-carboxylic acid, ethyl ester,
(2R)-2-(4-(4-tosyloxy) phenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2R)-2-(4-(4-tosyloxy) phenyl) morpholine-4-carboxylic acid phenyl ester and
(2R)-2-(4-(4-tosyloxy) phenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester.
In addition, also can prepare and have optically active 2-ethanolamine compound according to following scheme 7 (S type) or scheme 8 (R type).
Scheme 7
Scheme 8
Wherein the symbol in each scheme as hereinbefore defined.
In the step of scheme 7, by the Ru catalyzer and have optically active amino alcohol or condition that the amine ligand exists under, the compound shown in the formula 34 and Virahol or formic acid are reacted in solvent, thereby make the compound shown in the formula 35.
By described reactions steps, can make and have optically active 2-ethanolamine compound (S type), it is that the compound shown in the formula 35 (is worked as R
11During for hydrogen atom, this compound is the compound shown in the formula 5).
Can come embodiment 8 by the step similar to scheme 7, difference has been to use the optically active isomer with optically active amino alcohol or amine ligand to replace having optically active amino alcohol or amine ligand, can make thus and have optically active 2-ethanolamine compound (R type), it is that the compound shown in the formula 36 (is worked as R
11During for hydrogen atom, this compound is the compound shown in the formula 25).
As the representative example of the Ru catalyzer that uses in scheme 7 and the scheme 8, can mention: two chloro-(p-cymene) rutheniums (II) dimer, Benzene Chloride ruthenium (II) dimer etc.As representative example, can mention with optically active amino alcohol ligand: (1S, 2R)-suitable-1-amino-indane-2-alcohol, its optically active isomer etc.As representative example, can mention with optically active amine ligand: (R, R)-DPEN, (R, R)-MsDPEN, (R, R)-TsDPEN, it has optically active form etc.As the hydrogen source of described reaction, can mention: propyl alcohol, formic acid etc.Described reaction can be carried out under the condition of existence such as potassium hydroxide, triethylamine.
As the compound shown in the formula 34 of starting material is novel cpd.Particularly, preferred such compound: in this compound, R is for having 1 to 3 substituent phenyl, and wherein said substituting group is selected from halogen, C
1-C
6Alkyl, the C that is substituted
1-C
6Alkyl, C
1-C
6Alkoxyl group, the C that is substituted
1-C
6Alkoxyl group, nitro aralkoxy, C
1-C
6Alkylsulfonyloxy, aryl-sulfonyl oxygen and C
1-C
6The aryl-sulfonyl oxygen that alkyl replaces; More preferably such compound: in this compound, R is for having 1 to 3 substituent phenyl, and wherein said substituting group is selected from fluorine, chlorine, bromine, nitro, benzyloxy, mesyloxy, phenylsulfonyloxy and tosyloxy.Particularly, can mention following compounds:
2-(benzyl amino)-1-(4-fluorophenyl) ethyl ketone,
2-(4-methoxybenzyl amino)-1-(4-fluorophenyl) ethyl ketone,
2-(2,4-dimethoxy benzyl amino)-1-(4-fluorophenyl) ethyl ketone,
2-((1R)-1-benzene ethylamino)-1-(4-fluorophenyl) ethyl ketone,
2-((1S)-1-benzene ethylamino)-1-(4-fluorophenyl) ethyl ketone,
2-(2-benzene ethylamino)-1-(4-fluorophenyl) ethyl ketone,
2-(methylamino-)-1-(4-fluorophenyl) ethyl ketone,
2-(ethylamino)-1-(4-fluorophenyl) ethyl ketone,
2-(uncle's fourth amino)-1-(4-fluorophenyl) ethyl ketone,
2-(allyl amino)-1-(4-fluorophenyl) ethyl ketone,
2-amino-1-(4-fluorophenyl) ethyl ketone,
2-(benzyl amino)-1-(3-fluorophenyl) ethyl ketone,
2-(4-methoxybenzyl amino)-1-(3-fluorophenyl) ethyl ketone,
2-(2,4-dimethoxy benzyl amino)-1-(3-fluorophenyl) ethyl ketone,
2-((1R)-1-benzene ethylamino)-1-(3-fluorophenyl) ethyl ketone,
2-((1S)-1-benzene ethylamino)-1-(3-fluorophenyl) ethyl ketone,
2-(2-benzene ethylamino)-1-(3-fluorophenyl) ethyl ketone,
2-(methylamino-)-1-(3-fluorophenyl) ethyl ketone,
2-(ethylamino)-1-(3-fluorophenyl) ethyl ketone,
2-(uncle's fourth amino)-1-(3-fluorophenyl) ethyl ketone,
2-(allyl amino)-1-(3-fluorophenyl) ethyl ketone,
2-amino-1-(3-fluorophenyl) ethyl ketone,
2-(benzyl amino)-1-(4-chloro-phenyl-) ethyl ketone,
2-(4-methoxybenzyl amino)-1-(4-chloro-phenyl-) ethyl ketone,
2-(2,4-dimethoxy benzyl amino)-1-(4-chloro-phenyl-) ethyl ketone,
2-((1R)-1-benzene ethylamino)-1-(4-chloro-phenyl-) ethyl ketone,
2-((1S)-1-benzene ethylamino)-1-(4-chloro-phenyl-) ethyl ketone,
2-(2-benzene ethylamino)-1-(4-chloro-phenyl-) ethyl ketone,
2-(methylamino-)-1-(4-chloro-phenyl-) ethyl ketone,
2-(ethylamino)-1-(4-chloro-phenyl-) ethyl ketone,
2-(uncle's fourth amino)-1-(4-chloro-phenyl-) ethyl ketone,
2-(allyl amino)-1-(4-chloro-phenyl-) ethyl ketone,
2-amino-1-(4-chloro-phenyl-) ethyl ketone,
2-(benzyl amino)-1-(4-bromophenyl) ethyl ketone,
2-(4-methoxybenzyl amino)-1-(4-bromophenyl) ethyl ketone,
2-(2,4-dimethoxy benzyl amino)-1-(4-bromophenyl) ethyl ketone,
2-((1R)-1-benzene ethylamino)-1-(4-bromophenyl) ethyl ketone,
2-((1S)-1-benzene ethylamino)-1-(4-bromophenyl) ethyl ketone,
2-(2-benzene ethylamino)-1-(4-bromophenyl) ethyl ketone,
2-(methylamino-)-1-(4-bromophenyl) ethyl ketone,
2-(ethylamino)-1-(4-bromophenyl) ethyl ketone,
2-(uncle's fourth amino)-1-(4-bromophenyl) ethyl ketone,
2-(allyl amino)-1-(4-bromophenyl) ethyl ketone,
2-amino-1-(4-bromophenyl) ethyl ketone,
2-(benzyl amino)-1-(4-nitrophenyl) ethyl ketone,
2-(4-methoxybenzyl amino)-1-(4-nitrophenyl) ethyl ketone,
2-(2,4-dimethoxy benzyl amino)-1-(4-nitrophenyl) ethyl ketone,
2-((1R)-1-benzene ethylamino)-1-(4-nitrophenyl) ethyl ketone,
2-((1S)-1-benzene ethylamino)-1-(4-nitrophenyl) ethyl ketone,
2-(2-benzene ethylamino)-1-(4-nitrophenyl) ethyl ketone,
2-(methylamino-)-1-(4-nitrophenyl) ethyl ketone,
2-(ethylamino)-1-(4-nitrophenyl) ethyl ketone,
2-(uncle's fourth amino)-1-(4-nitrophenyl) ethyl ketone,
2-(allyl amino)-1-(4-nitrophenyl) ethyl ketone,
2-amino-1-(4-nitrophenyl) ethyl ketone,
2-(benzyl amino)-1-(4-benzyloxy phenyl) ethyl ketone,
2-(4-methoxybenzyl amino)-1-(4-benzyloxy phenyl) ethyl ketone,
2-(2,4-dimethoxy benzyl amino)-1-(4-benzyloxy phenyl) ethyl ketone,
2-((1R)-1-benzene ethylamino)-1-(4-benzyloxy phenyl) ethyl ketone,
2-((1S)-1-benzene ethylamino)-1-(4-benzyloxy phenyl) ethyl ketone,
2-(2-benzene ethylamino)-1-(4-benzyloxy phenyl) ethyl ketone,
2-(methylamino-)-1-(4-benzyloxy phenyl) ethyl ketone,
2-(ethylamino)-1-(4-benzyloxy phenyl) ethyl ketone,
2-(uncle's fourth amino)-1-(4-benzyloxy phenyl) ethyl ketone,
2-(allyl amino)-1-(4-benzyloxy phenyl) ethyl ketone,
2-amino-1-(4-benzyloxy phenyl) ethyl ketone,
2-(benzyl amino)-1-(4-mesyloxy phenyl) ethyl ketone,
2-(4-methoxybenzyl amino)-1-(4-mesyloxy phenyl) ethyl ketone,
2-(2,4-dimethoxy benzyl amino)-1-(4-mesyloxy phenyl) ethyl ketone,
2-((1R)-1-benzene ethylamino)-1-(4-mesyloxy phenyl) ethyl ketone,
2-((1S)-1-benzene ethylamino)-1-(4-mesyloxy phenyl) ethyl ketone,
2-(2-benzene ethylamino)-1-(4-mesyloxy phenyl) ethyl ketone,
2-(methylamino-)-1-(4-mesyloxy phenyl) ethyl ketone,
2-(ethylamino)-1-(4-mesyloxy phenyl) ethyl ketone,
2-(uncle's fourth amino)-1-(4-mesyloxy phenyl) ethyl ketone,
2-(allyl amino)-1-(4-mesyloxy phenyl) ethyl ketone,
2-amino-1-(4-mesyloxy phenyl) ethyl ketone,
2-(benzyl amino)-1-(4-phenylsulfonyloxy phenyl) ethyl ketone,
2-(4-methoxybenzyl amino)-1-(4-phenylsulfonyloxy phenyl) ethyl ketone,
2-(2,4-dimethoxy benzyl amino)-1-(4-phenylsulfonyloxy phenyl) ethyl ketone,
2-((1R)-1-benzene ethylamino)-1-(4-phenylsulfonyloxy phenyl) ethyl ketone,
2-((1S)-1-benzene ethylamino)-1-(4-phenylsulfonyloxy phenyl) ethyl ketone,
2-(2-benzene ethylamino)-1-(4-phenylsulfonyloxy phenyl) ethyl ketone,
2-(methylamino-)-1-(4-phenylsulfonyloxy phenyl) ethyl ketone,
2-(ethylamino)-1-(4-phenylsulfonyloxy phenyl) ethyl ketone,
2-(uncle's fourth amino)-1-(4-phenylsulfonyloxy phenyl) ethyl ketone,
2-(allyl amino)-1-(4-phenylsulfonyloxy phenyl) ethyl ketone,
2-amino-1-(4-phenylsulfonyloxy phenyl) ethyl ketone,
2-(benzyl amino)-1-(4-(4-tosyloxy) phenyl) ethyl ketone,
2-(4-methoxybenzyl amino)-1-(4-(4-tosyloxy) phenyl) ethyl ketone,
2-(2,4-dimethoxy benzyl amino)-1-(4-(4-tosyloxy) phenyl) ethyl ketone,
2-((1R)-1-benzene ethylamino)-1-(4-(4-tosyloxy) phenyl) ethyl ketone,
2-((1S)-1-benzene ethylamino)-1-(4-(4-tosyloxy) phenyl) ethyl ketone,
2-(2-benzene ethylamino)-1-(4-(4-tosyloxy) phenyl) ethyl ketone,
2-(methylamino-)-1-(4-(4-tosyloxy) phenyl) ethyl ketone,
2-(ethylamino)-1-(4-(4-tosyloxy) phenyl) ethyl ketone,
2-(uncle's fourth amino)-1-(4-(4-tosyloxy) phenyl) ethyl ketone,
2-(allyl amino)-1-(4-(4-tosyloxy) phenyl) ethyl ketone and
2-amino-1-(4-(4-tosyloxy) phenyl) ethyl ketone.
Can by with document J.Chem.Soc.Perkin Trans.1,16,1916, the similar method of method described in (2001) is come the compound shown in the preparation formula 34.
In the present invention, can prepare 3-oxo-3-(pyrimidine-4-yl) propionic ester with vitamin B13 as starting material according to following scheme 9.
Scheme 9
Wherein shown each symbol as hereinbefore defined.
In step 1, under the condition that alkali exists, vitamin B13 and the alkylating agent shown in the formula 51 reacted in solvent, thereby obtain the compound shown in the formula 52.
As alkylating agent, can mention: iodoethane, methyl iodide, monobromethane, monobromethane, methyl-sulfate, ethyl sulfate, methyl benzenesulfonate, o-toluene sulfonic acid methyl esters, methyl tosylate, ethyl benzenesulfonat, o-toluene sulfonic acid ethyl ester, ethyl p-toluenesulfonate etc.
Compound shown in the formula 51 with respect to 1 mole, the amount of used alkylating agent are generally 0.1 mole to 100 moles, are preferably 0.8 mole to 2 moles.
As alkali, can mention: 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene, 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene.
Compound shown in the formula 51 with respect to 1 mole, the amount of used alkali are generally 0.1 mole to 10 moles, are preferably 0.8 mole to 1.2 moles.
As solvent, can mention: N, dinethylformamide, N, N-diethyl acetamide, N-N-methyl-2-2-pyrrolidone N-, methyl-sulphoxide, its mixed solvent etc.
Described rapid in, described being reflected at carried out 0.1 hour to 10 hours under 40 ℃ to 100 ℃.
In step 2, under refluxad, compound and the chlorizating agent shown in the formula 52 together heated, thereby obtain the compound shown in the formula 53.
As chlorizating agent, can mention: phosphoryl chloride, phosphorus trichloride, phosphorus pentachloride, Vilsmeier intermediate (phosphoryl chloride+dimethyl formamide), phosphoryl chloride+N-N-methyl-2-2-pyrrolidone N-, thionyl chloride, SULPHURYL CHLORIDE etc.
Compound shown in the formula 52 with respect to 1 mole, the amount of used chlorizating agent are generally 1.5 moles to 10 moles, are preferably 2 moles to 3 moles.
Can under the condition that ammonium salt exists, use described chlorizating agent, as ammonium salt, can mention: benzyltriethylammonium chloride, tetraethylammonium chloride etc.
Compound shown in the formula 52 with respect to 1 mole, the amount of used ammonium salt are generally 0.1 mole to 10 moles, are preferably 0.1 mole to 2 moles.
Described step can be carried out in solvent, as described solvent, can mention: tetrahydrofuran (THF), 1,4-two alkane, 1,2-glycol dimethyl ether, toluene, dimethylbenzene, benzene, acetonitrile, propionitrile, its mixed solvent etc.
In described step, described reaction can under refluxad be heated 0.5 hour to 10 hours down at 60 ℃ to 90 ℃.
In step 3, under the condition that alkali exists, handle by the compound shown in the formula 53 being carried out dechlorination, thereby obtain the compound shown in the formula 54.
Preferably carry out described dechlorination and handle, as described reducing catalyst, can mention: palladium-carbon, palladium hydroxide etc. by catalytic reduction.
Compound shown in the formula 53 with respect to 1 mole, the amount of used reducing catalyst are generally 0.01 mole to 10 moles, are preferably 0.1 mole to 2 moles.
As alkali, can mention: triethylamine, N, N-Diethyl Aniline, N, accelerine, diisopropylethylamine, tributylamine, N-ethylpiperidine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene, 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene etc.
Compound shown in the formula 53 with respect to 1 mole, the amount of used alkali are generally 2 moles to 20 moles, are preferably 2 moles to 5 moles.
Above-mentioned catalytic reduction reaction carries out under hydrogen atmosphere.
Described step can be carried out in solvent, as described solvent, can mention: tetrahydrofuran (THF), 1,4-two alkane, 1,2-glycol dimethyl ether, benzene,toluene,xylene, Virahol, the trimethyl carbinol, tertiary amyl alcohol, ethyl acetate, butylacetate, its mixed solvent etc.
In described step, described being reflected at carried out 0.1 hour to 20 hours under 0 ℃ to 50 ℃.
In step 4, by under the condition that exists at alkali compound and the acetic ester shown in the formula 54 being reacted, thereby obtain the compound shown in the formula 55.
Compound shown in the formula 54 with respect to 1 mole, the amount of used acetic ester are generally 0.8 mole to 10 moles, are preferably 0.8 mole to 2 moles.
As alkali, can mention: sodium hydride, potassium hydride KH or derived from ROH (R is C
1-C
12Alkyl, as methyl, ethyl, the tertiary butyl, tert-pentyl, 3,7-dimethyl-3-octyl group etc.) sodium alkoxide or alkanol potassium, diisopropylamino lithium, (two trimethyl silyl) Lithamide, (two trimethyl silyl) sodium amide, (two trimethyl silyl) potassium amide etc.
Compound shown in the formula 54 with respect to 1 mole, the amount of used alkali are generally 1.5 moles to 10 moles, are preferably 1.5 moles to 3 moles.
Described step can be carried out in solvent, as described solvent, can mention: ethanol, diethyl ether, toluene, hexane, heptane, tetrahydrofuran (THF), 1,4-two alkane, 1,2-glycol dimethyl ether, dimethyl formamide, N-Methyl pyrrolidone, N,N-dimethylacetamide, dimethyl-imidazolinone, benzene,toluene,xylene, its mixed solvent etc.
In described step, described being reflected at-80 ℃ carried out 0.1 hour to 10 hours under 100 ℃.
Because vitamin B13 (compound shown in the formula 51) and ester (compound shown in the formula 52) thereof comprise the keto-enol tautomerism body, so their any isomer and mixture all can be used among the preparation method of the present invention.
In above-mentioned steps 1-4, step 1-3 is novel step.
3-oxo-3-(pyrimidine-4-yl) ethyl propionate that will make by above-mentioned steps synthesizes by following steps has 2-(2-aryl morpholine-4-yl)-1-methyl isophthalic acid H-[4 that tau protein kinases 1 suppresses active and can be used as the medicine that is used for Alzheimer etc., 4 '] connection pyrimidyl-6-ketone.
Wherein shown each symbol as hereinbefore defined.
Example
With reference to these examples, the present invention will be described in more detail.But scope of the present invention is not limited to following these examples.The numbering of the compound in the example is consistent with the numbering of this compound above.
Embodiment 1
(1) 2-chloro-(1S)-1-(4-fluorophenyl) alcoholic acid is synthetic
(concentration in tetrahydrofuran (THF) is the solution of 1.0M with borine-tetrahydrofuran complex, 60ml, 60 mmoles) in 15 minutes, be added drop-wise to (S)-CBS solution ((S)-2-methyl-CBS- azoles borine of-30 ℃, 12ml, concentration in toluene is the solution of 1.0M) in, and with gained mixture stirring 15 minutes.In 60 minutes, drip, and temperature is remained under-32 ℃ to-28 ℃ by 4-fluorobenzoyl methyl chloride (10.4g, 60 mmoles) formed solution in methylene dichloride (16ml).The gained solution stirring after 1 hour, is warmed to room temperature with it, and slowly adds methyl alcohol (20ml), in 10 minutes, drip the hydrochloric acid (120ml) of 1M subsequently.After the reaction mixture with gained stirs 40 minutes,, and use ethyl acetate extraction filtrate with its filtration.The organic layer that merges is used 1M spirit of salt and salt water washing in succession, and dry on anhydrous sodium sulphate.The gained organic layer is concentrated, thereby obtain the colorless oil of 2-chloro-(1S)-1-(4-fluorophenyl) ethanol (10.4g).
(2) (2S)-2-(4-fluorophenyl) oxyethane synthetic
1.6M aqueous sodium hydroxide solution (50ml) is joined by 2-chloro-(1S)-1-(4-fluorophenyl) ethanol (10.4g) in diethyl ether (40ml) in the formed solution, and the gained mixture was at room temperature stirred 5 hours.Organic layer is separated, and extract water layer with diethyl ether.With the organic layer salt water washing that merges, and dry on anhydrous sodium sulphate.With solvent evaporation, thereby obtain the colorless oil of (2S)-2-(4-fluorophenyl) oxyethane (8.28g).
(3) (1S)-1-(4-fluorophenyl)-2-(benzyl amino) alcoholic acid is synthetic
To heat 4 hours down at 80 ℃ by the mixture that (2S)-2-(4-fluorophenyl) oxyethane (8.28g) and benzylamine (19.3g, 180 mmoles) form.The reaction mixture of gained is poured in the water, and used ethyl acetate extraction.With the organic layer salt water washing that merges, and dry on anhydrous sodium sulphate.Remove desolvate after, filter collecting precipitation, and the gained precipitation washed, thereby obtain the white crystal (reaching 57%) of (1S)-1-(4-fluorophenyl)-2-(benzyl amino) ethanol (8.3g) through 3 step productive rates with hexane.
Use optically active column (CHIRAL PAK AS-H, solvent: heptane/Virahol (containing 0.1% diethylamine)) optical purity of gained compound is analyzed.Above-mentioned analysis condition is based on racemize 1-(4-fluorophenyl)-2-(benzyl amino) alcoholic acid analysis condition and is definite.
As described below, according to document J.Chem.Soc.Perkin Trans.1, the method similar methods described in 16,1916 (2001) is synthesized racemize 1-(4-fluorophenyl)-2-(benzyl amino) ethanol.
1-(4-fluorophenyl)-2-(benzyl amino) alcoholic acid synthetic method
In methylene dichloride, add triethylamine (7.6g, 75.0 mmoles) in the formed solution to benzylamine (1.29g, 12.1 mmoles), in gains, add 2-bromo-1-(4-fluorophenyl) ethyl ketone (3.27g, 15.1 mmoles) subsequently.In the reaction mixture of gained, add aqueous ammonium chloride solution, the mixture generation layering that obtains thus.Organic layer is dry on sodium sulfate, and concentrate, thus the oily matter of 2-(benzyl amino)-1-(4-fluorophenyl) ethyl ketone crude product (1.85g) obtained.This oily matter (1.50g) is dissolved in the mixed solvent that is formed by methyl alcohol (9mL) and water (1mL), and at room temperature adds sodium borohydride (0.8g).The gained reaction mixture is concentrated, and extract, concentrate the gained organic layer then with t-butyl methyl ether.In the gained resistates, add isopropyl acetate (4mL) and heptane (4mL), and the mixture that will obtain thus refluxes.Filter the crystal of collecting precipitation, and be dried, thereby obtain racemize 1-(4-fluorophenyl)-2-(benzyl amino) ethanol (0.21g).
1-(4-fluorophenyl)-2-(benzyl amino) ethanol:
1H-NMR (CDCl
3) δ: 2.70-2.73 (1H, m), 2.91-2.94 (1H, m), 3.80-3.88 (2H, m), 4.68-4.71 (1H, m), 7.00-7.52 (9H, m)
Embodiment 2
(1) (6S)-6-(4-fluorophenyl)-4-(benzyl) morpholine-3-ketone synthetic
Will be by chloroacetyl chloride (4.3g, 3.4ml, 38 mmoles) solution that forms in methylene dichloride (20ml) was added drop-wise in the ice-cooled mixture in 30 minutes, described mixture (1S)-1-(4-fluorophenyl)-2-(benzyl amino) ethanol (8.3g that serves as reasons, 34 mmoles) at the aqueous sodium hydroxide solution (40ml of methylene dichloride (100ml) and 1N, 40 mmoles) solution that forms in, and described mixture stirred 1 hour under uniform temp.Gained solution is used hydrochloric acid, saturated sodium bicarbonate aqueous solution and the salt water washing of 0.5M in succession, and dry on anhydrous magnesium sulfate.With solvent removed under reduced pressure, thereby obtain (1S)-1-(4-fluorophenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol.To adding potassium hydroxide (2.2g, 39 mmoles) in the formed solution by the gained compound in Virahol (60ml), and the mixture that will obtain thus stirred 4 hours.With solvent vacuum-evaporation, the layering between water and ethyl acetate of gained resistates.With the salt water washing of this organic layer, and dry on anhydrous magnesium sulfate.With solvent removed under reduced pressure, thereby obtain the yellow oil of (6S)-6-(4-fluorophenyl)-4-(benzyl) morpholine-3-ketone (9.7g).
(2) (2S)-2-(4-fluorophenyl)-4-(benzyl) morpholine synthetic
At room temperature will in 30 minutes, be added drop-wise to the lithium aluminium hydride (2.6g that is dissolved in tetrahydrofuran (THF) (200ml) in tetrahydrofuran (THF) (30ml) by the solution that (6S)-6-(4-fluorophenyl)-4-(benzyl) morpholine-3-ketone (9.7g) forms, 70 mmoles) in, and with the reaction mixture refluxed of gained 3 hours.By adding 0 ℃ water (10.6ml) and 15% aqueous sodium hydroxide solution (2.6ml) described reaction is quenched.The reaction mixture of gained is filtered, and filtrate is concentrated, thereby obtain the colorless oil of (2S)-2-(4-fluorophenyl)-4-(benzyl) morpholine (9.05g reaches 98% through 2 step productive rates).
1H-NMR(CDCl
3)δ：2.07(1H，dd，J＝10.8，10.8Hz)，2.27(1H，ddd，J＝11.4，11.4，3.3Hz)，2.75(1H，m)，2.87(1H，m)，3.54(3H，s)，3.82(1H，ddd，J＝11.4，11.4，2.4Hz)，3.82(1H，dd，J＝11.4，2.1Hz)，4.54(1H，dd，J＝11.4，2.1Hz)，6.96-7.03(2H，m)，7.23-7.33(7H，m)。
(3) (2S)-2-(4-fluorophenyl) morpholine hydrochloride synthetic
Under 70 ℃, chloroformic acid 1-chloroethene ester is added by (2S)-2-(4-fluorophenyl)-4-(benzyl) morpholine (9.05g) in ethylene dichloride (160ml) in the formed solution.After the gained reactant was refluxed 2 hours, with solvent removed under reduced pressure.Add methyl alcohol (100ml) in the gained resistates, the mixture that will obtain thus subsequently refluxed 30 minutes.With solvent evaporation, and filter collecting precipitation, thereby obtain the white crystal of (2S)-2-(4-fluorophenyl) morpholine hydrochloride (5.3g, 73%).
1H-NMR(d-DMSO)δ：2.99(1H，dd，J＝12.0，12.0Hz)，3.10(1H，ddd，J＝12.0，12.0，3.6Hz)，3.22-3.26(1H，m)，3.32(3H，s)，3.37-3.42(1H，m)，3.89-3.97(1H，m)，4.11(1H，dd，J＝12.3，3.3Hz)，4.77(1H，m)，7.20-7.26(2H，m)，7.42-7.47(2H，m)。
Embodiment 3
(1) (6S)-6-(4-fluorophenyl)-4-(benzyl) morpholine-3-ketone synthetic
At 5 ℃ under 15 ℃, will be by chloroacetyl chloride (9.3ml, 116.6 mmole) solution that forms in toluene (30ml) was added drop-wise in 1 hour by (1S)-1-(4-fluorophenyl)-2-(benzyl amino) ethanol (22.0g, 89.69 mmoles) in toluene (100ml) in the formed suspension.After stirring 2 hours, will be added drop-wise to temperature in 15 minutes by triethylamine (17.4ml, 123.7 mmoles) formed solution in toluene (20ml) is in 10 ℃ to 15 ℃ the said mixture.The mixture that obtains was thus at room temperature stirred 17 hours.After the HPLC analysis confirmation does not contain amino alcohol, said mixture is cooled to 2 ℃, and in 15 minutes, drips sodium methylate (52g, 269.07 mmoles, 28% methanol solution).The gained mixture was stirred 9 hours down at 2 ℃ to 5 ℃, and add entry (60ml).Formed organic layer is separated, and wash in succession with hydrochloric acid and the saturated sodium bicarbonate aqueous solution of 0.5N.With solvent removed under reduced pressure, thereby obtain the yellow oil of (6S)-6-(4-fluorophenyl)-4-(benzyl) morpholine-3-ketone (27.78g).
(2) (2S)-2-(4-fluorophenyl)-4-(benzyl) morpholine synthetic
Under 65 ℃, will (concentration in toluene be 70% solution by two (2-methoxy ethoxy) sodium aluminum hydride, 3.2ml, 11.4 mmole) solution that forms in tetrahydrofuran (THF) (5ml) was added drop-wise in 15 minutes by (6S)-6-(4-fluorophenyl)-4-(benzyl) morpholine-3-ketone (1.16g) in tetrahydrofuran (THF) (10ml) in the formed solution, and with gained reaction mixture refluxed 1.5 hours.After confirming not contain morpholine-3-ketone through HPLC, by add 0 ℃ water (0.6ml), 15% aqueous sodium hydroxide solution (0.6ml) and water (1.8ml) quenches described reaction.The gained reaction mixture is filtered and concentrated filtrate.In the gained resistates, add ethyl acetate and use 15% aqueous sodium hydroxide solution and water washing in succession.With solvent evaporation, thereby obtain the colorless oil of (2S)-2-(4-fluorophenyl)-4-(benzyl) morpholine (1.02g, productive rate 92%).
(3) (2S)-2-(4-fluorophenyl) morpholine synthetic
Under 89 ℃, in toluene (10ml), adding by Vinyl chloroformate (0.39ml, 4.04 mmoles) formed solution in toluene (5ml) in the formed solution by (2S)-2-(4-fluorophenyl)-4-(benzyl) morpholine (1.00g, 3.67 mmoles).The gained mixture was stirred 3 hours, and with solvent evaporation, thereby obtain the dark oil thing of (S)-2-(4-fluorophenyl) morpholine-4-carboxylic acid, ethyl ester (1.17g).
1H-NMR(CDCl
3)δ：1.28(t，3H，J＝7Hz)，2.7(1H，br)，3.1(1H，br)，3.65-3.69(1H，m)，4.0-4.1(2H，br)，4.19(q，2H，J＝7Hz)，4.4(1H，br)，4.5(1H，br)，7.0-7.4(4H，m)。
From above-mentioned resistates, collect the 100mg compound, and with potassium hydroxide aqueous solution (0.5ml) and ethanol (2ml) it is handled down at 80 ℃.After analyze confirming not contain initial morpholine,, and the gained mixture washed with ethyl acetate to the hydrochloric acid that wherein adds 5N (2ml) through HPLC.Formed water layer is handled with potassium hydroxide solution, and used ethyl acetate extraction.With solvent evaporation, thereby obtain the colorless solid of (2S)-2-(4-fluorophenyl) morpholine (35mg is 65% by the productive rate that (2S)-2-(4-fluorophenyl)-4-(benzyl) morpholine obtains).
1H-NMR(CDCl
3)δ：2.75(1H，dd，J＝12.0，12.0Hz)，2.90(1H，m)，2.95-3.05(2H，m)，3.73-3.77(1H，m)，4.01-4.04(1H，m)，4.44-4.47(1H，m)，7.00-7.04(2H，m)，7.31-7.34(2H，m)。
Embodiment 4
(1) (2S)-2-bromo-1-(4-bromophenyl) alcoholic acid is synthetic
With (S)-CBS ((S)-2-methyl-CBS- azoles borine, 50ml, make by Aldrich, concentration in toluene is the solution of 1.0M) be cooled to-30 ℃, and in 15 minutes, drip borine-tetrahydrochysene fluothane complex compound (270ml, 270 mmoles, the concentration in tetrahydrofuran (THF) are the solution of 1.0M).After the gained mixture is stirred 15 minutes; in 1 hour 10 minutes to wherein dripping by 4-benzoyl bromide monobromomethane (75.0g; 270 mmoles; make by Tokyo Kasei Kogyo company) formed solution in methylene dichloride (350ml), and temperature remained under-32 ℃ to-28 ℃.This mixture is being risen to 0 ℃ with temperature in stirring under the uniform temp after 1 hour, and methyl alcohol (10ml) is being divided into part adding several times in a small amount.Subsequently, in 10 minutes, in gains, drip the hydrochloric acid (300ml) of 0.5M, and the mixture that will obtain thus stirred at room temperature 40 minutes.Filter the precipitation of formation, and with the filtrate layering.The organic layer of gained is separated, and water layer is extracted with methylene dichloride.Organic layer is merged, with 0.5M salt acid elution once, wash twice and wash once with saturated brine with the 0.1M aqueous sodium hydroxide washes, dry on anhydrous magnesium sulfate then.With solvent removed under reduced pressure, thereby obtain the light brown oily thing of titled reference compound (77.0g, stoichiometry is 75.6g).
(2) (2S)-2-(4-bromophenyl) oxyethane synthetic
To be dissolved in the diethyl ether (400ml) by the compound (77.0g) that obtains in above-mentioned (1), at room temperature, gained solution be stirred 5 hours in the double-deck system that forms with 1M aqueous sodium hydroxide solution (400ml).After reaction finished, the gained demixing separated formed organic layer, and extracts water layer with diethyl ether.Organic layer is merged, wash once and drying on anhydrous magnesium sulfate with saturated brine.With the solvent drying under reduced pressure, thereby obtain the light brown oily thing of titled reference compound (55.0g, stoichiometry is 53.7g).
(3) (1S)-1-(4-bromophenyl)-2-((1R)-1-benzene ethylamino) alcoholic acid is synthetic
Will be by the compound (55.0g) that obtains in above-mentioned (2) and (R)-1-phenylethylamine (98.2g, 810 mmoles are made by Tokyo Kasei Kogyo company) stirred 6 hours in being heated to 80 ℃ oil bath.The amine that reduction vaporization is excessive, thus solid residue obtained.Adding isopropyl ether (200ml) is pulverized solid and filter and collect then, thereby obtains the white crystal of titled reference compound (57.0g).In addition, filtrate decompression is concentrated, and the gained resistates placed in refrigerator spend the night so that its partial crystallization.Add isopropyl ether (30ml), filter and collect the gained crystal, thereby obtain titled reference compound (5.60g).The gained crystal is merged, thereby obtain the titled reference compound (reaching 72.4%) of 62.6g through 3 step productive rates.
(4) (6S)-6-(4-bromophenyl)-4-((1R)-1-styroyl) morpholine-3-ketone synthetic
Under ice-cooled, will be by chloroacetyl chloride (24.3g, 215 mmoles, make by Tokyo KaseiKogyo Co., Ltd.) solution that forms in methylene dichloride (100ml) was added drop-wise to the compound (62.6g that obtains by in above-mentioned (3) in 30 minutes, 195 mmoles) and triethylamine (21.8g, 215 mmoles) in methylene dichloride (600ml) in the formed solution.When after ice-cooled reaction down 1 hour, the gained reaction mixture with 0.5M hydrochloric acid washed twice, is washed once with saturated sodium bicarbonate aqueous solution, and with the saturated brine washing once, dry on anhydrous magnesium sulfate again.With solvent removed under reduced pressure, the light brown oily thing of gained is dissolved in the Virahol (600ml), and to wherein adding potassium hydroxide aqueous solution (85%, 16.1g, 244 mmoles).The mixture that so obtains was at room temperature stirred 16 hours.With solvent removed under reduced pressure and add ethyl acetate.The gained mixture is washed with water once, with 0.5M hydrochloric acid washed twice, with the saturated sodium bicarbonate aqueous solution washing once, and with the saturated brine washing once, dry on anhydrous magnesium sulfate again.With solvent removed under reduced pressure, thereby obtain the brown oil of titled reference compound (70.2g, stoichiometry is 70.2g).
(5) (2R)-2-(4-bromophenyl)-4-((1R)-1-styroyl) morpholine synthetic
(concentration in tetrahydrofuran (THF) is the solution of 1.0M with borine-tetrahydrofuran complex under ice-cooled, 510ml, 510 mmoles) in 45 minutes, be added drop-wise to by the compound (70.2g) that obtains in above-mentioned (4) in tetrahydrofuran (THF) (510ml) in the formed solution.With the gained mixture in ice-cooled down reaction 1 hour, then at room temperature react 30 minutes after, this mixture is carried out once more ice-cooled, and methyl alcohol (60ml) be divided into a small amount of part add carefully several times to avoid producing foam.With solvent removed under reduced pressure, and in the gained resistates, add the aqueous sodium hydroxide solution (280ml) of methyl alcohol (750ml) and 1M.The mixture that obtains was thus stirred 1 hour in being heated to 80 ℃ oil bath, added 1M aqueous sodium hydroxide solution (70ml), and added altogether 3 times in per during this period 15 minutes.Reaction with the methyl alcohol reduction vaporization, and adds entry (500ml) after finishing.With twice of ethyl acetate extraction of gained mixture.The organic layer that obtains is thus merged, and wash with water once, use the saturated brine washed twice, dry on anhydrous magnesium sulfate again.With solvent removed under reduced pressure, thereby obtain the white crystal of titled reference compound (65.0g reaches 96.3% through 2 step productive rates).
IR(ATR)：1487，1449，1117，1098，809，758，699，550cm
-1
1H-NMR(CDCl
3)δ：1.35(3H，d)，2.10(2H，m)，2.60(1H，m)，3.05(1H，m)，3.35(1H，q)，3.75(1H，m)，3.89(1H，m)，4.55(1H，m)，7.25(7H，m)，7.46(2H，d)
HPLC: area is than 98.6%, the ratio 99.2% of diastereomer
Post: Inertsil ODS-3V 4.6 * 150mm
Developping agent: CH
3CN/H
2O=28/72 (0.1%TFA)
Flow velocity: 1.0ml/ minute
Detection: 230nm
Column temperature: 40 ℃
Retention time: 17.7 minutes
Embodiment 5
(2S)-2-(4-fluorophenyl) morpholine synthetic
33 ℃ under 35 ℃, will by the Pd-C (0.106g) of (2S)-2-(4-fluorophenyl)-4-(benzyl) morpholine (250mg) and 5% in ethanol (5ml) formed suspension with hydrogen treat 1 hour.With this suspension diatomite filtration, and use washing with alcohol.With solvent evaporation, thereby obtain the white solid of (2S)-2-(4-fluorophenyl) morpholine (160mg, 94%).
1H-NMR(CDCl
3)δ：2.75(1H，dd，J＝12.0，12.0Hz)，2.90(1H，m)，2.95-3.05(2H，m)，3.73-3.77(1H，m)，4.01-4.04(1H，m)，4.44-4.47(1H，m)，7.00-7.04(2H，m)，7.31-7.34(2H，m)。
Reference example 1
(1) 2-sulfydryl-1-methyl isophthalic acid H-[4,4 '] connection pyrimidyl-6-ketone synthetic
Will be by 3-oxo-3-pyrimidine-4-base-ethyl propionate (36.10g, 0.186 N-methyl-thiourea (25.40g mole),, 0.282 mole) and 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (29.11g, 0.191 mole) formed solution in ethanol (150ml) refluxed 21 hours.Remove the ethanol of half amount in decompression after, in gained solution, add hydrochloric acid.Formed sedimentation and filtration is collected, and washed with water, carry out drying then.To stir in the ethyl acetate (1L) that is deposited in heat that so obtains, and filter and collect this precipitation, carry out drying again, thereby obtain 2-sulfydryl-1-methyl isophthalic acid H-[4,4 '] connection pyrimidyl-6-ketone (33.91g, 83%).
1H-NMR(CDCl
3)δ：3.59(3H，s)，6.91(1H，s)，8.27(1H，d，J＝2.4Hz)，9.08(1H，d，J＝2.1Hz)，9.41(1H，s)，11.99(1H，s)
(2) 2-chloro-1-methyl isophthalic acid H-[4,4 '] connection pyrimidyl-6-ketone synthetic
Will be by 2-sulfydryl-1-methyl isophthalic acid H-[4,4 '] connection pyrimidyl-6-ketone (8.8g, 40 mmoles) at mixed solvent (by dimethyl formamide (30ml) and 1,2-ethylene dichloride (30ml) formation) suspension that forms in joins phosphoryl chloride (11.2ml, 120 mmoles) in, and the gained mixture stirred 50 minutes down at 65 ℃.After the solution that will so form is poured in the ice-cooled methylene dichloride (300ml), add entry, and with gained mixture vigorous stirring 5 minutes.To wherein adding aqueous sodium carbonate (25.4g, 240 mmoles are in water (100ml)), and its pH is transferred to 8 with saturated sodium bicarbonate aqueous solution.(concentration in water is 5%, 120ml) to wherein adding aqueous sodium hypochlorite solution.Gains are filtered by after the diatomite, organic layer is separated, and with twice of dichloromethane extraction of water layer.Organic layer is merged, and with the saturated sodium bicarbonate aqueous solution washing, dry on sodium sulfate again.With solvent removed under reduced pressure, by silica gel column chromatography (elutriant: ethyl acetate/hexane=1/1) purifying gained resistates, and wash with diethyl ether, thereby obtain 2-chloro-1-methyl isophthalic acid H-[4,4 '] connection pyrimidyl-6-ketone (2.2g, 62%, purity 98.7%) light yellow solid.
1H-NMR(CDCl
3)δ：3.74(3H，s)，7.58(1H，s)，8.19(1H，d，J＝5.7Hz)，8.92(1H，d，J＝5.2Hz)，9.31(1H，d，J＝1.1Hz)
(3) 2-[(2S)-2-(2-(4-fluorophenyl) morpholine-4-yl)]-1-methyl isophthalic acid H-[4,4 '] connection pyrimidyl-6-ketone synthetic
Will be by (2S)-2-(4-fluorophenyl) morpholine hydrochloride (108.6mg, 0.60 2-chloro-1-methyl isophthalic acid H-[4 mmole),, 4 '] connection pyrimidyl-6-ketone (88.4mg, 0.40 mmole) and triethylamine (0.27ml, 2.0 mmoles) formed solution at room temperature stirs several hours in tetrahydrofuran (THF) (2ml).Filter formed precipitation after the cooling, and with solvent vacuum-evaporation.With ethyl acetate washing gained resistates, thereby obtain titled reference compound (100mg, 74%).
1H-NMR(CDCI
3)δ：3.09(dd，J＝12.9，10.8Hz，1H)，3.29(m，1H)，3.52-3.64(m，2H)，3.59(s，3H)，4.00(m，1H)，4.21(m，1H)，4.72(dd，J＝10.5，2.1Hz，1H)，7.07-7.13(m，2H)，7.38-7.43(m，3H)，8.13(dd，J＝5.4，1.2Hz，1H)，8.88(d，J＝5.1Hz，1H)，9.28(s，1H)。
MS[M
+H]
+：367。
Embodiment 6
(1) the vitamin B13 ethyl ester is synthetic
Vitamin B13 monohydrate (53.19g, 0.306 mmole) is joined by 1, and 8-diazabicyclo [5.4.0] 11 carbon-7-alkene (46.51g, 0.306 mmole) are in dimethyl formamide (85ml) in the formed solution.With the gained solution stirring after 5 minutes, to wherein adding iodoethane (57.14g, 0.366 mmole), and the mixture that will form thus is 60 ℃ of heating 5 hours down.In this mixture, add entry (1L), filter and collect the gained precipitation, wash with water, and carry out drying, thereby obtain vitamin B13 ethyl ester (48.25g, 88%).
1H?NMR(DMSO-d
6)δ：1.29(3H，dt，J＝1.5，6.9Hz)，4.31(2H，dq，J＝1.2，7.2Hz)，6.04(1H，d，J＝1.2Hz)，11.11(1H，s)，11.37(1H，s)
Synthesizing of (2) 2,6-dichloro pyrimidine-4-carboxylic acid, ethyl ester
With N, N-Diethyl Aniline (60ml, 0-377 mmole) adds in the mixture that is formed by vitamin B13 ethyl ester (120ml, 1.31 moles) and phosphoryl chloride (97.70g, 0.531 mmole), and the gained mixture was refluxed 70 minutes.Formed solution is poured in the frozen water, filtered and collect the gained solid, and wash with water.Described solid is dissolved in the ethyl acetate, and the solution that will obtain thus is dry on sodium sulfate then by filtered through silica gel, carries out concentrating under reduced pressure again.By short silica gel column chromatography (elutriant: hexanol/ethyl acetate=2/1) purifying gained resistates, thereby obtain 2,6-dichloro pyrimidine-4-carboxylic acid, ethyl ester (99.94g, 85%).
1H?NMR(CDCl
3)δ：1.45(3H，t，J＝7.3Hz)，4.51(3H，q，J＝7.1Hz)，7.97(1H，s)
(3) pyrimidine-4-carboxylic acid, ethyl ester is synthetic
Triethylamine (48.03g, 0.475 mmole) is joined by 2, and 6-dichloro pyrimidine-4-carboxylic acid, ethyl ester (38.60g, 0.175 mmole) is in tetrahydrofuran (THF) (700ml) in the formed solution.To the palladium-carbon that wherein adds 5%, and the gained mixture stirred 6 hours under hydrogen atmosphere.Remove by filter the solid that generates in the reaction system, and filtrate decompression is concentrated.By silica gel column chromatography purifying gained resistates, thereby obtain pyrimidine-4-carboxylic acid, ethyl ester (23.06g, 87%).
1H?NMR(CDCl
3)δ：1.46(3H，t，J＝7.1Hz)，4.52(2H，q，J＝7.1Hz)，8.03(1H，dd，J＝1.7，5.0Hz)，9.00(1H，d，J＝5.0Hz)，9.42(1H，d，J＝1.4Hz)
(4) 3-oxo-3-(pyrimidine-4-yl) ethyl propionate is synthetic
Will be by ethanol (16.18g, 0.351 mole) solution that forms in diethyl ether (15ml) joins by sodium hydride (13.71g, 0.343 mole, the concentration in paraffin is 60%, removes deparaffnize with hexane wash) in diethyl ether (100ml) in the formed solution.After the gained mixture is stirred 30 minutes,, and add toluene (100ml) with solvent removed under reduced pressure.In gains, add formed solution in toluene (100ml), and the mixture that will obtain thus heated 3 hours down at 80 ℃ by pyrimidine-4-carboxylic acid, ethyl ester (30.86g, 0.203 mole) and ethyl acetate (30.48g, 0.346 mole).To wherein adding hydrochloric acid, add sodium bicarbonate subsequently being 4 with pH regulator.The solution that obtains thus layering between water and ethyl acetate.With salt water washing gained organic layer, and dry on sodium sulfate.With solvent removed under reduced pressure, thereby obtain 3-oxo-3-(pyrimidine-4-yl) ethyl propionate (36.10g, 92%).
1H?NMR(CDCl
3)δ：1.35(3H，t，J＝6.9Hz)，4.31(2H，q，J＝7.2Hz)，6.47(1H，s)，7.84(1H，dd，J＝1.5，5.4Hz)，8.89(1H，d，J＝5.1Hz)，9.24(1H，d，J＝1.2Hz)，12.22(1H，s)
(5) 3-oxo-3-(pyrimidine-4-yl) ethyl propionate is synthetic
At room temperature, to by tertiary amyl alcohol potassium solution (5.31g of formed 25% in toluene, 10.52 drip the solution that in toluene (2.4ml), forms by pyrimidine-4-carboxylic acid, ethyl ester (1.00g, 6.57 mmoles) and ethyl acetate (1.09ml, 11.1 mmoles) mmole).After analyze confirming not contain ethyl ester by HPLC, in said mixture, add entry (5ml), ethyl acetate (5ml) and concentrated hydrochloric acid (0.45ml), and extract this mixture with ethyl acetate (4ml).The gained organic layer is dry on sodium sulfate, and with solvent removed under reduced pressure, thereby 3-oxo-3-(pyrimidine-4-yl) ethyl propionate (0.97g, 76%) obtained.
Reference example 2
(1) 2-sulfydryl-1-methyl isophthalic acid H-[4,4 '] connection pyrimidyl-6-ketone synthetic
Will be by 3-oxo-3-(pyrimidine-4-yl) ethyl propionate (36.10g, 0.186 mole), N-methyl-thiourea (25.40g, 0.282 mole) and 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene formed solution in ethanol (150ml) refluxed 21 hours.Reduction vaporization falls the ethanol of half amount, and adds hydrochloric acid in gains.Filter and collect formed precipitation, and wash with water, carry out drying again.With described middle stirring of ethyl acetate (1L) that is deposited in heat, and filter and collect this precipitation, carry out drying again, thereby obtain 2-sulfydryl-1-methyl isophthalic acid H-[4,4 '] connection pyrimidyl-6-ketone (33.91g, 83%).
1H?NMR(CDCl
3)δ：3.59(3H，s)，6.91(1H，s)，8.27(1H，d，J＝2.4Hz)，9.08(1H，d，J＝2.1Hz)，9.41(1H，s)，11.99(1H，s)
(2) 2-chloro-1-methyl isophthalic acid H-[4,4 '] connection pyrimidyl-6-ketone synthetic
Will be by 2-sulfydryl-1-methyl isophthalic acid H-[4,4 '] connection pyrimidyl-6-ketone (8.8g, 40 mmoles) at mixed solvent (by dimethyl formamide (30ml) and 1,2-ethylene dichloride (30ml) formation) suspension that forms in joins phosphoryl chloride (11.2ml, 120 mmoles) in, and the gained mixture stirred 50 minutes down at 65 ℃.Gained solution is poured in the ice-cooled methylene dichloride (300ml), and added entry, then with gained mixture vigorous stirring 5 minutes.To wherein adding aqueous sodium carbonate (25.4g, 240 mmoles are in water-soluble (100ml)), and be 8 with its pH regulator with saturated aqueous solution of sodium bicarbonate.(concentration in water is 5% solution, 120ml) to add aqueous sodium hypochlorite solution in gains.By after the diatomite filtration, with gained organic layer dichloromethane extraction twice, and with the saturated sodium bicarbonate aqueous solution washing, dry on sodium sulfate then.With solvent removed under reduced pressure, and the resistates (elutriant: ethyl acetate/hexane=1/1), wash with diethyl ether again by silica gel column chromatography purifying gained, thereby obtain 2-chloro-1-methyl isophthalic acid H-[4,4 '] connection pyrimidyl-6-ketone (2.2g, 62%, purity 98.7%) light yellow solid.
1H-NMR(CDCl
3)δ：3.74(3H，s)，7.58(1H，s)，8.19(1H，d，J＝5.7Hz)，8.92(1H，d，J＝5.2Hz)，9.31(1H，d，J＝1.1Hz)
(3) 2-[(2S)-2-(2-(4-fluorophenyl) morpholine-4-yl)]-1-methyl isophthalic acid H-[4,4 '] connection pyrimidyl-6-ketone synthetic
Will be by (2S)-2-(4-fluorophenyl) morpholine hydrochloride (108.6mg, 0.60 2-chloro-1-methyl isophthalic acid H-[4 mmole),, 4 '] connection pyrimidyl-6-ketone (88.4mg, 0.40 mmole) and triethylamine (0.27ml, 2.0 mmoles) formed solution at room temperature stirs some hrs in tetrahydrofuran (THF) (2ml).Gained mixture cooled and filtered is gone out gained precipitation, and with solvent vacuum-evaporation.With ethyl acetate washing gained resistates, thereby obtain 2-[(2S)-2-(2-(4-fluorophenyl) morpholine-4-yl)]-1-methyl isophthalic acid H-[4,4 '] connection pyrimidyl-6-ketone (100mg, 74%).
1H-NMR(CDCI
3)δ：3.09(dd，J＝12.9，10.8Hz，1H)，3.29(m，1H)，3.52-3.64(m，2H)，3.59(s，3H)，4.00(m，1H)，4.21(m，1H)，4.72(dd，J＝10.5，2.1Hz，1H)，7.07-7.1?3(m，2H)，7.3?8-7.43(m，3H)，8.13(dd，J＝5.4，1.2Hz，1H)，8.88(d，J＝5.1Hz，1H)，9.28(s，1H)。
MS[M
+H]
+：367。
Industrial applicibility
Preparation in accordance with the present invention can be by industrial favourable method with higher productive rate Preparation has morpholinium compound and the 3-oxo-3-(pyrimidine-4-that optically active 2-aryl replaces Base) propionic ester, morpholinium compound and 3-oxo-3-(pyrimidine-4-yl) propionic ester that the 2-aryl replaces Have tau protein kinases 1 and suppress active and can be used as Alzheimer's etc. as synthetic Medicine compound (2-(2-aryl morpholine-4-yl)-1-methyl isophthalic acid H-[4 for example, 4 '] connection Pyrimidine radicals-6-ketone etc.) starting material is important.
The application is based on the patent application No.2005/213311,2005/267485 and 2006/015436 that submits in Japan, and these patent applications are all incorporated this paper into way of reference.
Claims (28)
1. preparation method by formula 5 expression with optically active compound, this method may further comprise the steps:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; X
1Be halogen; R
1Be C
1-C
6Alkyl, can randomly have substituent aralkyl or for C
2-C
6Thiazolinyl;
Step 1) is reacted the compound shown in the formula 1 and borine or its complex compound, thereby is obtained the compound shown in the formula 2 under the condition that (S)-2-methyl-CBS- azoles borine exists in solvent,
Step 2) compound and the alkali shown in the formula 2 is reacted in solvent, thereby obtain the compound of formula 3, and
Step 3) is reacted the amine shown in compound shown in the formula 3 and the formula 4, thereby obtains the compound shown in the formula 5.
2. preparation method by formula 10 expression with optically active morpholinium compound, this method may further comprise the steps:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; R
1Be C
1-C
6Alkyl, can randomly have substituent aralkyl or for C
2-C
6Thiazolinyl; R
2Be C
1-C
6Alkyl, C
1-C
6Haloalkyl, can randomly have substituent aryl or for can randomly have substituent benzyl; X
2Be halogen;
Step 1) is reacted the compound shown in the formula 5 and activatory Mono Chloro Acetic Acid or bromoacetic acid in solvent, thereby obtains the compound shown in the formula 6,
Step 2) compound and the alkali shown in the formula 6 is reacted, thereby obtains the compound shown in the formula 7,
Step 3) is reacted compound and the reductive agent shown in the formula 7 in solvent, thereby obtains the compound shown in the formula 8,
Step 4) is reacted compound and the chloro-formic ester shown in the formula 8, thereby obtains the compound shown in the formula 9, and
Step 5) is hydrolyzed the compound shown in the formula 9, thereby obtains the compound shown in the formula 10.
3. optically active compound or its salt that has by formula 11 expression:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; R
1Be C
1-C
6Alkyl, can randomly have substituent aralkyl or for C
2-C
6Thiazolinyl; R
10For hydrogen atom or be :-CO-CH by formula
2-X
2(X wherein
2Be halogen) represented group.
4. the described compound or its salt of claim 3, wherein R is for having 1 to 3 substituent phenyl, and wherein said substituting group is selected from: halogen, C
1-C
6Alkyl, the C that is substituted
1-C
6Alkyl, C
1-C
6Alkoxyl group, the C that is substituted
1-C
6Alkoxyl group, nitro, aralkoxy, C
1-C
6Alkylsulfonyloxy, aryl-sulfonyl oxygen and through C
1-C
6The aryl-sulfonyl oxygen that alkyl replaces.
5. compound or its salt according to claim 3, described compound is selected from:
(1S)-1-(4-fluorophenyl)-2-(benzyl amino) ethanol,
(1S)-1-(4-fluorophenyl)-2-(4-methoxybenzyl amino) ethanol,
(1S)-1-(4-fluorophenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1S)-1-(4-fluorophenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1S)-1-(4-fluorophenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1S)-1-(4-fluorophenyl)-2-(2-benzene ethylamino) ethanol,
(1S)-1-(4-fluorophenyl)-2-(methylamino-) ethanol,
(1S)-1-(4-fluorophenyl)-2-(ethylamino) ethanol,
(1S)-1-(4-fluorophenyl)-2-(uncle's fourth amino) ethanol,
(1S)-1-(4-fluorophenyl)-2-(allyl amino) ethanol,
(1S)-1-(3-fluorophenyl)-2-(benzyl amino) ethanol,
(1S)-1-(3-fluorophenyl)-2-(4-methoxybenzyl amino) ethanol,
(1S)-1-(3-fluorophenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1S)-1-(3-fluorophenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1S)-1-(3-fluorophenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1S)-1-(3-fluorophenyl)-2-(2-benzene ethylamino) ethanol,
(1S)-1-(3-fluorophenyl)-2-(methylamino-) ethanol,
(1S)-1-(3-fluorophenyl)-2-(ethylamino) ethanol,
(1S)-1-(3-fluorophenyl)-2-(uncle's fourth amino) ethanol,
(1S)-1-(3-fluorophenyl)-2-(allyl amino) ethanol,
(1S)-1-(4-chloro-phenyl-)-2-(benzyl amino) ethanol,
(1S)-1-(4-chloro-phenyl-)-2-(4-methoxybenzyl amino) ethanol,
(1S)-1-(4-chloro-phenyl-)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1S)-1-(4-chloro-phenyl-)-2-((1R)-1-benzene ethylamino) ethanol,
(1S)-1-(4-chloro-phenyl-)-2-((1S)-1-benzene ethylamino) ethanol,
(1S)-1-(4-chloro-phenyl-)-2-(2-benzene ethylamino) ethanol,
(1S)-1-(4-chloro-phenyl-)-2-(methylamino-) ethanol,
(1S)-1-(4-chloro-phenyl-)-2-(ethylamino) ethanol,
(1S)-1-(4-chloro-phenyl-)-2-(uncle's fourth amino) ethanol,
(1S)-1-(4-chloro-phenyl-)-2-(allyl amino) ethanol,
(1S)-1-(4-bromophenyl)-2-(benzyl amino) ethanol,
(1S)-1-(4-bromophenyl)-2-(4-methoxybenzyl amino) ethanol,
(1S)-1-(4-bromophenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1S)-1-(4-bromophenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1S)-1-(4-bromophenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1S)-1-(4-bromophenyl)-2-(2-benzene ethylamino) ethanol,
(1S)-1-(4-bromophenyl)-2-(methylamino-) ethanol,
(1S)-1-(4-bromophenyl)-2-(ethylamino) ethanol,
(1S)-1-(4-bromophenyl)-2-(uncle's fourth amino) ethanol,
(1S)-1-(4-bromophenyl)-2-(allyl amino) ethanol,
(1S)-1-(4-nitrophenyl)-2-(benzyl amino) ethanol,
(1S)-1-(4-nitrophenyl)-2-(4-methoxybenzyl amino) ethanol,
(1S)-1-(4-nitrophenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1S)-1-(4-nitrophenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1S)-1-(4-nitrophenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1S)-1-(4-nitrophenyl)-2-(2-benzene ethylamino) ethanol,
(1S)-1-(4-nitrophenyl)-2-(methylamino-) ethanol,
(1S)-1-(4-nitrophenyl)-2-(ethylamino) ethanol,
(1S)-1-(4-nitrophenyl)-2-(uncle's fourth amino) ethanol,
(1S)-1-(4-nitrophenyl)-2-(allyl amino) ethanol,
(1S)-1-(4-fluorophenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-fluorophenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1S)-1-(4-fluorophenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-fluorophenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-fluorophenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol,
(1S)-1-(4-fluorophenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol,
(1S)-1-(4-bromophenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-bromophenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1S)-1-(4-bromophenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-bromophenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-bromophenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol,
(1S)-1-(4-bromophenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol,
(1S)-1-(4-nitrophenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-nitrophenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1S)-1-(4-nitrophenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-nitrophenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-nitrophenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol,
(1S)-1-(4-nitrophenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(benzyl amino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(4-methoxybenzyl amino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(2-benzene ethylamino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(methylamino-) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(ethylamino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(uncle's fourth amino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(allyl amino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol,
(1S)-1-(4-benzyloxy phenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(benzyl amino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(4-methoxybenzyl amino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(2-benzene ethylamino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(methylamino-) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(ethylamino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(uncle's fourth amino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(allyl amino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol,
(1S)-1-(4-mesyloxy phenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(benzyl amino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(4-methoxybenzyl amino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(2-benzene ethylamino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(methylamino-) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(ethylamino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(uncle's fourth amino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(allyl amino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol,
(1S)-1-(4-phenylsulfonyloxy phenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(benzyl amino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(4-methoxybenzyl amino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(2-benzene ethylamino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(methylamino-) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(ethylamino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(uncle's fourth amino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(allyl amino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol and
(1S)-1-(4-(4-tosyloxy) phenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol.
6. one kind has optically active morpholinium compound or its salt by formula 12 expression:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; R
1aBe hydrogen atom, C
1-C
6Alkyl, can randomly have substituent aralkyl, C
2-C
6Thiazolinyl or be :-COOR by formula
2(R wherein
2Be C
1-C
6Alkyl, C
1-C
6Haloalkyl, can randomly have substituent aryl or for can randomly having substituent benzyl) represented group; Z is O or H
2,
Condition is to work as R
1aFor hydrogen atom, Z are H
2The time, R not should be the 4-fluorophenyl.
7. the described compound or its salt of claim 6, wherein R is for having 1 to 3 substituent phenyl, and wherein said substituting group is selected from halogen, C
1-C
6Alkyl, the C that is substituted
1-C
6Alkyl, C
1-C
6Alkoxyl group, the C that is substituted
1-C
6Alkoxyl group, nitro, aralkoxy, C
1-C
6Alkylsulfonyloxy, aryl-sulfonyl oxygen and through C
1-C
6The aryl-sulfonyl oxygen that alkyl replaces.
8. the described compound or its salt of claim 6, described compound is selected from:
(6S)-6-(4-fluorophenyl)-4-(benzyl) morpholine-3-ketone,
(6S)-6-(4-fluorophenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-fluorophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-fluorophenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-fluorophenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-fluorophenyl)-4-(2-styroyl) morpholine-3-ketone,
(6S)-6-(4-fluorophenyl)-4-(methyl) morpholine-3-ketone,
(6S)-6-(4-fluorophenyl)-4-(ethyl) morpholine-3-ketone,
(6S)-6-(4-fluorophenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6S)-6-(4-fluorophenyl)-4-(allyl group) morpholine-3-ketone,
(6S)-6-(4-fluorophenyl) morpholine-3-ketone,
(6S)-6-(3-fluorophenyl)-4-(benzyl) morpholine-3-ketone,
(6S)-6-(3-fluorophenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6S)-6-(3-fluorophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6S)-6-(3-fluorophenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6S)-6-(3-fluorophenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6S)-6-(3-fluorophenyl)-4-(2-styroyl) morpholine-3-ketone,
(6S)-6-(3-fluorophenyl)-4-(methyl) morpholine-3-ketone,
(6S)-6-(3-fluorophenyl)-4-(ethyl) morpholine-3-ketone,
(6S)-6-(3-fluorophenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6S)-6-(3-fluorophenyl)-4-(allyl group) morpholine-3-ketone,
(6S)-6-(3-fluorophenyl) morpholine-3-ketone,
(6S)-6-(4-chloro-phenyl-)-4-(benzyl) morpholine-3-ketone,
(6S)-6-(4-chloro-phenyl-)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-chloro-phenyl-)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-chloro-phenyl-)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-chloro-phenyl-)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-chloro-phenyl-)-4-(2-styroyl) morpholine-3-ketone,
(6S)-6-(4-chloro-phenyl-)-4-(methyl) morpholine-3-ketone,
(6S)-6-(4-chloro-phenyl-)-4-(ethyl) morpholine-3-ketone,
(6S)-6-(4-chloro-phenyl-)-4-(tertiary butyl) morpholine-3-ketone,
(6S)-6-(4-chloro-phenyl-)-4-(allyl group) morpholine-3-ketone,
(6S)-6-(4-bromophenyl)-4-(benzyl) morpholine-3-ketone,
(6S)-6-(4-bromophenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-bromophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-bromophenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-bromophenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-bromophenyl)-4-(2-styroyl) morpholine-3-ketone,
(6S)-6-(4-bromophenyl)-4-(methyl) morpholine-3-ketone,
(6S)-6-(4-bromophenyl)-4-(ethyl) morpholine-3-ketone,
(6S)-6-(4-bromophenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6S)-6-(4-bromophenyl)-4-(allyl group) morpholine-3-ketone,
(6S)-6-(4-nitrophenyl)-4-(benzyl) morpholine-3-ketone,
(6S)-6-(4-nitrophenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-nitrophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-nitrophenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-nitrophenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-nitrophenyl)-4-(2-styroyl) morpholine-3-ketone,
(6S)-6-(4-nitrophenyl)-4-(methyl) morpholine-3-ketone,
(6S)-6-(4-nitrophenyl)-4-(ethyl) morpholine-3-ketone,
(6S)-6-(4-nitrophenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6S)-6-(4-nitrophenyl)-4-(allyl group) morpholine-3-ketone,
(2S)-2-(4-fluorophenyl)-4-(benzyl) morpholine,
(2S)-2-(4-fluorophenyl)-4-(4-methoxy-benzyl) morpholine,
(2S)-2-(4-fluorophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2S)-2-(4-fluorophenyl)-4-((1R)-1-styroyl) morpholine,
(2S)-2-(4-fluorophenyl)-4-((1S)-1-styroyl) morpholine,
(2S)-2-(4-fluorophenyl)-4-(2-styroyl) morpholine,
(2S)-2-(4-fluorophenyl)-4-(methyl) morpholine,
(2S)-2-(4-fluorophenyl)-4-(ethyl) morpholine,
(2S)-2-(4-fluorophenyl)-4-(tertiary butyl) morpholine,
(2S)-2-(4-fluorophenyl)-4-(allyl group) morpholine,
(2S)-2-(3-fluorophenyl)-4-(benzyl) morpholine,
(2S)-2-(3-fluorophenyl)-4-(4-methoxy-benzyl) morpholine,
(2S)-2-(3-fluorophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2S)-2-(3-fluorophenyl)-4-((1R)-1-styroyl) morpholine,
(2S)-2-(3-fluorophenyl)-4-((1S)-1-styroyl) morpholine,
(2S)-2-(3-fluorophenyl)-4-(2-styroyl) morpholine,
(2S)-2-(3-fluorophenyl)-4-(methyl) morpholine,
(2S)-2-(3-fluorophenyl)-4-(ethyl) morpholine,
(2S)-2-(3-fluorophenyl)-4-(tertiary butyl) morpholine,
(2S)-2-(3-fluorophenyl)-4-(allyl group) morpholine,
(2S)-2-(3-fluorophenyl) morpholine,
(2S)-2-(4-chloro-phenyl-)-4-(benzyl) morpholine,
(2S)-2-(4-chloro-phenyl-)-4-(4-methoxy-benzyl) morpholine,
(2S)-2-(4-chloro-phenyl-)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2S)-2-(4-chloro-phenyl-)-4-((1R)-1-styroyl) morpholine,
(2S)-2-(4-chloro-phenyl-)-4-((1S)-1-styroyl) morpholine,
(2S)-2-(4-chloro-phenyl-)-4-(2-styroyl) morpholine,
(2S)-2-(4-chloro-phenyl-)-4-(methyl) morpholine,
(2S)-2-(4-chloro-phenyl-)-4-(ethyl) morpholine,
(2S)-2-(4-chloro-phenyl-)-4-(tertiary butyl) morpholine,
(2S)-2-(4-chloro-phenyl-)-4-(allyl group) morpholine,
(2S)-2-(4-bromophenyl)-4-(benzyl) morpholine,
(2S)-2-(4-bromophenyl)-4-(4-methoxy-benzyl) morpholine,
(2S)-2-(4-bromophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2S)-2-(4-bromophenyl)-4-((1R)-1-styroyl) morpholine,
(2S)-2-(4-bromophenyl)-4-((1S)-1-styroyl) morpholine,
(2S)-2-(4-bromophenyl)-4-(2-styroyl) morpholine,
(2S)-2-(4-bromophenyl)-4-(methyl) morpholine,
(2S)-2-(4-bromophenyl)-4-(ethyl) morpholine,
(2S)-2-(4-bromophenyl)-4-(tertiary butyl) morpholine,
(2S)-2-(4-bromophenyl)-4-(allyl group) morpholine,
(2S)-2-(4-bromophenyl) morpholine,
(2S)-2-(4-nitrophenyl)-4-(benzyl) morpholine,
(2S)-2-(4-nitrophenyl)-4-(4-methoxy-benzyl) morpholine,
(2S)-2-(4-nitrophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2S)-2-(4-nitrophenyl)-4-((1R)-1-styroyl) morpholine,
(2S)-2-(4-nitrophenyl)-4-((1S)-1-styroyl) morpholine,
(2S)-2-(4-nitrophenyl)-4-(2-styroyl) morpholine,
(2S)-2-(4-nitrophenyl)-4-(methyl) morpholine,
(2S)-2-(4-nitrophenyl)-4-(ethyl) morpholine,
(2S)-2-(4-nitrophenyl)-4-(tertiary butyl) morpholine,
(2S)-2-(4-nitrophenyl)-4-(allyl group) morpholine,
(2S)-2-(4-nitrophenyl) morpholine,
(2S)-2-(4-fluorophenyl) morpholine-4-carboxylate methyl ester,
(2S)-2-(4-fluorophenyl) morpholine-4-carboxylic acid, ethyl ester,
(2S)-2-(4-fluorophenyl) morpholine-4-carboxylic acid phenyl ester,
(2S)-2-(4-fluorophenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(2S)-2-(3-fluorophenyl) morpholine-4-carboxylate methyl ester,
(2S)-2-(3-fluorophenyl) morpholine-4-carboxylic acid, ethyl ester,
(2S)-2-(3-fluorophenyl) morpholine-4-carboxylic acid phenyl ester,
(2S)-2-(3-fluorophenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(2S)-2-(4-chloro-phenyl-) morpholine-4-carboxylate methyl ester,
(2S)-2-(4-chloro-phenyl-) morpholine-4-carboxylic acid, ethyl ester,
(2S)-2-(4-chloro-phenyl-) morpholine-4-carboxylic acid phenyl ester,
(2S)-2-(4-chloro-phenyl-) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(2S)-2-(4-bromophenyl) morpholine-4-carboxylate methyl ester,
(2S)-2-(4-bromophenyl) morpholine-4-carboxylic acid, ethyl ester,
(2S)-2-(4-bromophenyl) morpholine-4-carboxylic acid phenyl ester,
(2S)-2-(4-bromophenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(2S)-2-(4-nitrophenyl) morpholine 4-carboxylate methyl ester,
(2S)-2-(4-nitrophenyl) morpholine-4-carboxylic acid, ethyl ester,
(2S)-2-(4-nitrophenyl) morpholine-4-carboxylic acid phenyl ester,
(2S)-2-(4-nitrophenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(2S)-2-(4-fluorophenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2S)-2-(3-fluorophenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2S)-2-(4-chloro-phenyl-) morpholine-4-carboxylic acid 1-chloroethene ester,
(2S)-2-(4-bromophenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2S)-2-(4-nitrophenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(6S)-6-(4-benzyloxy phenyl)-4-(benzyl) morpholine-3-ketone,
(6S)-6-(4-benzyloxy phenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-benzyloxy phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-benzyloxy phenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-benzyloxy phenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-benzyloxy phenyl)-4-(2-styroyl) morpholine-3-ketone,
(6S)-6-(4-benzyloxy phenyl)-4-(methyl) morpholine-3-ketone,
(6S)-6-(4-benzyloxy phenyl)-4-(ethyl) morpholine-3-ketone,
(6S)-6-(4-benzyloxy phenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6S)-6-(4-benzyloxy phenyl)-4-(allyl group) morpholine-3-ketone,
(6S)-6-(4-benzyloxy phenyl) morpholine-3-ketone,
(2S)-2-(4-benzyloxy phenyl)-4-(benzyl) morpholine,
(2S)-2-(4-benzyloxy phenyl)-4-(4-methoxy-benzyl) morpholine,
(2S)-2-(4-benzyloxy phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2S)-2-(4-benzyloxy phenyl)-4-((1R)-1-styroyl) morpholine,
(2S)-2-(4-benzyloxy phenyl)-4-((1S)-1-styroyl) morpholine,
(2S)-2-(4-benzyloxy phenyl)-4-(2-styroyl) morpholine,
(2S)-2-(4-benzyloxy phenyl)-4-(methyl) morpholine,
(2S)-2-(4-benzyloxy phenyl)-4-(ethyl) morpholine,
(2S)-2-(4-benzyloxy phenyl)-4-(tertiary butyl) morpholine,
(2S)-2-(4-benzyloxy phenyl)-4-(allyl group) morpholine,
(2S)-2-(4-benzyloxy phenyl) morpholine-4-carboxylate methyl ester,
(2S)-2-(4-benzyloxy phenyl) morpholine-4-carboxylic acid, ethyl ester,
(2S)-2-(4-benzyloxy phenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2S)-2-(4-benzyloxy phenyl) morpholine-4-carboxylic acid phenyl ester,
(2S)-2-(4-benzyloxy phenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(6S)-6-(4-mesyloxy phenyl)-4-(benzyl) morpholine-3-ketone,
(6S)-6-(4-mesyloxy phenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-mesyloxy phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-mesyloxy phenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-mesyloxy phenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-mesyloxy phenyl)-4-(2-styroyl) morpholine-3-ketone,
(6S)-6-(4-mesyloxy phenyl)-4-(methyl) morpholine-3-ketone,
(6S)-6-(4-mesyloxy phenyl)-4-(ethyl) morpholine-3-ketone,
(6S)-6-(4-mesyloxy phenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6S)-6-(4-mesyloxy phenyl)-4-(allyl group) morpholine-3-ketone,
(6S)-6-(4-mesyloxy phenyl) morpholine-3-ketone,
(2S)-2-(4-mesyloxy phenyl)-4-(benzyl) morpholine,
(2S)-2-(4-mesyloxy phenyl)-4-(4-methoxy-benzyl) morpholine,
(2S)-2-(4-mesyloxy phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2S)-2-(4-mesyloxy phenyl)-4-((1R)-1-styroyl) morpholine,
(2S)-2-(4-mesyloxy phenyl)-4-((1S)-1-styroyl) morpholine,
(2S)-2-(4-mesyloxy phenyl)-4-(2-styroyl) morpholine,
(2S)-2-(4-mesyloxy phenyl)-4-(methyl) morpholine,
(2S)-2-(4-mesyloxy phenyl)-4-(ethyl) morpholine,
(2S)-2-(4-mesyloxy phenyl)-4-(tertiary butyl) morpholine,
(2S)-2-(4-mesyloxy phenyl)-4-(allyl group) morpholine,
(2S)-2-(4-mesyloxy phenyl) morpholine-4-carboxylate methyl ester,
(2S)-2-(4-mesyloxy phenyl) morpholine-4-carboxylic acid, ethyl ester,
(2S)-2-(4-mesyloxy phenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2S)-2-(4-mesyloxy phenyl) morpholine-4-carboxylic acid phenyl ester,
(2S)-2-(4-mesyloxy phenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(6S)-6-(4-phenylsulfonyloxy phenyl)-4-(benzyl) morpholine-3-ketone,
(6S)-6-(4-phenylsulfonyloxy phenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-phenylsulfonyloxy phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-phenylsulfonyloxy phenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-phenylsulfonyloxy phenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-phenylsulfonyloxy phenyl)-4-(2-styroyl) morpholine-3-ketone,
(6S)-6-(4-phenylsulfonyloxy phenyl)-4-(methyl) morpholine-3-ketone,
(6S)-6-(4-phenylsulfonyloxy phenyl)-4-(ethyl) morpholine-3-ketone,
(6S)-6-(4-phenylsulfonyloxy phenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6S)-6-(4-phenylsulfonyloxy phenyl)-4-(allyl group) morpholine-3-ketone,
(6S)-6-(4-phenylsulfonyloxy phenyl) morpholine-3-ketone,
(2S)-2-(4-phenylsulfonyloxy phenyl)-4-(benzyl) morpholine,
(2S)-2-(4-phenylsulfonyloxy phenyl)-4-(4-methoxy-benzyl) morpholine,
(2S)-2-(4-phenylsulfonyloxy phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2S)-2-(4-phenylsulfonyloxy phenyl)-4-((1R)-1-styroyl) morpholine,
(2S)-2-(4-phenylsulfonyloxy phenyl)-4-((1S)-1-styroyl) morpholine,
(2S)-2-(4-phenylsulfonyloxy phenyl)-4-(2-styroyl) morpholine,
(2S)-2-(4-phenylsulfonyloxy phenyl)-4-(methyl) morpholine,
(2S)-2-(4-phenylsulfonyloxy phenyl)-4-(ethyl) morpholine,
(2S)-2-(4-phenylsulfonyloxy phenyl)-4-(tertiary butyl) morpholine,
(2S)-2-(4-phenylsulfonyloxy phenyl)-4-(allyl group) morpholine,
(2S)-2-(4-phenylsulfonyloxy phenyl) morpholine-4-carboxylate methyl ester,
(2S)-2-(4-phenylsulfonyloxy phenyl) morpholine-4-carboxylic acid, ethyl ester,
(2S)-2-(4-phenylsulfonyloxy phenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2S)-2-(4-phenylsulfonyloxy phenyl) morpholine-4-carboxylic acid phenyl ester,
(2S)-2-(4-phenylsulfonyloxy phenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(6S)-6-(4-(4-tosyloxy) phenyl)-4-(benzyl) morpholine-3-ketone,
(6S)-6-(4-(4-tosyloxy) phenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-(4-tosyloxy) phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6S)-6-(4-(4-tosyloxy) phenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-(4-tosyloxy) phenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6S)-6-(4-(4-tosyloxy) phenyl)-4-(2-styroyl) morpholine-3-ketone,
(6S)-6-(4-(4-tosyloxy) phenyl)-4-(methyl) morpholine-3-ketone,
(6S)-6-(4-(4-tosyloxy) phenyl)-4-(ethyl) morpholine-3-ketone,
(6S)-6-(4-(4-tosyloxy) phenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6S)-6-(4-(4-tosyloxy) phenyl)-4-(allyl group) morpholine-3-ketone,
(6S)-6-(4-(4-tosyloxy) phenyl) morpholine-3-ketone,
(2S)-2-(4-(4-tosyloxy) phenyl)-4-(benzyl) morpholine,
(2S)-2-(4-(4-tosyloxy) phenyl)-4-(4-methoxy-benzyl) morpholine,
(2S)-2-(4-(4-tosyloxy) phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2S)-2-(4-(4-tosyloxy) phenyl)-4-((1R)-1-styroyl) morpholine,
(2S)-2-(4-(4-tosyloxy) phenyl)-4-((1S)-1-styroyl) morpholine,
(2S)-2-(4-(4-tosyloxy) phenyl)-4-(2-styroyl) morpholine,
(2S)-2-(4-(4-tosyloxy) phenyl)-4-(methyl) morpholine,
(2S)-2-(4-(4-tosyloxy) phenyl)-4-(ethyl) morpholine,
(2S)-2-(4-(4-tosyloxy) phenyl)-4-(tertiary butyl) morpholine,
(2S)-2-(4-(4-tosyloxy) phenyl)-4-(allyl group) morpholine,
(2S)-2-(4-(4-tosyloxy) phenyl) morpholine-4-carboxylate methyl ester,
(2S)-2-(4-(4-tosyloxy) phenyl) morpholine-4-carboxylic acid, ethyl ester,
(2S)-2-(4-(4-tosyloxy) phenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2S)-2-(4-(4-tosyloxy) phenyl) morpholine-4-carboxylic acid phenyl ester and
(2S)-2-(4-(4-tosyloxy) phenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester.
9. preparation method with optically active morpholinium compound by formula 10 expression, this method are included under the condition that transition-metal catalyst exists, and compound and the hydrogen shown in the formula 13 is reacted:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; R
3For can randomly having substituent benzyl, can randomly having substituent 1-styroyl or for can randomly have substituent carbobenzoxy-(Cbz).
10. preparation method by formula 25 expression with optically active compound, this method may further comprise the steps:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; X
1Be halogen; R
1Be C
1-C
6Alkyl, can randomly have substituent aralkyl or for C
1-C
6Thiazolinyl;
Step 1) is reacted the compound shown in the formula 21 and borine or its complex compound, thereby is obtained the compound shown in the formula 22 under the condition that (R)-2-methyl-CBS- azoles borine exists in solvent,
Step 2) compound and the alkali shown in the formula 22 is reacted in solvent, thereby obtain the compound shown in the formula 23, and
Step 3) is reacted the amine shown in compound shown in the formula 23 and the formula 24, thereby obtains the compound shown in the formula 25.
11. the preparation method with optically active morpholinium compound by formula 30 expressions, this method may further comprise the steps:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; R
1Be C
1-C
6Alkyl, can randomly have substituent aralkyl or for C
1-C
6Thiazolinyl; R
2Be C
1-C
6Alkyl, C
1-C
6Haloalkyl, can randomly have substituent aryl or for can randomly have substituent benzyl; X
2Be halogen,
Step 1) is reacted the compound shown in the formula 25 and activatory Mono Chloro Acetic Acid or bromoacetic acid in solvent, thereby obtains the compound shown in the formula 26,
Step 2) compound and the alkali shown in the formula 26 is reacted, thereby obtains the compound shown in the formula 27,
Step 3) is reacted compound and the reductive agent shown in the formula 27 in solvent, thereby obtains the compound shown in the formula 28,
Step 4) is reacted compound and the chloro-formic ester shown in the formula 28, from obtaining the compound shown in the formula 29, and
Step 5) is hydrolyzed the compound shown in the formula 29, thereby obtains the compound shown in the formula 30.
12. optically active compound or its salt that has by formula 31 expressions:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; R
1Be C
1-C
6Alkyl, can randomly have substituent aralkyl or for C
2-C
6Thiazolinyl; R
10For hydrogen atom or be :-CO-CH by formula
2-X
2(X wherein
2Be halogen) represented group.
13. the compound or its salt of claim 12, wherein R is for having 1 to 3 substituent phenyl, and wherein said substituting group is selected from halogen, C
1-C
6Alkyl, the C that is substituted
1-C
6Alkyl, C
1-C
6Alkoxyl group, the C that is substituted
1-C
6Alkoxyl group, nitro, aralkoxy, C
1-C
6Alkylsulfonyloxy, aryl-sulfonyl oxygen and through C
1-C
6The aryl-sulfonyl oxygen that alkyl replaces.
14. the compound or its salt of claim 12, described compound is selected from:
(1R)-1-(4-fluorophenyl)-2-(benzyl amino) ethanol,
(1R)-1-(4-fluorophenyl)-2-(4-methoxybenzyl amino) ethanol,
(1R)-1-(4-fluorophenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1R)-1-(4-fluorophenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1R)-1-(4-fluorophenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1R)-1-(4-fluorophenyl)-2-(2-benzene ethylamino) ethanol,
(1R)-1-(4-fluorophenyl)-2-(methylamino-) ethanol,
(1R)-1-(4-fluorophenyl)-2-(ethylamino) ethanol,
(1R)-1-(4-fluorophenyl)-2-(uncle's fourth amino) ethanol,
(1R)-1-(4-fluorophenyl)-2-(allyl amino) ethanol,
(1R)-1-(3-fluorophenyl)-2-(benzyl amino) ethanol,
(1R)-1-(3-fluorophenyl)-2-(4-methoxybenzyl amino) ethanol,
(1R)-1-(3-fluorophenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1R)-1-(3-fluorophenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1R)-1-(3-fluorophenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1R)-1-(3-fluorophenyl)-2-(2-benzene ethylamino) ethanol,
(1R)-1-(3-fluorophenyl)-2-(methylamino-) ethanol,
(1R)-1-(3-fluorophenyl)-2-(ethylamino) ethanol,
(1R)-1-(3-fluorophenyl)-2-(uncle's fourth amino) ethanol,
(1R)-1-(3-fluorophenyl)-2-(allyl amino) ethanol,
(1R)-1-(4-chloro-phenyl-)-2-(benzyl amino) ethanol,
(1R)-1-(4-chloro-phenyl-)-2-(4-methoxybenzyl amino) ethanol,
(1R)-1-(4-chloro-phenyl-)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1R)-1-(4-chloro-phenyl-)-2-((1R)-1-benzene ethylamino) ethanol,
(1R)-1-(4-chloro-phenyl-)-2-((1S)-1-benzene ethylamino) ethanol,
(1R)-1-(4-chloro-phenyl-)-2-(2-benzene ethylamino) ethanol,
(1R)-1-(4-chloro-phenyl-)-2-(methylamino-) ethanol,
(1R)-1-(4-chloro-phenyl-)-2-(ethylamino) ethanol,
(1R)-1-(4-chloro-phenyl-)-2-(uncle's fourth amino) ethanol,
(1R)-1-(4-chloro-phenyl-)-2-(allyl amino) ethanol,
(1R)-1-(4-bromophenyl)-2-(benzyl amino) ethanol,
(1R)-1-(4-bromophenyl)-2-(4-methoxybenzyl amino) ethanol,
(1R)-1-(4-bromophenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1R)-1-(4-bromophenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1R)-1-(4-bromophenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1R)-1-(4-bromophenyl)-2-(2-benzene ethylamino) ethanol,
(1R)-1-(4-bromophenyl)-2-(methylamino-) ethanol,
(1R)-1-(4-bromophenyl)-2-(ethylamino) ethanol,
(1R)-1-(4-bromophenyl)-2-(uncle's fourth amino) ethanol,
(1R)-1-(4-bromophenyl)-2-(allyl amino) ethanol,
(1R)-1-(4-nitrophenyl)-2-(benzyl amino) ethanol,
(1R)-1-(4-nitrophenyl)-2-(4-methoxybenzyl amino) ethanol,
(1R)-1-(4-nitrophenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1R)-1-(4-nitrophenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1R)-1-(4-nitrophenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1R)-1-(4-nitrophenyl)-2-(2-benzene ethylamino) ethanol,
(1R)-1-(4-nitrophenyl)-2-(methylamino-) ethanol,
(1R)-1-(4-nitrophenyl)-2-(ethylamino) ethanol,
(1R)-1-(4-nitrophenyl)-2-(uncle's fourth amino) ethanol,
(1R)-1-(4-nitrophenyl)-2-(allyl amino) ethanol,
(1R)-1-(4-fluorophenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-fluorophenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1R)-1-(4-fluorophenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-fluorophenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-fluorophenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol,
(1R)-1-(4-fluorophenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol,
(1R)-1-(4-bromophenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-bromophenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1R)-1-(4-bromophenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-bromophenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-bromophenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol,
(1R)-1-(4-bromophenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol,
(1R)-1-(4-nitrophenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-nitrophenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1R)-1-(4-nitrophenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-nitrophenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-nitrophenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol,
(1R)-1-(4-nitrophenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(benzyl amino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(4-methoxybenzyl amino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(2-benzene ethylamino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(methylamino-) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(ethylamino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(uncle's fourth amino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(allyl amino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol,
(1R)-1-(4-benzyloxy phenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(benzyl amino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(4-methoxybenzyl amino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(2-benzene ethylamino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(methylamino-) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(ethylamino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(uncle's fourth amino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(allyl amino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol,
(1R)-1-(4-mesyloxy phenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(benzyl amino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(4-methoxybenzyl amino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(2-benzene ethylamino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(methylamino-) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(ethylamino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(uncle's fourth amino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(allyl amino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol,
(1R)-1-(4-phenylsulfonyloxy phenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(benzyl amino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(4-methoxybenzyl amino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(2,4-dimethoxy benzyl amino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-((1R)-1-benzene ethylamino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-((1S)-1-benzene ethylamino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(2-benzene ethylamino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(methylamino-) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(ethylamino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(uncle's fourth amino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(allyl amino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(N-benzyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(N-benzyl-N-acetobrom amino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(N-(1R)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(N-(1S)-1-styroyl-N-chloro acetylamino) ethanol,
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(N-(1R)-1-styroyl-N-acetobrom amino) ethanol and
(1R)-1-(4-(4-tosyloxy) phenyl)-2-(N-(1S)-1-styroyl-N-acetobrom amino) ethanol.
15. one kind has optically active morpholinium compound or its salt by formula 32 expression:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; R
1aBe hydrogen atom, C
1-C
6Alkyl, can randomly have substituent aralkyl, C
2-C
6Thiazolinyl or be :-COOR by formula
2Represented group (R wherein
2Be C
1-C
6Alkyl, C
1-C
6Haloalkyl, can randomly have substituent aryl or can randomly have substituent benzyl); Z is O or H
2,
Condition is to work as R
1aFor hydrogen atom, Z are H
2The time, R not should be the 4-fluorophenyl.
16. the described compound or its salt of claim 15, wherein R is for having 1 to 3 substituent phenyl, and wherein said substituting group is selected from halogen, C
1-C
6Alkyl, the C that is substituted
1-C
6Alkyl, C
1-C
6Alkoxyl group, the C that is substituted
1-C
6Alkoxyl group, nitro, aralkoxy, C
1-C
6Alkylsulfonyloxy, aryl-sulfonyl oxygen and through C
1-C
6The aryl-sulfonyl oxygen that alkyl replaces.
17. the described compound or its salt of claim 15, described compound is selected from:
(6R)-6-(4-fluorophenyl)-4-(benzyl) morpholine-3-ketone,
(6R)-6-(4-fluorophenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-fluorophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-fluorophenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-fluorophenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-fluorophenyl)-4-(2-styroyl) morpholine-3-ketone,
(6R)-6-(4-fluorophenyl)-4-(methyl) morpholine-3-ketone,
(6R)-6-(4-fluorophenyl)-4-(ethyl) morpholine-3-ketone,
(6R)-6-(4-fluorophenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6R)-6-(4-fluorophenyl)-4-(allyl group) morpholine-3-ketone,
(6R)-6-(4-fluorophenyl) morpholine-3-ketone,
(6R)-6-(3-fluorophenyl)-4-(benzyl) morpholine-3-ketone,
(6R)-6-(3-fluorophenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6R)-6-(3-fluorophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6R)-6-(3-fluorophenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6R)-6-(3-fluorophenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6R)-6-(3-fluorophenyl)-4-(2-styroyl) morpholine-3-ketone,
(6R)-6-(3-fluorophenyl)-4-(methyl) morpholine-3-ketone,
(6R)-6-(3-fluorophenyl)-4-(ethyl) morpholine-3-ketone,
(6R)-6-(3-fluorophenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6R)-6-(3-fluorophenyl)-4-(allyl group) morpholine-3-ketone,
(6R)-6-(3-fluorophenyl) morpholine-3-ketone,
(6R)-6-(4-chloro-phenyl-)-4-(benzyl) morpholine-3-ketone,
(6R)-6-(4-chloro-phenyl-)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-chloro-phenyl-)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-chloro-phenyl-)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-chloro-phenyl-)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-chloro-phenyl-)-4-(2-styroyl) morpholine-3-ketone,
(6R)-6-(4-chloro-phenyl-)-4-(methyl) morpholine-3-ketone,
(6R)-6-(4-chloro-phenyl-)-4-(ethyl) morpholine-3-ketone,
(6R)-6-(4-chloro-phenyl-)-4-(tertiary butyl) morpholine-3-ketone,
(6R)-6-(4-chloro-phenyl-)-4-(allyl group) morpholine-3-ketone,
(6R)-6-(4-bromophenyl)-4-(benzyl) morpholine-3-ketone,
(6R)-6-(4-bromophenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-bromophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-bromophenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-bromophenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-bromophenyl)-4-(2-styroyl) morpholine-3-ketone,
(6R)-6-(4-bromophenyl)-4-(methyl) morpholine-3-ketone,
(6R)-6-(4-bromophenyl)-4-(ethyl) morpholine-3-ketone,
(6R)-6-(4-bromophenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6R)-6-(4-bromophenyl)-4-(allyl group) morpholine-3-ketone,
(6R)-6-(4-nitrophenyl)-4-(benzyl) morpholine-3-ketone,
(6R)-6-(4-nitrophenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-nitrophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-nitrophenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-nitrophenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-nitrophenyl)-4-(2-styroyl) morpholine-3-ketone,
(6R)-6-(4-nitrophenyl)-4-(methyl) morpholine-3-ketone,
(6R)-6-(4-nitrophenyl)-4-(ethyl) morpholine-3-ketone,
(6R)-6-(4-nitrophenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6R)-6-(4-nitrophenyl)-4-(allyl group) morpholine-3-ketone,
(2R)-2-(4-fluorophenyl)-4-(benzyl) morpholine,
(2R)-2-(4-fluorophenyl)-4-(4-methoxy-benzyl) morpholine,
(2R)-2-(4-fluorophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2R)-2-(4-fluorophenyl)-4-((1R)-1-styroyl) morpholine,
(2R)-2-(4-fluorophenyl)-4-((1S)-1-styroyl) morpholine,
(2R)-2-(4-fluorophenyl)-4-(2-styroyl) morpholine,
(2R)-2-(4-fluorophenyl)-4-(methyl) morpholine,
(2R)-2-(4-fluorophenyl)-4-(ethyl) morpholine,
(2R)-2-(4-fluorophenyl)-4-(tertiary butyl) morpholine,
(2R)-2-(4-fluorophenyl)-4-(allyl group) morpholine,
(2R)-2-(3-fluorophenyl)-4-(benzyl) morpholine,
(2R)-2-(3-fluorophenyl)-4-(4-methoxy-benzyl) morpholine,
(2R)-2-(3-fluorophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2R)-2-(3-fluorophenyl)-4-((1R)-1-styroyl) morpholine,
(2R)-2-(3-fluorophenyl)-4-((1S)-1-styroyl) morpholine,
(2R)-2-(3-fluorophenyl)-4-(2-styroyl) morpholine,
(2R)-2-(3-fluorophenyl)-4-(methyl) morpholine,
(2R)-2-(3-fluorophenyl)-4-(ethyl) morpholine,
(2R)-2-(3-fluorophenyl)-4-(tertiary butyl) morpholine,
(2R)-2-(3-fluorophenyl)-4-(allyl group) morpholine,
(2R)-2-(3-fluorophenyl) morpholine,
(2R)-2-(4-chloro-phenyl-)-4-(benzyl) morpholine,
(2R)-2-(4-chloro-phenyl-)-4-(4-methoxy-benzyl) morpholine,
(2R)-2-(4-chloro-phenyl-)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2R)-2-(4-chloro-phenyl-)-4-((1R)-1-styroyl) morpholine,
(2R)-2-(4-chloro-phenyl-)-4-((1S)-1-styroyl) morpholine,
(2R)-2-(4-chloro-phenyl-)-4-(2-styroyl) morpholine,
(2R)-2-(4-chloro-phenyl-)-4-(methyl) morpholine,
(2R)-2-(4-chloro-phenyl-)-4-(ethyl) morpholine,
(2R)-2-(4-chloro-phenyl-)-4-(tertiary butyl) morpholine,
(2R)-2-(4-chloro-phenyl-)-4-(allyl group) morpholine,
(2R)-2-(4-bromophenyl)-4-(benzyl) morpholine,
(2R)-2-(4-bromophenyl)-4-(4-methoxy-benzyl) morpholine,
(2R)-2-(4-bromophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2R)-2-(4-bromophenyl)-4-((1R)-1-styroyl) morpholine,
(2R)-2-(4-bromophenyl)-4-((1S)-1-styroyl) morpholine,
(2R)-2-(4-bromophenyl)-4-(2-styroyl) morpholine,
(2R)-2-(4-bromophenyl)-4-(methyl) morpholine,
(2R)-2-(4-bromophenyl)-4-(ethyl) morpholine,
(2R)-2-(4-bromophenyl)-4-(tertiary butyl) morpholine,
(2R)-2-(4-bromophenyl)-4-(allyl group) morpholine,
(2R)-2-(4-bromophenyl) morpholine,
(2R)-2-(4-nitrophenyl)-4-(benzyl) morpholine,
(2R)-2-(4-nitrophenyl)-4-(4-methoxy-benzyl) morpholine,
(2R)-2-(4-nitrophenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2R)-2-(4-nitrophenyl)-4-((1R)-1-styroyl) morpholine,
(2R)-2-(4-nitrophenyl)-4-((1S)-1-styroyl) morpholine,
(2R)-2-(4-nitrophenyl)-4-(2-styroyl) morpholine,
(2R)-2-(4-nitrophenyl)-4-(methyl) morpholine,
(2R)-2-(4-nitrophenyl)-4-(ethyl) morpholine,
(2R)-2-(4-nitrophenyl)-4-(tertiary butyl) morpholine,
(2R)-2-(4-nitrophenyl)-4-(allyl group) morpholine,
(2R)-2-(4-nitrophenyl) morpholine,
(2R)-2-(4-fluorophenyl) morpholine-4-carboxylate methyl ester,
(2R)-2-(4-fluorophenyl) morpholine-4-carboxylic acid, ethyl ester,
(2R)-2-(4-fluorophenyl) morpholine-4-carboxylic acid phenyl ester,
(2R)-2-(4-fluorophenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(2R)-2-(3-fluorophenyl) morpholine-4-carboxylate methyl ester,
(2R)-2-(3-fluorophenyl) morpholine-4-carboxylic acid, ethyl ester,
(2R)-2-(3-fluorophenyl) morpholine-4-carboxylic acid phenyl ester,
(2R)-2-(3-fluorophenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(2R)-2-(4-chloro-phenyl-) morpholine-4-carboxylate methyl ester,
(2R)-2-(4-chloro-phenyl-) morpholine-4-carboxylic acid, ethyl ester,
(2R)-2-(4-chloro-phenyl-) morpholine-4-carboxylic acid phenyl ester,
(2R)-2-(4-chloro-phenyl-) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(2R)-2-(4-bromophenyl) morpholine-4-carboxylate methyl ester,
(2R)-2-(4-bromophenyl) morpholine-4-carboxylic acid, ethyl ester,
(2R)-2-(4-bromophenyl) morpholine-4-carboxylic acid phenyl ester,
(2R)-2-(4-bromophenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(2R)-2-(4-nitrophenyl) morpholine-4-carboxylate methyl ester,
(2R)-2-(4-nitrophenyl) morpholine-4-carboxylic acid, ethyl ester,
(2R)-2-(4-nitrophenyl) morpholine-4-carboxylic acid phenyl ester,
(2R)-2-(4-nitrophenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(2R)-2-(4-fluorophenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2R)-2-(3-fluorophenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2R)-2-(4-chloro-phenyl-) morpholine-4-carboxylic acid 1-chloroethene ester,
(2R)-2-(4-bromophenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2R)-2-(4-nitrophenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(6R)-6-(4-benzyloxy phenyl)-4-(benzyl) morpholine-3-ketone,
(6R)-6-(4-benzyloxy phenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-benzyloxy phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-benzyloxy phenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-benzyloxy phenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-benzyloxy phenyl)-4-(2-styroyl) morpholine-3-ketone,
(6R)-6-(4-benzyloxy phenyl)-4-(methyl) morpholine-3-ketone,
(6R)-6-(4-benzyloxy phenyl)-4-(ethyl) morpholine-3-ketone,
(6R)-6-(4-benzyloxy phenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6R)-6-(4-benzyloxy phenyl)-4-(allyl group) morpholine-3-ketone,
(6R)-6-(4-benzyloxy phenyl) morpholine-3-ketone,
(2R)-2-(4-benzyloxy phenyl)-4-(benzyl) morpholine,
(2R)-2-(4-benzyloxy phenyl)-4-(4-methoxy-benzyl) morpholine,
(2R)-2-(4-benzyloxy phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2R)-2-(4-benzyloxy phenyl)-4-((1R)-1-styroyl) morpholine,
(2R)-2-(4-benzyloxy phenyl)-4-((1S)-1-styroyl) morpholine,
(2R)-2-(4-benzyloxy phenyl)-4-(2-styroyl) morpholine,
(2R)-2-(4-benzyloxy phenyl)-4-(methyl) morpholine,
(2R)-2-(4-benzyloxy phenyl)-4-(ethyl) morpholine,
(2R)-2-(4-benzyloxy phenyl)-4-(tertiary butyl) morpholine,
(2R)-2-(4-benzyloxy phenyl)-4-(allyl group) morpholine,
(2R)-2-(4-benzyloxy phenyl) morpholine-4-carboxylate methyl ester,
(2R)-2-(4-benzyloxy phenyl) morpholine-4-carboxylic acid, ethyl ester,
(2R)-2-(4-benzyloxy phenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2R)-2-(4-benzyloxy phenyl) morpholine-4-carboxylic acid phenyl ester,
(2R)-2-(4-benzyloxy phenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(6R)-6-(4-mesyloxy phenyl)-4-(benzyl) morpholine-3-ketone,
(6R)-6-(4-mesyloxy phenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-mesyloxy phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-mesyloxy phenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-mesyloxy phenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-mesyloxy phenyl)-4-(2-styroyl) morpholine-3-ketone,
(6R)-6-(4-mesyloxy phenyl)-4-(methyl) morpholine-3-ketone,
(6R)-6-(4-mesyloxy phenyl)-4-(ethyl) morpholine-3-ketone,
(6R)-6-(4-mesyloxy phenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6R)-6-(4-mesyloxy phenyl)-4-(allyl group) morpholine-3-ketone,
(6R)-6-(4-mesyloxy phenyl) morpholine-3-ketone,
(2R)-2-(4-mesyloxy phenyl)-4-(benzyl) morpholine,
(2R)-2-(4-mesyloxy phenyl)-4-(4-methoxy-benzyl) morpholine,
(2R)-2-(4-mesyloxy phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2R)-2-(4-mesyloxy phenyl)-4-((1R)-1-styroyl) morpholine,
(2R)-2-(4-mesyloxy phenyl)-4-((1S)-1-styroyl) morpholine,
(2R)-2-(4-mesyloxy phenyl)-4-(2-styroyl) morpholine,
(2R)-2-(4-mesyloxy phenyl)-4-(methyl) morpholine,
(2R)-2-(4-mesyloxy phenyl)-4-(ethyl) morpholine,
(2R)-2-(4-mesyloxy phenyl)-4-(tertiary butyl) morpholine,
(2R)-2-(4-mesyloxy phenyl)-4-(allyl group) morpholine,
(2R)-2-(4-mesyloxy phenyl) morpholine-4-carboxylate methyl ester,
(2R)-2-(4-mesyloxy phenyl) morpholine-4-carboxylic acid, ethyl ester,
(2R)-2-(4-mesyloxy phenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2R)-2-(4-mesyloxy phenyl) morpholine-4-carboxylic acid phenyl ester,
(2R)-2-(4-mesyloxy phenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(6R)-6-(4-phenylsulfonyloxy phenyl)-4-(benzyl) morpholine-3-ketone,
(6R)-6-(4-phenylsulfonyloxy phenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-phenylsulfonyloxy phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-phenylsulfonyloxy phenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-phenylsulfonyloxy phenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-phenylsulfonyloxy phenyl)-4-(2-styroyl) morpholine-3-ketone,
(6R)-6-(4-phenylsulfonyloxy phenyl)-4-(methyl) morpholine-3-ketone,
(6R)-6-(4-phenylsulfonyloxy phenyl)-4-(ethyl) morpholine-3-ketone,
(6R)-6-(4-phenylsulfonyloxy phenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6R)-6-(4-phenylsulfonyloxy phenyl)-4-(allyl group) morpholine-3-ketone,
(6R)-6-(4-phenylsulfonyloxy phenyl) morpholine-3-ketone,
(2R)-2-(4-phenylsulfonyloxy phenyl)-4-(benzyl) morpholine,
(2R)-2-(4-phenylsulfonyloxy phenyl)-4-(4-methoxy-benzyl) morpholine,
(2R)-2-(4-phenylsulfonyloxy phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2R)-2-(4-phenylsulfonyloxy phenyl)-4-((1R)-1-styroyl) morpholine,
(2R)-2-(4-phenylsulfonyloxy phenyl)-4-((1S)-1-styroyl) morpholine,
(2R)-2-(4-phenylsulfonyloxy phenyl)-4-(2-styroyl) morpholine,
(2R)-2-(4-phenylsulfonyloxy phenyl)-4-(methyl) morpholine,
(2R)-2-(4-phenylsulfonyloxy phenyl)-4-(ethyl) morpholine,
(2R)-2-(4-phenylsulfonyloxy phenyl)-4-(tertiary butyl) morpholine,
(2R)-2-(4-phenylsulfonyloxy phenyl)-4-(allyl group) morpholine,
(2R)-2-(4-phenylsulfonyloxy phenyl) morpholine-4-carboxylate methyl ester,
(2R)-2-(4-phenylsulfonyloxy phenyl) morpholine-4-carboxylic acid, ethyl ester,
(2R)-2-(4-phenylsulfonyloxy phenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2R)-2-(4-phenylsulfonyloxy phenyl) morpholine-4-carboxylic acid phenyl ester,
(2R)-2-(4-phenylsulfonyloxy phenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester,
(6R)-6-(4-(4-tosyloxy) phenyl)-4-(benzyl) morpholine-3-ketone,
(6R)-6-(4-(4-tosyloxy) phenyl)-4-(4-methoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-(4-tosyloxy) phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine-3-ketone,
(6R)-6-(4-(4-tosyloxy) phenyl)-4-((1R)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-(4-tosyloxy) phenyl)-4-((1S)-1-styroyl) morpholine-3-ketone,
(6R)-6-(4-(4-tosyloxy) phenyl)-4-(2-styroyl) morpholine-3-ketone,
(6R)-6-(4-(4-tosyloxy) phenyl)-4-(methyl) morpholine-3-ketone,
(6R)-6-(4-(4-tosyloxy) phenyl)-4-(ethyl) morpholine-3-ketone,
(6R)-6-(4-(4-tosyloxy) phenyl)-4-(tertiary butyl) morpholine-3-ketone,
(6R)-6-(4-(4-tosyloxy) phenyl)-4-(allyl group) morpholine-3-ketone,
(6R)-6-(4-(4-tosyloxy) phenyl) morpholine-3-ketone,
(2R)-2-(4-(4-tosyloxy) phenyl)-4-(benzyl) morpholine,
(2R)-2-(4-(4-tosyloxy) phenyl)-4-(4-methoxy-benzyl) morpholine,
(2R)-2-(4-(4-tosyloxy) phenyl)-4-(2, the 4-dimethoxy-benzyl) morpholine,
(2R)-2-(4-(4-tosyloxy) phenyl)-4-((1R)-1-styroyl) morpholine,
(2R)-2-(4-(4-tosyloxy) phenyl)-4-((1S)-1-styroyl) morpholine,
(2R)-2-(4-(4-tosyloxy) phenyl)-4-(2-styroyl) morpholine,
(2R)-2-(4-(4-tosyloxy) phenyl)-4-(methyl) morpholine,
(2R)-2-(4-(4-tosyloxy) phenyl)-4-(ethyl) morpholine,
(2R)-2-(4-(4-tosyloxy) phenyl)-4-(tertiary butyl) morpholine,
(2R)-2-(4-(4-tosyloxy) phenyl)-4-(allyl group) morpholine,
(2R)-2-(4-(4-tosyloxy) phenyl) morpholine-4-carboxylate methyl ester,
(2R)-2-(4-(4-tosyloxy) phenyl) morpholine-4-carboxylic acid, ethyl ester,
(2R)-2-(4-(4-tosyloxy) phenyl) morpholine-4-carboxylic acid 1-chloroethene ester,
(2R)-2-(4-(4-tosyloxy) phenyl) morpholine-4-carboxylic acid phenyl ester and
(2R)-2-(4-(4-tosyloxy) phenyl) morpholine-4-carboxylic acid 4-nitro phenyl ester.
18. the preparation method with optically active morpholinium compound by formula 30 expressions, this method is included under the condition of transition-metal catalyst existence, and compound and the hydrogen shown in the formula 33 is reacted:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; R
3For can randomly having substituent benzyl, can randomly have substituent 1-styroyl or can randomly having substituent carbobenzoxy-(Cbz).
19. the preparation method by formula 35 expression, this method with optically active compound be included in ruthenium catalyst and have optically active amino alcohol or condition that the amine ligand exists under, the compound shown in the formula 34 and Virahol or formic acid are reacted:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; R
1' be hydrogen atom, C
1-C
6Alkyl, can randomly have substituent aralkyl or for C
2-C
6Thiazolinyl; R
11Be hydrogen atom or tertbutyloxycarbonyl.
20. compound or its salt by formula 34 expressions:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; R
1' be hydrogen atom, C
1-C
6Alkyl, can randomly have substituent aralkyl or for C
2-C
6Thiazolinyl; R
11Be hydrogen atom or tertbutyloxycarbonyl.
21. the described compound or its salt of claim 20, described compound is selected from:
2-(benzyl amino)-1-(4-fluorophenyl) ethyl ketone,
2-(4-methoxybenzyl amino)-1-(4-fluorophenyl) ethyl ketone,
2-(2,4-dimethoxy benzyl amino)-1-(4-fluorophenyl) ethyl ketone,
2-((1R)-1-benzene ethylamino)-1-(4-fluorophenyl) ethyl ketone,
2-((1S)-1-benzene ethylamino)-1-(4-fluorophenyl) ethyl ketone,
2-(2-benzene ethylamino)-1-(4-fluorophenyl) ethyl ketone,
2-(methylamino-)-1-(4-fluorophenyl) ethyl ketone,
2-(ethylamino)-1-(4-fluorophenyl) ethyl ketone,
2-(uncle's fourth amino)-1-(4-fluorophenyl) ethyl ketone,
2-(allyl amino)-1-(4-fluorophenyl) ethyl ketone,
2-amino-1-(4-fluorophenyl) ethyl ketone,
2-(benzyl amino)-1-(3-fluorophenyl) ethyl ketone,
2-(4-methoxybenzyl amino)-1-(3-fluorophenyl) ethyl ketone,
2-(2,4-dimethoxy benzyl amino)-1-(3-fluorophenyl) ethyl ketone,
2-((1R)-1-benzene ethylamino)-1-(3-fluorophenyl) ethyl ketone,
2-((1S)-1-benzene ethylamino)-1-(3-fluorophenyl) ethyl ketone,
2-(2-benzene ethylamino)-1-(3-fluorophenyl) ethyl ketone,
2-(methylamino-)-1-(3-fluorophenyl) ethyl ketone,
2-(ethylamino)-1-(3-fluorophenyl) ethyl ketone,
2-(uncle's fourth amino)-1-(3-fluorophenyl) ethyl ketone,
2-(allyl amino)-1-(3-fluorophenyl) ethyl ketone,
2-amino-1-(3-fluorophenyl) ethyl ketone,
2-(benzyl amino)-1-(4-chloro-phenyl-) ethyl ketone,
2-(4-methoxybenzyl amino)-1-(4-chloro-phenyl-) ethyl ketone,
2-(2,4-dimethoxy benzyl amino)-1-(4-chloro-phenyl-) ethyl ketone,
2-((1R)-1-benzene ethylamino)-1-(4-chloro-phenyl-) ethyl ketone,
2-((1S)-1-benzene ethylamino)-1-(4-chloro-phenyl-) ethyl ketone,
2-(2-benzene ethylamino)-1-(4-chloro-phenyl-) ethyl ketone,
2-(methylamino-)-1-(4-chloro-phenyl-) ethyl ketone,
2-(ethylamino)-1-(4-chloro-phenyl-) ethyl ketone,
2-(uncle's fourth amino)-1-(4-chloro-phenyl-) ethyl ketone,
2-(allyl amino)-1-(4-chloro-phenyl-) ethyl ketone,
2-amino-1-(4-chloro-phenyl-) ethyl ketone,
2-(benzyl amino)-1-(4-bromophenyl) ethyl ketone,
2-(4-methoxybenzyl amino)-1-(4-bromophenyl) ethyl ketone,
2-(2,4-dimethoxy benzyl amino)-1-(4-bromophenyl) ethyl ketone,
2-((1R)-1-benzene ethylamino)-1-(4-bromophenyl) ethyl ketone,
2-((1S)-1-benzene ethylamino)-1-(4-bromophenyl) ethyl ketone,
2-(2-benzene ethylamino)-1-(4-bromophenyl) ethyl ketone,
2-(methylamino-)-1-(4-bromophenyl) ethyl ketone,
2-(ethylamino)-1-(4-bromophenyl) ethyl ketone,
2-(uncle's fourth amino)-1-(4-bromophenyl) ethyl ketone,
2-(allyl amino)-1-(4-bromophenyl) ethyl ketone,
2-amino-1-(4-bromophenyl) ethyl ketone,
2-(benzyl amino)-1-(4-nitrophenyl) ethyl ketone,
2-(4-methoxybenzyl amino)-1-(4-nitrophenyl) ethyl ketone,
2-(2,4-dimethoxy benzyl amino)-1-(4-nitrophenyl) ethyl ketone,
2-((1R)-1-benzene ethylamino)-1-(4-nitrophenyl) ethyl ketone,
2-((1S)-1-benzene ethylamino)-1-(4-nitrophenyl) ethyl ketone,
2-(2-benzene ethylamino)-1-(4-nitrophenyl) ethyl ketone,
2-(methylamino-)-1-(4-nitrophenyl) ethyl ketone,
2-(ethylamino)-1-(4-nitrophenyl) ethyl ketone,
2-(uncle's fourth amino)-1-(4-nitrophenyl) ethyl ketone,
2-(allyl amino)-1-(4-nitrophenyl) ethyl ketone,
2-amino-1-(4-nitrophenyl) ethyl ketone,
2-(benzyl amino)-1-(4-benzyloxy phenyl) ethyl ketone,
2-(4-methoxybenzyl amino)-1-(4-benzyloxy phenyl) ethyl ketone,
2-(2,4-dimethoxy benzyl amino)-1-(4-benzyloxy phenyl) ethyl ketone,
2-((1R)-1-benzene ethylamino)-1-(4-benzyloxy phenyl) ethyl ketone,
2-((1S)-1-benzene ethylamino)-1-(4-benzyloxy phenyl) ethyl ketone,
2-(2-benzene ethylamino)-1-(4-benzyloxy phenyl) ethyl ketone,
2-(methylamino-)-1-(4-benzyloxy phenyl) ethyl ketone,
2-(ethylamino)-1-(4-benzyloxy phenyl) ethyl ketone,
2-(uncle's fourth amino)-1-(4-benzyloxy phenyl) ethyl ketone,
2-(allyl amino)-1-(4-benzyloxy phenyl) ethyl ketone,
2-amino-1-(4-benzyloxy phenyl) ethyl ketone,
2-(benzyl amino)-1-(4-mesyloxy phenyl) ethyl ketone,
2-(4-methoxybenzyl amino)-1-(4-mesyloxy phenyl) ethyl ketone,
2-(2,4-dimethoxy benzyl amino)-1-(4-mesyloxy phenyl) ethyl ketone,
2-((1R)-1-benzene ethylamino)-1-(4-mesyloxy phenyl) ethyl ketone,
2-((1S)-1-benzene ethylamino)-1-(4-mesyloxy phenyl) ethyl ketone,
2-(2-benzene ethylamino)-1-(4-mesyloxy phenyl) ethyl ketone,
2-(methylamino-)-1-(4-mesyloxy phenyl) ethyl ketone,
2-(ethylamino)-1-(4-mesyloxy phenyl) ethyl ketone,
2-(uncle's fourth amino)-1-(4-mesyloxy phenyl) ethyl ketone,
2-(allyl amino)-1-(4-mesyloxy phenyl) ethyl ketone,
2-amino-1-(4-mesyloxy phenyl) ethyl ketone,
2-(benzyl amino)-1-(4-phenylsulfonyloxy phenyl) ethyl ketone,
2-(4-methoxybenzyl amino)-1-(4-phenylsulfonyloxy phenyl) ethyl ketone,
2-(2,4-dimethoxy benzyl amino)-1-(4-phenylsulfonyloxy phenyl) ethyl ketone,
2-((1R)-1-benzene ethylamino)-1-(4-phenylsulfonyloxy phenyl) ethyl ketone,
2-((1S)-1-benzene ethylamino)-1-(4-phenylsulfonyloxy phenyl) ethyl ketone,
2-(2-benzene ethylamino)-1-(4-phenylsulfonyloxy phenyl) ethyl ketone,
2-(methylamino-)-1-(4-phenylsulfonyloxy phenyl) ethyl ketone,
2-(ethylamino)-1-(4-phenylsulfonyloxy phenyl) ethyl ketone,
2-(uncle's fourth amino)-1-(4-phenylsulfonyloxy phenyl) ethyl ketone,
2-(allyl amino)-1-(4-phenylsulfonyloxy phenyl) ethyl ketone,
2-amino-1-(4-phenylsulfonyloxy phenyl) ethyl ketone,
2-(benzyl amino)-1-(4-(4-tosyloxy) phenyl) ethyl ketone,
2-(4-methoxybenzyl amino)-1-(4-(4-tosyloxy) phenyl) ethyl ketone,
2-(2,4-dimethoxy benzyl amino)-1-(4-(4-tosyloxy) phenyl) ethyl ketone,
2-((1R)-1-benzene ethylamino)-1-(4-(4-tosyloxy) phenyl) ethyl ketone,
2-((1 S)-1-benzene ethylamino)-1-(4-(4-tosyloxy) phenyl) ethyl ketone,
2-(2-benzene ethylamino)-1-(4-(4-tosyloxy) phenyl) ethyl ketone,
2-(methylamino-)-1-(4-(4-tosyloxy) phenyl) ethyl ketone,
2-(ethylamino)-1-(4-(4-tosyloxy) phenyl) ethyl ketone,
2-(uncle's fourth amino)-1-(4-(4-tosyloxy) phenyl) ethyl ketone,
2-(allyl amino)-1-(4-(4-tosyloxy) phenyl) ethyl ketone and
2-amino-1-(4-(4-tosyloxy) phenyl) ethyl ketone.
22. the preparation method by formula 36 expression, this method with optically active compound be included in the Ru catalyzer and have optically active amino ferment or condition that the amine ligand exists under, the compound shown in the formula 34 and Virahol or formic acid are reacted:
Wherein R is for can randomly having substituent aryl or for can randomly have substituent heteroaryl; R
1' be hydrogen atom, C
1-C
6Alkyl, can randomly have substituent aralkyl or for C
2-C
6Thiazolinyl; R
11Be hydrogen atom or tertbutyloxycarbonyl.
23. the preparation method by the compound of formula 55 expressions, this method may further comprise the steps:
R wherein
aAnd R
bBe identical or different, and be C
1-C
6Alkyl;
Step 1) is reacted vitamin B13 and the alkylating agent shown in the formula 51, thereby is obtained the compound shown in the formula 52 under the condition that alkali exists in solvent,
Step 2) under refluxad, compound and the chlorizating agent shown in the formula 52 together heated, thereby obtains the compound shown in the formula 53,
Step 3) is carried out dechlorination reaction with the compound shown in the formula 53, thereby is obtained the compound shown in the formula 54 under the condition that alkali exists, and
Step 4) is reacted compound and the acetic ester shown in the formula 54, thereby is obtained the compound shown in the formula 55 under the condition that alkali exists.
24. the preparation method by the compound of formula 52 expressions, this method is included under the existence of alkali, and vitamin B13 and the alkylating agent shown in the formula 51 reacted in solvent:
R wherein
aBe C
1-C
6Alkyl.
25. the preparation method by the compound of formula 53 expressions, this method comprises under refluxad, and compound and the chlorizating agent shown in the formula 52 together heated:
R wherein
aBe C
1-C
6Alkyl.
26. the preparation method by the compound of formula 54 expression, this method are included under the condition of existence of alkali, and the compound shown in the formula 53 is carried out dechlorination reaction,
R wherein
aBe C
1-C
6Alkyl.
27. the preparation method with optically active compound by formula (I) expression, this method comprises any described method in the claim 1,2,9,11,18,19,22,23,24,25 and 26:
Wherein R be for can randomly having substituent aryl or for can randomly have substituent heteroaryl, and is asymmetric carbon atoms by the * marked carbon atoms.
28. comprising, the preparation method with optically active compound by formula (I) expression, this method use any described compound among claim 3-8, the 12-17,20 and 21:
Wherein R be for can randomly having substituent aryl or for can randomly have substituent heteroaryl, and is asymmetric carbon atoms by the * marked carbon atoms.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP213311/2005 | 2005-07-22 | ||
| JP2005213311 | 2005-07-22 | ||
| JP267485/2005 | 2005-09-14 | ||
| JP015436/2006 | 2006-01-24 |
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| CN2010105660813A Division CN102120741A (en) | 2005-07-22 | 2006-07-21 | Production method of an optically active compound |
| CN2010105661568A Division CN102050820A (en) | 2005-07-22 | 2006-07-21 | Preparation method of compound with optical activity |
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| CN111148731A (en) * | 2017-09-13 | 2020-05-12 | 阿托基公司 | Fluorophenyl β -hydroxyethylamine and use thereof in the treatment of hyperglycaemia |
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2006
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| CN111148731A (en) * | 2017-09-13 | 2020-05-12 | 阿托基公司 | Fluorophenyl β -hydroxyethylamine and use thereof in the treatment of hyperglycaemia |
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