CN100343228C - Selective prepn process of single antimer of 2-dibenzylsulfenyl-acetamide with higher antimer - Google Patents
Selective prepn process of single antimer of 2-dibenzylsulfenyl-acetamide with higher antimer Download PDFInfo
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- CN100343228C CN100343228C CNB200610023954XA CN200610023954A CN100343228C CN 100343228 C CN100343228 C CN 100343228C CN B200610023954X A CNB200610023954X A CN B200610023954XA CN 200610023954 A CN200610023954 A CN 200610023954A CN 100343228 C CN100343228 C CN 100343228C
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Abstract
The present invention relates to an enantiomer selectivity catalyzing oxidation method for preparing optics activity enantiomers or optics pure enantiomer 2-ibenzylsulfenyl-acetamide. The present invention uses metal tiron and chiral bidentate ligand to generate titanium-containing catalytic agents in situ, and enantiomers catalyze and oxidize 2-dibenzylsulfenyl-acetamide selectively under the action of oxidant.
Description
Invention field
The present invention relates to the method that a kind of enantio-selectivity catalysed oxidation processes prepares optical activity enantiomorph or optical purity enantiomorph modafinil.
Background technology
Compound 2-benzhydrylsulfinyl base-ethanamide (common modafinil by name) is a kind of novel nervous system stimulant with non-amphetamine new texture; be a kind of active synthesis of acetyl sulfonamide derivatives of the awakening of promotion that has, its structure and synthetic French Patent No.7805510 and the US4177290 of being described in.Modafinil is used for the treatment of and the associated over-drastic of narcolepsy sleepiness in the daytime by food and drug administration approval, sells on market with title Provigil .
In the sulfoxide compound of asymmetric replacement, sulphur atom is a chirality.The chirality of modafinil just shows on the sulphur atom of sulfoxide.In fact, modafinil also exists a pair of enantiomer, (R)-(-)-the enantiomorph correspondence be exactly (R)-modafinil, (S)-(+)-the enantiomorph correspondence be exactly (S)-modafinil.
US4177290 has described a kind of method for preparing modafinil raceme compound.US4927855 has described a kind of method for preparing left-handed modafinil isomer.Use (-)-Alpha-Methyl benzylamine and modafinil acid-respons to obtain a pair of diastereomeric salt, use the method for recrystallization disconnected from each other, acidifying obtains the single enantiomer of modafinil acid respectively again.And then further esterification and the synthetic optical purity modafinil of amination.But the fractionation efficient of this method is very low, and productive rate only has 6%.
Hereafter, the synthetic method of single optical antipode modafinil is not just appeared in the newspapers, and up to the second half year in 2004, just has the document of two pieces of chiral separation openly to report the synthetic of two optical antipodes of modafinil.
First method (Prisinzano, T.; Podobinski, J.; Tidgewell, K.; Luo, M.; Swenson, D.Tetrahedron:Asymmetry 2004,15, and 1053-1058.) acid splits same resolution reagent (-)-Alpha-Methyl benzylamine of use and US4927855 to modafinil, further again synthesizing optical pure modafinil.Fractionation efficient increases, and two kinds of enantiomorph productive rates are respectively 21% and 44%.
Second method (Osorio-Lozada, A.; Prisinzano, T.; Olivo, H.F.Tetrahedron:Asymmetry 2004,15,3811-3814.) use (4R)-phenyl-thiazolidine thioketones and modafinil acid-respons to obtain a pair of diastereomer acid amides, utilize the isolating method of silicagel column disconnected from each other, the synthetic optical purity modafinil of direct amination splits efficient and improves respectively, and productive rate is respectively 77% and 85%.
Although use the method for chiral selectors to split modafinil, their fractionation efficient all remains further to be improved, even and split efficient and reach 100%, also still have the raw material of half to be wasted.
Although the research of enantio-selectivity catalyzed oxidation thioether is many in the document, various enantio-selectivity catalytic oxidation systems also emerge in an endless stream,, the method for the direct enantio-selectivity catalyzed oxidation thioether of modafinil is not seen any report yet.Prisinzano is in the document of his report, once attempted to use the method for classical enantio-selectivity catalyzed oxidation thioether, as the enantio-selectivity catalytic oxidation system of diethyl tartrate, titanium tetraisopropylate and cumene hydroperoxide, do not obtain good result yet.Therefore, just adopted the method for chiral separation to obtain the single enantiomer of modafinil.
Therefore, need a kind of effectively direct enantio-selectivity catalyzed oxidation 2-benzhydryl thioacetamide of development to prepare the method for modafinil single enantiomer.
Goal of the invention
The purpose of this invention is to provide the method that a kind of novel enantio-selectivity catalysed oxidation processes prepares optical activity enantiomorph or optical purity enantiomorph (S)-modafinil.
Method preparation (the S)-modafinil that the purpose of this invention is to provide an easy and cheap enantio-selectivity catalyzed oxidation, in the presence of the bitooth ligand catalyzer, do not add any organic bases, use gentle cheap oxygenant direct oxidation 2-benzhydryl thioacetamide.
The method of enantio-selectivity catalyzed oxidation has related to different Preparation of Catalyst optical activity enantiomorphs or optical purity enantiomorph 2-benzhydrylsulfinyl base-ethanamide (modafinil) among the present invention.
Brief summary of the invention
The invention provides the method that a simple and cheap method prepares optical activity enantiomorph or optical purity enantiomorph 2-benzhydrylsulfinyl base-ethanamide (modafinil); under the situation that the bitooth ligand catalyzer exists; do not add any organic bases, use gentle cheap oxygenant direct oxidation 2-benzhydryl thioacetamide.
Summary of the invention
The compound of the method preparation of passing through the enantio-selectivity catalyzed oxidation that the present invention describes is optical activity enantiomorph or optical purity enantiomorph 2-benzhydrylsulfinyl base-ethanamide (modafinil).
The method for preparing optical activity enantiomorph or optical purity enantiomorph 2-benzhydrylsulfinyl base-ethanamide that the present invention describes, it is characterized in that under the situation that chirality bitooth ligand metal complex catalyst exists, do not add any organic bases, use gentle cheap oxygenant direct oxidation 2-benzhydryl thioacetamide; This method may further comprise the steps:
In organic solvent and exist or when not having water, chirality bitooth ligand, metal titanium reagent, 2-benzhydryl thioacetamide and oxygenant obtained optical activity enantiomorph or optical purity enantiomorph 2-benzhydrylsulfinyl base-ethanamide in 1～24 hour-78 ℃～50 ℃ reactions;
The mol ratio of described chirality bitooth ligand, metal titanium reagent, 2-benzhydryl thioacetamide and oxygenant is respectively 0.01～1: 0.005～0.5: 1: 0.5～3;
Described chirality bitooth ligand is to have following structural formula
(R, R) or (S, S)-1,2-is disubstituted-1,2-glycol, or have following structural formula
(R, R) or (S, S)-1,1 '-binaphthol derivative;
Wherein, R
5For
R
6, R
7, R
8, R
9, R
10, R
11, R
12Or R
13Be hydrogen, C independently
1～6Alkyl, C
1～6Alkoxyl group or ester group, halogen, phenyl, trifluoromethyl or nitro; R
14, R
15, R
16Or R
17Be hydrogen, C independently
1～6Alkyl, C
1～6Alkoxyl group or ester group, halogen, phenyl, pyridyl, trifluoromethyl or nitro; Described metal titanium reagent is four C
1-4Alkoxy titanium compound;
Described oxygenant is hydrogen peroxide, C
1～4Alkyl peroxide or C
1～4The alkyl phenyl superoxide.
The chirality bitooth ligand that the present invention describes can have (R, R) or (S, S)-1,2-is disubstituted-1, the structure of 2-glycol or can have (R, R) or (S, S)-1, the structure of 1 '-binaphthol derivative, preferably (R, R) or (S, S)-1,1 '-binaphthol derivative, (R more preferably, R) or (S, S)-1,1 '-dinaphthol.The molar ratio of chirality bitooth ligand and 2-benzhydryl thioacetamide can be preferably 0.1: 1 for 0.01: 1 to 1: 1.
The bitooth ligand titanium complex catalyzer that the present invention describes can be by chirality bitooth ligand and the preparation of metal titanium reagent react.Metal titanium reagent is preferably four alkoxy titanium compounds, more preferably the titanium tetraisopropylate compound.The molar ratio of metal titanium reagent and 2-benzhydryl thioacetamide can be 0.005: 1 to 0.5: 1, preferably 0.05: 1.
The enantio-selectivity oxidation that the present invention describes can be carried out in the existence of water or not.The molar ratio of water and 2-benzhydryl thioacetamide can be 0.01: 1 to 2: 1, preferably 1: 1.
The oxygenant that the present invention describes can be hydrogen peroxide, alkyl peroxide and alkyl phenyl base superoxide, preferably alkyl phenyl superoxide, more preferably propyloxy phenyl base hydrogen peroxide, called after cumene hydroperoxide again.The molar ratio of oxygenant and 2-benzhydryl thioacetamide can be 0.5: 1 to 3: 1, preferably 2: 1.
The enantio-selectivity oxidation system that the present invention describes does not need to add any organic bases.
The organic solvent that the present invention describes can be methylene dichloride, chloroform, tetracol phenixin, hexane, benzene, toluene, chlorobenzene, oil of mirbane, dimethylbenzene, ether, tertbutyl ether, tetrahydrofuran (THF) and dioxane or their mixture.Chloroform preferably.
The temperature of reaction of the enantio-selectivity oxidation that the present invention describes can be-78 ℃ to 25 ℃, preferably 0 ℃ to 25 ℃, and more preferably 20 ℃ to 25 ℃.The time of reaction can be 1 to 24 hour, preferably 12 to 18 hours.
The modafinil that the present invention describes can improve optical purity by the method for recrystallization.The solvent that recrystallization uses can be methylene dichloride, chloroform, tetracol phenixin, hexane, benzene, toluene, chlorobenzene, oil of mirbane, dimethylbenzene, ether, tertbutyl ether, tetrahydrofuran (THF) and dioxane or their mixture.Chloroform preferably.
The inventive method is easy, and product optical purity height is a kind of method of suitable suitability for industrialized production.
Embodiment
Below the embodiment by the embodiment form is described in further detail foregoing of the present invention again.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment, all technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1 general operation
In the time of 25 ℃, titanium tetraisopropylate (0.025 mmole) joins in 2 milliliters of organic solutions of chirality bitooth ligand (0.05 mmole).Add entry (0.5 mmole) then and continue to stir, add 2-benzhydryl thioacetamide (0.5 mmole) again, slowly add oxygenant (1.0 mmole) at last, continue to be stirred to reaction and finish.Conventional aftertreatment obtains white (R)-modafinil solid.M.p.155℃。
1H NMR(DMSO 300MHz)δ3.19(d，2H)，3.34(d，2H)，5.30(s，1H)，7.29-7.50(m，10H)。Chirality HPLC condition is: Chirabiotic
The T analytical column, (methyl alcohol: acetate: triethylamine=100: 1: 1) flow velocity is: 0.7mL/min, ultraviolet monitoring wavelength are 229nm to moving phase.Retention time t
R=6.081, t
S=6.559.
The bitooth ligand type was to the influence of reaction when embodiment 2 oxygenants were tertbutyl peroxide
Experimental implementation is with embodiment 1, and ingredient proportion is as follows: the 2-benzhydryl thioacetamide: chirality bitooth ligand: titanium tetraisopropylate: water: oxygenant=1: 0.1: 0.05: 1: 2.Change the type of chirality bitooth ligand, investigate their influences reaction result.The organic solvent that uses in this reaction is a toluene, and oxygenant is a tertbutyl peroxide.Experimental result such as table 1.
Table 1
| Entry | Part | Productive rate (%) | Ee(％) | Configuration |
| 1 2 3 4 | (R)-BINOL (R)-Taddol L-DET (R, R)-1,2-diphenylethane | 60 23 9 37 | 44 12 —— 60 | R S —— S |
Annotate: BINOL is a dinaphthol, and Taddol is 2,2-dimethyl-α, and α, α ', α '-tetraphenyl-1,3-dioxolane-4,5-dimethanol, DET are diethyl tartrates.
Ee is an enantio-selectivity.
---be not react.
Which kind of part no matter does not all show gratifying catalytic activity as can be seen from Table 1.
The bitooth ligand type was to the influence of reaction when embodiment 3 oxygenants were cumene hydroperoxide
Experimental implementation is with embodiment 1, and ingredient proportion is as follows: the 2-benzhydryl thioacetamide: chirality bitooth ligand: titanium tetraisopropylate: water: oxygenant=1: 0.1: 0.05: 1: 2.Change the type of chirality bitooth ligand, investigate their influences reaction result.The organic solvent that uses in this reaction is a toluene, and oxygenant is a cumene hydroperoxide.Experimental result such as table 2.
Table 2
| Entry | Part | Productive rate (%) | Ee(％) | Configuration |
| 1 2 3 4 | (R)-BINOL (R)-Taddol L-DET (R, R)-1,2-diphenylethane | 73 23 43 63 | 91 10 —— 83 | R S —— S |
Annotate: BINOL is a dinaphthol, and Taddol is 2,2-dimethyl-α, and α, α ', α '-tetraphenyl-1,3-dioxolane-4,5-dimethanol, DET are diethyl tartrates.
Ee is an enantio-selectivity.
---be not react.
Chirality bitooth ligand BINOL shows best catalytic activity in this reaction as can be seen from Table 2.
Embodiment 4 organic solvents are to the influence of reaction
Experimental implementation is with embodiment 1, and ingredient proportion is as follows: the 2-benzhydryl thioacetamide: chirality bitooth ligand: titanium tetraisopropylate: water: oxygenant=1: 0.1: 0.05: 1: 2.Change the employed organic solvent of reaction, investigate their influences reaction result.The bitooth ligand that uses in this reaction is (R)-dinaphthol, and oxygenant is a cumene hydroperoxide.Experimental result such as table 3.
Table 3
| Entry | Solvent | Productive rate (%) | Ee(％) | Configuration |
| 1 2 3 4 5 | Toluene methylene dichloride tetrahydrofuran (THF) tetracol phenixin chloroform | 73 65 53 78 83 | 91 60 43 67 92 | R R R R R |
Annotate: Ee is an enantio-selectivity.
As can be seen from Table 3, when organic solvent used chloroform, the productive rate and the enantio-selectivity of reaction were the highest.
Embodiment 5 temperature of reaction are to the influence of reaction
Experimental implementation is with embodiment 1, and ingredient proportion is as follows: the 2-benzhydryl thioacetamide: chirality bitooth ligand: titanium tetraisopropylate: water: oxygenant=1: 0.1: 0.05: 1: 2.Change temperature of reaction, investigate their influences reaction result.The bitooth ligand that uses in this reaction is (R)-dinaphthol, and oxygenant is a cumene hydroperoxide, and solvent is a chloroform.Experimental result such as table 4.
Table 4
| Entry | Temperature of reaction | Productive rate (%) | Ee(％) | Configuration |
| 1 2 3 4 | 50℃ 25℃ 0℃ -20℃ | 53 83 45 29 | 62 92 87 88 | R R R R |
Annotate: Ee is an enantio-selectivity.
As can be seen from Table 4, when temperature of reaction was 25 ℃, productive rate and enantio-selectivity were all relatively good.When temperature of reaction raise or reduce, productive rate and enantio-selectivity all had decline in various degree.
Embodiment 6 catalyst levelss are to the influence of reaction
Experimental implementation is with embodiment 1, and ingredient proportion is as follows: 2-benzhydryl thioacetamide: water: oxygenant=1: 1: 2.Keep the chirality bitooth ligand: the ratio of titanium tetraisopropylate=2: 1, change the consumption of chirality bitooth ligand, investigate their influences to reaction result.The bitooth ligand that uses in this reaction is (R)-dinaphthol, and oxygenant is a cumene hydroperoxide, and solvent is a chloroform.Experimental result such as table 5.
Table 5
| Entry | Part consumption (%) | Productive rate (%) b | Ee(％) c | Configuration d |
| 1 2 | 100 40 | 73 100 | 88 89 | R R |
| 3 4 5 6 7 | 20 10 5 2.5 1 | 85 83 91 59 54 | 92 92 88 92 79 | R R R R R |
Annotate: Ee is an enantio-selectivity.
As can be seen from Table 5, the part consumption to the enantio-selectivity of product by certain influence.Between 20% to 5%, it is all little that chemical yield and optical yield differ, and therefore, we have selected 10% as catalyst consumption.
The substituent effect of embodiment 7 (R)-dinaphthol is to the influence of reaction
Experimental implementation is with embodiment 1, and ingredient proportion is as follows: the 2-benzhydryl thioacetamide: chirality bitooth ligand (S)-binaphthol derivative: titanium tetraisopropylate: water: oxygenant=1: 0.1: 0.05: 1: 2.Change temperature of reaction, investigate their influences reaction result.The bitooth ligand that uses in this reaction is (R)-binaphthol derivative, and oxygenant is a cumene hydroperoxide, and solvent is a chloroform.Experimental result such as table 6.
Table 6
| Entry | (S)-binaphthol derivative | Productive rate (%) | Ee(％) | Configuration |
| 1 2 3 4 5 6 | (S)-dinaphthol, (S)-the 6-Br-dinaphthol, (S)-6-Br-6 '-Br-dinaphthol, (S)-3-I-3 '-I-dinaphthol, (S)-3-Ph-3 '-Ph-dinaphthol, (S)-6-Py-6 '-Py-dinaphthol | 83 69 73 70 48 61 | 92 59 77 —— 1 9 | S S S — R R |
Annotate: Ee is an enantio-selectivity.
---be not react.
As can be seen from Table 6, dinaphthol 3, have under the substituent situation on 3 ', do not have catalytic activity basically; And at 6 or 6, have under the substituent situation on 6 ', productive rate and enantio-selectivity all descend to some extent, and when substituting group be during than macoradical such as phenyl, pyridyl, productive rate and enantio-selectivity all have obvious decline, even make enantio-selectivity overturn.
Embodiment 8 water are to the influence of reaction
Experimental implementation is with embodiment 1, and ingredient proportion is as follows: the 2-benzhydryl thioacetamide: chirality bitooth ligand (R)-dinaphthol: titanium tetraisopropylate: oxygenant=1: 0.1: 0.05: 2.Under the situation of not adding water, investigate the influence of water to reaction.The oxygenant that uses in this reaction is a cumene hydroperoxide, and solvent is a chloroform.Productive rate is 72%, and the ee value is 38%.
Embodiment 9 adopts the reaction result of titanium tetraisopropylate, L-diethyl tartrate and organic bases system
Experimental implementation is with embodiment 1, and ingredient proportion (the optimum charging ratio example of this type of asymmetry catalysis system) is as follows: 2-benzhydryl thioacetamide: L-diethyl tartrate: titanium tetraisopropylate: water: organic bases: oxygenant=1: 0.6: 0.3: 0.1: 0.3: 0.97.Change the kind and the oxygenant of organic bases, investigate their influences reaction result.The oxygenant that uses in this reaction is a cumene hydroperoxide, and solvent is a toluene.Experimental result such as table 7.
Table 7
| Entry | Oxygenant | Organic bases | Productive rate (%) | Ee(％) | Configuration |
| 1 2 3 4 5 6 7 | TBHP CHP TBHP TBHP TBHP TBHP TBHP | iPr 2NEt iPr 2NEt NEt 3 TMEDA Me 2NPh NPh 3 DIBACO | 29 26 29 15 38 44 14 | 75 74 47 68 47 60 37 | S S S S S S S |
Annotate: Ee is an enantio-selectivity.
As can be seen from Table 7, this kind catalyst system is catalysis 2-benzhydryl thioacetamide effectively, and catalytic efficiency is low, and the productive rate of product is compared with embodiment 2-7 with enantio-selectivity, significantly decreases.
The recrystallization of embodiment 10 modafinils
The ee value is 80% modafinil adding organic solvent, recrystallization, the modafinil of the optical purity that is improved.Experimental result such as table 8.
Table 8
| Entry | Solvent | Productive rate (%) | Ee(％) | Configuration |
| 1 2 3 4 5 6 | Toluene methylene dichloride chloroform methyl tertbutyl ketone tetrahydrofuran (THF) tetracol phenixin | 93 90 91 85 89 92 | 80 83 97 90 85 81 | R R R R R R |
Annotate: Ee is an enantio-selectivity.
Claims (11)
1. an enantio-selectivity catalyzed oxidation prepares the method for optical activity enantiomorph or optical purity enantiomorph 2-benzhydrylsulfinyl base-ethanamide, it is characterized in that under the situation that chirality bitooth ligand metal complex catalyst exists, do not add any organic bases, use gentle cheap oxygenant direct oxidation 2-benzhydryl thioacetamide; This method may further comprise the steps:
In organic solvent and exist or when not having water, chirality bitooth ligand, metal titanium reagent, 2-benzhydryl thioacetamide and oxygenant obtained optical activity enantiomorph or optical purity enantiomorph 2-benzhydrylsulfinyl base-ethanamide in 1～24 hour-78 ℃～50 ℃ reactions;
The mol ratio of described chirality bitooth ligand, metal titanium reagent, 2-benzhydryl thioacetamide and oxygenant is respectively 0.01～1: 0.005～0.5: 1: 0.5～3;
Described chirality bitooth ligand is to have following structural formula
(R, R) or (S, S)-1,2-is disubstituted-1,2-glycol, or have following structural formula
(R, R) or (S, S)-1,1 '-binaphthol derivative;
Wherein, R
5For
Described metal titanium reagent is four (C
1～4Alkoxyl group) titanium compound;
Described oxygenant is hydrogen peroxide, C
1～4Alkyl peroxide or C
1～4The alkyl phenyl superoxide.
2. method according to claim 1, it is characterized in that described bitooth ligand be (R, R) or (S, S)-dinaphthol.
3. method according to claim 1 is characterized in that the molar ratio of described chirality bitooth ligand and 2-benzhydryl thioacetamide is 0.1: 1.
4. method according to claim 1 is characterized in that described metal titanium reagent is titanium tetraisopropylate.
5. method according to claim 1 is characterized in that the mol ratio of described metal titanium reagent and 2-benzhydryl thioacetamide is 0.05: 1.
6. it is characterized in that according to claim 1 is described described oxygenant is a propyloxy phenyl base hydrogen peroxide.
7. method according to claim 1 is characterized in that the mol ratio of described oxygenant and 2-benzhydryl thioacetamide is 2: 1.
8. method according to claim 1 is characterized in that described organic solvent is methylene dichloride, chloroform, tetracol phenixin, hexane, benzene, toluene, chlorobenzene, oil of mirbane, dimethylbenzene, ether, tertbutyl ether, tetrahydrofuran (THF), dioxane or their mixture.
9. method according to claim 1 is characterized in that this is reflected in the organic solvent earlier by chirality bitooth ligand and metal titanium reagent preparation catalyzer, then in the presence of water, again with 2-benzhydryl thioacetamide and oxidant reaction.
10. method according to claim 1, the mol ratio that it is characterized in that described water and 2-benzhydryl thioacetamide is 0.01～2: 1.
11. method according to claim 1 is characterized in that after the described reaction or after separating, described modafinil improves optical purity by the method for organic solvent recrystallization.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6462089B1 (en) * | 2000-01-31 | 2002-10-08 | Laboratoire L. Lafon | Method for correcting the vigilance disorders associated with myopathies |
| CN1656064A (en) * | 2002-05-23 | 2005-08-17 | 赛福伦公司 | Preparations of a sulfinyl acetamide |
| WO2005077894A1 (en) * | 2004-02-06 | 2005-08-25 | Cephalon, Inc. | Modafinil compositions |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6462089B1 (en) * | 2000-01-31 | 2002-10-08 | Laboratoire L. Lafon | Method for correcting the vigilance disorders associated with myopathies |
| CN1656064A (en) * | 2002-05-23 | 2005-08-17 | 赛福伦公司 | Preparations of a sulfinyl acetamide |
| WO2005077894A1 (en) * | 2004-02-06 | 2005-08-25 | Cephalon, Inc. | Modafinil compositions |
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