CN1823065A - Method for the enantioselective preparation of sulphoxide derivatives - Google Patents
Method for the enantioselective preparation of sulphoxide derivatives Download PDFInfo
- Publication number
- CN1823065A CN1823065A CN 200480008537 CN200480008537A CN1823065A CN 1823065 A CN1823065 A CN 1823065A CN 200480008537 CN200480008537 CN 200480008537 CN 200480008537 A CN200480008537 A CN 200480008537A CN 1823065 A CN1823065 A CN 1823065A
- Authority
- CN
- China
- Prior art keywords
- methyl
- amino
- methoxyl group
- pyridyl
- chemical formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B45/00—Formation or introduction of functional groups containing sulfur
- C07B45/04—Formation or introduction of functional groups containing sulfur of sulfonyl or sulfinyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention relates to a method for the enantioselective preparation of substituted sulphoxide derivatives. The method comprises carrying out an enantioselective oxidation of a sulphide of general formula (I): A - CH2 - S - B (I), where A = a variously-substituted pyridyl nucleus and B = a heterocyclic group with a benzimidazole or imidazopyridyl nucleus, by means of an oxidising agent in the presence of a catalyst based on tungsten or vanadium and a chiral ligand, followed, where necessary, by salt formation with a base to give the sulphoxide: A - CH2 - SO - B (Ia). The above is of application to the enantioselective preparation of compounds such as the enantiomers of tenatoprazole and other comparable sulphoxides.
Description
Technical field
The present invention relates to the method that enantioselectivity prepares the sulfoxide substitutive derivative, more specifically, relate to the method for the enantiomorph of enantioselectivity preparation example such as tenatoprazole (tenatoprazole) and other similar compound.
Background technology
Several derivatives of known sulfoxide, especially pyridyl-methyl-sulfinyl benzoglyoxaline as having the proton pump of inhibition performance, that is to say gastric acid inhibitory excretory medicine, are suitable in the therapeutics and suitable treatment stomach ulcer and duodenal ulcer.The derivative of this series proton pump inhibitor of knowing the earliest is the omeprazole of describing in patent EP 005.129 (omeprazole); or 5-methoxyl group-2-[[(4-methoxyl group-3; 5-dimethyl-2-pyridyl) methyl] sulfinyl]-the 1H-benzoglyoxaline, it has gastric acid inhibitory excretory performance and is widely used as anti ulcer agent in the human body therapy.The derivative of other benzoglyoxaline is to be known with their generic name; rabeprazole (rabeprazole) for example; pantoprazole (pantoprazole); lansoprazole (lansoprazole), and all groups that all show similar structure and belong to pyridyl-methyl-sulfinyl-benzoglyoxaline.
Tenatoprazole (tenatoprazole) has been described in patent EP 254.588, that is, 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl]-imidazo [4,5-b] pyridine.It also is considered to the proton pump inhibitor drug moiety, and also can be used for the treatment of stomach-esophageal reflux, digestive tract hemorrhage and maldigestion.
These all compounds all are to show asymmetrical sulfoxide at the sulphur atom place, thereby and may become the form of the racemic mixture of two kinds of enantiomorphs.Have R and a S configuration with what they divided optionally respectively that any specified property may be significantly different, perhaps (+) or
(1) enantiomorph is useful.
Having described several method in scientific literature comes with selectivity or accounts for leading mode to prepare any in these sulfoxide enantiomorphs, especially omeprazole (omeprazole) and its S configuration enantiomorph, esomeprazole (esomeprazole), and its salt for example sodium salt or magnesium salts.
So, the method for magnesium salts that the ester that comprises chirality acyloxy methyl group that uses it prepares (-) enantiomorph of omeprazole has been described among the patent EP 652.872, the separation of diastereomer and in basic solution molten from.The microorganism that a kind of use contains the DMSO reductase enzyme has been described among the United States Patent (USP) 5.776.765, in corresponding sulfoxide, utilize the method for the racemic mixture of stereoselectivity biological reducing sulfide, compare with (+) enantiomorph, this method makes it possible to obtain quite to be rich in the mixture of (-) enantiomorph.United States Patent (USP) 5.948.789 relates to by in the presence of titanium complex and chiral ligand, prepares sulfoxide by the corresponding sulfide enantioselectivity of hydroperoxide oxidation, especially (-) enantiomorph of omeprazole or its sodium salt.According to employed part, the method described in this patent makes it may obtain to be rich in (-) and (+) enantiomorph any mixture.
Till now, shown by the work that the applicant carried out, in the presence of specific tungsten or catalytic component based on vanadium, passed through the corresponding sulfide of enantioselectivity oxidation, can be under good purity and productive rate condition in the enantioselectivity mode, obtain the enantiomorph of sulfoxide derivant, especially tenatoprazole.
Summary of the invention
Thereby the present invention relates to be used for showing as the enantioselectivity preparation method of asymmetrical sulfoxide derivant at the sulphur atom place, this method is produced in this enantiomorph any with gratifying output and purity.
More specifically, the present invention relates to a kind of preparation method, this method can be with (-) and (+) enantiomorph of enantioselectivity mode production tenatoprazole significantly.Used in the above term " in enantioselectivity mode significantly " means in a selective manner or obtains desirable enantiomorph with respect to other enantiomorph to account for leading amount.
Preparation in accordance with the present invention in the presence of tungsten or catalytic component based on vanadium and chiral ligand, uses oxygenant that the sulfide with following general formula (I) is carried out the enantioselectivity oxidation, if necessary, and next by the alkali salify,
A-CH
2-S-B (I)
Wherein A is the different pyridine rings that replace, and B is the heterocyclic radical that comprises benzoglyoxaline or imidazo-pyridine.
In the superincumbent general formula (I), A preferably represents pyridyl or has one or more substituent pyridyl, these substituting groups are selected from linearity or the branched-chain alkyl with 1-6 carbon atom, linearity or branched alkoxy with 1-6 carbon atom, methyl or ethyl by one or several halogen atom replacement, amino, wherein moieties is linear or the alkylamino that all comprises 1-5 carbon atom or the dialkyl amido of side chain; The B representative is selected from benzoglyoxaline or imidazo-[4,5-b]-heterocycle of pyridyl, if necessary, have the linearity or the branched-chain alkyl of 1-6 carbon atom by one or several, linearity or branched alkoxy with 1-6 carbon atom replace, and preferably on one or several carbon by methyl, ethyl, methoxyl group or trihalogenmethyl replace.
In the superincumbent general formula (I), A is preferably by one or several methyl, ethyl, and the 2-pyridyl that methoxyl group or trifluoromethyl replace, and more specifically be 4-methoxyl group-3,5-dimethyl-2-pyridyl.B preferably 5-methoxyl group-1H-benzimidazolyl-or B is 5-methoxyl group-imidazo-[4,5-b]-pyridyl.
Sulfide corresponding to top general formula (I) is known product, and it can for example make according to the method for describing in patent EP 254.588 and EP 103.553 according to the several method of describing in the literature.
Obtained to have the sulfoxide of following chemical formula like this.
A-CH
2-SO-B (Ia)
Wherein A and B have top definition of being given.
Used in the method for the invention oxygenant is superoxide preferably, for example hydrogen peroxide, or hydroperoxide, for example cumene or tertbutyl peroxide.According to a favourable implementation method, use high density, for example be higher than 30% hydrogen peroxide, or the compound hydrogen peroxide of urea (UHP: perhydrit H
2NCONH
2.H
2O
2), be called " UHP " hereinafter).
Tungsten or catalytic component based on vanadium are the requisite items of the inventive method, and it reaction takes place and desirable derivative is obtained with good productive rate.According to the present invention, the preferred use is for example by vanadium acetylacetonate VO (acac)
2The oxo vanadium complexes of the V that makes, or other tungsten derivative trioxide WO for example
3Catalyzer.Such catalyzer can be buied from the market.Also can use by Vanadosulfuric acid VOSO
4The complex compound that makes.
The selection of ligand has constituted another characteristic element of the present invention, and this is that ground points to the enantiomorph of wishing because it allows reaction preference.
According to the present invention, under the situation of catalytic component based on vanadium, this part is three teeth preferably.
This part can advantageously be represented by following general formula (II):
RO-CR
1R
2-CR
3R
4-NR
5R
6 (II)
Wherein R is hydrogen atom or the linearity with 1-6 carbon atom or branched-chain alkyl or aryl or heteroaryl;
R
1-R
4Can be identical or different, representative can comprise for example sulphur of heteroatoms, nitrogen and oxygen and/or the linearity with 1-6 carbon atom or the branched-chain alkyl that are replaced by amino; Aryl; Alkylaryl; Alkoxy carbonyl; Heteroaryl or heterocycle; Or heteroarylalkyl or Heterocyclylalkyl, be R with condition
1With R
2Inequality, and/or R
3With R
4Inequality, so that part comprises 1 or two asymmetric centers;
R
1And R
2Represent carbonyl C=O together;
R
1And R
3, or R
2And R
4Together, one of them ring that can form the carbocyclic ring with 5 or 6 carbon atoms or have 9 or 10 carbon atoms can be the bicyclic system of aromatic ring;
Similarly, R
4And R
5Can form 5 yuan or 6 yuan of heterocycles with nitrogen-atoms;
R
5And R
6, no matter be identical or different, all represent linearity or branched-chain alkyl or 5 or 6 yuan of carbocyclic rings with 1-6 carbon atom, perhaps form the heterocycle that links together by nitrogen-atoms, perhaps R
5And R
6Represent together with nitrogen-the two keys of N=CHAr that wherein Ar may be replaced by 1-3 group, and preferably has the aryl of hydroxyl.
Preferably, Ar can substituted 2 '-hydroxy phenyl on this aryl.
R
1And R
3, or R
2And R
4, preferably represent hydrogen atom, yet, R
2And R
4, or R
1And R
3Be respectively linearity or branched-chain alkyl with 1-6 carbon atom, aryl or form together that to have the carbocyclic ring of 5 or 6 carbon atoms or have 9 or 10 one of them rings of carbon atom can be the aryl of aromatic bicyclic system.
According to the present invention:
" aryl " means preferably have one or more phenyl that comprise, naphthyl, tetralyl, 2, the list of the aromatic ring of 3-indanyl and binaphthylyl or polycyclic system.Aryl can be replaced by 1-3 substituting group, and these substituting groups are independently selected from hydroxyl, contain the linearity or the branched-chain alkyl of 1-4 carbon atom, methyl for example, ethyl, propyl group or preferred tertiary butyl, nitro, (C
1-C
4) alkoxyl group and halogen atom, chlorine for example, bromine or iodine,
-" aralkyl " means the aryl that preferably appends to the alkyl that contains 1-4 carbon atom,
-" carbalkoxy " means the alkoxyl group that contains 1-4 carbon atom that preferably appends on the carbonyl, methoxycarbonyl for example,
-" heteroaryl " mean and preferably contain 1-3 heteroatoms, nitrogen for example, and the aryl of sulphur or oxygen comprises pyridyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl etc.,
-" heterocycle " or " heterocyclic radical " mean and preferably contain for example sulphur of 1-3 heteroatoms, 5 yuan or 6 yuan of rings of nitrogen or oxygen.This definition also comprises the ring of dicyclo, wherein as defined heterocyclic radical in front and phenyl, and cyclohexyl or any other heterocyclic fused.In heterocyclic group, can quote imidazolinyl, indyl ， isoxazolyl, furyl, pyrazolyl, thienyl, etc.
-" heteroaralkyl " means and preferably appends to the alkyl that contains 1-4 carbon atom, preferable methyl, heteroaryl,
-" Heterocyclylalkyl " mean and preferably append to the alkyl preferable methyl that contains 1-4 carbon atom, on heterocyclic radical, 4-imidazolinyl methyl for example.
More specifically, have chemical formula (II) part can derived from:
-have amino-alcohol of chemical formula (III)
R wherein
1, R
2, R
3And R
4Defined as the front.In amino alcohol with chemical formula (III), can quote L-(S-(+)-) or D-valerian ammonia alcohol (R-(-)-2-amino-3-methyl isophthalic acid-butanols), uncle's R-leucinol (R-(-)-2-amino-3,3-dimethyl-1-butanols), uncle's S-leucinol (S-(+)-2-amino-3,3-dimethyl-1-butanols), (1S, 2R)-(-)-or (1R, 2S)-(+)-1-amino-2-indanol
-have the amino ethers of chemical formula (IV)
R wherein
1, R
2, R
3And R
4Defined as the front.
-have the amino acid of chemical formula V
Wherein R ' adopts and the given R in front
3Or R
4Identical definition.In having the amino acid of chemical formula V, can quote L-Xie Ansuan or D-Xie Ansuan, L-phenylalanine or D-phenylalanine, L-methionine(Met) or D-methionine(Met), L-Histidine or D-Histidine and L-Methionin or D-Methionin.
-have the amino ester of chemical formula (VI)
Wherein R ' adopts and the given R in front
3Or R
4Identical definition and R " adopt the definition of R.
Preferably, in order to obtain particularly advantageous part, that is, Schiff's base, these have chemical formula (III) respectively, (VI), amino alcohol (V) and (VI), amino ethers, amino acid and amino ester and have the salicylic aldehyde reaction of chemical formula (VII)
R wherein
7Represent 1-2 substituting group, these substituting groups are independently selected from hydroxyl, contain the linearity or the branched-chain alkyl of 1-4 carbon atom, methyl for example, ethyl, propyl group or preferred tertiary butyl, nitro, (C
1-C
4) alkoxyl group and halogen atom, chlorine for example, bromine or iodine.
In framework of the present invention, the part with chemical formula (II) is particularly preferred, and described part is derived from the amino alcohol with chemical formula (III), wherein, and R
5And R
6Represent two key-N=CHAr together with nitrogen-atoms, wherein Ar is the aryl that contains 1-3 substituting group and at least one hydroxyl, Ar phenyl preferably wherein,
R
1And R
3, or R
2And R
4, represent hydrogen atom, yet, R
2And R
4, or R
1And R
3Be respectively linearity or the branched-chain alkyl that contains 1-6 carbon atom separately independently of each other, the preferred tertiary butyl, or form the bicyclic system that has the carbocyclic ring of 5 or 6 carbon atoms or have 9 or 10 carbon atoms together, one of them ring can be an aromatic series, preferably 2, the 3-indanyl.
According to the present invention, can advantageously select part according to employed catalyzer, for example under the situation of tungsten, can use part according to the enantiomorph of being sought, described part:
-belong to cinchona alkaloid (quinquina alcaloids) family, quinine for example, quinidine, dihydro-quinidine (DHQD) or hydroquinine (DHQ),
-derived from quinquina alcaloids, for example hydroquinine 2,5-phenylbenzene-4,6-pyridine two basic diether (DHQ)
2-PYR or hydroquinidine 2,5-phenylbenzene-4,6-pyridine two basic diether (DHQD)
2-PYR.
Under the situation of catalytic component based on vanadium, preferred use is represented by top chemical formula (II), contains substituent part on nitrogen-atoms, for example derived from the bigcatkin willow acid anhydrides and Schiff's base chiral amino alcohol that replaces.
Usually, under the situation of vanadium acetylacetonate, preferably use derived from the part that has respectively as top defined chemical formula (III) or amino alcohol (IV) or amino ethers as catalytic component based on vanadium.On the contrary, under the situation of Vanadosulfuric acid as catalytic component based on vanadium, preferred use has chemical as defined above formula V and the amino acid (VI) and the part of amino ester respectively.
Thereby, adopt under the situation of vanadium acetylacetonate as catalytic component based on vanadium preferred, can make this reaction preference be directed to the part 2 of the isomer of being sought, 4-two-tertiary butyl-6-[1-R-methylol-2-methyl-propyl group imino-]-methyl]-phenol and its isomer 2,4-two-tertiary butyl-6-[1-S-methylol-2-methyl-propyl group imino-]-methyl]-phenol is particularly preferred.Thereby, use 2,4-two-tertiary butyl-6-[1-R-methylol-2-methyl-propyl group imino-]-methyl]-phenol allows selective fixed to 5-methoxyl group-2-[[4-methoxyl group-3,5-dimethyl-2 pyridyl] methyl] sulfo-] oxidizing reaction of imidazo [4,5-b] pyridine to be to obtain as following represented S-tenatoprazole.
Equally, adopt under the situation of acetyl acid vanadium as catalytic component based on vanadium preferred, always especially preferably derived from as the part of the aminoidan alcohol of amino alcohol (1R, 2S)-1-[2-hydroxyl-3,5-two-tertiary butyl-benzylidene]-amino]-indane-2-alcohol.
Thereby it is selective fixed to 5-methoxyl group-2-[[4-methoxyl group-3 to use described part to allow, 5-dimethyl-2 pyridyl] methyl] sulfo-] oxidizing reaction of imidazo [4,5-b] pyridine obtains as following represented S-tenatoprazole with selectivity.
Under operational condition, this part preferably three teeth and form asymmetrical complex compound, wherein oxidized dose of oxidation of this metal with metal catalyst.
According to feature of the present invention, this reaction can be in neutrality or weak alkaline medium, by selecting sulfide specific solvent and part specific solvent preferably to carry out in solvent mixture at solvent, these solvents are selected from methyl alcohol, tetrahydrofuran (THF), methylene dichloride, acetonitrile, toluene, acetone, chloroform, DMF (dimethyl formamide) or the single solvent of NMP (N-Methyl pyrrolidone) or their mixture.The alkali that may use can be tertiary amine, for example pyridine, diisopropylethylamine or triethylamine.
According to another scheme, can not add alkali and implement this method, but preferably avoid in acidic medium, operating, because it may cause the degraded of the finished product.
According to the present invention, in acetonitrile solution, use catalytic component based on vanadium and part, simultaneously sulfide is dissolved in chlorinated solvent for example in the methylene dichloride, then these two kinds of solution are mixed, and to carry out this oxidizing reaction be particularly advantageous.
This oxidizing reaction is easily carried out under low temperature or room temperature.In order to improve enantioselectivity, at 0-10 ℃ and preferably under 4-5 ℃ temperature it to be induced may be favourable.
Because oxygenant and catalyzer both can buy widely from the market, cheap and processing easily, thereby method of the present invention is particularly advantageous.In addition, this catalyzer can be used effectively and with considerably less amount.The output of the enantiomorph that is obtained is good, and in addition, this catalyzer and part can recycle under the good state without any the enantiomorph supplementary loss usually.
Method of the present invention is particularly advantageous in preparation can be by the enantiomorph of the tenatoprazole of following chemical formulation:
Thereby the method according to this invention is in order to obtain (-)-5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] imidazo [4,5-b] pyridine, can be at tungstic oxide and (DHQD)
2Under the existence of-PYR, by hydrogen peroxide to 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfo-] imidazo [4,5-b] pyridine carries out very favorable enantioselectivity oxidation.
More specifically, have been found that, when in acetonitrile solution, being used in combination catalytic component based on vanadium and by 2,4-two-tertiary butyl-6-[1-R-hydroxyl-methyl-2-methyl-propyl group imino-]-methyl]-phenol or (1R, 2S)-1-[2-hydroxyl-3,5-two-tertiary butyl-benzylidene]-amino]-the pure part of forming of indane-2-, simultaneously, sulfide is dissolved in respectively among dichloromethane solution or acetone or the NMP, and the oxidation of top sulfide allows to have with good purity and the acquisition of output situation (-) enantiomorph of S-configuration.
On the contrary, by using 2,4-two-tertiary butyl-6-[1-S-hydroxyl-methyl-2-methyl-propyl group imino-]-methyl]-phenol or (1S, 2R)-1-[2-hydroxyl-3,5-two-tertiary butyl-benzylidene]-amino]-indane-2-alcohol is as part, also can obtain have (+) isomer of R configuration with good selectivity and output.
(-) of tenatoprazole and (+) enantiomorph can use with the form of salt, and specifically with an alkali metal salt or rare-earth alkali metal-salt, for example with sodium, potassium, lithium, the form of magnesium or calcium salt is used.These salt can pass through salify according to the processing method of standard by previous (-) or (+) enantiomorph of isolating tenatoprazole, for example obtain by the alkaline inorganic reagent that comprises alkali or alkaline earth counter ion.
Certainly, use any suitable separation method, by the preparative column chromatogram, for example chirality or HPLC chromatogram can obtain to be somebody's turn to do (-) or (+) enantiomorph from racemic mixture with pure optical form simply.The enantiomorph of Huo Deing can be used for contrast like this." pure optical form " means that (-) enantiomorph does not have or only contain (+) enantiomorph of trace basically, and vice versa.Then if necessary, in order to form salt, particularly alkaline or alkaline-earth salts carries out salify by alkali in suitable solvent.
The chiral chromatography ratio juris is known, and its chirality that is based on the avidity difference that is present between (+) and (-) enantiomorph and stationary phase is selected.This method makes Separation of Enantiomers have gratifying output.
(-) enantiomorph of tenatoprazole is corresponding to (-)-5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] imidazo [4,5-b] pyridine, perhaps (-)-tenatoprazole.This form can use the technology of standard to determine by optics rotary test instrument.Like this, the optics rotation angle of (-)-tenatoprazole is left-handed in dimethyl formamide and acetonitrile, and its fusing point is 130 ° (decomposition).
Under the situation of chiral separation tenatoprazole, can use known method as the racemic mixture of starting material, for example obtain according to the method described in the patent EP 254.588.Like this, can use oxygenant under the condition of heating, for example peroxybenzoic acid is handled the corresponding sulfide that is produced by mercaptan and pyridine condensation, preferably at suitable solvent, for example, exists in the ethanol to make this racemic mixture in alkali such as the potassium hydroxide.
In the disease of being mentioned below handling, (-) of tenatoprazole and (+) enantiomorph can be to be suitable for selected administration route, the outer route of for example oral or gi tract, the standard form administration of preferred oral or vein route.
For example, can use the tablet or the capsule product that contain as (-) and (+) enantiomer of any tenatoprazole of activeconstituents, or other oral liquid or emulsion or be used for containing of gi tract external administration and have the solution that pharmacy can be accepted the tenatoprazole salt of standard substrate.The salt of tenatoprazole enantiomorph can be for example, sodium, and potassium, lithium is selected in magnesium or the calcium salt.
Use (-) and (+) enantiomorph of the tenatoprazole that method of the present invention obtains can be used for preparation and be used for the treatment of digestive disorder, especially hydrochloric acid in gastric juice suppresses in the essential strong and secular digestive disorder, be used in processing other proton pump inhibitor is had drug-fast stomach and intestine esophageal reflux, in digestive tract hemorrhage symptom and the disease.
The dosage of taking in is to be determined according to patient's the state and the severity of the state of an illness by the pharmacist.This pharmaceutical quantities is generally 10-120mg every day, is preferably (-) or (+) enantiomorph of 20-80mg tenatoprazole.
For the present invention is described but do not limit this application, the embodiment of preparation enantiomorph is described below.
Embodiment
Embodiment 1
(S)-(-)-preparation of tenatoprazole
The 10g WO that will between 4-5 ℃ temperature, keep stirring
3, 73g (DHQD)
2-PYR, 3.5L THF and 330g 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfo-] imidazo [4,5-b] pyridine, put in the 5L flask, and add 120mL 30% hydrogen peroxide inwards.This reaction medium was stirred 48 hours.At room temperature filter this catalyzer then and filtrate is diluted in the 10L methylene dichloride.
Wash this organic phase with water, dry and concentrated in decompression then to it.Obtained 242g and wished that the enantiomeric excess that obtains surpasses the enantiomorph of 90% (70% productive rate).
In methanol or DMF/ vinyl acetic monomer mixture, carry out recrystallize, and obtained to have enantiomeric excess and surpass 99% enantiomorph.Enantiomeric excess is that (250 * 4,6m) high pressure liquid chromatography of post is determined under 25 ℃, and eluent is that acetonitrile (1mL/min) and detection are to be carried out under 305nm by the U.V spectrography by having CHIRALPAKAS-H 20 μ m.Retention time that should (S)-(-)-isomer equals 7.7 minutes, and (R)-(+)-and the retention time of isomer equals 5.2 minutes.
T
F：129-130℃
[α]
20 D：-186.6(c 0，1，DMF)
Ultimate analysis:
| Element | C | H | N | S |
| Theoretical | 55.48 | 5.24 | 16.17 | 9.26 |
| Observe | 55.66 | 5.22 | 16.16 | 9.37 |
UV spectrum (methanol-water): λ max:272nm (∈=6180), 315nm (∈=24877).
Infrared (KBr): 3006,1581,1436,1364,1262,1026,1040 and 823cm
-1
RMN
1H (DMSO d
6, reference: DMS) δ (ppm): 2.20 (s, 6H), 3.70 (s, 3H), 3.92 (s, 3H), 4.69-4.86 (m, 2H), 6.80 (d, J8.5Hz, 1H), 7.99 (d, J6.5Hz, 1H), 5.16 (s, H), 13.92 (s, 1H).
RMN
13C (DMSO d
6, reference: TMS) δ (ppm): 13.2; 15.0; 56.6; 60.9; 62.6; 107.2; 129.5; 130.4; 131.9; 135.1; 150.5; 152.4; 156.9; 160.7; 163.0; 166.6.
Embodiment 2
(R)-(+)-preparation of tenatoprazole
Use with embodiment 1 in set identical condition, and use identical catalyzer, but usefulness (DHQ)
2-PYR replaces (DHQD)
2-PYR makes the 5-methoxyl group-2-[[(4-methoxyl group-3 of same amount set among 120mL hydrogen peroxide and the embodiment 1,5-dimethyl-2-pyridyl) methyl] sulfo-] reaction of imidazo [4,5-b] pyridine.
In the DMF/ ethyl acetate mixture, behind the recrystallize, obtained the desired enantiomeric excess that has that obtains like this and surpassed (+) enantiomorph of 99%.
The specific rotation of measuring with polariscope in dimethyl formamide is [D]
20 D:+186 °.
(R)-(+)-and the physics of tenatoprazole and spectroscopy constant are identical with (S)-(-)-tenatoprazole, and just specific rotatory power is: [α]
20 D:+185.9 (c 0.1, DMF).
Embodiment 3
(S)-(-)-preparation of omeprazole (esomeprazole)
Use with embodiment 1 in set identical condition, and use 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfo-]-1H-benzoglyoxaline replacement 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfo-] imidazo [4,5-b] pyridine, obtained to have the product (esomeprazole) that enantiomeric excess obtains near the hope of 90% (72% productive rate).
The product that obtains meets available analytical data in the document.
Embodiment 4
(S)-(-)-preparation of tenatoprazole
With the 3L methylene dichloride,, 5-dimethyl-2-pyridyl) methyl then with 360g 5-methoxyl group-2-[[(4-methoxyl group-3] sulfo-] imidazo [4,5-b] pyridine is incorporated in the 5L flask.This mixture was at room temperature stirred 30 minutes.
With the 700ml acetonitrile, 5.22g 2 then, 4-two-tertiary butyl-6-[1-S-methylol-2-methyl-propyl group imino-]-methyl]-phenol, then 2.9g methyl ethyl diketone vanadyl is splashed in the 2L flask one by one.After at room temperature stirring 30 minutes, this mixture is joined among the former.
At room temperature stir under the 20h, the hydrogen peroxide of 135ml 30% is joined in this mixture.After water phase separated, wash organic phase twice with water, then drying under reduced pressure and concentrated.Having obtained 283g has enantiomeric excess and surpasses the enantiomorph that the hope of 80% (75% productive rate) obtains.In methanol or DMF/ vinyl acetic monomer mixture, carry out two successive recrystallize, and obtained to have enantiomeric excess and surpass 99% enantiomorph.
T
F：127.5℃
[α]
20 D：-182(c 0.1，DMF)
Embodiment 5
(R)-(+)-preparation of tenatoprazole
Adopt with embodiment 4 in identical program, still 2,4-two-tertiary butyl-6-[1-R-methylol-2-methyl-propyl group imino-]-methyl]-phenol is by 2,4-two-tertiary butyl-6-[1-S-methylol-2-methyl-propyl group imino-]-methyl]-phenol replaces.
Obtained desirable enantiomorph like this.
[α]
20 D：+185.9(c 0.1，DMF)
Embodiment 6
(S)-(-)-preparation of tenatoprazole
With 1.2L NMP,, 5-dimethyl-2-pyridyl) methyl then with 240g 5-methoxyl group-2-[[(4-methoxyl group-3] sulfo-] imidazo [4,5-b] pyridine is incorporated in the 5L flask.This mixture was at room temperature stirred 1 hour 30 minutes.
With 18ml NMP, 2.9g (1R, 2S)-1-[2-hydroxyl-3,5-two-tertiary butyl-benzylidene]-amino]-indane-2-alcohol, and then the 1.9g vanadium acetylacetonate is incorporated in the 50mL round-bottomed flask in proper order according to this.At room temperature stir this mixture.After stirring 1 hour 30 minutes, this solution is joined in the reaction mixture.
At room temperature stir under the 20h, the hydrogen peroxide of 95ml 30% is joined in this mixture.Precipitate this reaction mixture by adding 500mL water.
By this throw out of filtered and recycled, be poured into then in the 5L chloroform.Wash this organic phase with water, then drying under reduced pressure and concentrated.Having obtained 126g has enantiomeric excess and surpasses the enantiomorph that the hope of 30% (productive rate 50%) obtains.In DMF/ vinyl acetic monomer mixture, carry out crystallization several times then, and obtained to have enantiomeric excess and surpass 99% enantiomorph.
Embodiment 7
(S)-(-)-preparation of tenatoprazole
With 3.7L acetone,, 5-dimethyl-2-pyridyl) methyl then with 30g 5-methoxyl group-2-[[(4-methoxyl group-3] sulfo-] imidazo [4,5-b] pyridine is incorporated in the 10L flask.This mixture stayed under the room temperature stirred 30 minutes.
With the 30mL acetonitrile, 1.66g (1R, 2S)-1-[2-hydroxyl-3,5-two-tertiary butyl-benzylidene]-amino]-indane-2-alcohol, then the 1.19g vanadium acetylacetonate is incorporated in the 100mL round-bottomed flask.At room temperature stir this mixture.After stirring 1 hour 30 minutes, this suspension is joined in the reaction mixture.
Stirring under 6 hours, 10g is being dissolved in urea-H in the 7ml water
2O
2Join in this mixture with 50ml acetone.This mixture was stayed room temperature following 12 hours then.Add sodium metabisulphate, add 20% ammoniacal liquor and concentrated acetone then.After with the washing of 100mL chloroform, collect water and neutralize with acetate then.Extract twice with the 200mL chloroform.After water phase separated, dry this organic phase and under reduced pressure concentrated.Having obtained 19g has enantiomeric excess and surpasses the enantiomorph that the hope of 50% (productive rate 60%) obtains.In DMF/ vinyl acetic monomer mixture, carry out crystallization several times, and obtained to have enantiomeric excess and surpass 99% enantiomorph.
Embodiment 8
(S)-(-)-preparation of tenatoprazole
With 4L acetone,, 5-dimethyl-2-pyridyl) methyl then with 30g 5-methoxyl group-2-[[(4-methoxyl group-3] sulfo-] imidazo [4,5-b] pyridine is incorporated in the 10L flask.This mixture stayed under the room temperature stirred 30 minutes.
With the 25mL acetonitrile, 1.66g (1R, 2S)-1-[2-hydroxyl-3,5-two-tertiary butyl-benzylidene]-amino]-indane-2-alcohol, then the 1.19g vanadium acetylacetonate is incorporated in the 100mL round-bottomed flask in proper order with this.At room temperature stir this mixture.After stirring 1 hour 30 minutes, this suspension is joined in the reaction mixture.
Stirring under 6 hours, with 30g sodium sulfate, 10g is dissolved in the urea-H in the 7ml water
2O
2Join in this mixture with 50ml acetone.Then this mixture is stayed under the room temperature and stirred 12 hours.Add sodium metabisulphate, add 20% ammoniacal liquor and concentrated acetone then.After with the washing of 100mL chloroform, collect water and neutralize with acetate then.Extract twice with the 200mL chloroform.After water phase separated, dry this organic phase and under reduced pressure concentrated.Having obtained 20.1g has enantiomeric excess and surpasses the enantiomorph that the hope of 65% (productive rate 64%) obtains.In DMF/ vinyl acetic monomer mixture, carry out crystallization several times, and obtained to have enantiomeric excess and surpass 99% enantiomorph.
Claims (29)
1, a kind ofly be used for the method that enantioselectivity prepares sulfoxide derivant or its subsalt, it is characterized in that, in the presence of tungsten or catalytic component based on vanadium and chiral ligand, use oxygenant that the sulfide with following general formula (I) is carried out the enantioselectivity oxidation,
A-CH
2-S-B (I)
Wherein A is the different pyridine rings that replace, and B is the heterocyclic radical that comprises benzoglyoxaline or imidazo-pyridine ring,
If necessary, next by the alkali salify, so that obtain sulfoxide A-CH
2-SO-B (Ia).
2, method according to claim 1, it is characterized in that, in general formula (I), A represents pyridyl or has one or more substituent pyridyl, and methyl that these substituting groups are selected from linearity or the branched-chain alkyl with 1-6 carbon atom, the linearity with 1-6 carbon atom or branched alkoxy, replaced by one or several halogen atom or ethyl, amino, wherein moieties is linear or the alkylamino that all comprises 1-5 carbon atom or the dialkyl amido of side chain; The B representative is selected from the heterocycle of benzoglyoxaline or imidazo-[4,5-b]-pyridyl, and if necessary, it has the linearity or the branched-chain alkyl of 1-6 carbon atom, the linearity with 1-6 carbon atom or branched alkoxy by one or several and replaces.
According to the method for claim 2, it is characterized in that 3, A and B group are replaced by methyl, ethyl, methoxyl group or trihalogenmethyl on one or several carbon atom.
According to the method for claim 3, it is characterized in that 4, A is the 2-pyridyl that is replaced by one or several methyl, ethyl, methoxyl group or trifluoromethyl.
According to each described method in claim 3 and 4, it is characterized in that 5, A is a 4-methoxyl group-3,5-dimethyl-2-pyridyl and B are 5-methoxyl group-1H-benzimidazolyl-or 5-methoxyl group-imidazo-[4,5-b]-pyridyl.
According to each described method in the claim of front, it is characterized in that 6, the enantiomorph that is obtained is by the salify with the alkaline inorganic reagent reaction that comprises alkali or alkaline earth counter ion.
7, method according to claim 6, wherein said salt are sodium, potassium, lithium, magnesium or calcium salt.
8, according to each described method among the claim 1-7, wherein said oxygenant is superoxide or hydroperoxide.
9, method according to claim 8, wherein said oxygenant is a hydrogen peroxide, urea-H
2O
2(UHP) or cumene or tert-butyl hydroperoxide.
10, according to each described method among the claim 1-9, wherein said catalyzer is the derivative of (V) vanadyl complex or tungsten.
11, according to the method for claim 10, wherein said complex compound or derivative are by tungstic oxide, vanadium acetylacetonate or Vanadosulfuric acid preparation.
According to each described method of claim 1-11, it is characterized in that 12, described catalyzer is that the part vanadium base and described is three teeth.
According to each described method of claim 1-12, it is characterized in that 13, described part is to be represented by following general formula (II):
RO-CR
1R
2-CR
3R
4-NR
5R
6(II)
Wherein R is hydrogen atom or the linearity with 1-6 carbon atom or branched-chain alkyl or aryl or heteroaryl;
R
1-R
4Can be identical or different, representative can comprise heteroatoms such as sulphur, nitrogen and oxygen and/or by amino linearity or branched-chain alkyl that replace, that have 1-6 carbon atom; Aryl; Alkylaryl; Alkoxy carbonyl; Heteroaryl or heterocycle; Heteroarylalkyl or Heterocyclylalkyl, condition are R
1Should be not and R
2Identical, and/or R
3Should be not and R
4Identical, so that described part comprises one or two asymmetric center;
R
1And R
2Can represent carbonyl C=O together;
R
1And R
3, or R
2And R
4Can form carbocyclic ring together or have 9 or 10 carbon atoms and one of them ring can be the bicyclic system of aromatic ring with 5 or 6 carbon atoms;
R
4And R
5Can be identical or different, can form 5 yuan or 6 yuan of heterocycles with nitrogen-atoms;
R
5And R
6Can be identical or different, representative has linearity or branched-chain alkyl or 5 or 6 yuan of carbocyclic rings of 1-6 carbon atom, perhaps forms heterocycle with the nitrogen-atoms that they connected, perhaps
R
5And R
6Represent together with nitrogen-the two keys of N=CHAr that wherein Ar is the aryl that can be replaced and preferably be had hydroxyl by 1-3 group.
14, method according to claim 13 is characterized in that Ar is can substituted 2 '-hydroxy phenyl on aryl.
15, according to claim 13 or 14 described methods, it is characterized in that R
1And R
3, or R
2And R
4, represent hydrogen atom, and R
2And R
4, or R
1And R
3, be respectively to have the linearity of 1-6 carbon atom or branched-chain alkyl, aryl or form together to have the carbocyclic ring of 5 or 6 carbon atoms or have 9 or 10 carbon atoms and one of them ring can be the bicyclic system of aromatic ring.
16, according to each described method among the claim 13-15, it is characterized in that described aryl is selected from phenyl, naphthyl, tetralyl, 2,3-indanyl and binaphthylyl, wherein this aryl can be selected from hydroxyl by 1-3, comprise the linearity of 1-4 carbon atom or branched-chain alkyl, nitro, (C
1-C
4) substituting group of alkoxyl group and halogen atom replaces.
17, according to each described method of claim 13-16, it is characterized in that having chemical formula (II) part alternatively derived from:
-have the amino alcohol of chemical formula (III):
R wherein
1, R
2, R
3And R
4Such as claim 13-16 in each definition,
-have the amino ethers of chemical formula (IV):
R wherein
1, R
2, R
3And R
4Such as claim 13-16 in each definition,
-have the amino acid of chemical formula V
Wherein R ' adopt according to claim 13-16 each to R
3Or R
4Definition, perhaps
-have the amino ester of chemical formula (VI)
Wherein R ' adopt according to claim 13-16 each to R
3Or R
4Definition and R " adopt each definition of claim 13-16 to R.
18, method according to claim 17, it is characterized in that: the amino alcohol with chemical formula (III) is selected from L or D-valerian ammonia alcohol, uncle's R-leucinol, uncle's S-leucinol and (1S, 2R)-(-)-or (1R, 2S)-(+)-and 1-amino-2-indanol, and the amino acid that wherein has a chemical formula V is selected from L-Xie Ansuan or D-Xie Ansuan, L-phenylalanine or D-phenylalanine, L-methionine(Met) or D-methionine(Met), L-Histidine or D-Histidine and L-Methionin or D-Methionin.
19, according to each described method of claim 13-18, it is characterized in that, part with chemical formula (II) is to obtain by making as the defined salicylic aldehyde reaction that has chemical formula (III), (IV), (V) and amino alcohol (VI), amino ethers, amino acid or amino ester respectively and have a chemical formula (VII) in claim 17 or 18
R wherein
7Represent 1-2 to be selected from hydroxyl, the linearity that contains 1-4 carbon atom or branched-chain alkyl, nitro, (C separately independently of each other
1-C
4) substituting group of alkoxyl group and halogen atom.
20,, it is characterized in that using by the catalyzer of vanadium acetylacetonate preparation with derived from as the defined part that has chemical formula (III) or amino alcohol (IV) or amino ethers respectively in claim 17 or 18 according to each described method of claim 13-19.
21, method according to claim 20 is characterized in that, the part with chemical formula (II) is derived from as defined in claim 17 the amino alcohol with chemical formula (III), wherein, and R
5And R
6Represent two key-N=CHAr together with nitrogen-atoms, wherein Ar is the aryl that contains 1-3 substituting group and at least one hydroxyl, and Ar is phenyl preferably,
R
1And R
3, or R
2And R
4, represent hydrogen atom, and R
2And R
4, or R
1And R
3Be respectively linearity or the branched-chain alkyl that has 1-6 carbon atom separately independently of each other, the tertiary butyl or form the bicyclic system have the carbocyclic ring of 5 or 6 carbon atoms or to have 9 or 10 carbon atoms together preferably, one of them ring can be an aromatic ring, preferably 2, and the 3-indanyl.
22, according to each described method of claim 13-19, it is characterized in that, use by the catalyzer of Vanadosulfuric acid preparation with derived from as the defined part that has chemical formula V or amino acid (VI) or amino ester respectively in claim 17 or 18.
23, according to each described method among the claim 1-21, it is characterized in that this part is 2,4-two-tertiary butyl-6-[1-R-methylol-2-methyl-propyl group imino-]-methyl]-phenol, 2,4-two-tertiary butyl-6-[1-S-methylol-2-methyl-propyl group imino-]-methyl]-phenol, (1R, 2S)-1-[2-hydroxyl-3,5-two-tertiary butyl-benzylidene]-amino]-indane-2-alcohol or (1S, 2R)-1-[2-hydroxyl-3,5-two-tertiary butyl-benzylidene]-amino]-indane-2-alcohol.
24, method according to claim 23 is characterized in that, described part is in acetonitrile solution.
25; according to claim 23 or 24 described methods; it is characterized in that: by in acetonitrile solution, being used in combination catalytic component based on vanadium and by 2; 4-two-tertiary butyl-6-[1-R-methylol-2-methyl-propyl group imino-]-methyl]-phenol or (1R; 2S)-1-[2-hydroxyl-3; 5-two-tertiary butyl-benzylidene]-amino]-the pure part of forming of indane-2-; carry out 5-methoxyl group-2-[[(4-methoxyl group-3; 5-dimethyl-2-pyridyl) methyl] sulfo-] imidazo [4; 5-b] the enantioselectivity oxidation of pyridine to be to obtain (-)-5-methoxyl group-2-[[(4-methoxyl group-3; 5-dimethyl-2-pyridyl) methyl] sulfinyl] imidazo [4; 5-b] pyridine, sulfide is respectively in methylene dichloride or acetone or N-Methyl pyrrolidone solution simultaneously.
26,, it is characterized in that described catalyzer is that tungsten derivative and described part are hydroquinines 2,5-phenylbenzene-4,6-pyridyl diether (DHQ) according to claim 10 or 11 described methods
2-PYR or hydroquinidine 2,5-phenylbenzene-4,6-pyridyl diether (DHQD)
2-PYR.
27, method according to claim 26 is characterized in that, at tungstic oxide and (DHQD)
2Under the existence of-PYR; carry out 5-methoxyl group-2-[[(4-methoxyl group-3 by hydrogen peroxide; 5-dimethyl-2-pyridyl) methyl] sulfo-] imidazo [4; 5-b] the enantioselectivity oxidation of pyridine; so that obtain (-)-5-methoxyl group-2-[[(4-methoxyl group-3; 5-dimethyl-2-pyridyl) methyl] sulfinyl] imidazo [4,5-b] pyridine.
28,, it is characterized in that described oxidizing reaction is in solvent, carry out in neutrality or weak alkaline medium according to the described method of each claim of front.
29, method according to claim 28, it is characterized in that, the solvent mixture that described solvent is made up of sulfide specific solvent and part specific solvent, wherein these solvents are to be selected from the single solvent of methyl alcohol, tetrahydrofuran (THF), methylene dichloride, acetonitrile, toluene, acetone, chloroform, dimethyl formamide and N-Methyl pyrrolidone or their mixture, and described alkali is the tertiary amine that is selected from pyridine, diisopropylethylamine and triethylamine.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0303914 | 2003-03-28 | ||
| FR0303914A FR2852956B1 (en) | 2003-03-28 | 2003-03-28 | PROCESS FOR THE ENANTIOSELECTIVE PREPARATION OF SULFOXIDE DERIVATIVES |
| FR0314679 | 2003-12-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1823065A true CN1823065A (en) | 2006-08-23 |
Family
ID=32947286
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200480008537 Pending CN1823065A (en) | 2003-03-28 | 2004-03-26 | Method for the enantioselective preparation of sulphoxide derivatives |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN1823065A (en) |
| FR (1) | FR2852956B1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102471290A (en) * | 2009-07-16 | 2012-05-23 | 拜尔农作物科学股份公司 | Process for preparing chiral 3-triazolyl sulphoxide derivatives |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE7804231L (en) * | 1978-04-14 | 1979-10-15 | Haessle Ab | Gastric acid secretion |
| DE3336751A1 (en) * | 1983-10-08 | 1985-04-18 | Bayer Ag, 5090 Leverkusen | METHOD FOR PRODUCING AMINOBENZOL ALKYL SULPHONES OR -SULFOXIDES |
| DK171989B1 (en) * | 1987-08-04 | 1997-09-08 | Takeda Chemical Industries Ltd | Process for the preparation of 2- (2-pyridylmethylsulfinyl) benzimidazoles |
| SE504459C2 (en) * | 1994-07-15 | 1997-02-17 | Astra Ab | Process for the preparation of substituted sulfoxides |
| WO2003089408A2 (en) * | 2002-04-22 | 2003-10-30 | Sun Pharmaceutical Industries Limited | Optically active substituted pyridinylmethyl-sulphinyl-benzimidazole and salts |
-
2003
- 2003-03-28 FR FR0303914A patent/FR2852956B1/en not_active Expired - Fee Related
-
2004
- 2004-03-26 CN CN 200480008537 patent/CN1823065A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102471290A (en) * | 2009-07-16 | 2012-05-23 | 拜尔农作物科学股份公司 | Process for preparing chiral 3-triazolyl sulphoxide derivatives |
| CN102471290B (en) * | 2009-07-16 | 2016-02-03 | 拜耳知识产权有限责任公司 | The preparation method of chiral 3-triazolyl sulfoxide derivant |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2852956B1 (en) | 2006-08-04 |
| FR2852956A1 (en) | 2004-10-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Bai et al. | Quinine-catalyzed asymmetric domino Mannich-cyclization reactions of 3-isothiocyanato oxindoles with imines for the synthesis of spirocyclic oxindoles | |
| CN1753893A (en) | The enantiomer of tenatoprazole and the use thereof in therapy | |
| US20060281782A1 (en) | Method for the enantioselective preparation of sulphoxide derivatives | |
| Talero et al. | Sharpless asymmetric dihydroxylation on α, β-unsaturated diazoketones: a new entry for the synthesis of disubstituted furanones | |
| JP5213444B2 (en) | Mirror image selective method for producing sulfoxide derivatives | |
| CN100345849C (en) | Enantiomer (-) of tenatoprazole and the therapeutic use thereof | |
| CN1823065A (en) | Method for the enantioselective preparation of sulphoxide derivatives | |
| CN108033866B (en) | Method for preparing polyaromatic substituted naphthalene derivative by cyclization reaction of ruthenium-catalyzed dibenzyl ketone and internal alkyne and application | |
| CN102432526A (en) | Chiral 2',5-dicarbonyl-3-aryl spiro[cyclohexane-1,3'-indole]-2,2-dinitrile derivative and preparation method thereof | |
| CN115246798A (en) | Method for synthesizing photocatalytic beta-C heteroaryl substituted alcohol | |
| JP5561577B2 (en) | Method for producing optically active 3'-fluorothalidomide derivative | |
| FR2871800A1 (en) | SODIUM SALT S-TENATOPRAZOLE MONOHYDRATE AND THERAPEUTIC APPLICATION | |
| CN115181051B (en) | Preparation method of sulfoxide compound containing indole skeleton | |
| EP4249470A1 (en) | Method for preparing alpha-amino acids | |
| Sharma et al. | Ligand-free Pd-catalyzed double Heck reaction of N-(o-bromoaryl) acrylamides with α-F/CF 3-acrylates | |
| CN111704590B (en) | Synthesis method of iron-catalyzed 2-arylbenzothiazole compound | |
| RU2339631C1 (en) | Method of obtaining esomeprazole | |
| MXPA05010250A (en) | Method for the enantioselective preparation of sulphoxide derivatives | |
| FR2863611A1 (en) | Enantioselective oxidation of sulfides to form sulfoxides, especially tenatoprazole, using an oxidizing agent in the presence of a tungsten or vanadium-based catalyst and a chiral ligand | |
| Wang et al. | A Copper Catalyzed Doyle− Kirmse Reaction between Vinyl Diazosuccinimide and Allyl-Phenyl Thioetherfor the Concise and Effective Preparation of Multifunctional 3-Allyl-3-(Thio) Succinimides | |
| FR2925899A1 (en) | Enantioselective preparation of substituted sulfoxide derivative, useful to treat gastric and duodenal ulcers, comprises coupling sulfinate core with an organometallic compound, where the sulfinate is in the form of diastereoisomer | |
| CN101386616A (en) | 1,4-thioxane sulfinylimines compounds and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Open date: 20060823 |