CN100500660C - Process for preparing (s)-pantoprazole - Google Patents
Process for preparing (s)-pantoprazole Download PDFInfo
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- CN100500660C CN100500660C CNB2003801044098A CN200380104409A CN100500660C CN 100500660 C CN100500660 C CN 100500660C CN B2003801044098 A CNB2003801044098 A CN B2003801044098A CN 200380104409 A CN200380104409 A CN 200380104409A CN 100500660 C CN100500660 C CN 100500660C
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- tartrate
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- acid amides
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- 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
Abstract
The invention relates to a novel process for preparing (S)-pantoprazole using a chiral zirconium complex or a chiral hafnium complex.
Description
Technical field
The present invention relates to the novel method of active compound (S)-pantoprazole that a kind of preparation can be used for preparing the medicine industry Chinese traditional medicine.
Background technology
As (for example) known pyridine-2-ylmethyl sulfinyl-1 H-benzimidazole and the closely-related compound of structure from EP-A-0005129, EP-A-0166287, EP-A-0174726 and EP-A-0268956,, its H+/K+-ATPase restraining effect has remarkable importance because of increasing in the relevant disease with gastric acid secretion in treatment.
Example from the active compound of this compounds in commercially available or the clinical development is 5-methoxyl group-2-[(4-methoxyl group-3; 5-dimethyl-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline (INN: omeprazole (omeprazole)); (S)-5-methoxyl group-2-[(4-methoxyl group-3; 5-dimethyl-2-pyridyl) methyl-sulfinyl]-1H-benzoglyoxaline (INN: esomeprazole (esomeprazole)); 5-difluoro-methoxy-2-[(3; 4-dimethoxy-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline (INN: pantoprazole (pantoprazole)); 2-[3-methyl-4-(2; 2; the 2-trifluoro ethoxy)-and the 2-pyridyl] methylsulfinyl]-1H-benzoglyoxaline (INN: lansoprazole (lansoprazole)); 2-{[4-(3-methoxy propoxy)-3-picoline-2-yl] methylsulfinyl }-rabeprazole (rabeprazole)) and 5-methoxyl group-2-((4-methoxyl group-3 1H-benzoglyoxaline (INN:; 5-dimethyl-2-pyridylmethyl) sulfinyl)-and the 1H-imidazo (4,5-b) pyridine (INN: tenatoprazole (tenatoprazole)).
Because its mechanism of action, the above-mentioned sulfenyl derivant that is otherwise known as proton pump inhibitor or is abbreviated as PPI is a chipal compounds.The method that is generally used for preparing PPI is the corresponding sulfide of oxidation.This oxygenizement produces the racemic mixture that (unless taking any special measures) comprises two kinds of enantiomers (steric isomer) of about same ratio, meaning promptly (+)-and (-)-form or (R)-with (S)-PPI of form.
Because relatively stable on the enantiomerism body heat content, meaning is its racemization (especially solid form) not in storage, and the past has been made a large amount of effort to separating the PPI enantiomeric mixture or preparing in various degree the PPI enantiomer of respective pure form.
Prior art
International application WO91/12221 has described a kind of method of using cellulase to separate enantiomer.By this method, one of active compound that is separable into enantiomer of being mentioned is an omeprazole.
International application WO92/08716 has described a kind of chemical process first, and its permission is separated into its optical isomer with pyridine-2-ylmethyl sulfinyl-1 H-benzimidazole class.Compound, the especially compound of having mentioned (+) with the exemplary manner preparation-and (-)-5-difluoro-methoxy-2-[(3,4-dimethoxy-2-pyridyl) methylsulfinyl]-the 1H-benzoglyoxaline [=(+)-and (-)-pantoprazole].The optical isomer (meaning i.e. (+)-and (-)-enantiomer or (R)-and (S)-enantiomer) that international application WO92/08716 mentions pyridine-2-base-methylsulfinyl-1H-benzimidazoles can be used as the active compound of treatment gastrointestinal disorder medicine.About the mode of administration and the dosage of active compound, with reference to (especially) European patent 166 287.
International application WO94/27988 has described the use chiral auxiliary(reagent) racemic omeprazole has been separated into enantiomer.
International application WO96/02535 (=USP 5,948,789) has described a kind of use Chiral Titanium complex compound and has carried out PPI enantio-selectivity synthetic method.Its especially described (+)-and (-)-[perhaps with different modes be expressed as (R)-and (S)]-pantoprazole synthetic, be used for (+)-pantoprazole synthetic chiral auxiliary(reagent) for (+)-diethyl tartrate, and the chiral auxiliary(reagent) that is used for preparing (-)-pantoprazole is (-)-diethyl tartrate.
International application WO96/17076 and WO96/17077 have described the use certain micro-organisms and have carried out enantio-selectivity bio-oxidation or biological reducing, to be used to prepare PPI enantiomer-pure or the enantiomerism enrichment.
International application WO97/02261 describes and carries out the enrichment of PPI enantiomer by selective precipitation.
International application WO94/24867 and WO94/25028 advocate compound (-)-and (+)-pantoprazole be used for the treatment of the purposes of human stomach trouble.It is said that each steric isomer other steric isomer more separately has medical advantages.
Tetrahedron, Asymmetry, (2000), and 11, describe the enantio-selectivity sulfoxide among the 3819-3825 and turned usefulness into, thereby used the Chiral Titanium complex compound to prepare esomeprazole ((S)-omeprazole) on a large scale.
J.Org.Chem., (1999), 64 (4), 1327 have described that the enantio-selectivity sulfoxide of arylalkyl sulfide and dialkyl sulfide turns usefulness in the presence of the Zr catalyst with polygamy position polymerization of olefin using catalyst body.
Summary of the invention
The invention provides the method that is used for preparation (-)-or (S)-pantoprazole.Described method feature is that the oxygenizement of corresponding sulfide is to carry out in the presence of chirality zirconium complex or chirality hafnium complex, and employed chiral auxiliary(reagent) is (+)-L-tartaric acid derivatives.
When using a chirality zirconium complex or chirality hafnium complex preparation (-)-or (S)-pantoprazole, may as chiral auxiliary(reagent) use preferred for (+)-L-tartaric acid derivatives but not the fact of (-)-D-tartaric acid derivatives is wonderful and especially favourable, because (+)-L-tartaric acid derivatives is more cheap with respect to more very common natural (+)-L-tartrate, and therefore highly be suitable for plant-scale preparation.
Above-mentioned oxidizing reaction is preferably carried out in an organic solvent, such as ethyl acetate, toluene, methylene dichloride, dioxane or be preferably methyl iso-butyl ketone (MIBK), wherein the solvent of being mentioned needn't be anhydrous fully, but the perhaps anhydrous solvent water of fusion regulation ratio according to circumstances in all cases wherein is for example up to 0.5 normal maximum value.For the reaction that use is less than 0.5 normal zirconium or hafnium complex, preferably use anhydrous solvent.The solvent that is adopted can commercially available quality use.
If a solvent contains at least 50%, preferably at least 90%, especially a kind of specific solvent of at least 95% then claims this solvent to comprise described specific solvent basically.Anhydrous solvent is anhydrous basically, contains and is less than 5%, preferably is less than 1%, especially is less than 0.3% water.
Suitable oxygenant wherein it is worth mentioning hydroperoxide, such as tertbutyl peroxide or especially isopropyl benzene hydroperoxide especially for all are generally used for the agent of PPI synthetic dry oxidation.Generally speaking, the oxygenant consumption is 0.90 to 1.3 oxidation equivalent, preferred 0.95 to 1.05 equivalent.
Suitable zirconium complex is (for example) methyl ethyl diketone zirconium (IV), butoxy zirconium (IV), tert.-butoxy zirconium (IV), oxyethyl group zirconium (IV), particularly n-propoxyzirconium (IV) (being preferably the solution that is stored in the n-propyl alcohol), or isopropoxy zirconium (IV) form of isopropoxy zirconium (IV)/Virahol mixture (preferably with).Suitable hafnium complex is (for example) methyl ethyl diketone hafnium (IV), butoxy hafnium (IV), positive propoxy hafnium (IV), isopropoxy hafnium (IV) form of isopropoxy hafnium (IV)/Virahol mixture (preferably with), oxyethyl group hafnium (IV), particularly tert.-butoxy hafnium (IV).Preferably use zirconium complex.
Usually use 0.01 to 2 equivalent, preferably 0.05 to 0.9 normal zirconium complex or hafnium complex.
Suitable (+)-L-tartaric acid derivatives is (for example) tartrate amides, such as (+)-L-tartrate two-(N, N-diallyl acid amides), (+)-L-tartrate is two-(N, N-dibenzyl acid amides), (+)-L-tartrate is two-(N, the N-diisopropylamide), (+)-L-tartrate is two-(N, the N-dimethylformamide), (+)-L-tartrate is two-and (N-tetramethyleneimine acid amides), (+)-L-tartrate is two-and (N-piperidines acid amides), (+)-L-tartrate is two-and (N-morpholine acid amides), (+)-L-tartrate is two-and (N-suberyl acid amides) or (+)-L-tartrate is two-(N-4-methyl-N-piperazine amide), or tartrate dialkyl class, such as (+)-L-dibutyl tartrate, (+)-L-tartrate di tert butyl carbonate, (+)-L-tartrate diisopropyl ester, (+)-L-dimethyl tartrate and (+)-L-diethyl tartrate.Generally speaking, adopt 0.02 to 4 equivalent, preferably 0.1 to 2 normal (+)-L-tartaric acid derivatives.
Particularly preferred tartaric acid derivatives be (+)-L-tartrate two-(N, N-dimethylformamide), (+)-L-tartrate is two-(N-tetramethyleneimine acid amides), (+)-L-tartrate is two-(N-morpholine acid amides).
Described oxygenizement is preferably carried out under the temperature between-20 and 50 ℃, particularly at room temperature carries out, and optionally carries out in the presence of alkali, and suitable alkali is organic bases particularly, is preferably tertiary amine, such as triethylamine or N-ethyl diisopropyl amine.
If carry out described method, then obtain (-)-or (S)-pantoprazole greater than 95% optical purity with suitable manner.By other step,, might further significantly increase optical purity such as the redeposition and/or the recrystallize of the control of the potential of hydrogen in suitable solvent (such as Virahol).Via preparation suitable salt intermediate,, carry out the redeposition effect such as sodium salt (salt that other is possible is seen, for example EP-A-166287).
Be described in more detail the present invention by following example, but limit the present invention in no instance.Dummy suffix notation h representative hour.
Embodiment
Example
1. prepare (-)-5-difluoro-methoxy-2-[(3 with (+)-L-diethyl tartrate and isopropoxy zirconium (IV)/Virahol, 4-dimethoxy-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline [=(-)-pantoprazole or (S)-pantoprazole]
A) under the room temperature, with 5-difluoro-methoxy-2-[(3 of 20.2g, 4-dimethoxy-2-pyridyl) methylthio group]-the 1H-benzoglyoxaline together with the aqueous suspension of isopropoxy zirconium (the IV)/Virahol of (+)-diethyl tartrate of 17.9g, 13.4g and 0.1ml in the methyl iso-butyl ketone (MIBK) of 100ml.40 ℃ of following heated mixt 1 hour, cause forming almost transparent solution.Behind cool to room temperature, add the N-ethyl diisopropyl amine of 4.1ml.The isopropyl benzene hydroperoxide that then quantitatively slowly adds 11ml.Continue under the room temperature to stir and finish (monitoring) by TLC up to oxidising process.Use in 54ml water 0.9g Sulfothiorine and the NaOH of 30.3g 40% (weight ratio) end this clear solution, and restir 14h.After adding 25g sodium-chlor, separate described phase.Use the methyl iso-butyl ketone (MIBK) aqueous phase extracted of 50ml.Use the 25ml saturated nacl aqueous solution to wash the organic phase that merged together.The water of 150ml is added in the methyl isobutyl ketone solution, and use (weight ratio) NaOH of 10% that the pH value is adjusted to 13.Separate described phase, and when pH value 13, use the water extraction methyl iso-butyl ketone (MIBK) phase of 50ml.Merge water, and under 40 ℃, decompression, stand the initial stage distillation.In the time of 40-50 ℃, add 10% strength acetic acid and make the pH value become 9, thereby be settled out (-)-pantoprazole.Under the control of pH value, stir again lasting 12h.Filter out cream-coloured crystallization and use the water washing of 50ml.This measure produces optical purity greater than 90% title compound.
Be to increase purity, will (-)-pantoprazole be dissolved among water/NaOH and then make the pH value become 9 and be settled out (-)-pantoprazole by interpolation acetate.It is 145 ℃ (decomposition) and optical purity greater than 95% cream-coloured powder that drying obtains fusing point.If described powder from 2-PrOH crystallization again, then can obtain specific rotation be aD20=-140 (c=0.5, MeOH) and fusing point be the clear crystal of 147-149 ℃ (decomposition).
B) or, example 1 described reaction can be at the toluene of 100ml but not is carried out in the methyl iso-butyl ketone (MIBK).Carry out if be reflected in the toluene, after termination, must leach zirconates and directly reaction product (as (the S)-pantoprazole of sodium salt) is extracted into aqueous phase so.Then can under in check pH value, go out (S)-pantoprazole from described aqueous phase precipitation.This measure produces optical purity greater than 95% beige crystals.
With (+)-L-tartrate two-(N; the N-dimethylformamide) and isopropoxy zirconium (IV)/Virahol prepare (-)-5-difluoro-methoxy-2-[(3,4-dimethoxy-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline [=(-)-pantoprazole or (S)-pantoprazole]
Under the room temperature, 5-difluoro-methoxy-2-[(3 with 20.2g, 4-dimethoxy-2-pyridyl) methylthio group]-the 1H-benzoglyoxaline together with (+)-L-tartrate of 18.0g two-isopropoxy zirconium (IV)-Virahol of (N, N-dimethylformamide) and 13.4g is suspended in the methyl iso-butyl ketone (MIBK) of 100ml.40 ℃ of following heated mixt 1 hour, cause forming almost transparent solution.Behind cool to room temperature, add the N-ethyl diisopropyl amine of 4.1ml.The isopropyl benzene hydroperoxide that then quantitatively slowly adds 11ml.Stir the mixture under the room temperature and finish (5-10 hour, monitor) by TLC up to oxidising process.Use the methyl iso-butyl ketone (MIBK) of 100ml to dilute described clear solution, and use the 1.8g Sulfothiorine in 140ml water to end solution, and stir 14h in addition.After being separated, adding 55ml saturated sodium bicarbonate solution and 55ml methyl iso-butyl ketone (MIBK) to aqueous phase, and separate described phase.Add other 55ml saturated sodium bicarbonate solution and 55ml methyl iso-butyl ketone (MIBK) to aqueous phase, and separate described phase.Then use twice of the methyl iso-butyl ketone (MIBK) phase that 55ml saturated sodium bicarbonate solution washing merged.With the water of 150ml add to methyl iso-butyl ketone (MIBK) mutually in, and use the aqueous sodium hydroxide solution of 40 weight % concentration that the pH value is adjusted to 13.After described being separated, be to use the water extraction methyl iso-butyl ketone (MIBK) phase of 50ml at 13 o'clock in the pH value.Merge water, and under 40 ℃ and decompression, stand the initial stage distillation.In the time of 40-50 ℃, make the pH value equal 9.0 by the acetate that adds 10% concentration, and be settled out (-)-pantoprazole.Mixture restir 12h monitors the pH value therebetween.Filter out cream-coloured crystallization and use the water washing of 50ml.Obtain about 15g (theoretical value 73%) output and optical purity greater than 95% title compound.
Be to increase purity, pH value be (-)-pantoprazole was dissolved in water/aqueous sodium hydroxide solution in 13 o'clock and the pH value equal 9.0 o'clock use acetate (10%) be settled out (-)-pantoprazole once more.
With (+)-L-tartrate two-(N; N-tetramethyleneimine acid amides) and isopropoxy zirconium (IV)/Virahol prepare (-)-5-difluoro-methoxy-2-[(3,4-dimethoxy-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline [=(-)-pantoprazole or (S)-pantoprazole]
Under the room temperature, 5-difluoro-methoxy-2-[(3 with 20.2g, 4-dimethoxy-2-pyridyl) methylthio group]-the 1H-benzoglyoxaline is together with (the 2R of 22.6g, 3R)-(+)-and L-tartrate is two-and (N, N-tetramethyleneimine acid amides) and isopropoxy zirconium (IV)-Virahol of 13.4g be suspended in the methyl iso-butyl ketone (MIBK) of 100ml.40 ℃ of following heated mixt 1 hour, cause forming almost transparent solution.Behind cool to room temperature, add the N-ethyl diisopropyl amine of 4.1ml.The isopropyl benzene hydroperoxide that then quantitatively slowly adds 11ml.Stir the mixture under the room temperature and finish (5-10 hour, monitor) by TLC up to oxidising process.Use the methyl iso-butyl ketone (MIBK) of 100ml to dilute described clear solution, and use the Sulfothiorine of 1.8g in the 140ml saturated sodium bicarbonate solution to end solution, and stir 14h in addition.After being separated, use the 55ml saturated sodium bicarbonate solution to wash described mixture twice.With the water of 150ml add to methyl iso-butyl ketone (MIBK) mutually in, and use the aqueous sodium hydroxide solution of 40 weight % concentration that the pH value is adjusted to the pH value to equal 13.After described being separated, be to use the water extraction methyl iso-butyl ketone (MIBK) phase of other 50ml at 13 o'clock in the pH value.Merge water, and under 40 ℃, decompression, stand the initial stage distillation.In the time of 40-50 ℃, make the pH value equal 9.0 by the acetate that adds 10% concentration, and be settled out (-)-pantoprazole.Mixture restir 12h monitors the pH value therebetween.Filter out cream-coloured crystallization and use the water washing of 50ml.Obtain about 17g (theoretical value 80%) output and optical purity greater than 98% title compound.
Be to increase purity, pH value equal (-)-pantoprazole to be dissolved in water/aqueous sodium hydroxide solution in 13 o'clock and the pH value equal 9.0 o'clock use acetate (10%) precipitate (-)-pantoprazole once more.
With (+)-L-tartrate two-(N; N-tetramethyleneimine acid amides) and n-propoxyzirconium (IV) prepare (-)-5-difluoro-methoxy-2-[(3,4-dimethoxy-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline [=(-)-pantoprazole or (S)-pantoprazole]
Under the room temperature, 5-difluoro-methoxy-2-[(3 with 20.2g, 4-dimethoxy-2-pyridyl) methylthio group]-the 1H-benzoglyoxaline together with (+)-L-tartrate of 22.6g two-(N, N-tetramethyleneimine acid amides) and the n-propoxyzirconium (IV) (in the propyl alcohol, 70%) of 16.5g be suspended in the methyl iso-butyl ketone (MIBK) of 100ml.40 ℃ of following heated mixt 1 hour, cause forming almost transparent solution.Behind cool to room temperature, add the N-ethyl diisopropyl amine of 4.1ml.The isopropyl benzene hydroperoxide that then quantitatively slowly adds 11ml.Stir the mixture under the room temperature and finish (5-24 hour, monitor) by TLC up to oxidising process.Use the methyl iso-butyl ketone (MIBK) of 100ml to dilute described clear solution, and use the Sulfothiorine of 1.8g in the 140ml saturated sodium bicarbonate solution to end solution, and stir 14h in addition.After being separated, use the 55ml saturated sodium bicarbonate solution to wash described mixture twice.With the water of 150ml add to methyl iso-butyl ketone (MIBK) mutually in, and use the aqueous sodium hydroxide solution of 40 weight % concentration that the pH value is adjusted to the pH value to equal 13.After described being separated, be to use the water extraction methyl iso-butyl ketone (MIBK) phase of other 50ml at 13 o'clock in the pH value.Merge water, and under 40 ℃, decompression, stand the initial stage distillation.In the time of 40-50 ℃, make the pH value equal 9.0 by the acetate that adds 10% concentration, and be settled out (-)-pantoprazole.Mixture restir 12h monitors the pH value therebetween.Filter out cream-coloured crystallization and use the water washing of 50ml.Obtain about 16g (theoretical value 75%) output and optical purity greater than 98% title compound.
Be to increase purity, pH value equal (-)-pantoprazole to be dissolved in water/aqueous sodium hydroxide solution in 13 o'clock and the pH value equal 9.0 o'clock use acetate (10%) precipitate (-)-pantoprazole once more.
With (+)-L-tartrate two-(N; N-tetramethyleneimine acid amides) and n-propoxyzirconium (IV) prepare (-)-5-difluoro-methoxy-2-[(3,4-dimethoxy-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline [=(-)-pantoprazole or (S)-pantoprazole]
Be similar to example 4, except not adding the N-ethyl diisopropyl amine, under other the same terms, 5-difluoro-methoxy-2-[(3,4-dimethoxy-2-pyridyl) methylthio group]-65% output, optical purity that the reaction of 1H-benzoglyoxaline produces theoretical value is greater than 98% title compound.
With (+)-L-tartrate of catalytic amount two-(N-tetramethyleneimine acid amides) and n-propoxyzirconium (IV) prepare (-)-5-difluoro-methoxy-2-[(3,4-dimethoxy-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline [=(-)-pantoprazole or (S)-pantoprazole] and
Be similar to example 4, except use 0.1 normal n-propoxyzirconium, 0.25 normal (+)-L-tartrate two-(N-tetramethyleneimine acid amides) and 0.07 normal Hunig alkali, under other the same terms, 5-difluoro-methoxy-2-[(3,4-dimethoxy-2-pyridyl) methylthio group]-80% output, optical purity that the reaction (behind the oxidization time of 48-72h) of 1H-benzoglyoxaline produces theoretical value is greater than 98% title compound.
With (+)-L-tartrate of catalytic amount two-(N-tetramethyleneimine acid amides) and n-propoxyzirconium (IV) prepare (-)-5-difluoro-methoxy-2-[(3,4-dimethoxy-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline [=(-)-pantoprazole or (S)-pantoprazole]
Under the room temperature, with 5-difluoro-methoxy-2-[(3 of 50.0g, 4-dimethoxy-2-pyridyl) methylthio group]-(+)-L-tartrate of 1H-benzoglyoxaline and 5.2g is two-and (N-tetramethyleneimine acid amides) (0.15 equivalent) be suspended in the methyl iso-butyl ketone (MIBK) (MIBK) of 360ml.Under 40-45 ℃, add hot suspension, distill out the MIBK of 60ml, remove the water that is present in mixture to be used for azeotropic.Under this temperature, add the n-propoxyzirconium (IV) (70%, 0.05 equivalent in the propyl alcohol) of 3.2g, and stirred this mixture 1 hour.After being cooled to 30 ℃, add the N-ethyl diisopropyl amine of 0.9ml.The isopropyl benzene hydroperoxide (in the isopropyl benzene, 80%) that then quantitatively slowly adds 27.1g.Continue down to stir up to exothermic oxidation end of processing (20 hours, monitor) at 30 ℃ by TLC or HPLC.Use the 2-propyl alcohol of 60ml to dilute described suspension, and use the Sulfothiorine of 1.69g in the 100ml saturated sodium bicarbonate solution to end solution, and stirred at least 2 hours in addition.After being separated, use the 50ml saturated sodium bicarbonate solution to wash described mixture twice.With the water of 150ml add to methyl iso-butyl ketone (MIBK) mutually in, and use the aqueous sodium hydroxide solution (40% (weight ratio)) of 10ml that the pH value is adjusted to 12.5-13.After described being separated, when equaling 12.5-13, the pH value use the water of 100ml and the aqueous sodium hydroxide solution (40% (weight ratio)) of 2ml that methyl iso-butyl ketone (MIBK) is extracted more than 2 times mutually.Use water that the methyl iso-butyl ketone (MIBK) of 50ml was combined extracting twice again, and under 40 ℃, decompression, stand the initial stage distillation.In the time of 40-50 ℃, make the pH value equal 9.0 by the acetate that adds 10% concentration, and be settled out (-)-pantoprazole.Under the control of pH value, continue again to stir 12 hours.Filter out cream-coloured crystallization and use twice of the water washing of 50ml.82% of theoretical value output when this measure produces 95% chemical purity, optical purity are greater than 95% title compound.
Be to increase purity, pH value equal (-)-pantoprazole to be dissolved in water/aqueous sodium hydroxide solution in 13 o'clock and the pH value equal 9.0 o'clock use acetate (10%) precipitate (-)-pantoprazole once more.This can obtain productive rate be theoretical value 75%, chemical purity greater than 97% and optical purity greater than 98% title compound.
With (+)-L-tartrate of catalytic amount two-(N-tetramethyleneimine acid amides) and isopropoxy zirconium (IV)/Virahol prepare (-)-5-difluoro-methoxy-2-[(3,4-dimethoxy-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline [=(-)-pantoprazole or (S)-pantoprazole]
Under the room temperature,, 4-dimethoxy-2-pyridyl) methylthio group with 5-difluoro-methoxy-2-[(3 of 10.0g]-(+)-L-tartrate of 1H-benzoglyoxaline and 1.05g is two-and (N-tetramethyleneimine acid amides) (0.15 equivalent) be suspended in the methyl iso-butyl ketone (MIBK) of 72ml.Heat this suspension down at 40 to 45 ℃, the MIBK that distills out 12ml removes the water that is present in this mixture with azeotropic.Under this temperature, add isopropoxy zirconium (IV)/Virahol (0.05 equivalent) of 0.53g, and stirred this mixture 1 hour.After being cooled to 30 ℃, add the N-ethyl diisopropyl amine of 0.16ml.Then be metered into the isopropyl benzene hydroperoxide (80%, in isopropyl benzene) of 5.5g lentamente.Continue down to stir up to exothermic oxidation end of processing (20 hours, monitor) at 30 ℃ by TLC or HPLC.The HPLC of this reaction shows 82% optical purity greater than 95% title compound.
With (+)-L-tartrate of catalytic amount two-(N-tetramethyleneimine acid amides) and n-propoxyzirconium (IV) prepare (-)-5-difluoro-methoxy-2-[(3,4-dimethoxy-2-pyridyl) methylsulfinyl]-1H-benzoglyoxaline [=(-)-pantoprazole or (S)-pantoprazole]
Under the room temperature,, 4-dimethoxy-2-pyridyl) methylthio group with 5-difluoro-methoxy-2-[(3 of 50.0g]-(+)-L-tartrate of 1H-benzoglyoxaline and 13.9g is two-and (N-tetramethyleneimine acid amides) (0.40 equivalent) be suspended in the methyl iso-butyl ketone (MIBK) of 360ml.Heat this suspension down at 40 to 45 ℃, the MIBK that distills out 60ml removes the water that is present in this mixture with azeotropic.Under this temperature, the n-propoxyzirconium (IV) of interpolation 6.4g (70%, in propyl alcohol, 0.10 equivalent), and stirred this mixture 1 hour.After being cooled to 30 ℃, add the N-ethyl diisopropyl amine of 1.8ml.Then be metered into the isopropyl benzene hydroperoxide (80%, in isopropyl benzene) of 27.1g lentamente.30 ℃ continue down to stir up to the exothermic oxidation end of processing (20 hours, monitor by TLC or HPLC: chemical purity: 90% pantoprazole sulphoxide).Use the 2-propyl alcohol of 120ml to dilute described suspension, and add the 1.69g Sulfothiorine that is stored in the 100ml saturated sodium bicarbonate solution fast, and stirred at least 2 hours in addition.After being separated, use the 50ml saturated sodium bicarbonate solution to wash described mixture twice.With the water of 350ml add to methyl iso-butyl ketone (MIBK) mutually in, and use the aqueous sodium hydroxide solution (40% (weight ratio)) of 10ml that the pH value is adjusted to 12.5 to 13.After being separated, equal to use the water of 100ml and the aqueous sodium hydroxide solution (40% (weight ratio)) of 2ml again methyl iso-butyl ketone (MIBK) to be extracted 2 times mutually at 12.5 to 13 o'clock in the pH value.Use water that the methyl iso-butyl ketone (MIBK) of 50ml is combined extracting twice again, and under 40 ℃, low pressure, stand predistillation.Under 40 to 45 ℃, equal 9.0 by acetate to the pH value of adding 10% concentration and be settled out (-)-pantoprazole.Under pH value controlled condition, continue again to stir 12 hours.Filter out twice of the water washing of beige crystals and each 50ml of use.
85% of theoretical value output when this measure produces 95% chemical purity, optical purity are greater than 95% title compound.Be to increase purity, pH value equal (-)-pantoprazole to be dissolved in water/aqueous sodium hydroxide solution in 13 o'clock and the pH value equal 9.0 o'clock use acetate (10%) precipitate (-)-pantoprazole once more.This measure produce chemical purity greater than the output of the 75-80% of 98% o'clock theoretical value, optical purity greater than 99% title compound.
With (+)-L-tartrate two-(N; N-tetramethyleneimine acid amides) and tert.-butoxy hafnium (IV) preparation (-)-5-difluoro-methoxy-2-[(3, methylsulfinyl 4-dimethoxy-2-pyridyl)]-1H-benzoglyoxaline [=(-)-pantoprazole or (S)-pantoprazole]
Under the room temperature, 5-difluoro-methoxy-2-[(3 with 3.67g, 4-dimethoxy-2-pyridyl) methylthio group]-(+)-L-tartrate of 1H-benzoglyoxaline and 4.10g is two-and (N, N-tetramethyleneimine acid amides) and 2.60ml tert.-butoxy hafnium be suspended in the methyl iso-butyl ketone (MIBK) of 18.5ml.40 ℃ of following heated mixt 1 hour, during form almost transparent solution.Behind cool to room temperature, add N-ethyl-diisopropylamine of 0.74ml.The isopropyl benzene hydroperoxide that then quantitatively slowly adds 2.2ml.Stir the mixture under the room temperature and finish (48 hours, monitor) by TLC up to oxidising process.Use the methyl iso-butyl ketone (MIBK) of 20ml to dilute described clear solution, and use the Sulfothiorine of 0.3g in the 25ml saturated sodium bicarbonate solution to end solution, and stir 14h in addition.After being separated, use the 10ml saturated sodium bicarbonate solution to wash described mixture more than twice.With the water of 30ml add to methyl iso-butyl ketone (MIBK) mutually in, and use 40% concentration (weight ratio) aqueous sodium hydroxide solution that the pH value is adjusted to 13.After described being separated, be to use the water of 10ml to extract the methyl iso-butyl ketone (MIBK) phase once more at 13 o'clock in the pH value.Merge water, and under 40 ℃ and decompression, stand the initial stage distillation.In the time of 40-50 ℃, make the pH value equal 9.0 by the acetate that adds 10% concentration, and be settled out (-)-pantoprazole.Under the control of pH value, stir and continued again 12 hours.Filter out cream-coloured crystallization and use the water washing of 10ml.This measure produces the title compound of optical purity greater than 95% 2.5g (theoretical value 65%) output.Be to increase purity, pH value equal (-)-pantoprazole to be dissolved in water/aqueous sodium hydroxide solution in 13 o'clock and the pH value equal 9.0 o'clock use acetate (10%) precipitate (-)-pantoprazole once more.
Claims (18)
1. method that is used to prepare (S)-pantoprazole enantiomer-pure or the enantiomerism enriched form (pantoprazole), it is by oxidation 5-difluoro-methoxy-2-[(3,4-dimethoxy-2-pyridyl) methylthio group]-the 1H-benzoglyoxaline carries out, it is characterized in that: described oxygenizement is to carry out in the presence of a chirality zirconium complex or a chirality hafnium complex, and it is characterized in that employed described chiral auxiliary(reagent) is (+)-L-tartaric acid derivatives.
2. method according to claim 1 is characterized in that obtaining optical purity greater than (S)-pantoprazole of 90%.
3. method according to claim 1 is characterized in that using isopropyl benzene hydroperoxide to carry out described oxygenizement.
4. method according to claim 1 is characterized in that using methyl ethyl diketone zirconium (IV), butoxy zirconium (IV), tert.-butoxy zirconium (IV), oxyethyl group zirconium (IV), n-propoxyzirconium (IV), isopropoxy zirconium (IV) or isopropoxy zirconium (IV)/Virahol mixture or methyl ethyl diketone hafnium (IV), butoxy hafnium (IV), tert.-butoxy hafnium (IV), oxyethyl group hafnium (IV), positive propoxy hafnium (IV), isopropoxy hafnium (IV) or isopropoxy hafnium (IV)/Virahol mixture.
5. method according to claim 1, it is characterized in that employed described chiral auxiliary(reagent) for (+)-L-tartrate two-(N, N-diallyl acid amides), (+)-L-tartrate is two-(N, N-dibenzyl acid amides), (+)-L-tartrate is two-(N, the N-diisopropylamide), (+)-L-tartrate is two-and (N, N-dimethylformamide), (+)-L-tartrate is two-and (N-tetramethyleneimine acid amides), (+)-L-tartrate is two-and (N-piperidines acid amides), (+)-L-tartrate is two-and (N-morpholine acid amides), (+)-L-tartrate is two-and (N-suberyl acid amides) or (+)-L-tartrate is two-(N-4-methyl-N-piperazine amide), (+)-L-dibutyl tartrate, (+)-L-tartrate di tert butyl carbonate, (+)-L-tartrate diisopropyl ester, (+)-L-dimethyl tartrate or (+)-L-diethyl tartrate.
6. method according to claim 1, it is characterized in that employed described chiral auxiliary(reagent) for (+)-L-tartrate two-(N, N-dimethylformamide), (+)-L-tartrate is two-(N-tetramethyleneimine acid amides) or (+)-L-tartrate is two-(N-morpholine acid amides).
7. method according to claim 1 is characterized in that described oxygenizement carries out in the presence of an organic bases.
8. method according to claim 1 is characterized in that described oxygenizement carries out in the presence of a tertiary amine.
9. method according to claim 1 is characterized in that described oxygenizement carries out in organic solvent.
10. method according to claim 1 is characterized in that described oxygenizement carries out in the organic solvent of the water that comprises 0 to 0.3 volume %.
11. method according to claim 1 is characterized in that described oxygenizement carries out in the solvent of commercially available quality.
12. method according to claim 1, it is characterized in that described oxygenizement comprises in the organic solvent of methyl iso-butyl ketone (MIBK) basically one carries out.
13. method according to claim 1, it is characterized in that employed described zirconium component is methyl ethyl diketone zirconium (IV), butoxy zirconium (IV), tert.-butoxy zirconium (IV), oxyethyl group zirconium (IV), n-propoxyzirconium (IV), isopropoxy zirconium (IV) or isopropoxy zirconium (IV)/Virahol mixture, be employed described chiral auxiliary(reagent) for (+)-L-tartrate two-(N, N-diallyl acid amides), (+)-L-tartrate is two-(N, N-dibenzyl acid amides), (+)-L-tartrate is two-(N, the N-diisopropylamide), (+)-L-tartrate is two-and (N, N-dimethylformamide), (+)-L-tartrate is two-and (N-tetramethyleneimine acid amides), (+)-L-tartrate is two-and (N-piperidines acid amides), (+)-L-tartrate is two-and (N-morpholine acid amides), (+)-L-tartrate is two-and (N-suberyl acid amides) or (+)-L-tartrate is two-(N-4-methyl-N-piperazine amide), (+)-L-dibutyl tartrate, (+)-L-tartrate di tert butyl carbonate, (+)-L-tartrate diisopropyl ester, (+)-L-dimethyl tartrate or (+)-L-diethyl tartrate.
14. method according to claim 1, it is characterized in that employed described zirconium component is methyl ethyl diketone zirconium (IV), butoxy zirconium (IV), tert.-butoxy zirconium (IV), oxyethyl group zirconium (IV), n-propoxyzirconium (IV), isopropoxy zirconium (IV) or isopropoxy zirconium (IV)/Virahol mixture, be employed described chiral auxiliary(reagent) for (+)-L-tartrate two-(N, N-diallyl acid amides), (+)-L-tartrate is two-(N, N-dibenzyl acid amides), (+)-L-tartrate is two-(N, the N-diisopropylamide), (+)-L-tartrate is two-(N, the N-dimethylformamide), (+)-L-tartrate is two-and (N-tetramethyleneimine acid amides), (+)-L-tartrate is two-and (N-piperidines acid amides), (+)-L-tartrate is two-and (N-morpholine acid amides), (+)-L-tartrate is two-and (N-suberyl acid amides) or (+)-L-tartrate is two-(N-4-methyl-N-piperazine amide), (+)-L-dibutyl tartrate, (+)-L-tartrate di tert butyl carbonate, (+)-L-tartrate diisopropyl ester, (+)-L-dimethyl tartrate or (+)-L-diethyl tartrate, and be that described oxygenizement carries out in the presence of an organic bases.
15. method according to claim 1, it is characterized in that employed described zirconium component is n-propoxyzirconium (IV), isopropoxy zirconium (IV) or isopropoxy zirconium (IV)/Virahol mixture, be employed described chiral auxiliary(reagent) for (+)-L-tartrate two-(N, the N-dimethylformamide), (+)-L-tartrate is two-and (N-tetramethyleneimine acid amides) or (+)-L-tartrate is two-(N-morpholine acid amides), and is that described oxygenizement uses isopropyl benzene hydroperoxide to carry out.
16. method according to claim 1, it is characterized in that employed described zirconium component is n-propoxyzirconium (IV), isopropoxy zirconium (IV) or isopropoxy zirconium (IV)/Virahol mixture, be employed described chiral auxiliary(reagent) for (+)-L-tartrate two-(N, the N-dimethylformamide), (+)-L-tartrate is two-and (N-tetramethyleneimine acid amides) or (+)-L-tartrate is two-(N-morpholine acid amides), and is that described oxygenizement uses isopropyl benzene hydroperoxide to carry out in the presence of a tertiary amine.
17. method that is used to prepare (S)-pantoprazole enantiomer-pure or the enantiomerism enriched form, it is by oxidation 5-difluoro-methoxy-2-[(3,4-dimethoxy-2-pyridyl) methylthio group]-the 1H-benzoglyoxaline carries out, it is characterized in that: described oxygenizement is to carry out in the presence of a chirality zirconium complex, and it is characterized in that employed described chiral auxiliary(reagent) is (+)-L-tartaric acid derivatives.
18. method according to claim 17 is characterized in that using methyl ethyl diketone zirconium (IV), butoxy zirconium (IV), tert.-butoxy zirconium (IV), oxyethyl group zirconium (IV), n-propoxyzirconium (IV), isopropoxy zirconium (IV) or isopropoxy zirconium (IV)/Virahol mixture.
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| CN102807560B (en) * | 2011-06-21 | 2014-07-23 | 寿光富康制药有限公司 | New method for synthesizing esomeprazole through asymmetrically catalytic oxidation |
| CN102603716B (en) * | 2012-03-31 | 2014-04-16 | 广东华南药业集团有限公司 | Method for preparing (S)-pantoprazole in high-enantioselectivity way |
| CN103880819B (en) * | 2012-12-20 | 2017-02-08 | 四川海思科制药有限公司 | Preparation method of optically pure lansoprazole |
| CN106632248A (en) * | 2016-09-30 | 2017-05-10 | 青岛云天生物技术有限公司 | Preparation process of (S)-pantoprazole sodium |
| CN106632249A (en) * | 2016-09-30 | 2017-05-10 | 青岛云天生物技术有限公司 | Method for preparing (S)-pantoprazole sodium |
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| Title |
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| J. Org. Chem.. Marella Bonchio， et al,1326-1330. 1999 |
| J. Org. Chem.. Marella Bonchio， et al,1326-1330. 1999 * |
| 特表平8-509738 1996.10.15 |
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