CN105440018A - Asymmetric oxidation synthesis method of zirconium-catalyzed dexlansoprazole - Google Patents

Asymmetric oxidation synthesis method of zirconium-catalyzed dexlansoprazole Download PDF

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CN105440018A
CN105440018A CN201510851215.9A CN201510851215A CN105440018A CN 105440018 A CN105440018 A CN 105440018A CN 201510851215 A CN201510851215 A CN 201510851215A CN 105440018 A CN105440018 A CN 105440018A
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dexlansoprazole
reaction
methyl
asymmetric oxidation
zirconium
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陈忠
赵学清
廖伟科
陈家煊
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Fuzhou Minhai Pharmaceutical Co Ltd
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Fuzhou Minhai Pharmaceutical Co Ltd
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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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
    • B01J31/2208—Oxygen, e.g. acetylacetonates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/70—Oxidation reactions, e.g. epoxidation, (di)hydroxylation, dehydrogenation and analogues
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/40—Complexes comprising metals of Group IV (IVA or IVB) as the central metal
    • B01J2531/48—Zirconium

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention discloses an asymmetric oxidation synthesis method of zirconium-catalyzed dexlansoprazole. In an organic solvent, a zirconium catalyst and a ligand of the zirconium catalyst have a complex reaction in the presence of a 4A molecular sieve, then a product is mixed with cumyl hydroperoxide in a certain proportion, and 2-[[[3-methyl-4-(2,2,2 trifluoroethoxy)-2-pyridyl]methyl]thio]-1H-benzimidazole is oxidized at the low temperature for synthesis of the dexlansoprazole. The enantiomer excess value of the dexlansoprazole synthesized with the method is higher than 99.3%, the yield is higher than 82%, and the method is good in process stability and high in enantioselectivity and has the bright industrial production prospect.

Description

A kind of asymmetric oxidation synthetic method of Dexlansoprazole of zirconium catalysis
Technical field
The invention belongs to chemosynthesis Application Areas, be specifically related to a kind of asymmetric oxidation synthetic method of Dexlansoprazole of zirconium catalysis.
Background technology
Dexlansoprazole (dexlansoprazole) is the proton pump inhibitor of new generation of Japanese Wu Tian company exploitation.Chemistry 2-[[[3-methyl-4-(2,2,2-trifluoro ethoxy)-2-pyridyl] methyl] sulfinyl]-1H benzoglyoxaline by name, it efficiently can suppress H fast +/ K +-ATP enzyme, thus the effect reaching gastric acid secretion inhibiting, be mainly used in treating the pyrosis sick relevant to Non-erosive gastroesophageal reflux and erosive esophagitis in various degree clinically.Its biphasic controlled release capsule obtained U.S. FDA approval listing in 2009, trade(brand)name: Dexliant tM.
The synthetic method of existing Dexlansoprazole is mainly divided into two kinds: (1). chiral separation: in traditional chiral separation method, chiral reagent is relatively costly, and the left lansoprazole obtained after splitting cannot reuse, cause the waste of raw material, patent DE403545 describes a kind of by the method for lansoprazole selectivity nitrogen for derivatize, by introducing new chiral centre in the molecule, thus former raceme is separated, again the chiral radicals newly introduced dissociated and obtain R-lansoprazole, the method needs to use two-step reaction, process is more complicated and yield is not high, be not suitable for suitability for industrialized production, (2). asymmetric oxidation: patent CN102558151 discloses the application of a kind of iodonium part in synthesis of chiral sulfoxide compound, it comprises the method with iodonium part synthesis R-lansoprazole, in the method, the synthesis of iodonium part is loaded down with trivial details, and reaction solvent uses the larger chloroform of toxicity, under patent WO9208716 have employed the existence of cbiral titanium complex and organic bases, obtain chiral sulfoxide structure by hydrogen peroxide analog derivative, but aftertreatment is more loaded down with trivial details, and needs to use a large amount of irritating ammoniacal liquor extractions, other patents as in CN103113351, CN102558150, CN102977076, CN103694225 etc. report, various chiral alcohol or the Chiral Amine part of the titanium salt used are relatively expensive, wherein the consumption of some part reaches more than 1.5 times of thioether, is not suitable for suitability for industrialized production.Therefore the method studying enantioselective oxidation is further significant.
Table 1
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, provide a kind of asymmetric oxidation synthetic method of Dexlansoprazole of zirconium catalysis, the inventive method technology stability is good, and enantioselectivity is high, and cost is low, better can be applied to suitability for industrialized production.
For achieving the above object, the present invention adopts following technical scheme:
An asymmetric oxidation synthetic method for the Dexlansoprazole of zirconium catalysis, comprises the following steps:
1) in organic solvent, Zr catalyst and part thereof carry out complex reaction under 4A molecular sieve existence condition;
2) in above-mentioned reaction solution, add hydrogen phosphide cumene, 2-[[[3-methyl-4-(2,2,2 trifluoro ethoxies)-2-pyridine] methyl] sulfenyl]-1H-benzoglyoxaline, after oxidizing reaction, obtain the Dexlansoprazole of single enantiomer form.
Described organic solvent is toluene, chlorobenzene or methylene dichloride.
Described Zr catalyst is zirconic acid four tert-butyl ester, and part is (L)-tartrate diisopropyl ester.
The mol ratio of described zirconic acid four tert-butyl ester and (L)-tartrate diisopropyl ester is 1:1.0-1.2.
The mol ratio of described 2-[[[3-methyl-4-(2,2,2 trifluoro ethoxies)-2-pyridine] methyl] sulfenyl]-1H-benzoglyoxaline, hydrogen phosphide cumene, zirconic acid four tert-butyl ester is 1:2.0-2.5:0.2-0.3.
Described step 1) temperature of reaction be 20-30 DEG C.
Described step 2) temperature of reaction be-40 ~-20 DEG C.
Further, the asymmetric oxidation synthetic method of the Dexlansoprazole of zirconium catalysis of the present invention, its concrete steps are:
1) Zr catalyst and part thereof, 4A molecular sieve are joined in organic solvent, 20-30 DEG C of reaction 1-1.2h;
2) above-mentioned reaction system is cooled to-40 ~-20 DEG C, then hydrogen phosphide cumene and 2-[[[3-methyl-4-(2 is added, 2,2 trifluoro ethoxies)-2-pyridine] methyl] sulfenyl] chlorobenzene solution of-1H-benzoglyoxaline, reaction 10-12h, reaction product, through subsequent disposal, obtains the Dexlansoprazole of single enantiomer form.
In prior art, in the process of titanium catalyst and ligand complex, Ti-O key is unstable, and therefore the unstable of titanium (IV) catalyst complex in explained hereafter is the important factor of yield and the ee value instability causing reacting.And Zr catalyst zirconic acid four tert-butyl ester and part (L)-tartrate diisopropyl ester are used for the epoxidation of homoallylic alcohol originally, the present invention considers the stability of Zr-O key, zirconium (IV) catalyst system is applied in the asymmetric oxidation reaction of Dexlansoprazole, overcomes the deficiencies in the prior art.
The present invention adopts above technical scheme, its beneficial effect is: the mixture after zirconic acid four tert-butyl ester and the complexing of (L)-tartrate diisopropyl ester, structural asymmetry is higher, higher ee value can be obtained in asymmetry catalysis oxidation, and aftertreatment is relatively simple, and cost is low, be easy to suitability for industrialized production.
Embodiment
An asymmetric oxidation synthetic method for the Dexlansoprazole of zirconium catalysis, comprises the following steps:
1) Zr catalyst and part thereof, 4A molecular sieve are joined in organic solvent, 20-30 DEG C of reaction 1-1.2h;
Wherein, Zr catalyst is zirconic acid four tert-butyl ester, and part is (L)-tartrate diisopropyl ester, and its mol ratio is 1:1.0-1.2, and described organic solvent is toluene, chlorobenzene or methylene dichloride;
2) above-mentioned reaction system is cooled to-40 ~-20 DEG C, then hydrogen phosphide cumene and 2-[[[3-methyl-4-(2 is added, 2,2 trifluoro ethoxies)-2-pyridine] methyl] sulfenyl] chlorobenzene solution of-1H-benzoglyoxaline, reaction 10-12h, reaction product, through subsequent disposal, obtains the Dexlansoprazole of single enantiomer form;
Wherein, the mol ratio of described 2-[[[3-methyl-4-(2,2,2 trifluoro ethoxies)-2-pyridine] methyl] sulfenyl]-1H-benzoglyoxaline, hydrogen phosphide cumene, zirconic acid four tert-butyl ester is 1:2.0-2.5:0.2-0.3.
Embodiment 1
Get 250mL eggplant type bottle, add medium size stirrer, get L-TARTARIC ACID isopropyl ester 0.514g (2.2mmol), molecular sieve 4A1g, chlorobenzene 60mL, add Zr (Ot-Bu) 40.768g (2mmol), 20 DEG C of reaction 1h, be cooled to-40 DEG C, then hydrogen phosphide cumene 3.04g (20mmol) and 2-[[[3-methyl-4-(2 is added, 2,2 trifluoro ethoxies)-2-pyridine] methyl] sulfenyl] chlorobenzene solution of-1H-benzoglyoxaline 3.53g (10mmol), continue reaction 10h, with the saturated Na of 20mL 2sO 4reaction is terminated with 50mL ether, reaction solution diatomite filtration, separatory, organic phase concentrates, crude product is used 15mL acetone solution, add 0.03mL ammoniacal liquor, under stirring state, instill 30mL normal hexane, drip and finish, 1h is left standstill at 0 DEG C, suction filtration obtains white or off-white color Dexlansoprazole powder 3.15g, productive rate 85.5%, fusing point 143 ~ 146 DEG C.(ChiralPakIAC184.6 × 250mm is detected through HPLC; 5 μm, column temperature: 30 DEG C, moving phase: methyl tertiary butyl ether: ethyl acetate: ethanol: diethylamine (60:40:5:0.1), flow velocity: 1.2ml/min), optical purity is 99.6%.
Embodiment 2
Get 250mL eggplant type bottle, add medium size stirrer, get L-TARTARIC ACID isopropyl ester 0.468g (2.0mmol), molecular sieve 4A1g, chlorobenzene 60mL, add Zr (Ot-Bu) 40.768g (2.0mmol), 20 DEG C of reaction 1h, are cooled to-40 DEG C.Add hydrogen phosphide cumene 3.34g (22mmol) and 2-[[[3-methyl-4-(2,2,2 trifluoro ethoxies)-2-pyridine] methyl] sulfenyl] chlorobenzene solution of-1H-benzoglyoxaline 3.53g (10mmol), continue reaction 12h, with the saturated Na of 20mL 2sO 4reaction is terminated with 50mL ether, with diatomite filtration, separatory, organic phase concentrates, crude product is used 15mL acetone solution, add 0.03mL ammoniacal liquor, under stirring state, instill 30mL normal hexane, drip and finish, 1h is left standstill at 0 DEG C, suction filtration obtains white or off-white color Dexlansoprazole powder 2.98g, productive rate 81.0%, and detecting (testing conditions is with embodiment 1) optical purity through HPLC is 98.8%.
Embodiment 3
Get 250mL eggplant type bottle, add medium size stirrer, get L-TARTARIC ACID isopropyl ester 0.702g (3.0mmol), molecular sieve 4A1g, chlorobenzene 60mL, add Zr (Ot-Bu) 40.960g (2.5mmol), 20 DEG C of reaction 1.2h, are cooled to-40 DEG C.Add hydrogen phosphide cumene 3.04g (20mmol) and 2-[[[3-methyl-4-(2,2,2 trifluoro ethoxies)-2-pyridine] methyl] sulfenyl] chlorobenzene solution of-1H-benzoglyoxaline 3.53g (10mmol), continue reaction 10h, with the saturated Na of 20mL 2sO 4reaction is terminated with 50mL ether, with diatomite filtration, separatory, organic phase concentrates, crude product is used 15mL acetone solution, add 0.03mL ammoniacal liquor, under stirring state, instill 30mL normal hexane, drip and finish, 1h is left standstill at 0 DEG C, suction filtration obtains white or off-white color Dexlansoprazole powder 3.06g, productive rate 82.9%, and detecting (testing conditions is with embodiment 1) optical purity through HPLC is 99.0%.
Embodiment 4
Get 250mL eggplant type bottle, add medium size stirrer, get L-TARTARIC ACID isopropyl ester 0.842g (3.6mmol), molecular sieve 4A1g, toluene 60mL, add Zr (Ot-Bu) 41.152g (3.0mmol), 25 DEG C of reaction 1h, are cooled to-20 DEG C.Add hydrogen phosphide cumene 3.80g (25mmol) and 2-[[[3-methyl-4-(2,2,2 trifluoro ethoxies)-2-pyridine] methyl] sulfenyl] chlorobenzene solution of-1H-benzoglyoxaline 3.53g (10mmol), continue reaction 12h, with the saturated Na of 20mL 2sO 4reaction is terminated with 50mL ether, with diatomite filtration, separatory, organic phase concentrates, and crude product is used 15mL acetone solution, add 0.03mL ammoniacal liquor, instill 30mL normal hexane under stirring state, drip and finish, at 0 DEG C, leave standstill 1h, suction filtration obtains white or off-white color Dexlansoprazole powder 3.13g, productive rate 84.8%.Detecting (testing conditions is with embodiment 1) optical purity through HPLC is 98.4%.
Embodiment 5
Get 250mL eggplant type bottle, add medium size stirrer, get L-TARTARIC ACID isopropyl ester 0.566g (2.4mmol), molecular sieve 4A1g, methylene dichloride 60mL, add Zr (Ot-Bu) 40.848g (2.2mmol), 30 DEG C of reaction 1h, are cooled to-30 DEG C.Add hydrogen phosphide cumene 3.34g (22mmol) and 2-[[[3-methyl-4-(2,2,2 trifluoro ethoxies)-2-pyridine] methyl] sulfenyl] chlorobenzene solution of-1H-benzoglyoxaline 3.53g (10mmol), continue reaction 10h, with the saturated Na of 20mL 2sO 4reaction is terminated with 50mL ether, with diatomite filtration, separatory, organic phase concentrates, crude product is used 15mL acetone solution, add 0.03mL ammoniacal liquor, under stirring state, instill 30mL normal hexane, drip and finish, 1h is left standstill at 0 DEG C, suction filtration obtains white or off-white color Dexlansoprazole powder 2.90g, productive rate 78.5%, fusing point 143 ~ 146 DEG C.Detecting (testing conditions is with embodiment 1) optical purity through HPLC is 99.8%.
The foregoing is only preferred embodiment of the present invention, all equalizations done according to the present patent application the scope of the claims change and modify, and all should belong to covering scope of the present invention.

Claims (8)

1. an asymmetric oxidation synthetic method for the Dexlansoprazole of zirconium catalysis, is characterized in that: it comprises the following steps:
1) in organic solvent, Zr catalyst and part thereof carry out complex reaction under 4A molecular sieve existence condition;
2) in above-mentioned reaction solution, add hydrogen phosphide cumene, 2-[[[3-methyl-4-(2,2,2 trifluoro ethoxies)-2-pyridine] methyl] sulfenyl]-1H-benzoglyoxaline, after oxidizing reaction, obtain Dexlansoprazole.
2. the asymmetric oxidation synthetic method of the Dexlansoprazole of a kind of zirconium catalysis according to claim 1, is characterized in that: described organic solvent is toluene, chlorobenzene or methylene dichloride.
3. the asymmetric oxidation synthetic method of the Dexlansoprazole of a kind of zirconium catalysis according to claim 1, is characterized in that: described Zr catalyst is zirconic acid four tert-butyl ester, and part is (L)-tartrate diisopropyl ester.
4. the asymmetric oxidation synthetic method of the Dexlansoprazole of a kind of zirconium catalysis according to claim 3, is characterized in that: the mol ratio of described zirconic acid four tert-butyl ester and (L)-tartrate diisopropyl ester is 1:1.0-1.2.
5. the asymmetric oxidation synthetic method of the Dexlansoprazole of a kind of zirconium catalysis according to claim 3, it is characterized in that: described 2-[[[3-methyl-4-(2,2,2 trifluoro ethoxies)-2-pyridine] methyl] sulfenyl]-1H-benzoglyoxaline, hydrogen phosphide cumene, zirconic acid four tert-butyl ester mol ratio be 1:2.0-2.5:0.2-0.3.
6. the asymmetric oxidation synthetic method of the Dexlansoprazole of a kind of zirconium catalysis according to claim 1, is characterized in that: the temperature of reaction of described step 1) is 20-30 DEG C.
7. the asymmetric oxidation synthetic method of the Dexlansoprazole of a kind of zirconium catalysis according to claim 1, is characterized in that: described step 2) temperature of reaction be-40 ~-20 DEG C.
8. the asymmetric oxidation synthetic method of the Dexlansoprazole of a kind of zirconium catalysis according to claim 1, is characterized in that: it comprises the following steps:
1) Zr catalyst and part thereof, 4A molecular sieve are joined in organic solvent, 20-30 DEG C of reaction 1-1.2h;
2) above-mentioned reaction system is cooled to-40 ~-20 DEG C, then hydrogen phosphide cumene and 2-[[[3-methyl-4-(2 is added, 2,2 trifluoro ethoxies)-2-pyridine] methyl] sulfenyl] chlorobenzene solution of-1H-benzoglyoxaline, reaction 10-12h, reaction product obtains Dexlansoprazole after subsequent disposal.
CN201510851215.9A 2015-11-27 2015-11-27 Asymmetric oxidation synthesis method of zirconium-catalyzed dexlansoprazole Pending CN105440018A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1101214A (en) * 1993-01-29 1995-04-05 艾利森电话股份有限公司 Method and apparatus for encoding/decoding of background sounds
CN1717403A (en) * 2002-12-06 2006-01-04 艾塔那法玛公司 Process for preparing optically pure active compounds
CN104177336A (en) * 2013-05-28 2014-12-03 上海汇伦生命科技有限公司 Method for antipodal selective synthesis of (R)-lansoprazole

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1101214A (en) * 1993-01-29 1995-04-05 艾利森电话股份有限公司 Method and apparatus for encoding/decoding of background sounds
CN1717403A (en) * 2002-12-06 2006-01-04 艾塔那法玛公司 Process for preparing optically pure active compounds
CN104177336A (en) * 2013-05-28 2014-12-03 上海汇伦生命科技有限公司 Method for antipodal selective synthesis of (R)-lansoprazole

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Application publication date: 20160330