CN106146460A - The synthesis of a kind of Esomeprazole sodium and process for purification - Google Patents
The synthesis of a kind of Esomeprazole sodium and process for purification Download PDFInfo
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- CN106146460A CN106146460A CN201510132818.3A CN201510132818A CN106146460A CN 106146460 A CN106146460 A CN 106146460A CN 201510132818 A CN201510132818 A CN 201510132818A CN 106146460 A CN106146460 A CN 106146460A
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Abstract
The present invention relates to the field of chemical synthesis, it is specifically related to the synthesis of a kind of Esomeprazole sodium and refined new method, with omeprazole thioether as raw material, by specific solvent species and ratio are selected in preparation process so that the method is simple to operate, and process stabilizing is reliable, asymmetric oxidation selectivity is high, the product yield obtained is high, and optical purity (ee% value) is high, is especially suitable for the production method of the Esomeprazole sodium of extensive industrialization.
Description
Technical field
The present invention relates to the field of chemical synthesis, be specifically related to the synthesis of a kind of Esomeprazole sodium and refined new method.
Background technology
Esomeprazole sodium; full name: (S)-5-methoxyl group-2{ [(4-methoxyl group-3; 5-dimethyl-2-pyridine radicals) methyl] sulfinyl }-1H-benzimidazole sodium; English name: Esomeprazole sodium, injection Esomeprazole sodium is in FDA approval AstraZeneca AB listing on April 3rd, 2007.Esomeprazole sodium is the S isomer of omeprazole, is first proton pump inhibitor developing into isomer, is used for treating short-term gastroesophageal reflux.Its structure is as follows:
So far, the synthesis patent documentation of esomeprazole is the abundantest, finds main have following three synthetic routes by our investigation and analysis:
One, use the method for chiral selectors that raceme omeprazole splits (such as WO 9427988, WO 04/002982 etc.)
Two, use biochemical method, use enzyme omeprazole thioether is aoxidized or omeprazole sulfone is reduced, obtain the single enantiomer of omeprazole (such as WO
9617076, WO9617017 etc.)
Three, the method using chemistry asymmetric oxidation, uses the prothetic group of chirality or catalyst to prepare the single enantiomer of omeprazole (such as WO
9602535, WO 03/089408 etc.)
By relative analysis: first method uses traditional method for splitting to be difficult to effectively split omeprazole free alkali, and this method can waste the omeprazole raw material of half；Second method needs special experimental provision and experimental technique, the most loaded down with trivial details and trouble；The third method is more convenient easy relative to for the above two, wherein CN102633776
CN103936714A, CN103896916A, CN103739592A etc. all refer to the synthetic route of asymmetric oxidation reaction.
The synthetic route synthesizing Esomeprazole sodium for the asymmetric oxidation reaction of thioether in prior art is studied, finding generally to there is cost of material high, yield is low, purity is low, it is impossible to reach the other requirement of pharmaceutical grade, and the response time is long, is difficult to industry's enlarging production.Therefore, developing a kind of new low cost, yield is high, the response time is short, toxicity is low, it is adaptable to esomeprazole and the Esomeprazole sodium preparation method of industrialized great production are very important.
Summary of the invention
High in order to solve in above prior art cost of material present in Esomeprazole sodium synthesis, product yield is low, optical purity is low, the problem being difficult to industry's enlarging production, the invention provides a kind of simple to operate, process stabilizing is reliable, and asymmetric oxidation selectivity is high, and the product yield obtained is high, optical purity (ee% value) is high, is especially suitable for the production method of the Esomeprazole sodium of extensive industrialization.
The present invention is achieved by the following measures:
The preparation method of the Esomeprazole sodium that the present invention provides,
Comprise the steps:
(1) by 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl thio-1H-benzimidazole (omeprazole thioether) dissolves with toluene, add D-(-) diethyl tartrate., water, tetraisopropyl titanate and alkali, constitute chiral catalytic system；Add oxidant and carry out chiral oxidization reaction, obtain intermediate；
(2) add sodium hydroxide after above-mentioned reaction terminates, obtain Esomeprazole sodium crude product；
(3) the Esomeprazole sodium crude product of said process gained is refined.
Wherein, the alkali in step (1) is DIPEA, further, 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl thio-1H-benzimidazole and N, the mass ratio of N-diisopropylethylamine is 3-4, preferably 3.5.
Wherein, in step (1), oxidant is cumyl hydroperoxide, and the mass concentration of cumyl hydroperoxide is 90%.
Further, 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl thio-1H-benzimidazole is 2-3 with the mass volume ratio of cumyl hydroperoxide, preferably 2.3.
Wherein, the response time of step (1) is 1-2 hour.
Wherein, the step of step (2) including: after being dissolved by intermediate methanol, drips the methanol solution of 10% sodium hydroxide, stirring, adds ethyl acetate, stirring, filters, be dried, obtain Esomeprazole sodium crude product after concentrating under reduced pressure.
Preferably, concentrating under reduced pressure steams to there are about 1 times of volumes methanol residue of product quality.
Wherein, the step of step (3) including: by Esomeprazole sodium dissolving crude product in methanol, activated carbon stirring is added after heating, stirring, again sucking filtration is continued after sucking filtration, concentrating under reduced pressure, Temperature fall, collect after ethyl acetate washing filter cake, oven drying, after vacuum drying, obtains Esomeprazole sodium fine work.
Preferably, Esomeprazole sodium crude product is 1:5 with the mass volume ratio of methanol.
Below technical scheme is specifically described:
One, oxidant and amount ranges thereof are studied
WithRuss.J.Org.Chem2008,vol
On the basis of 44, NO.1, pp.124 ~ 127, oxidant and consumption thereof being groped research, process is as follows:
Table
1
The selection of oxidant type
Table
2
The selection of oxidizer
Table 1 shows, hydrogen peroxide effectiveness comparison is poor；Tert-butyl hydroperoxide is suitable with the effect of cumyl hydroperoxide, but the latter is more excellent, and therefore we select cumyl hydroperoxide as the oxidant in technique.
Table 2 shows, the w/v of initiation material and oxidant can obtain preferable conversion ratio when being 2-3, and preferably 2.3.
Two, the alkali impact on reaction:
1) being studied the type of alkali to the impact of reaction on the basis of the route of lot number 100920-3 in table 2, result is as follows:
Doing alkali with triethylamine, course of reaction is more miscellaneous, and TLC detection has a string point；Alkali is done, it is possible to obtain reasonable result with DIPEA.Therefore select N, N-diisopropylethylamine as reaction alkali.
2) on the basis of the route of lot number 100920-3 in table 2, the impact of reaction is studied by the consumption of alkali:
Table
3
The consumption of alkali selects
Table 3 shows, can obtain preferable conversion ratio when omeprazole thioether and alkali weight ratio are 3-4, preferably 3.5.
Three, the selection of solvent dosage in crude product preparation process
WithRuss.J.Org.Chem2008,vol
On the basis of 44, NO.1, pp.124 ~ 127, preparing crude product when concentrating methanol in one step, the consumption of methanol surplus and dropping ethyl acetate is tested, and records thick product yield (%)
Table
4
The impact on thick product yield of the amount of methanol and ethyl acetate
Test shows: when methanol surplus is 0.5 times of volume, become thickness wax-like, more difficult formation good solid during dropping ethyl acetate；When methanol surplus is 2 times of volumes, yield entirety is on the low side；When methanol surplus is 1 times of volume, the ethyl acetate of 5 times of volumes of dropping, thick product yield is on the low side, therefore, being concentrated into 1 times of volumes methanol residue, the key point that 8 times of volume of ethylacetate crystallizes of dropping operate as this step.
Four, process for purification selects:
1) with laboratory common solvent methanol, ethyl acetate, acetone, crude product is refined by acetonitrile.
Method: be added in the solvent of 10 times of volumes by thick for 5g product (HPLC purity 98.0, sulfone accounts for 1.5%), stirs 2h, is then naturally cooling to room temperature, filter at 50 DEG C.
Result is as follows:
Table
5
The selection of refining solvent
Result shows, first three solvent is the most undesirable to the purification effect of Esomeprazole sodium, abandons；And the non-crystallize of methanol, therefore attempt reducing the consumption of methanol, test crystallize purification effect.
The selection of methanol usage: this product is found through experiments the best in the dissolubility of methanol, attempts using the fewest methanol to carry out recrystallization.Operational approach: weigh 5g crude product respectively molten in 25mL, 15mL, 10mL methanol, then ice-water bath cooling, stirs 5 hours, filters.Result is as follows:
Table
6
The refining methanol of different volumes
Result shows, when methanol usage is 5 times of quality volumes of product, (1g product 5mL recrystallizing methanol) is substantially obvious than additive method to the refining effect of product, and therefore we select the method as the process for purification in technique.
The present invention concretely comprises the following steps:
1) concretely comprising the following steps of intermediate is prepared:
(I) by 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl thio-1H-benzimidazole and toluene stirring and dissolving, heat up 60 ± 5 DEG C, then pure water it is sequentially added into, D-diethyl tartrate. and tetraisopropyl titanate, stir 1h, cooling.
(II) above-mentioned reactant liquor is cooled to 30 ± 3 DEG C, adds DIPEA, after stirring 15min, in 30min, be slowly added dropwise cumyl hydroperoxide, after dropping, stirring；
(III) extracting 3 times with the ammonia of 12%, merge aqueous phase, add dichloromethane, then with vinegar acid for adjusting pH to about 8, separatory, organic facies pure water and each 20mL of saturated aqueous common salt washed once, and anhydrous sodium sulfate is dried, and filters, is concentrated to give brown oil.
2) concretely comprising the following steps of Esomeprazole sodium crude product is prepared:
(I) dissolving grease with methanol, drip the methanol solution of 10% sodium hydroxide, stirring, concentrating under reduced pressure steaming to there are about 1 times of volumes methanol residue of product quality, the rear ethyl acetate adding 8 times of volumes of product quality, stirring, filtering, being dried, obtain Esomeprazole sodium crude product.
3) detailed process of Esomeprazole sodium crude product refining is:
(I) during crude product is dissolved in methanol, crude product and methanol quality volume ratio are 1:5, are heated to 40 DEG C of stirring and dissolving, add activated carbon, stirring, filtered while hot；
(II) by above-mentioned filtrate reduced in volume to specifying scale, close vacuum, after being naturally cooling to room temperature, at 0 DEG C, continue stirring 5 hours, sucking filtration；
(III) washing filter cake by ethyl acetate, collect filter cake, load in heated-air circulation oven, oven temperature 35 DEG C is dried, and then proceeds to be dried in vacuum drying oven, obtains fine work Esomeprazole sodium.
The preparation of Esomeprazole sodium of present invention offer and having the beneficial effect that of process for purification
1., during preparing intermediate, use oxidant and the alkali of special ratios, the process condition of dropping oxidant is controlled simultaneously, not only effectively reduces production cost；And height optionally produces the esomeprazole that optical purity is high, toxicity in course of reaction is greatly reduced, shortens the response time simultaneously.
2., when concentrating methanol in Esomeprazole sodium crude product prepares a step, the consumption of methanol surplus and dropping ethyl acetate is controlled, and is effectively improved the yield of crude product.
3. in Esomeprazole sodium subtractive process, by choosing specific solvent and consumption proportion, controlling temperature conditions, product yield is high, up to more than 87%, and enantiomer-pure angle value more than 99.7%, purity more than 99.9%.
Detailed description of the invention
For making the object, technical solutions and advantages of the present invention clearer, below in conjunction with specific embodiment, the present invention is described in more detail.
Embodiment 1
The preparation of intermediate:
By 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl thio-1H-benzimidazole 5.67g is added in 100mL there-necked flask, add toluene 25mL, stirring, it is heated to 60 DEG C, is then sequentially added into pure water 90uL, D-diethyl tartrate. 2.3g and tetraisopropyl titanate 28g, stirring 1h, cooling.When T=27 DEG C, add DIPEA 1.89g, after 15min, in 30min, be slowly added dropwise cumyl hydroperoxide 2.8mL.TLC detection, a small amount of starting material left after reaction.Ammonia with 12% extracts 3 times, merges aqueous phase, adds dichloromethane, and then with vinegar acid for adjusting pH to about 8, separatory, organic facies pure water and each 20mL of saturated aqueous common salt washed once, and anhydrous sodium sulfate is dried, and filters, is concentrated to give brown oil 5.56g.
The preparation of Esomeprazole sodium crude product:
Take 2.8kg intermediate, dissolve with 5L methanol, drip the methanol solution 2.35L of 10% sodium hydroxide, stir 2h.Concentrating under reduced pressure steams to there are about 1 times of volumes methanol residue of product quality, drips 23L ethyl acetate, stirs 5h, filter, is dried, obtains 1.57kg off-white color solid.
Refining of Esomeprazole sodium:
In essence dries bag, 10L there-necked flask I adds methanol 6.9L, opens stirring, put into 1.37kg Esomeprazole sodium crude product, it is heated to 30 DEG C, molten clearly, add 140g activated carbon stir 30 minutes, sucking filtration is to 10L there-necked flask II while hot, it is evaporated to regulation scale, close vacuum, after being naturally cooling to room temperature, at 0 DEG C, continue stirring 5 hours, sucking filtration, wash filter cake by 300ml ethyl acetate, collect filter cake, load in heated-air circulation oven, oven temperature 35 DEG C is dried, then proceed to vacuum drying oven is dried, obtain Esomeprazole sodium fine work, yield: 87.2%.M.p.246-249 DEG C, detect HPLC chemical purity 99.90%, ee%=99.65%, [α] 20D+43.1 DEG C (c=0.1%, water) according to import quality standard；nullESI/MS m/z: 344.0,[M-H]-，IR (KBr): 3050，2998，2935，2826，1609，1475，1565，1478，1565，1473，1465，1390，1362，1271，1200，1075，1151，1021，828，808，685，694cm-1，1HNMR (CDCl3): 2.17(s，3H)，2.26(s，3H)，3.65(s，3H)，3.70(s，3H)，4.36(d，1H)，4.36(d，1H)，4.68(d，1H)，6.52(dd，1H)，6.98(d，1H)，7.10(d，1H)，8.16(s，1H)，Through thin layer chromatography、EMI-MS、The target compound of 1H-NMR confirmation synthesis is Esomeprazole sodium.
Embodiment 2
The preparation of intermediate:
By 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl thio-1H-benzimidazole 5.67g is added in 100mL there-necked flask, add toluene 25mL, stirring, it is heated to 65 DEG C, is then sequentially added into pure water 90uL, D-diethyl tartrate. 2.3g and tetraisopropyl titanate 28g, stirring 1h, cooling.When T=33 DEG C, add DIPEA 1.4g, after 15min, in 30min, be slowly added dropwise cumyl hydroperoxide 1.89mL.TLC detection, a small amount of starting material left after reaction.Ammonia with 12% extracts 3 times, merges aqueous phase, adds dichloromethane, and then with vinegar acid for adjusting pH to about 8, separatory, organic facies pure water and each 20mL of saturated aqueous common salt washed once, and anhydrous sodium sulfate is dried, and filters, is concentrated to give brown oil 5.55g.
The preparation of Esomeprazole sodium crude product:
Take 2.8kg intermediate, dissolve with 5L methanol, drip the methanol solution 2.35L of 10% sodium hydroxide, stir 2h.Concentrating under reduced pressure steams to there are about 1 times of volumes methanol residue of product quality, drips 23L ethyl acetate, stirs 5h, filter, is dried, obtains 1.57kg off-white color solid.
Refining of Esomeprazole sodium:
In essence dries bag, 10L there-necked flask I adds methanol 6.9L, opens stirring, put into 1.37kg Esomeprazole sodium crude product, it is heated to 40 DEG C, molten clearly, add 140g activated carbon stir 30 minutes, sucking filtration is to 10L there-necked flask II while hot, it is evaporated to regulation scale, close vacuum, after being naturally cooling to room temperature, at 0 DEG C, continue stirring 5 hours, sucking filtration, wash filter cake by 300ml ethyl acetate, collect filter cake, load in heated-air circulation oven, oven temperature 35 DEG C is dried, then proceed to vacuum drying oven is dried, obtain Esomeprazole sodium fine work, yield: 87.3%.M.p.246-249 DEG C, detect HPLC chemical purity 99.91%, ee%=99.63%, [α] 20D+43.1 DEG C (c=0.1%, water) according to import quality standard；nullESI/MS m/z: 344.0,[M-H]-，IR (KBr): 3050，2998，2935，2826，1609，1475，1565，1478，1565，1473，1465，1390，1362，1271，1200，1075，1151，1021，828，808，685，694cm-1，1HNMR (CDCl3): 2.17(s，3H)，2.26(s，3H)，3.65(s，3H)，3.70(s，3H)，4.36(d，1H)，4.36(d，1H)，4.68(d，1H)，6.52(dd，1H)，6.98(d，1H)，7.10(d，1H)，8.16(s，1H)，Through thin layer chromatography、EMI-MS、The target compound of 1H-NMR confirmation synthesis is Esomeprazole sodium.
Embodiment 3
The preparation of intermediate:
By 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl thio-1H-benzimidazole 5.67g is added in 100mL there-necked flask, add toluene 25mL, stirring, it is heated to 65 DEG C, is then sequentially added into pure water 90uL, D-diethyl tartrate. 2.3g and tetraisopropyl titanate 28g, stirring 1h, cooling.When T=30 DEG C, add DIPEA 1.6g, after 15min, in 30min, be slowly added dropwise cumyl hydroperoxide 2.5mL.TLC detection, a small amount of starting material left after reaction.Ammonia with 12% extracts 3 times, merges aqueous phase, adds dichloromethane, and then with vinegar acid for adjusting pH to about 8, separatory, organic facies pure water and each 20mL of saturated aqueous common salt washed once, and anhydrous sodium sulfate is dried, and filters, is concentrated to give brown oil 5.6g.
The preparation of Esomeprazole sodium crude product:
Take 2.8kg intermediate, dissolve with 5L methanol, drip the methanol solution 2.35L of 10% sodium hydroxide, stir 2h.Concentrating under reduced pressure steams to there are about 1 times of volumes methanol residue of product quality, drips 23L ethyl acetate, stirs 5h, filter, is dried, obtains 1.57kg off-white color solid.
Refining of Esomeprazole sodium:
In essence dries bag, 10L there-necked flask I adds methanol 6.9L, opens stirring, put into 1.37kg Esomeprazole sodium crude product, it is heated to 40 DEG C, molten clearly, add 140g activated carbon stir 30 minutes, sucking filtration is to 10L there-necked flask II while hot, it is evaporated to regulation scale, close vacuum, after being naturally cooling to room temperature, at 0 DEG C, continue stirring 5 hours, sucking filtration, wash filter cake by 300ml ethyl acetate, collect filter cake, load in heated-air circulation oven, oven temperature 35 DEG C is dried, then proceed to vacuum drying oven is dried, obtain Esomeprazole sodium fine work, yield: 87.5%.M.p.246-249 DEG C, detect HPLC chemical purity 99.91%, ee%=99.7%, [α] 20D+43.1 DEG C (c=0.1%, water) according to import quality standard；nullESI/MS m/z: 344.0,[M-H]-，IR (KBr): 3050，2998，2935，2826，1609，1475，1565，1478，1565，1473，1465，1390，1362，1271，1200，1075，1151，1021，828，808，685，694cm-1，1HNMR (CDCl3): 2.17(s，3H)，2.26(s，3H)，3.65(s，3H)，3.70(s，3H)，4.36(d，1H)，4.36(d，1H)，4.68(d，1H)，6.52(dd，1H)，6.98(d，1H)，7.10(d，1H)，8.16(s，1H)，Through thin layer chromatography、EMI-MS、The target compound of 1H-NMR confirmation synthesis is Esomeprazole sodium.
Claims (9)
1. a preparation method for Esomeprazole sodium, comprises the steps:
(1) by 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl thio-1H-benzimidazole toluene dissolves, add D-(-) diethyl tartrate., water, tetraisopropyl titanate and alkali, add oxidant and carry out chiral oxidization reaction, obtain intermediate；
(2) add sodium hydroxide after above-mentioned reaction terminates, obtain Esomeprazole sodium crude product；
(3) the Esomeprazole sodium crude product of said process gained is refined.
The preparation method of Esomeprazole sodium the most according to claim 1, it is characterised in that the alkali described in step (1) is DIPEA.
The preparation method of Esomeprazole sodium the most according to claim 2, it is characterized in that, in step (1), 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl thio-1H-benzimidazole is 3-4 with the mass ratio of DIPEA.
The preparation method of Esomeprazole sodium the most according to claim 1, it is characterised in that the oxidant described in step (1) be mass concentration be the cumyl hydroperoxide of 90%.
The preparation method of Esomeprazole sodium the most according to claim 4, it is characterized in that, in step (1), 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl thio-1H-benzimidazole is 2-3 with the mass volume ratio of cumyl hydroperoxide.
The preparation method of Esomeprazole sodium the most according to claim 1, it is characterised in that the temperature of the chiral oxidization reaction of step (1) is 30 ± 3 DEG C.
The preparation method of Esomeprazole sodium the most according to claim 1, it is characterized in that, step (2) including: after being dissolved by intermediate methanol, drip the methanol solution of 10% sodium hydroxide, stirring, add ethyl acetate after concentrating under reduced pressure, stirring, filter, be dried, obtain Esomeprazole sodium crude product.
The preparation method of Esomeprazole sodium the most according to claim 1, it is characterized in that, step (3) including: by Esomeprazole sodium dissolving crude product in methanol, activated carbon stirring is added after heating, after sucking filtration, concentrating under reduced pressure, Temperature fall, continue stirring, again sucking filtration, collect after ethyl acetate washing filter cake, oven drying, after vacuum drying, obtain Esomeprazole sodium fine work.
The preparation method of Esomeprazole sodium the most according to claim 8, it is characterised in that Esomeprazole sodium crude product is 1:5 with the mass volume ratio of methanol.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107400117A (en) * | 2017-08-29 | 2017-11-28 | 信泰制药（苏州）有限公司 | The preparation method of esomeprazole and its sodium salt |
| CN116496250A (en) * | 2023-04-18 | 2023-07-28 | 新沂大江化工有限公司 | Esomeprazole sodium synthesis process |
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2015
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107400117A (en) * | 2017-08-29 | 2017-11-28 | 信泰制药（苏州）有限公司 | The preparation method of esomeprazole and its sodium salt |
| CN116496250A (en) * | 2023-04-18 | 2023-07-28 | 新沂大江化工有限公司 | Esomeprazole sodium synthesis process |
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Application publication date: 20161123 |