CN106674198A - Preparation method for key intermediate rabeprazole thioether - Google Patents
Preparation method for key intermediate rabeprazole thioether Download PDFInfo
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- CN106674198A CN106674198A CN201611211919.0A CN201611211919A CN106674198A CN 106674198 A CN106674198 A CN 106674198A CN 201611211919 A CN201611211919 A CN 201611211919A CN 106674198 A CN106674198 A CN 106674198A
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- rabeprazole
- reaction
- preparation
- thioether
- rabeprazole thioether
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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 discloses a preparation method for rabeprazole thioether 2-[[[4-(3- methoxypropoxy)-3-methylpyridin-2-yl] methyl] sulfo]-1H-benzimidazole. By using Mitsunobu reaction, the rabeprazole thioether is prepared from rabeprazole oxhydryl in one-step synthesis way without chlorination reaction. In the reaction process, the high-corrosive chloride agent, such as, thionyl chloride, is not used, so that the violent corrosion of the reaction to the device is obviously reduced, and meanwhile, the reaction yield is obviously increased due to the shortened reaction step. According to the invention, the process is simple, the reaction condition is mild, the corrosion to the device is small, the yield is higher (70%-80%) and the method is suitable for industrial production.
Description
Technical field
The present invention relates to medicinal chemistry art, and in particular to a kind of preparation side of rabeprazole key intermediate thioether
Method.
Background technology
Under the synthetic route of rabeprazole is mainly passed through with 2,3- dimethyl -4- chloropyridines as initiation material in prior art
State synthetic route.
The preparation process of rabeprazole thioether is usually first reacted with chlorination reagent using hydroxylic species and generates chloride, so
Afterchlorinate thing reacts in the basic conditions generation thioether with mercaptobenzimidazole.Chlorination reagent can with selective chlorination sulfoxide, three
Phosphorus chloride, phosphorus oxychloride, phosphorus pentachloride and sulfonic acid chloride.Thionyl chloride is preferably chlorination reagent in chlorination reaction.The reaction
Temperature range be -5-30 DEG C.Chloride needs to be carried out under the conditions of inorganic base or organic base with mercaptobenzimidazole reaction.
Inorganic base is primarily referred to as hydroxide, carbonate and bicarbonate.Hydroxide includes sodium hydroxide, potassium hydroxide and hydroxide
Barium.Carbonate mainly includes sodium carbonate, potassium carbonate and brium carbonate.Bicarbonate includes sodium bicarbonate and potassium bicarbonate.Organic base
Select triethylamine, ethylamine, ammonia and diisopropylethylamine.Reaction temperature is 15-55 DEG C.Patent documentation
WO2014091450A1, WO2008045777A2, WO2009116072A2 are carried out to chlorination reaction and thioether synthetic reaction
More detailed narration.The chlorination yield of patent WO2009116072A report is 99%, and sulfide synthesis thing yield is 67.8%,
Total recovery is 67.122%, and the total recovery of document EP0268956 reports is 67%.
Above-mentioned reaction thioether yield is relatively low, and preparation process is complicated, and because chlorination reaction uses thionyl chloride, tri-chlorination
The chlorination reagent of the severe corrosive such as phosphorus and phosphorus oxychloride, and the strong basic reagent such as sodium hydroxide, potassium hydroxide and barium hydroxide, make
The heavy corrosion of paired equipment.
The content of the invention
In order to solve the above problems, the present invention is using rabeprazole hydroxylic species with mercaptobenzimidazole through Mi tsunobu
Single step reaction synthesize rabeprazole thioether, yield more than 70%, meanwhile, high purity more than 98%.And do not use chlorination
Reagent and strong basic reagent, reaction condition is gentle, and equipment corrosion is little, is suitable for industrialized production.
The present invention is achieved through the following technical solutions：
Make rabeprazole hydroxylic species with mercaptobenzimidazole in the presence of catalyst and reaction dissolvent, by single step reaction system
It is standby to obtain rabeprazole thioether.The catalyst is triphenylphosphine and diethylazodicarboxylate (DEAD) or azo-2-carboxylic acid
The mixture of diisopropyl ester (DIAD).Preferably, the mol ratio of triphenylphosphine and diethylazodicarboxylate is 1:1, or triphen
The mol ratio of base phosphine and diisopropyl azo-2-carboxylic acid is 1:1.Reaction dissolvent be tetrahydrofuran, 1,4- dioxane, ether, two
One or more in chloromethanes, toluene.The temperature of reaction is at 0-40 DEG C.The time of reaction is 5-24h, preferred 5-10h.It is preferred that
Reaction carries out recrystallization purification after terminating, and recrystallization solvent is preferably methanol.Triphenylphosphine and rabeprazole hydroxylic species mole
Than being preferably about 1.1:1.
The rabeprazole hydroxylic species structural formula is as follows：
After obtaining rabeprazole thioether, rabeprazole thioether can be oxidized to by rabeprazole by using NaClO,
Finally there is salt-forming reaction with NaOH and generate RABEPRAZOLE SODIUM.
Concrete reaction equation is as follows：
Description of the drawings
The rabeprazole thioether hydrogen of accompanying drawing 1 is composed
The rabeprazole hydrogen of accompanying drawing 2 is composed
The RABEPRAZOLE SODIUM hydrogen of accompanying drawing 3 is composed
The rabeprazole thioether mass spectrum of accompanying drawing 4
The rabeprazole mass spectrum of accompanying drawing 5
The RABEPRAZOLE SODIUM mass spectrum of accompanying drawing 6
Specific embodiment
Prepare embodiment 1
Take 100g rabeprazole hydroxylic species (473.35mmol) to be added in 2L three-neck flasks, be subsequently adding 1L tetrahydrochysene furans
Mutter, 71.10g mercaptobenzimidazoles (473.35mmol), 136.58g triphenylphosphines (520.69mmol).Open stirring and by temperature
Degree control is at 0-10 DEG C.Dropwise Deca 90.678g (520.69mmol) diethylazodicarboxylate afterwards.After completion of dropping,
Insulation reaction 5h-10h, point plate monitoring reaction is complete.After reaction terminates, tetrahydrofuran is evaporated, then using recrystallizing methanol
Rabeprazole thioether 130.0g is obtained, yield 80%, HPLC test purity is 98.3%.1H-NMR (CDCl3,600MHz) δ:
8.36~8.37 (d, J=6.0Hz, 1H, NH), 7.56 (s, 2H), 7.19~7.20 (t, 2H), 6.79~6.80 (d, J=
6.0Hz, 1H), 4.40 (s, 2H), 4.14~4.16 (t, 2H), 3.58~3.60 (t, 2H), 3.38 (s, 3H), 2.28 (s, 3H),
2.11~2.13 (t, 2H).EI-MS m/z:343.9[M+1].Concrete data collection of illustrative plates is shown in accompanying drawing 1 and 4.
Prepare embodiment 2
Take 50g rabeprazole hydroxylic species (236.68mol) to be added in 1L three-neck flasks, be subsequently adding 500ml1,4- bis-
The 35.55g mercaptobenzimidazoles (236.68mol) of oxygen six, 68.29g triphenylphosphines (260.35mmol).Open stirring and by temperature
Control is at 0-10 DEG C.Dropwise Deca 52.59g (260.35mmol) diisopropyl azo-2-carboxylic acid afterwards.After completion of dropping, protect
Temperature reaction 5h-10h, point plate monitoring reaction is complete.After reaction terminates, tetrahydrofuran is evaporated, then using recrystallizing methanol
Rabeprazole thioether 56.83g, yield 70%, HPLC test purity is 98.5%.
Application Example 3
Take 50g rabeprazole thioethers (145.59mmol) to be added in 1L three-neck flasks, be subsequently adding 500ml acetonitriles/
Water mixed liquid (V/V=2/1), stirs and adds sodium hydrate solid 11.65g (291.18mmol).Then 0-5 DEG C is cooled to,
Start dropwise Deca 140.89g 10%NaClO solution (189.27mmol), insulated and stirred reaction 2h after completion of dropping.Point plate
Monitoring reaction is complete, and 0-5 DEG C is slowly added dropwise 11.51gNa2S2O3(72.80mmol) solution in 100ml water is quenched unreacted
Sodium hypochlorite, then using 5% acetic acid adjust PH to 8-8.5, separate out solid, insulated and stirred 2h.Sucking filtration, solid is placed in vacuum
In baking oven, 40-45 DEG C of forced air drying 12h.Samples weighing obtains rabeprazole 39.22g (109.11mmol), yield 74.94%,
HPLC test purity is 99.0%.1H-NMR(DMSO-d6, 600MHz) and δ:13.52 (S, 1H, NH), 8.22~8.23 (d, J=
6.0Hz, 1H), 7.66 (s, 2H), 7.31 (s, 2H), 6.95~6.96 (d, J=6.0Hz, 1H) 4.78~4.81 (d, J=
18.0Hz, 1H), 4.71~4.73 (d, J=12.0Hz, 1H), 4.11~4.12 (d, J=6.0Hz, 2H), 3.48~3.50 (t,
J=12.0Hz, 2H), 3.25 (s, 3H), 2.15 (s, 3H), 1.97~1.99 (t, 2H).EI-MS m/z:359.9[M+1].Tool
Volume data collection of illustrative plates is shown in accompanying drawing 2 and 5.
Application Example 4
1L three-neck flasks are taken, solution of 4g (0.1mol) sodium hydroxide in 100ml methanol is added, 36g thunders are subsequently adding
Shellfish draws azoles (0.1mol), reaction 1h is stirred at room temperature and obtains settled solution.Filter, filtrate is spin-dried for obtaining crude product.Room temperature condition is used
Then dissolving crude product is slowly added dropwise 400ml normal heptane by 150ml dichloromethane, and solution gradually becomes cloudy, after completion of dropping again
1h is stirred at room temperature.Sucking filtration, filter cake uses normal heptane drip washing, filter cake to be placed in vacuum drying oven, 40-45 DEG C of forced air drying 12h, weighs
To RABEPRAZOLE SODIUM finished product 35.62g (0.093mol), it is 99.5% that yield is 93%, HPLC test purity.1H-NMR(DMSO-
d6, 600MHz) and δ:8.30~8.31 (d, J=6.0Hz, 1H), 7.50~7.51 (t, 2H), 6.94~6.95 (d, J=6.0Hz,
1H), 6.91~6.92 (m, 2H), 4.64~4.66 (d, J=12.0Hz, 1H), 4.49~4.51 (d, J=12.0Hz, 1H),
4.12~4.13 (d, J=6.0Hz, 2H), 3.50~3.51 (t, 2H), 3.27 (s, 3H), 2.17 (s, 3H), 1.99~2.01
(t,2H).EI-MS m/z:359.9[M+1]m/z:359.9[M+1].Concrete data collection of illustrative plates is shown in accompanying drawing 3 and 6.
Claims (10)
1. a kind of preparation method of rabeprazole thioether, it is characterised in that：Make rabeprazole hydroxylic species and mercaptobenzimidazole
In the presence of catalyst and reaction dissolvent, rabeprazole thioether is prepared by single step reaction.
2. the preparation method of rabeprazole thioether according to claim 1, it is characterised in that：The rabeprazole hydroxyl
Thing structural formula is as follows：
3. the preparation method of rabeprazole thioether according to claim 1 and 2, it is characterised in that：The catalyst is
Triphenylphosphine and diethylazodicarboxylate, or triphenylphosphine and diisopropyl azo-2-carboxylic acid.
4. the preparation method of the rabeprazole thioether according to claim 1-3 any one claim, its feature exists
In：The mol ratio of triphenylphosphine and diethylazodicarboxylate is 1:1, or triphenylphosphine and diisopropyl azo-2-carboxylic acid rub
You are than being 1:1.
5. the preparation method of the rabeprazole thioether according to claim 1-4 any one claim, its feature exists
In：Triphenylphosphine is about 1.1 with the mol ratio of rabeprazole hydroxylic species:1.
6. the preparation method of the rabeprazole thioether according to claim 1-5 any one claim, its feature exists
In：Reaction dissolvent is one or more in tetrahydrofuran, 1,4- dioxane, ether, dichloromethane, toluene.
7. the preparation method of the rabeprazole thioether according to claim 1-6 any one claim, its feature exists
In：The temperature of the reaction is at 0-40 DEG C.
8. the preparation method of rabeprazole thioether according to claim 7, it is characterised in that：The temperature of the reaction is
0-10℃。
9. the preparation method of the rabeprazole thioether according to claim 1-8 any one claim, its feature exists
In：The time of the reaction is 5-24h.
10. the preparation method of rabeprazole thioether according to claim 9, it is characterised in that：The time of the reaction
For 5-10h.
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| CN201611211919.0A CN106674198A (en) | 2016-12-25 | 2016-12-25 | Preparation method for key intermediate rabeprazole thioether |
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| CN201611211919.0A CN106674198A (en) | 2016-12-25 | 2016-12-25 | Preparation method for key intermediate rabeprazole thioether |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109134354A (en) * | 2018-09-19 | 2019-01-04 | 天津科技大学 | The synthetic method of 2- picolyl thioether and the synthesis technology of related drugs |
| CN114394956A (en) * | 2022-03-29 | 2022-04-26 | 寿光富康制药有限公司 | Preparation method of high-purity rabeprazole and sodium salt thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6423846B1 (en) * | 2001-09-28 | 2002-07-23 | Hanmi Pharm. Co., Ltd. | High-yield method for preparing lansoprazole |
| CN102174039A (en) * | 2011-03-10 | 2011-09-07 | 上海交通大学 | Preparation method of high-optical-purity pitavastatin calcium key intermediate |
-
2016
- 2016-12-25 CN CN201611211919.0A patent/CN106674198A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6423846B1 (en) * | 2001-09-28 | 2002-07-23 | Hanmi Pharm. Co., Ltd. | High-yield method for preparing lansoprazole |
| CN102174039A (en) * | 2011-03-10 | 2011-09-07 | 上海交通大学 | Preparation method of high-optical-purity pitavastatin calcium key intermediate |
Non-Patent Citations (2)
| Title |
|---|
| BADDAM, SUDHAKAR REDDY等: "Zinc triflate catalyzed synthesis of thioethers", 《CHEMISTRY & BIOLOGY INTERFACE》 * |
| JOSEPH, KARA M.; LARRAZA-SANCHEZ, ISABEL: "Synthesis of benzyl bromides with hexabromoacetone: an alternative path to drug intermediates", 《TETRAHEDRON LETTERS》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109134354A (en) * | 2018-09-19 | 2019-01-04 | 天津科技大学 | The synthetic method of 2- picolyl thioether and the synthesis technology of related drugs |
| CN109134354B (en) * | 2018-09-19 | 2022-03-25 | 天津科技大学 | Synthesis method of 2-pyridylmethyl thioether and synthesis process of related drugs |
| CN114394956A (en) * | 2022-03-29 | 2022-04-26 | 寿光富康制药有限公司 | Preparation method of high-purity rabeprazole and sodium salt thereof |
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