CN101973997A - Method for preparing sitagliptin phosphate side chain - Google Patents
Method for preparing sitagliptin phosphate side chain Download PDFInfo
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- CN101973997A CN101973997A CN 201010299595 CN201010299595A CN101973997A CN 101973997 A CN101973997 A CN 101973997A CN 201010299595 CN201010299595 CN 201010299595 CN 201010299595 A CN201010299595 A CN 201010299595A CN 101973997 A CN101973997 A CN 101973997A
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Abstract
The invention discloses a method for preparing a sitagliptin phosphate side chain which has a structure shown by a formula 1. The method comprises the following steps of: a) preparing 2-piperazine thioketone with structure shown by a formula 4 by vulcanizing 2-piperazine ketone with structure shown by a formula 2 with a vulcanizing reagent, wherein the vulcanizing reagent is phosphorus pentasulfide or a Lawesson reagent with structure shown by a formula 3; and b) performing cyclization on trifluoro ethyl hydrazine and the 2-piperazine thioketone through Pellizzari reaction and adding hydrochloric acid to form salt so as to obtain 3-trifluoromethyl-[1,2,4] triazole [4,3-a] piperazine hydrochloride serving as a target product. The method of the invention has short route, cheap and readily available raw material, high yield of each step and relatively low cost and is simple to operate.
Description
(1) technical field
The present invention relates to a kind of preparation sitagliptin phosphate side chain is the variation route of 3-trifluoromethyl-[1,2,4] triazole [4,3-a] piperazine hydrochloride.
(2) background technology
3-trifluoromethyl-[1,2,4] triazole [4,3-a] piperazine hydrochloride is the important intermediate of the new drug sitagliptin phosphate of Merck company exploitation.Sitagliptin phosphate is the new drug that is used for the treatment of type ii diabetes that obtained the drugs approved by FDA listing in 2006.
When the blood sugar for human body level raises, sitagliptin phosphate can be by effectively suppressing dipeptidyl peptidase-4 (DPP-4) thereby is reached and promote two kinds of incretin---glucagon kind polypeptide-1 and glucose-dependent-insulinotropic polypeptide (GIP) thus the g protein coupled receptor that activates islet cells promotes the release of Regular Insulin, Regular Insulin then can lowering blood glucose.For existing ofhypoglycemic medicine, sitagliptin phosphate can not produce hypoglycemia.And also beneficial to blood fat and blood pressure, possible depress appetite and losing weight especially has provide protection to the insulin B cell, so is a kind of reasonable hypoglycemic agents.
WO2004103276 discloses with glycine methyl ester and (has got N-(N-tertbutyloxycarbonyl) ethyl glycine methyl esters with 2-(N-tertbutyloxycarbonyl) aminoacetaldehyde through reduction amination; use benzyloxy dicarbonyl chloride (Cbz-Cl) protection secondary amino group then; then under acidic conditions, take off tertbutyloxycarbonyl and get N-benzyl-Ethylglycocoll; cyclization under the trimethyl aluminium effect; hydrogenolysis gets 2-thioketones-4-(N-tertbutyloxycarbonyl)-piperazine with tertbutyloxycarbonyl protection secondary amino group after taking off the Cbz protecting group again; again with trimethylammonium oxygen Tetrafluoroboric acid react corresponding methoxyl group group with imine moiety; with the hydrazine effect; again with acid anhydrides or acyl chlorides effect; further hot cyclization gets 3-trifluoromethyl-[1 in methyl cellosolve; 2; 4] triazole [4; 3-a]-4-(N-tertbutyloxycarbonyl) piperazine; (example hydrochloric acid dioxane solution) deprotection gets 3-trifluoromethyl-[1 under acidic conditions; 2; 4] triazole [4,3-a] piperazine.But this route is longer, and has used comparatively expensive Me3OBF4, adopts protecting group, has increased the step of last protection and deprotection, and is comparatively loaded down with trivial details.
U.S. Pat 6699871 has been announced another method, with chloro pyrazine and hydrazine hydrate react the 2-hydrazine for pyrazine, under the trifluoroacetic anhydride effect, obtain 2-trifluoro hydrazides pyrazine, get 3-trifluoromethyl-[1,2 with polyphosphoric acid (PPA) cyclization, 4] triazole [4,3-a] pyrazine, through the Pd/C catalytic hydrogenation reduce target product 3-trifluoromethyl-[1,2,4] triazole [4,3-a] piperazine.Wherein, the 2-hydrazine also can obtain 3-trifluoromethyl-[1,2,4] triazole [4,3-a] pyrazine for pyrazine and the direct condensation of trifluoroacetic acid triethyl; Or in PPA with trifluoroacetic acid react 3-trifluoromethyl-[1,2,4] triazole [4,3-a] pyrazine.Raw material cheaply is easy to get, as the chloro pyrazine (150 yuan/kg), but this route yield is lower, and the first step requires high temperature, hydrazine hydrate under this reaction conditions easily with water formation azeotrope, cause the blast of anhydrous hydrazine.
WO2004087650 has announced after the reaction of hydrazine and Trifluoroacetic Acid Ethyl Ester and to have reacted to such an extent that two replace hydrazines with chloroacetyl chloride, closed loop gets 2-(chloromethyl)-5-(trifluoromethyl)-1 under the phosphorus oxychloride effect then, 3,4-three oxygen azoles, the trifluoroacetyl hydrazine pyrazine closed loop in the hydrochloric acid soln of methyl alcohol that obtains with reacting ethylenediamine gets target product 3-trifluoromethyl-[1 again, 2,4] triazole [4,3-a] piperazine.
(3) summary of the invention
The technical problem to be solved in the present invention provides the method for a kind of preparation 3-trifluoromethyl-[1,2,4] triazole [4,3-a] piperazine hydrochloride, and this method not only route is shorter, and raw material cheaply is easy to get, and simultaneously simple to operate, it is higher that each goes on foot yield, and cost is relatively low.
For solving the problems of the technologies described above, the present invention adopts following technical scheme:
The preparation method of a kind of structure 3-trifluoromethyl-[1,2,4] triazole [4,3-a] piperazine hydrochloride as shown in Equation 1 comprises the steps:
A) make structure 2-piperazine ketone sulfuration as shown in Equation 2 obtain structure 2-piperazine thioketones as shown in Equation 4 with sulfuration reagent; Described sulfo-reagent is thiophosphoric anhydride or structure Lawesson reagent as shown in Equation 3;
B) make trifluoroacetic acid hydrazine shown in the formula 5 and 2-piperazine thioketones react cyclization, add the hydrochloric acid salify, promptly obtain target product 3-trifluoromethyl-[1,2,4] triazole [4,3-a] piperazine hydrochloride by Pellizzari.
Reaction formula of the present invention is as follows:
The structural formula of described Lawesson reagent is as follows:
Formula 3
Further, reactions steps of the present invention a) in, described vulcanization reaction with the mixture of following a kind of or any several solvents as reaction solvent: tetrahydrofuran (THF), acetonitrile, 1,4-dioxane.
Further, reactions steps of the present invention a) in, the vulcanization reaction temperature is 15～60 ℃.Preferred 2-4 of vulcanization reaction time hour.
Further, reactions steps of the present invention a) in, the molar ratio of described Vanadium Pentoxide in FLAKES and 2-piperazine ketone is 1～1.2: 1; The molar ratio of perhaps described Lawesson reagent and 2-piperazine ketone is 0.6～1.0: 1.
Further, reactions steps of the present invention a) in, after vulcanization reaction is complete, can obtain intermediate product 2-piperazine thioketones by aftertreatment, described post-treating method is recommended as follows: vulcanization reaction fully after, the gained reaction solution is handled with alkali lye (such as sodium hydroxide solution) earlier, then through organic solvent (ethyl acetate) extraction, concentratedly obtain thick product, thick product is refining through refining solvent (preferred toluene), can obtain 2-piperazine thioketones.
Further, reactions steps b of the present invention) in, described Pellizzari reaction with the mixture of following a kind of or any several solvents as reaction solvent: normal butane, ethanol, pyridine.
Further, reactions steps b of the present invention) in, the temperature of reaction of described Pellizzari reaction is 60～120 ℃.The Pellizzari reaction times is generally at 4-24 hour.
Further, reactions steps b of the present invention) in, the molar ratio of described 2-piperazine thioketones and trifluoroacetic acid hydrazine is 1: 1～1.4.
Further, reactions steps b of the present invention) in, described trifluoroacetic acid hydrazine and 2-piperazine thioketones preferably carry out cyclization in the presence of sodium acetate, can shorten the reaction times greatly.The molar ratio of described sodium acetate and 2-piperazine thioketones is recommended as 1～1.2: 1.
Further, reactions steps b of the present invention) in, described adding hydrochloric acid salify is: after Pellizzari reacts completely, add the hydrochloric acid soln stirring reaction, preferred 1-1.5 of reaction times hour in reaction system.The add-on of described hydrochloric acid soln is HCl:2-piperazine thioketones=1.1-1.2: 1.
Further, reactions steps b of the present invention) in, after adding the hydrochloric acid salify, can obtain target product 3-trifluoromethyl-[1,2 by simple aftertreatment, 4] triazole [4,3-a] piperazine hydrochloride, the present invention recommends to adopt following post-treating method: after adding the hydrochloric acid salify, add methyl tertiary butyl ether (MTBE) and react, cool off then, filter and obtain crude product, crude product obtains target product through washing, drying.The mixed solution of washing reagent preferred alcohol and methyl tertiary butyl ether.
Compared with prior art, beneficial effect of the present invention is:
A) route of the present invention is shorter, and raw material cheaply is easy to get.
B) the present invention is simple to operate, and it is higher that each goes on foot yield, and cost is relatively low.
(4) embodiment
Be described further with regard to technical scheme of the present invention below in conjunction with embodiment, but protection scope of the present invention is not limited thereto:
Embodiment 1
Under nitrogen protection, to P
2S
5(4.3g, and adding 2-piperazine ketone in THF 10mmol) (150mL) solution (1g, 10mmol); Electronic stirring reaction 2h under the room temperature uses 30mL 3Mol/L NaOH (aq) processing reaction liquid then, uses ethyl acetate extraction again, concentrates organic layer, and thick oil adds 60mL toluene, back flow reaction 4h, and standing demix decants toluene layer while hot, reduces to room temperature gradually; Remaining oil continues to add 60mL toluene, and behind the back flow reaction 3h, standing demix decants toluene layer while hot, slowly reduces to room temperature.Two toluene are blended in-4 ℃ of cooling 12h post crystallizations down mutually, filter and collect, and wash twice, obtain yellow solid 0.95g, yield 81.7% with cold toluene.Products obtained therefrom does not need to be further purified, and can be directly used in next step reaction.
MS(ESI)：m/z＝139(M+Na
+)。
Embodiment 2
Under nitrogen protection, with P
2S
5(5.2g, 12mmol) and 2-piperazine ketone (1g 10mmol) adds 30mL 1, in the 4-dioxane, the electronic stirring reaction 3h of room temperature.Use 30mL 3Mol/L NaOH (aq) processing reaction liquid then, use ethyl acetate extraction again, concentrate organic layer, thick oil adds 60mL toluene, back flow reaction 4h, and standing demix decants toluene layer while hot, reduces to room temperature gradually; Remaining oil continues to add 60mL toluene, and behind the back flow reaction 3h, standing demix decants toluene layer while hot, slowly reduces to room temperature.Two toluene are blended in-4 ℃ of cooling 12h post crystallizations down mutually, filter and collect, and wash twice, obtain yellow solid 0.91g, yield 78.4% with cold toluene.Products obtained therefrom does not need to be further purified, and can be directly used in next step reaction.
Embodiment 3
Under nitrogen protection, with LR (2.43,6mmol) be dissolved among the THF (150mL), (1g 10mmol), reacts 4h under the room temperature to add 2-piperazine ketone under vigorous stirring.Use 30mL 3Mol/L NaOH (aq) processing reaction liquid then, use ethyl acetate extraction again, concentrate organic layer, thick oil adds 60mL toluene, back flow reaction 4h, and standing demix decants toluene layer while hot, reduces to room temperature gradually; Remaining oil continues to add 60mL toluene, and behind the back flow reaction 3h, standing demix decants toluene layer while hot, slowly reduces to room temperature.Two toluene are blended in-4 ℃ of cooling 12h post crystallizations down mutually, filter and collect, and wash twice, obtain yellow solid 0.97g, yield 83.6% with cold toluene.Products obtained therefrom does not need to be further purified, and can be directly used in next step reaction.
Embodiment 4
Under nitrogen protection, with LR (4.04,10mmol) be dissolved among the THF (200mL), (1g 10mmol), reacts 3h under the room temperature to add 2-piperazine ketone under vigorous stirring.Use 30mL 3Mol/L NaOH (aq) processing reaction liquid then, use ethyl acetate extraction again, concentrate organic layer, thick oil adds 60mL toluene, back flow reaction 4h, and standing demix decants toluene layer while hot, reduces to room temperature gradually; Remaining oil continues to add 60mL toluene, and behind the back flow reaction 3h, standing demix decants toluene layer while hot, slowly reduces to room temperature.Two toluene are blended in-4 ℃ of cooling 12h post crystallizations down mutually, filter and collect, and wash twice, obtain yellow solid 0.96g, yield 82.7% with cold toluene.Products obtained therefrom does not need to be further purified, and can be directly used in next step reaction.
Embodiment 5
With 2-piperazine thioketones (1.05g, 9mmol) with trifluoroacetic acid hydrazine (1.16g, 9mmol) be blended in the 30mL dehydrated alcohol, back flow reaction 24h, slowly drip 37%HCl solution (0.8mL then, 10mmol) stir 1h, add 30mL methyl tertiary butyl ether (MTBE) reaction 1h then, again reaction solution is cooled to 2 ℃ and stirs after-filtration half an hour.Solid to use 50mL ethanol: MTBE (v/v=1: 3) flushing, product vacuum-drying, final white solid 1.65g, yield 81%, HPLC purity is 98-99%.
MS(ESI)：m/z＝193(M+H
+)，215(M+Na
+)。
1H-NMR(500MHz，DMSO-d
6)：δ3.6(t，2H)，4.4(t，2H)，4.6(s，2H)，10.6(s，2H)。
Embodiment 6
With 2-piperazine thioketones (1.05g, 9mmol) with trifluoroacetic acid hydrazine (1.35g, 10.8mmol) mix, join in the 100mL normal butane, add then sodium acetate (1.44g, 18mmol), back flow reaction 4h, (0.8mL 10mmol) stirs 1h, adds 30mLMTBE reaction 1h then slowly to drip 37%HCl solution then.Again reaction solution is cooled to 2 ℃ and stirs after-filtration half an hour.Solid will be used 50mL ethanol: MTBE (1: 3) flushing, product vacuum-drying, and the final white solid 1.7g that gets, yield 83.5%, HPLC purity is 98-99%.
Embodiment 7
With 2-piperazine thioketones (1.05g, 9mmol) (1.62g 12.6mmol) is blended in 120mL pyridine/normal butane (1: 1) with the trifluoroacetic acid hydrazine, back flow reaction 24h, (0.8mL 10mmol) stirs 1h, adds 30mL MTBE reaction 1h then slowly to drip 37%HCl solution then.Again reaction solution is cooled to 2 ℃ and stirs after-filtration half an hour.Solid will be used 50mL ethanol: MTBE (1: 3) flushing, product vacuum-drying, and the final white solid 1.68g that gets, yield 82.5%, HPLC purity is 98-99%.
Claims (9)
1. the preparation method of structure 3-trifluoromethyl-[1,2,4] triazole [4,3-a] piperazine hydrochloride as the formula (1) comprises the steps:
A) make structure 2-piperazine ketone sulfuration as the formula (2) obtain structure 2-piperazine thioketones as the formula (4) with sulfuration reagent; Described sulfo-reagent is thiophosphoric anhydride or structure Lawesson reagent as the formula (3);
B) make trifluoroacetic acid hydrazine shown in the formula (5) and 2-piperazine thioketones react cyclization, add the hydrochloric acid salify, promptly obtain target product 3-trifluoromethyl-[1,2,4] triazole [4,3-a] piperazine hydrochloride by Pellizzari;
Formula 1 formula 2 formulas 3
Formula 4 formulas 5.
2. preparation method according to claim 1 is characterized in that reactions steps is a), described vulcanization reaction with the mixture of following a kind of or any several solvents as reaction solvent: tetrahydrofuran (THF), acetonitrile, 1,4-dioxane.
3. preparation method according to claim 2 is characterized in that reactions steps temperature of reaction a) is 15～60 ℃.
4. preparation method according to claim 1 is characterized in that reactions steps a), and the molar ratio of described Vanadium Pentoxide in FLAKES and 2-piperazine ketone is 1～1.2: 1; The molar ratio of perhaps described Lawesson reagent and 2-piperazine ketone is 0.6～1.0: 1.
5. preparation method according to claim 1 is characterized in that reactions steps b) in, described Pellizzari reaction with the mixture of following a kind of or any several solvents as reaction solvent: normal butane, ethanol, pyridine.
6. preparation method according to claim 5 is characterized in that reactions steps b) the Pellizzari temperature of reaction be 60～120 ℃.
7. preparation method according to claim 1 is characterized in that reactions steps b) in, the molar ratio of described 2-piperazine thioketones and trifluoroacetic acid hydrazine is 1～1.4: 1.
8. according to the described preparation method of one of claim 1～7, it is characterized in that reactions steps b) in, described trifluoroacetic acid hydrazine and 2-piperazine thioketones carry out cyclization in the presence of sodium acetate.
9. preparation method according to claim 8, the molar ratio that it is characterized in that described sodium acetate and trifluoroacetic acid hydrazine is 1～1.2: 1.
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| CN2010102995957A CN101973997B (en) | 2010-09-30 | 2010-09-30 | Method for preparing sitagliptin phosphate side chain |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102898387A (en) * | 2012-09-26 | 2013-01-30 | 浙江工业大学 | Channelized method for continuously producing N-[(2Z)-piperazine-2-subunit]-2, 2, 2-trifluoroacetyl hydrazine |
| CN112979564A (en) * | 2019-12-02 | 2021-06-18 | 上海复星星泰医药科技有限公司 | Preparation method of sitagliptin intermediate |
| CN113461691A (en) * | 2020-12-31 | 2021-10-01 | 浙江美诺华药物化学有限公司 | Sitagliptin impurity, preparation method and detection method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004080958A2 (en) * | 2003-03-07 | 2004-09-23 | Merck & Co. Inc. | Process to tetrahydrotriazolopyrazines and intermediates |
| CN1832949A (en) * | 2003-06-24 | 2006-09-13 | 麦克公司 | Phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor |
| WO2009084024A2 (en) * | 2007-11-02 | 2009-07-09 | Glenmark Generics Limited | A process for the preparation of r-sit agliptin and its pharmaceutically acceptable salts thereof |
-
2010
- 2010-09-30 CN CN2010102995957A patent/CN101973997B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004080958A2 (en) * | 2003-03-07 | 2004-09-23 | Merck & Co. Inc. | Process to tetrahydrotriazolopyrazines and intermediates |
| CN1832949A (en) * | 2003-06-24 | 2006-09-13 | 麦克公司 | Phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor |
| WO2009084024A2 (en) * | 2007-11-02 | 2009-07-09 | Glenmark Generics Limited | A process for the preparation of r-sit agliptin and its pharmaceutically acceptable salts thereof |
Non-Patent Citations (1)
| Title |
|---|
| 《中国医药工业杂志》 20081231 孙桂芳等 西他列汀合成路线图解 383-386 1-9 第39卷, 第5期 2 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102898387A (en) * | 2012-09-26 | 2013-01-30 | 浙江工业大学 | Channelized method for continuously producing N-[(2Z)-piperazine-2-subunit]-2, 2, 2-trifluoroacetyl hydrazine |
| CN102898387B (en) * | 2012-09-26 | 2015-01-07 | 浙江工业大学 | Channelized method for continuously producing N-[(2Z)-piperazine-2-subunit]-2, 2, 2-trifluoroacetyl hydrazine |
| CN112979564A (en) * | 2019-12-02 | 2021-06-18 | 上海复星星泰医药科技有限公司 | Preparation method of sitagliptin intermediate |
| CN113461691A (en) * | 2020-12-31 | 2021-10-01 | 浙江美诺华药物化学有限公司 | Sitagliptin impurity, preparation method and detection method thereof |
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