CN107245078A - A kind of synthetic method of sitagliptin - Google Patents
A kind of synthetic method of sitagliptin Download PDFInfo
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- CN107245078A CN107245078A CN201710695149.XA CN201710695149A CN107245078A CN 107245078 A CN107245078 A CN 107245078A CN 201710695149 A CN201710695149 A CN 201710695149A CN 107245078 A CN107245078 A CN 107245078A
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- compound
- anhydrous
- reaction
- sitagliptin
- synthetic method
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention provides a kind of formula（1）The synthetic method of compound sitagliptin, by formula（2）As initiation material, through following series reaction, formula is finally made in compound（1）Compound, i.e., described sitagliptin：
Description
Technical field
The present invention relates to a kind of synthetic method of sitagliptin, belong to technical field of medicine synthesis.
Background technology
Sitagliptin (common name：Sitagliptin, trade name Januvia), entitled (the 3R) -3- amino -1- of chemistry
[3- (trifluoromethyl) -5,6,7,8- tetrahydrochysene -1,2,4- triazols [4,3-a] pyrazine -7- bases] -4- (2,4,5- trifluorophenyls)
Butyl- 1- ketone.The molecular weight of sitagliptin：407.32；CAS registration numbers：486460-32-6；Structural formula is shown in formula 1：
Formula 1
Sitagliptin is researched and developed by Merck ＆ Co., Inc..The medicine for the treatment type II diabetes ratified in the U.S. on October 17th, 2006,
Anuvia is the granted medicine of first kind in DPP-4 inhibitor class medicines.Sitagliptin phosphate action character is to stimulate pancreas islet
While element secretion, hunger can be mitigated, and increased weight will not be made, will not also occur hypoglycemia and oedema phenomenon, be adapted to
Glycemic control is bad and diabetic of frequent generation hypoglycemia uses.
Prior art literature
Non-patent literature： 1 ：Nat Rev Drug Discov, 2007, 6, 2, P109-P10；Non-patent literature 2：
Tonyobyo Karento Raiburari, 2009, 10, Tonyobyo Chiryo no Atarashii Tenkai,
P46-P51
Patent document：WO2013110085A1 and EP2586782A1.
In the prior art, the synthesis technique of sitagliptin, often more complicated, and cost is higher, but also there are product receipts
The low and ropy defect of rate, it is impossible to be adapted to industrialized production.
The content of the invention
Goal of the invention：In order to overcome the deficiencies in the prior art, the invention provides a kind of synthesis of sitagliptin
Method.
Technical scheme：To achieve the above object, the invention provides a kind of formula（1）The synthesis side of compound sitagliptin
Method, by formula（2）As initiation material, through following series reaction, formula is finally made in compound（1）Compound, i.e., it is described west he
Arrange spit of fland：
。
Preferably, the compound（2）Compound is made through asymmetric Isosorbide-5-Nitrae-addition reaction（3）；Final compound（3）
Compound is made through deprotection reaction（1）, i.e., described sitagliptin.
Preferably, the compound（2）Through in asymmetric Isosorbide-5-Nitrae-addition reaction：The rhodium catalyst is selected from Rh2
(pfb)4、Rh2(OAc)4、RhCl3、Rh2(OCOt-Bu)4, mandelic acid rhodium, trifluoroacetic acid rhodium and [Rh (cod)2]BF4In it is any
It is a kind of；The solvent of reaction be anhydrous tetrahydro furan, absolute ether, anhydrous methyl tertbutyl ether, anhydrous methylene chloride, without water beetle
Benzene, anhydrous tertbutyl ether, anhydrous 2- methyltetrahydrofurans, absolute methanol, absolute ethyl alcohol, anhydrous isopropyl alcohol, anhydrous propanone and nothing
One or more in water-acetonitrile；The temperature of reaction is 20 DEG C~80 DEG C；The compound（2）Mol ratio with benzylamine is 1:（1
~2.0）；The part of reaction is：；The part is 1 with rhodium catalyst mol ratio；1~1.05；Rhodium is urged
Agent and compound（2）Mol ratio is 1：100~1000；
Preferably, the compound（3）In deprotection reaction：Reaction dissolvent is selected from absolute methanol, absolute ethyl alcohol, anhydrous second third
One or several kinds in alcohol, anhydrous acetonitrile, anhydrous tetrahydro furan and anhydrous 2- methyltetrahydrofurans；Reaction temperature is 20~80
℃；Catalyst used in reaction is selected from Pd/C, Pt/C, Pd (OH)2/ C, Pd/Al2O3, Pd/CaCO3And Pt/Al2O3In
It is one or several kinds of；
Beneficial effect：Many relative to sitagliptin synthesis step in the prior art, synthesis technique is complicated, synthetic method letter of the present invention
Single easy, cost is relatively low, and yield is higher, and product quality preferably, is adapted to big industrialized production.
Embodiment
The present invention is further described with reference to embodiment.
The method of sitagliptin intermediate HPLC of the present invention detection purity：
Test apparatus：The high performance liquid chromatographs of Agilent 1100（DAD detectors）.
Chromatographic condition：With OB-H (4.6 × 250mm, 5 μm) for chromatographic column, flow velocity：0.5ml/min.
Mobile phase A：Isopropanol；Mobile phase B：Normal heptane
According to the form below carries out linear gradient elution：
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 1 | 99 |
| 30 | 5 | 95 |
| 50 | 25 | 75 |
| 60 | 45 | 55 |
Ultraviolet detection wavelength：210nm.
Embodiment
Compound（3）Preparation
Under nitrogen protection, at ambient temperature toward the L and 3.9 kg of addition reaction dissolvent dry toluene 20 in 50L reactors
(10 mol) compound（2）, add 57 g（0.1mol）Catalyst is Rh2(OCOt-Bu)4With the g of part 66（0.1 mol）,
Reaction solution is warming up to 75 DEG C or so after adding, benzylamine is then slowly added into（6 hours）1.18 kg (11 mol), TLC tracking are anti-
Should, reaction terminates after 5 hours, is cooled to 5 DEG C or so, stirring and crystallizing 2 hours, filtering, filter cake is washed with cold toluene 10L, dries
Compound is made（3）4.66 kg（9.37 mol）, yield is 93.7%.HPLC detects purity：98.8%(ee 99.5%).
1H NMR (400 MHz, DMSO-d 6) δ 7.41 – 7.15 (m, 5H), 7.01 – 6.70 (m, 2H),
5.44 (d, J = 16.6 Hz, 1H), 4.70 – 4.46 (m, 3H), 4.12 – 3.90 (m, 2H), 3.86 –
3.75 (m, 1H), 3.59 – 3.27 (m, 1H), 3.22 – 2.90 (m, 2H), 2.65 – 2.18 (m, 3H),
1.46 (br, 1H).
ESI+ [M+H]+=498.
Compound（1）Preparation
At ambient temperature toward adding 4.47 kg in 50L autoclaves（9 mol）Compound（3）In 25L absolute methanols,
Add Pt/Al2O345 g (1%), add acetic acid 45g（1%）.Reacted under 5 kg hydrogen pressure, TLC monitoring reactions are completed
Afterwards, filtered first through diatomite, be concentrated under reduced pressure to obtain compound（1）Crude product, crude product obtains the kg of highly finished product 3.54 through re crystallization from toluene
（8.7 mol）, yield is 96.7%.HPLC detects purity：99.6%.
1H NMR (400 MHz, DMSO-d 6) δ 7.06-7.28 (m, 1H), 6.91-6.97 (m, 1H),
4.95-5.10 (m, 2H), 3.96-4.18 (m, 4H), 3.60 (s, 1H), 2.68-2.84 (m, 2H), 2.38-
2.58 (m, 2H).
ESI+ [M+H]+=408.
Embodiments of the invention are the foregoing is only, are not intended to limit the scope of the invention, it is every to be said using the present invention
Equivalent structure or equivalent flow conversion that bright book content is made, or other related technical fields are directly or indirectly used in,
Similarly it is included within the scope of the present invention.
Claims (4)
1. a kind of formula（1）The synthetic method of compound sitagliptin, it is characterised in that by formula（2）Compound as initiation material,
Through following series reaction, formula is finally made（1）Compound, i.e., described sitagliptin：
。
2. the synthetic method of sitagliptin according to claim 1, it is characterised in that the compound（2）Through asymmetric
Compound is made in Isosorbide-5-Nitrae-addition reaction（3）；Final compound（3）Compound is made through deprotection reaction（1）, i.e., described Xi Talie
Spit of fland.
3. the synthetic method of sitagliptin according to claim 2, it is characterised in that the compound（2）Through not right
Claim in Isosorbide-5-Nitrae-addition reaction：The rhodium catalyst is selected from Rh2(pfb)4、Rh2(OAc)4、RhCl3、Rh2(OCOt-Bu)4, mandelic acid
Rhodium, trifluoroacetic acid rhodium and [Rh (cod)2]BF4In any one；The solvent of reaction is anhydrous tetrahydro furan, absolute ether, nothing
Water methyl tertiary butyl ether(MTBE), anhydrous methylene chloride, dry toluene, anhydrous tertbutyl ether, anhydrous 2- methyltetrahydrofurans, without water beetle
One or more in alcohol, absolute ethyl alcohol, anhydrous isopropyl alcohol, anhydrous propanone and anhydrous acetonitrile；The temperature of reaction is 20 DEG C~80
℃；The compound（2）Mol ratio with benzylamine is 1:（1~2.0）；The part of reaction is：；Institute
It is 1 that part, which is stated, with rhodium catalyst mol ratio；1~1.05；Rhodium catalyst and compound（2）Mol ratio is 1：100~1000.
4. the synthetic method of sitagliptin according to claim 2, it is characterised in that the compound（3）Deprotection is anti-
Ying Zhong：Reaction dissolvent is selected from absolute methanol, absolute ethyl alcohol, anhydrous b propanol, anhydrous acetonitrile, anhydrous tetrahydro furan and anhydrous 2- first
One or several kinds in base tetrahydrofuran；Reaction temperature is 20~80 DEG C；Catalyst used in reaction is selected from Pd/C,
Pt/C, Pd (OH)2/ C, Pd/Al2O3, Pd/CaCO3And Pt/Al2O3In one or several kinds.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007050485A2 (en) * | 2005-10-25 | 2007-05-03 | Merck & Co., Inc. | Combination of a dipeptidyl peptidase-4 inhibitor and an anti-hypertensive agent for the treatment of diabetes and hypertension |
| WO2011060213A2 (en) * | 2009-11-12 | 2011-05-19 | Dr. Reddy's Laboratories Ltd. | Preparation of sitagliptin and salts thereof |
| CN102485718A (en) * | 2010-12-03 | 2012-06-06 | 浙江海翔药业股份有限公司 | Sitagliptin intermediate and its preparation method |
| KR20130068819A (en) * | 2011-12-16 | 2013-06-26 | 제일약품주식회사 | Preparation of intermediate of sitagliptin |
| CN105949248A (en) * | 2016-05-26 | 2016-09-21 | 河南省科学院化学研究所有限公司 | Synthesis method of Josiphos chiral ferrocenyl phosphine ligands |
-
2017
- 2017-08-15 CN CN201710695149.XA patent/CN107245078A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007050485A2 (en) * | 2005-10-25 | 2007-05-03 | Merck & Co., Inc. | Combination of a dipeptidyl peptidase-4 inhibitor and an anti-hypertensive agent for the treatment of diabetes and hypertension |
| WO2011060213A2 (en) * | 2009-11-12 | 2011-05-19 | Dr. Reddy's Laboratories Ltd. | Preparation of sitagliptin and salts thereof |
| CN102485718A (en) * | 2010-12-03 | 2012-06-06 | 浙江海翔药业股份有限公司 | Sitagliptin intermediate and its preparation method |
| KR20130068819A (en) * | 2011-12-16 | 2013-06-26 | 제일약품주식회사 | Preparation of intermediate of sitagliptin |
| CN105949248A (en) * | 2016-05-26 | 2016-09-21 | 河南省科学院化学研究所有限公司 | Synthesis method of Josiphos chiral ferrocenyl phosphine ligands |
Non-Patent Citations (3)
| Title |
|---|
| HANS-ULRICH BLASER，等: "Solvias Josiphos ligands: from discovery to technical applications", 《TOPICS IN CATALYSIS》 * |
| PAVOL JAKUBEC，等: "Crystallisation-induced asymmetric transformation (CIAT) for the synthesis of dipeptides containing homophenylalanine", 《TETRAHEDRON: ASYMMETRY》 * |
| STEPHEN G. DAVIES，等: "Asymmetric synthesis of (-)-(R)-sitagliptin", 《TETRAHEDRON LETTERS》 * |
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Application publication date: 20171013 |