CN107365313A - A kind of asymmetric process of sitagliptin - Google Patents
A kind of asymmetric process of sitagliptin Download PDFInfo
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- CN107365313A CN107365313A CN201710689482.XA CN201710689482A CN107365313A CN 107365313 A CN107365313 A CN 107365313A CN 201710689482 A CN201710689482 A CN 201710689482A CN 107365313 A CN107365313 A CN 107365313A
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- compound
- sitagliptin
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- anhydrous
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a kind of formula（1）The method of asymmetric synthesis of compound sitagliptin, by formula（2）And formula（3）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 method of asymmetric synthesis 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 medicine that first kind is granted 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, hypoglycemia and oedema phenomenon will not also occur, be adapted to
Glycemic control is bad and the 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, cost is higher, but also product receipts be present
The low and ropy defect of rate, can not 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 asymmetric conjunction of compound sitagliptin
Into method, by formula（2）And formula（3）As initiation material, through following series reaction, formula is finally made in compound（1）Compound,
I.e. described sitagliptin：
。
Preferably, the compound（2）And compound（3）Reacted through Asymmetrical substitute and chipal compounds are made（4）；Most
Chipal compounds afterwards（4）Compound is made through reduction reaction（1）, i.e., described sitagliptin.
Preferably, the compound（2）And compound（3）Asymmetrical substitute reaction in：The solvent of reaction is anhydrous
Tetrahydrofuran, absolute ether, anhydrous methyl tertbutyl ether, anhydrous methylene chloride, dry toluene, anhydrous tertbutyl ether, anhydrous 2-
One or more in methyltetrahydrofuran, absolute methanol, absolute ethyl alcohol, anhydrous isopropyl alcohol, anhydrous propanone and anhydrous acetonitrile；Instead
The temperature answered is 0 DEG C~30 DEG C；The compound（2）And compound（3）Mol ratio be 1:（1~2.0）；The chirality of reaction is urged
Agent is：；Chiral catalyst and compound（2）Mol ratio is 1：100~1000；Used in reaction
Alkali is selected from potassium carbonate, saleratus, sodium carbonate, sodium acid carbonate, lithium carbonate, LiHMDS, NaHMDS, KHMDS, cesium carbonate, tertiary fourth
Base sodium alkoxide, tert-butyl group potassium alcoholate, triethylamine, diisopropylethylamine, DMA and the carbon -7- of 1,8- diazabicylo 11
Alkene（DBU）In one or several kinds.
Beneficial effect：More 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 is preferable, 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（4）Preparation
Under the conditions of 0 DEG C, compound is added in 50L reactors（2）2.05 kg（10 mol）And compound（3）2.95 kg
（11 mol）In 20L anhydrous methylene chlorides, the g of catalyst 292 is added（0.5 mol）, diisopropyl is added after stirring dissolved clarification
The kg of ethamine 1.42（11 mol）, after the completion of TLC monitoring reactions, reaction solution is poured into 20L water, and liquid separation, organic phase is through being concentrated under reduced pressure
Obtain compound（4）Crude product, crude product obtain 3.92 kg through re crystallization from toluene（8.97 mol）, yield 89.7%.HPLC detects purity：
95.6%（ee 98.2%）.
1H NMR (400 MHz, DMSO-d 6) δ 6.97 – 6.63 (m, 2H), 5.45 (d, J = 18.3 Hz,
1H), 5.31– 5.21 (m, 1H), 4.82 – 4.51 (m, 3H), 4.21– 4.10 (m, 1H), 3.63 – 3.36
(m, 2H), 3.30 (dd, J = 12.4, 7.0 Hz, 1H), 3.17– 3.02 (m, 1H), 2.91 (dd, J =
12.3, 7.0 Hz, 1H).
ESI+ [M+H]+=438.
Compound（1）Preparation
At ambient temperature toward adding 3.50 kg in 50L autoclaves（8 mol）Compound（4）In 25L absolute methanols,
Add the g of Pd/C 35 (1%).React under 5 kg hydrogen pressure, after the completion of TLC monitoring reactions, filtered first through diatomite,
Be concentrated under reduced pressure to obtain compound（1）Crude product, crude product obtain the kg of highly finished product 3.17 through re crystallization from toluene（7.8 mol）, yield 97.5%.
HPLC detects purity：99.7%.
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
The 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 (3)
- A kind of 1. formula（1）The method of asymmetric synthesis of compound sitagliptin, it is characterised in that by formula（2）And formula（3）Compound As initiation material, through following series reaction, formula is finally made（1）Compound, i.e., described sitagliptin：。
- 2. the method for asymmetric synthesis of sitagliptin according to claim 1, it is characterised in that the compound（2）With Compound（3）Reacted through Asymmetrical substitute and chipal compounds are made（4）；Last chipal compounds（4）Through reduction reaction obtainedization Compound（1）, i.e., described sitagliptin.
- 3. the method for asymmetric synthesis of sitagliptin according to claim 2, it is characterised in that the compound（2）With Compound（3）Asymmetrical substitute reaction in：The solvent of reaction is anhydrous tetrahydro furan, absolute ether, the anhydrous methyl tert-butyl group Ether, anhydrous methylene chloride, dry toluene, anhydrous tertbutyl ether, anhydrous 2- methyltetrahydrofurans, absolute methanol, absolute ethyl alcohol, nothing One or more in water isopropanol, anhydrous propanone and anhydrous acetonitrile；The temperature of reaction is 0 DEG C~30 DEG C；The compound（2） And compound（3）Mol ratio be 1:（1~2.0）；The chiral catalyst of reaction is：；Chiral catalyst with Compound（2）Mol ratio is 1：100~1000；Alkali used in reaction is selected from potassium carbonate, saleratus, sodium carbonate, carbonic acid Hydrogen sodium, lithium carbonate, LiHMDS, NaHMDS, KHMDS, cesium carbonate, tert-butyl group sodium alkoxide, tert-butyl group potassium alcoholate, triethylamine, diisopropyl Ethamine, DMA and the carbon -7- alkene of 1,8- diazabicylo 11（DBU）In one or several kinds.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710689482.XA CN107365313A (en) | 2017-08-14 | 2017-08-14 | A kind of asymmetric process of sitagliptin |
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| CN201710689482.XA CN107365313A (en) | 2017-08-14 | 2017-08-14 | A kind of asymmetric process of sitagliptin |
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| CN107365313A true CN107365313A (en) | 2017-11-21 |
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| CN201710689482.XA Pending CN107365313A (en) | 2017-08-14 | 2017-08-14 | A kind of asymmetric process of sitagliptin |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2392575A1 (en) * | 2010-06-04 | 2011-12-07 | LEK Pharmaceuticals d.d. | A novel synthetic approach to ß-aminobutyryl substituted compounds |
| CN103038236A (en) * | 2010-06-04 | 2013-04-10 | 力奇制药公司 | A novel synthetic approach to beta-aminobutyryl substituted compounds |
-
2017
- 2017-08-14 CN CN201710689482.XA patent/CN107365313A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2392575A1 (en) * | 2010-06-04 | 2011-12-07 | LEK Pharmaceuticals d.d. | A novel synthetic approach to ß-aminobutyryl substituted compounds |
| CN103038236A (en) * | 2010-06-04 | 2013-04-10 | 力奇制药公司 | A novel synthetic approach to beta-aminobutyryl substituted compounds |
Non-Patent Citations (2)
| Title |
|---|
| KATURI J. V. PAUL,等: "A novel strategy toward the synthesis of N-(b-glycosyl)asparagines based on the alkylation of ethyl nitroacetate using N-(b-glycosyl)iodoacetamides", 《TETRAHEDRON LETTERS》 * |
| SACHIN NARUTE,等: "Iron Phosphate Catalyzed Asymmetric Cross-Dehydrogenative Coupling of 2-Naphthols with β-Ketoesters", 《ORGANIC LETTERS》 * |
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Application publication date: 20171121 |