CN107311944A - Application of the asymmetric hydrogenation in Yi Gelieting synthesis - Google Patents
Application of the asymmetric hydrogenation in Yi Gelieting synthesis Download PDFInfo
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- CN107311944A CN107311944A CN201710683565.8A CN201710683565A CN107311944A CN 107311944 A CN107311944 A CN 107311944A CN 201710683565 A CN201710683565 A CN 201710683565A CN 107311944 A CN107311944 A CN 107311944A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
- C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a kind of formula（1）Compound Yi Gelieting synthetic 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 Yi Gelieting：
Description
Technical field
The present invention relates to a kind of Yi Gelieting synthetic method, belong to technical field of medicine synthesis.
Background technology
Yi Gelieting (common names：EVOGLIPTIN, trade name Suganon), chemistry is entitled:(R) -4- ((R) -3- ammonia
Base -4- (2,4,5- trifluorophenyls) bytyry) -3- (tert-butyl alcohol ether methyl) piperazine -2- ketone.Yi Gelieting molecular weight：
401.42；CAS registration numbers：1222102-29-5；Structural formula is shown in formula 1：
Formula 1
Yi Gelieting is researched and developed by East Asia drugmaker of South Korea.On October 2nd, 2015 obtains Korean foods drug safety portion in South Korea
（MFDS）The medicine of the treatment type II diabetes of approval, Yi Gelieting is DPP-4 inhibitor class medicines, for treating 2 type glycosurias
Disease.Dosage strengths：Yi Gelieting 5mg/ pieces.
Prior art literature
Non-patent literature： 1 ：Lab. Invest., 2016, 96, 5, P547-P560；Non-patent literature 2：Bioorg
Med Chem Lett, 2011, 21, 12, P3809-P12；
Patent document：CN102883721A and CN103922971B.
In the prior art, Yi Gelieting synthesis technique, 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 Yi Gelieting synthesis
Method.
Technical scheme：To achieve the above object, the invention provides a kind of formula（1）Compound Yi Gelieting synthesis side
Method, by formula（2）And formula（3）As initiation material, through following series reaction, formula is finally made in compound（1）Compound, i.e. institute
State Yi Gelieting：
。
Preferably, the compound（2）And compound（3）Compound is made through amidation process（4）；Compound（4）
Compound is made through imidization（5）；Final compound（5）Compound is made through asymmetric hydrogenation（1）, i.e., it is described according to
Ge Lieting.
Preferably, the compound（2）And compound（3）Amidation process in, reaction dissolvent be selected from anhydrous tetrahydrochysene
Furans, absolute ether, anhydrous methyl tertbutyl ether, anhydrous methylene chloride, dry toluene, anhydrous tertbutyl ether, anhydrous 2- methyl
One or more in tetrahydrofuran and anhydrous acetonitrile；The temperature of reaction is 0 DEG C~30 DEG C；Reaction reagent is selected from DCC（Two hexamethylenes
Base carbodiimide）, EDC（1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides）, EDCI (1- (3- dimethylaminos
Propyl group) -3- ethyl-carbodiimide hydrochlorides), DIC（N, N'- DIC）, oxalyl chloride, POCl3 and dichloro
One or more in sulfoxide；
Preferably, the compound（4）Imidization in, reaction dissolvent be selected from 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 and anhydrous acetonitrile；The temperature of reaction is 20 DEG C~80 DEG C；
Preferably, the compound（5）Through in asymmetric hydrogenation：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；Reaction
Solvent be anhydrous tetrahydro furan, absolute ether, anhydrous methyl tertbutyl ether, anhydrous methylene chloride, dry toluene, anhydrous tertiary fourth
One or more in base ether, anhydrous 2- methyltetrahydrofurans, absolute methanol, absolute ethyl alcohol, anhydrous isopropyl alcohol and anhydrous acetonitrile；
The temperature of reaction is 20 DEG C~80 DEG C；The part of reaction is：；The part rubs with rhodium catalyst
You are than being 1；1~1.05；Rhodium catalyst and compound（5）Mol ratio is 1：100~1000；
Beneficial effect：Many relative to Yi Gelieting synthesis steps 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 Yi Gelieting intermediates 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
Change under the conditions of 0 DEG C toward the L and 2.5 kg (11 mol) of addition reaction dissolvent anhydrous methylene chloride 20 in 50L reactors
Compound（2）, it is slow added into 1.5 kg（11 mol）Oxalyl chloride (3 hours), maintains the temperature at 0 DEG C or so, adds rear TLC tracking
Reaction, reacts after 3 hours and terminates.
Toward the L of addition reaction dissolvent anhydrous methylene chloride 10 and 1.86 in another 50L reactor under the conditions of 0 DEG C
Kg (10 mol) compound（3）, add 1.11 kg（11 mol）Triethylamine, is slow added into above-mentioned acyl chlorides, keeping temperature
At 0 DEG C or so, rear TLC tracking reaction is added, it is water-soluble that reaction solution is added into the sodium acid carbonates of 20L 5% after reaction terminates after 3 hours
In liquid, point liquid, organic phase is concentrated under reduced pressure to obtain compound（4）3.76 kg（9.39 mol）, yield is 93.9%.HPLC detections are pure
Degree：97.8%.
1H NMR (400 MHz, DMSO-d 6) δ 7.47 – 7.21 (m, 1H), 6.88 – 6.76 (m, 1H),
6.53 (s, 1H), 4.91 (t, J = 5.8 Hz, 1H), 4.86 – 4.69 (m, 1H), 4.52 (dd, J =
12.5, 1.0 Hz, 1H), 3.83 (dd, J = 12.4, 5.8 Hz, 1H), 3.69 (d, J = 12.5 Hz,
1H), 3.62 – 3.34 (m, 6H), 1.13 (s, 9H).
ESI+ [M+H]+=401.
Compound（5）Preparation
At ambient temperature toward the L of addition reaction dissolvent absolute ethyl alcohol 20 and 3.6 kg (9mol) compound in 50L reactors
（4）, add 771 g（10 mol）Ammoniom-Acetate, backflow is warming up to after adding by reaction solution, and TLC tracking reactions are anti-after 7 hours
It should terminate, be cooled to 25 DEG C or so, add 20L water, stirring and crystallizing 2 hours, filtering, filter cake is washed with water 10L, dries obtainedization
Compound（5）3.34 kg（8.37 mol）, yield is 93%.HPLC detects purity：97.6%.
1H NMR (400 MHz, DMSO-d 6) δ 8.16 (s, 2H), 7.12 (m, 1H), 6.83 (m, 1H),
6.53 (s, 1H), 5.12 (t, J = 1.0 Hz, 1H), 4.49 (m, 1H), 4.27 (t, J = 6.1 Hz,
1H), 3.83 (dd, J = 12.4, 6.1 Hz, 1H), 3.69 – 3.51 (m, 1H), 3.54 – 3.37 (m,
3H), 3.37 – 3.13 (m, 2H), 1.13 (s, 9H).
ESI+ [M+H]+=400.
Compound（1）Preparation
At ambient temperature toward adding 3.6 kg in 50L autoclaves（8 mol）Compound（5）In 25L anhydrous methylene chlorides
In, add [Rh (cod)2]BF4 32 g (0.08 mol) and the g of part 59 (0.08 mol).It is anti-under 20 kg hydrogen pressure
Should, after the completion of TLC monitoring reactions, filtered first through diatomite, be concentrated under reduced pressure to obtain compound（1）Crude product, crude product is tied again through toluene
It is brilliant to obtain the kg of highly finished product 3.08（7.67 mol）, yield is 95.8%.HPLC detects purity：99.6%（de 99.8%）.
1H NMR (400 MHz, DMSO-d 6) δ 7.43-7.31 (m, 1H), 7.30-7.16 (m, 1H),
4.86-4.74 (m, 1H), 4.59-4.40 (m, 2H), 3.99-3.83 (m, 2H), 3.90-3.83 (m, 2H),
3.77-3.63 (m, 1H), 3.45-3.33 (m, 2H), 3.33-3.21 (m, 1H), 3.14-3.00 (m, 2H),
2.89-2.66 (m, 2H),1.18 (s, 3H), 1.11 (s, 6H).
ESI+ [M+H]+=402.
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 (5)
1. a kind of formula（1）Compound Yi Gelieting synthetic method, it is characterised in that by formula（2）And formula（3）Compound as rise
Beginning raw material, through following series reaction, is finally made formula（1）Compound, i.e., described Yi Gelieting：
。
2. Yi Gelieting according to claim 1 synthetic method, it is characterised in that the compound（2）And compound
（3）Compound is made through amidation process（4）；Compound（4）Compound is made through imidization（5）；Final compound（5）
Compound is made through asymmetric hydrogenation（1）, i.e., described Yi Gelieting.
3. Yi Gelieting according to claim 2 synthetic method, it is characterised in that the compound（2）And compound
（3）Amidation process in, reaction dissolvent be selected from anhydrous tetrahydro furan, absolute ether, anhydrous methyl tertbutyl ether, anhydrous dichloro
One or more in methane, dry toluene, anhydrous tertbutyl ether, anhydrous 2- methyltetrahydrofurans and anhydrous acetonitrile；Reaction
Temperature is 0 DEG C~30 DEG C；Reaction reagent is selected from DCC（Dicyclohexylcarbodiimide）, EDC（1- (3- dimethylamino-propyls) -3-
Ethyl-carbodiimide hydrochloride）, EDCI (1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides), DIC（N,N'-
DIC）, oxalyl chloride, the one or more in POCl3 and thionyl chloride.
4. Yi Gelieting according to claim 2 synthetic method, it is characterised in that the compound（4）Imidization
In reaction, reaction dissolvent be selected from anhydrous tetrahydro furan, absolute ether, anhydrous methyl tertbutyl ether, anhydrous methylene chloride, without water beetle
In benzene, anhydrous tertbutyl ether, anhydrous 2- methyltetrahydrofurans, absolute methanol, absolute ethyl alcohol, anhydrous isopropyl alcohol and anhydrous acetonitrile
It is one or more of；The temperature of reaction is 20 DEG C~80 DEG C.
5. Yi Gelieting according to claim 2 synthetic method, it is characterised in that the compound（5）Through not right
Claim in hydrogenation：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, without water beetle
Base tertbutyl ether, anhydrous methylene chloride, dry toluene, anhydrous tertbutyl ether, anhydrous 2- methyltetrahydrofurans, absolute methanol, nothing
One or more in water-ethanol, anhydrous isopropyl alcohol and anhydrous acetonitrile；The temperature of reaction is 20 DEG C~80 DEG C；The part of reaction
For：；The part is 1 with rhodium catalyst mol ratio；1~1.05；Rhodium catalyst and compound
（5）Mol ratio is 1：100~1000.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710683565.8A CN107311944A (en) | 2017-08-11 | 2017-08-11 | Application of the asymmetric hydrogenation in Yi Gelieting synthesis |
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|---|---|---|---|
| CN201710683565.8A CN107311944A (en) | 2017-08-11 | 2017-08-11 | Application of the asymmetric hydrogenation in Yi Gelieting synthesis |
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| CN107311944A true CN107311944A (en) | 2017-11-03 |
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| CN201710683565.8A Withdrawn CN107311944A (en) | 2017-08-11 | 2017-08-11 | Application of the asymmetric hydrogenation in Yi Gelieting synthesis |
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Application publication date: 20171103 |