CN105399744B - A kind of Ao Gelieting synthetic method - Google Patents
A kind of Ao Gelieting synthetic method Download PDFInfo
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- CN105399744B CN105399744B CN201510947176.2A CN201510947176A CN105399744B CN 105399744 B CN105399744 B CN 105399744B CN 201510947176 A CN201510947176 A CN 201510947176A CN 105399744 B CN105399744 B CN 105399744B
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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
Abstract
The invention provides a kind of formula (1) compound Ao Gelieting synthetic method, initiation material is used as by formula (2) and formula (3) compound, through following series reaction, formula (1) compound, i.e., described Ao Gelieting is finally made：
Description
Technical field
The present invention relates to a kind of Ao Gelieting synthetic method, belong to technical field of medicine synthesis.
Background technology
Ao Gelieting (common names：Omarigliptin, trade name Marizev), entitled ((2R, 3S, the 5R) -2- of chemistry
(2,5- difluorophenyls) -5- (2- (mesyl) pyrroles [3,4-c] pyrazolyl -5 (2H, 4H, 6H)-yl) tetrahydrochysene -2H- pyrans -
3- amine).Ao Gelieting molecular weight：398.43；CAS registration numbers：1226781-44-7；Structural formula is shown in formula 1：
Ao Gelieting is researched and developed by Merck ＆ Co., Inc..The medicine of the treatment type II diabetes in Japan's approval on the 30th of September in 2015,
Omarigliptin is a class DPP-4 inhibitor, it is only necessary to is taken weekly and can reach curative effect.
Prior art literature
Non-patent literature：1：Org.Lett.,2014,vol.16,pp5422-5425；Non-patent literature 2：
J.Med.Chem.,2014,vol.57,pp3205-3212
Patent document：WO 2013/003249 and US2010/120863A1.
In the prior art, Ao 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 Ao Gelieting synthesis
Method.
Technical scheme：To achieve the above object, the invention provides a kind of formula (1) compound Ao Gelieting synthesis side
Method, by formula (2) and formula (3) compound as initiation material, through following series reaction, is finally made formula (1) compound, i.e. institute
State Ao Gelieting：
Preferably, chipal compounds (4) are made through asymmetric Henry reaction in the compound (2) and compound (3)；
Compound (5) is made through Intra-molecular condensation in compound (4)；Compound (6) is made in the oxidized reaction of compound (5)；Chemical combination
Compound (8) is made through addition reaction in thing (6) and compound (7)；Compound (1) is made through reduction reaction in final compound (8),
I.e. described Ao Gelieting.
As further preferred, reaction dissolvent is selected from anhydrous tetrahydrochysene furan in the reaction of the compound (2) and compound (3)
Mutter, absolute ether, anhydrous methyl tertbutyl ether, anhydrous methylene chloride, dry toluene, anhydrous acetonitrile, anhydrous tertbutyl ether and nothing
One or several kinds in water 2- methyltetrahydrofurans, wherein preferred solvent are anhydrous tetrahydro furan and dry toluene；Reaction temperature
Spend for -78~110 DEG C, wherein preferable temperature is 20-30 DEG C；
The mol ratio of compound (2) and compound (3) is 1:1~2.0, wherein preferred molar ratio is 1:1.2；Institute in reaction
The alkali used is selected from potassium carbonate, saleratus, sodium carbonate, sodium acid carbonate, lithium carbonate, LiHMDS, NaHMDS, KHMDS, carbonic acid
Caesium, tert-butyl group sodium alkoxide, tert-butyl group potassium alcoholate, triethylamine, diisopropylethylamine, DMA and 1,8- diazabicylo ten
One or several kinds in one carbon -7- alkene (DBU), wherein it is preferred that alkali is NaHMDS, tert-butyl group potassium alcoholate and diisopropylethylamine.
In the reaction of the compound (2) and compound (3)：Catalysts are in catalyst shown in following structure
One or several kinds, wherein preferably catalyst 3；Compound (2) is 200 with the mol ratio of catalyst:1~20：
In the Intra-molecular condensation of the compound (4)：Reaction dissolvent be selected from anhydrous DMA, dry DMF, anhydrous DMSO,
One or several kinds in anhydrous acetonitrile, anhydrous propanone, anhydrous tetrahydro furan and anhydrous 2- methyltetrahydrofurans, wherein it is preferred that molten
Agent is anhydrous tetrahydro furan and anhydrous DMA；Reaction temperature is 20~80 DEG C, and wherein preferable temperature is 65-75 DEG C；Made in reaction
Alkali is selected from triethylamine (NEt3), diisopropylethylamine (DIPEA), DMA, DABCO, sodium acid carbonate, carbonic acid
One or several kinds in hydrogen potassium, sodium carbonate, potassium carbonate, cesium carbonate and the carbon -7- alkene (DBU) of 1,8- diazabicylo 11, its
In preferably alkali be sodium acid carbonate and DBU；Metallic catalyst used in reaction is selected from two (triphenylphosphine) palladium chlorides, four
(triphenylphosphine) palladium, double (bis- Ya Benzyl benzylacetones) palladium, 1,1'- bis- (diphenylphosphoryl group) ferrocene palladium chloride, [RuCl2
(C10H14)]2,RuCl3,RuClCp(PPh3)2,[(3-F-Ph)3P]3RhCl, Rh (COD) BF4With one kind in Rh (COD) Cl or
Person is several, and wherein preferred catalyst is [RuCl2(C10H14)]2；Compound (4) is 100 with the mol ratio of catalyst:1~10；Instead
Part used in answering is selected from triphenylphosphine (PPh3), 1,1'- dinaphthalene -2,2'- diphenyl phosphine (BINAP), MonoPhos,
PipPhos, JosiPhos, rev-JosiPhos, tri-butyl phosphine, tricyclohexyl phosphine and (3-FPh)3It is a kind of or several in P
Kind, wherein it is preferred that part is MonoPhos.
In the oxidation reaction of the compound (5)：Reaction dissolvent be selected from anhydrous methylene chloride, anhydrous propanone, absolute methanol,
One or several kinds in absolute ethyl alcohol, anhydrous isopropyl alcohol, anhydrous tetrahydro furan and anhydrous 2- methyltetrahydrofurans, wherein it is preferred that
Solvent is anhydrous tetrahydro furan and anhydrous methylene chloride；Reaction temperature is -78~20 DEG C, and wherein preferable temperature is -30~-20
℃；Oxidant used in reaction is selected from one kind in dimethyl ethylene oxide, ozone, metachloroperbenzoic acid and hydrogen peroxide
Or it is several, wherein preferred oxidant is dimethyl ethylene oxide.
In the addition reaction of the compound (6) and compound (7)：Reaction dissolvent is selected from anhydrous DMSO, dry DMF, nothing
One or several kinds in water DMA, anhydrous acetonitrile, anhydrous tetrahydro furan and anhydrous 2- methyltetrahydrofurans, wherein preferred solvent
For anhydrous tetrahydro furan and anhydrous DMA；Reaction temperature is -78~20 DEG C, and wherein preferable temperature is -15~-5 DEG C；Institute in reaction
The reducing agent used is selected from sodium borohydride, potassium borohydride, lithium borohydride, lithium aluminium hydride reduction, Sodium triacetoxyborohydride and cyano group boron
One or several kinds in sodium hydride, wherein it is preferred that reducing agent is lithium borohydride and sodium borohydride.
In the reduction reaction of the compound (8)：Reaction dissolvent is selected from absolute methanol, absolute ethyl alcohol, anhydrous isopropyl alcohol, nothing
One or several kinds in water normal propyl alcohol, anhydrous normal butyl alcohol and anhydrous 2- butanol, wherein preferred solvent are absolute ethyl alcohol；Reaction temperature
Spend for 0~40 DEG C, wherein preferable temperature is 20~30 DEG C.
Beneficial effect：Many relative to Ao Gelieting synthesis steps in the prior art, synthesis technique is complicated, synthesis side of the invention
Method is simple and easy to apply, and 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.
Embodiment 1
The preparation of compound (4)
Under nitrogen protection, at ambient temperature toward addition 1.2kg (12mol) compound (3) and 31g in 50L reactors
1.42kg (10mol) compound (2) is slowly added dropwise in 20L anhydrous tetrahydro furans in (0.05mol) catalyst 3.Stir half an hour
After be slowly added to 1.94kg (15mol) diisopropylethylamine, after the completion of TLC monitoring reactions, reaction solution is neutralized to pH with acetic acid and is
6.8, filtering, filter cake is washed with 5L tetrahydrofurans, and merging filtrate and cleaning solution are concentrated to give compound (4) crude product, crude product is through acetic acid
Ethyl ester recrystallizes to obtain compound (4) highly finished product 2.13kg (8.83mol) twice, and yield is 88.3%.HPLC detects purity：
98.2%.
1H NMR(400MHz,DMSO-d6)δ7.25-7.15(m,1H),7.13-7.06(m,2H),7.40-5.27(m,
2H),2.97-2.87(m,1H),2.93(s,1H),2.72-2.62(m,1H).
ESI+[M+H]+=242.
The preparation of compound (5)
Under nitrogen protection, at ambient temperature toward addition 2.0kg (8.3mol) compound (4), catalysis in 50L reactors
Agent [RuCl2(C10H14)]250.8g (0.083mol) and part MonoPhos 59.7g (0.166mol) is in the anhydrous tetrahydrochysene furans of 20L
In muttering.1.39kg (9.13mol) DBU is slowly added dropwise after stirring half an hour, 70 DEG C or so (gentle reflux states), TLC are warming up to
After the completion of monitoring reaction, reaction solution is neutralized to pH with acetic acid for 7.0, and filtering, filter cake wash with 5L tetrahydrofurans, merging filtrate with
Cleaning solution, is concentrated to give compound (5) crude product, and crude product recrystallizes to obtain compound (5) highly finished product through ethyl acetate/normal heptane (1/3)
1.83kg (7.61mol), yield is 91.7%.HPLC detects purity：96.9%.
1H NMR(400MHz,DMSO-d6) δ 7.24-7.18 (m, 1H), 7.16-7.07 (m, 2H), 6.62 (d, J=20Hz,
1H), 6.02 (d, J=20Hz, 1H), 5.58-5.47 (m, 1H), 4.69-4.60 (m, 1H), 3.12-3.01 (m, 1H), 2.88-
2.77(m,1H).
ESI+[M+H]+=242.
The preparation of compound (6)
Under nitrogen protection, at ambient temperature toward addition 1.8kg (7.5mol) compound (5) and pyrrole in 50L reactors
Pyridine 712g (9mol) is in 20L anhydrous methylene chlorides.- 30 DEG C are cooled to after stirring half an hour, isobutylene second is slowly added to
Alkane 650g (9mol), keeping temperature is less than -20 DEG C, after the completion of TLC monitoring reactions, is slowly added to dimethyl sulfide 620g
(10mol), is warmed to room temperature, and is detected after stirring half an hour with starch potassium iodide paper and 10kg water is added after reaction solution non-oxidative,
Point liquid after 30min is stirred, aqueous phase is extracted with 10kg dichloromethane, merges organic phase, be concentrated to give compound (6) crude product, crude product again
Compound (6) highly finished product 1.84kg (7.14mol) is obtained through acetone recrystallization, yield is 95.2%.HPLC detects purity：
99.1%.
1H NMR(400MHz,DMSO-d6)δ7.21-7.18(m,1H),7.14-7.10(m,2H),5.90-5.84(m,
2H),4.48(s,2H),3.07-3.03(m,1H),2.81-2.77(m,1H).
ESI+[M+H]+=258.
The preparation of compound (8)
Under nitrogen protection, at ambient temperature toward add in 50L reactors 1.8kg (7.0mol) compound (6) and
1.57kg (8.4mol) compound (7) is in the anhydrous DMA of 20L.Stirring is cooled to -10 DEG C after one hour, is slowly added to hydroboration
Sodium 114g (3.0mol), keeping temperature is less than -10 DEG C, after the completion of TLC monitoring reactions, is slowly added to ammoniacal liquor 2.0kg and water 10kg,
It is warmed to room temperature, filters to obtain compound (8) crude product, crude product obtains compound (8) highly finished product 2.87kg (6.7mol) through recrystallizing methanol,
Yield is 95.7%.HPLC detects purity：99.2%.
1H NMR(400MHz,DMSO-d6)δ2.50-2.60(m,1H),3.12-3.15(m,1H),3.34-3.38(m,
1H),3.08(s,3H),3.82-4.37(m,6H),5.27-5.44(m,2H),7.06-7.22(m,2H),7.18-7.30(m,
1H),7.86(s,1H).
ESI+[M+H]+=429.
Ao Gelieting (1) preparation
At ambient temperature toward addition 2.8kg (6.5mol) compound (8) and 4.1kg (65mol) zinc powder in 50L reactors
In 20L absolute ethyl alcohols.It is stirred vigorously down and is slowly added to acetic acid 7.8kg (130mol), keep room temperature, TLC monitoring reactions is completed
Afterwards, filter celite, solution is neutralized to pH=10 with sodium hydrate aqueous solution (2N), then is extracted with dichloromethane (2*10L), dense
Contracting get Ao Gelieting (1) 1.94kg (6.5mol), yield is 100%.HPLC detects purity：99.2%.
1H NMR(400MHz,DMSO-d6) δ 1.72 (q, 1H, J=12Hz), 2.55-2.60 (m, 1H), 3.10-3.16 (m,
1H), 3.34-3.37 (m, 1H), 3.46 (t, 1H, J=12Hz), 3.87-3.93 (m, 4H), 4.28-4.32 (m, 1H), 4.51
(d, 1H, J=12Hz), 7.12-7.21 (m, 2H), 7.25-7.28 (m, 1H), 7.86 (s, 1H)
ESI+[M+H]+=399.
Embodiment 2
The preparation of compound (4)
According to the method for embodiment 1, reaction dissolvent replaces with dry toluene；Reaction temperature is -78 DEG C, compound (2) and change
The mol ratio of compound (3) is 1:1；Alkali used in reaction replaces with NaHMDS.Catalysts are catalyst 3；Compound
(2) it is 200 with the mol ratio of catalyst:1, compound (4) highly finished product are finally obtained, yield is 87.4%.HPLC detects purity：
97.8%.
The preparation of compound (5)
According to the method for embodiment 1, solvent replaces with anhydrous DMA, and reaction temperature is 20~80 DEG C, and wherein preferable temperature is
65-75 DEG C, alkali replaces with sodium acid carbonate, and catalyst replaces with two (triphenylphosphine) palladium chlorides, compound (4) and catalyst
Mol ratio is 100:1；Part replaces with PipPhos, finally obtains compound (5) highly finished product, yield is 92.6%.HPLC detections are pure
Degree：97.2%.
The preparation of compound (6)
According to the method for embodiment 1, reaction dissolvent replaces with anhydrous propanone；Reaction temperature is -78 DEG C；Used in reaction
Oxidant replaces with metachloroperbenzoic acid, finally obtains compound (6) highly finished product, yield is 95.4%.HPLC detects purity：
99.3%.
The preparation of compound (8)
According to the method for embodiment 1, reaction dissolvent replaces with anhydrous DMSO；Reaction temperature is -78 DEG C；Used in reaction
Reducing agent replaces with potassium borohydride, last compound (8) highly finished product, and yield is 95.5%.HPLC detects purity：99.4%.
Ao Gelieting (1) preparation
According to the method for embodiment 1, reaction dissolvent replaces with absolute methanol；Reaction temperature is 0 DEG C, last get Ao Gelieting
(1), yield is 100%.HPLC detects purity：99.4%.
Embodiment 3
The preparation of compound (4)
According to the method for embodiment 1, reaction dissolvent replaces with anhydrous methylene chloride；Reaction temperature is 110 DEG C, compound (2)
Mol ratio with compound (3) is 1:2.0；Alkali used in reaction replaces with tert-butyl group potassium alcoholate.Catalysts are catalysis
Agent 5；Compound (2) is 200 with the mol ratio of catalyst:1~20, compound (4) highly finished product are finally obtained, yield is 89.3%.
HPLC detects purity：98.8%.
The preparation of compound (5)
According to the method for embodiment 1, solvent replaces with dry DMF, and reaction temperature is 80 DEG C, and alkali replaces with triethylamine, catalysis
Agent is replaced with [(3-F-Ph)3P]3RhCl, compound (4) is 100 with the mol ratio of catalyst:10；Part replaces with BINAP, most
Compound (5) highly finished product are obtained afterwards, and yield is 93.6%.HPLC detects purity：97.9%.
The preparation of compound (6)
According to the method for embodiment 1, reaction dissolvent replaces with anhydrous propanone；Reaction temperature is 20 DEG C；Used in reaction
Oxidant replaces with ozone, finally obtains compound (6) highly finished product, yield is 95.6%.HPLC detects purity：99.8%.
The preparation of compound (8)
According to the method for embodiment 1, reaction dissolvent replaces with anhydrous acetonitrile；Reaction temperature is 20 DEG C；Used in reaction
Reducing agent replaces with lithium aluminium hydride reduction, last compound (8) highly finished product, and yield is 94.8%.HPLC detects purity：99.3%.
Ao Gelieting (1) preparation
According to the method for embodiment 1, reaction dissolvent replaces with anhydrous isopropyl alcohol；Reaction temperature is 40 DEG C, last get Ao Gelie
Spit of fland (1), yield is 100%.HPLC detects purity：99.5%.
Embodiment 4
The preparation of compound (4)
According to the method for embodiment 1, reaction dissolvent replaces with dry toluene；Reaction temperature is 20 DEG C；Compound (2) and chemical combination
The mol ratio of thing (3) is 1:1.2；Alkali used in reaction replaces with tert-butyl group sodium alkoxide, and catalysts are catalyst 3；Change
Compound (2) is 200 with the mol ratio of catalyst:5, compound (4) highly finished product are finally obtained, yield is 89.7%.HPLC detections are pure
Degree：98.5%.
The preparation of compound (5)
According to the method for embodiment 1, solvent is replaced with anhydrous 2- methyltetrahydrofurans, and reaction temperature is 65 DEG C, and alkali is replaced
For DMA, catalyst replaces with two (triphenylphosphine) palladium chlorides, and compound (4) and the mol ratio of catalyst are
100:3；Part replaces with JosiPhos, finally obtains compound (5) highly finished product, yield is 93.3%.HPLC detects purity：
97.2%.
The preparation of compound (6)
According to the method for embodiment 1, reaction dissolvent replaces with absolute methanol；Reaction temperature is -30 DEG C；Used in reaction
Oxidant replaces with hydrogen peroxide, finally obtains compound (6) highly finished product, yield is 96.8%.HPLC detects purity：99.3%.
The preparation of compound (8)
According to the method for embodiment 1, reaction dissolvent replaces with dry DMF；Reaction temperature is -15 DEG C；Used in reaction
Reducing agent replaces with lithium borohydride, last compound (8) highly finished product, and yield is 94.9%.HPLC detects purity：99.8%.
Ao Gelieting (1) preparation
According to the method for embodiment 1, reaction dissolvent replaces with anhydrous normal propyl alcohol；Reaction temperature is 20 DEG C, last get Ao Gelie
Spit of fland (1), yield is 100%.HPLC detects purity：99.1%.
Embodiment 5
The preparation of compound (4)
According to the method for embodiment 1, reaction dissolvent replaces with anhydrous methylene chloride；Reaction temperature is 30 DEG C；Compound (2) and
The mol ratio of compound (3) is 1:1.8；Alkali used in reaction replaces with tert-butyl group sodium alkoxide.Catalysts are catalyst
3；Compound (2) is 200 with the mol ratio of catalyst:15, compound (4) highly finished product are finally obtained, yield is 89.5%.HPLC is examined
Survey purity：99.1%.
The preparation of compound (5)
According to the method for embodiment 1, solvent replaces with anhydrous DMSO, and reaction temperature is 75 DEG C, and alkali replaces with sodium acid carbonate, urges
Agent replaces with double (bis- Ya Benzyl benzylacetones) palladium, compound (5) highly finished product are finally obtained, yield is 93.2%.HPLC detections are pure
Degree：95.9%.
The preparation of compound (6)
According to the method for embodiment 1, reaction dissolvent replaces with absolute ethyl alcohol；Reaction temperature is -20 DEG C；Used in reaction
Oxidant replaces with metachloroperbenzoic acid, finally obtains compound (6) highly finished product, yield is 94.9%.HPLC detects purity：
99.5%.
The preparation of compound (8)
According to the method for embodiment 1, reaction dissolvent replaces with anhydrous DMA；Reaction temperature is -5 DEG C；Going back used in reaction
Former agent replaces with Sodium triacetoxyborohydride, last compound (8) highly finished product, and yield is 94.5%.HPLC detects purity：
98.7%.
Ao Gelieting (1) preparation
According to the method for embodiment 1, reaction dissolvent replaces with anhydrous normal butyl alcohol；Reaction temperature is 30 DEG C, last get Ao Gelie
Spit of fland (1), yield is 100%.HPLC detects purity：99.9%.
Embodiments of the invention are the foregoing is only, are not intended to limit the scope of the invention, it is every to utilize this hair
Equivalent structure or equivalent flow conversion that bright description is made, or directly or indirectly it is used in other related technology necks
Domain, is included within the scope of the present invention.
Claims (8)
1. a kind of formula (1) compound Ao Gelieting synthetic method, it is characterised in that by formula (2) and formula (3) compound as
Beginning raw material, through following series reaction, is finally made formula (1) compound, i.e., described Ao Gelieting：
2. Ao Gelieting according to claim 1 synthetic method, it is characterised in that the compound (2) and compound
(3) chipal compounds (4) are made through asymmetric Henry reaction；Compound (5) is made through Intra-molecular condensation in compound (4)；
Compound (6) is made in the oxidized reaction of compound (5)；Compound (8) is made through addition reaction in compound (6) and compound (7)；
Compound (1), i.e., described Ao Gelieting is made through reduction reaction in final compound (8).
3. Ao Gelieting according to claim 2 synthetic method, it is characterised in that the compound (2) and compound
(3) in reaction：Reaction dissolvent be selected from anhydrous tetrahydro furan, absolute ether, anhydrous methyl tertbutyl ether, anhydrous methylene chloride,
One or several kinds in dry toluene, anhydrous acetonitrile, anhydrous tertbutyl ether and anhydrous 2- methyltetrahydrofurans；Reaction temperature
For -78~110 DEG C；
The mol ratio of the compound (2) and compound (3) is 1:1~2.0；Alkali used in reaction is selected from potassium carbonate, carbon
Potassium hydrogen phthalate, sodium carbonate, sodium acid carbonate, lithium carbonate, LiHMDS, NaHMDS, KHMDS, cesium carbonate, tert-butyl group sodium alkoxide, tert-butyl group alcohol
One kind in potassium, triethylamine, diisopropylethylamine, DMA and the carbon -7- alkene (DBU) of 1,8- diazabicylo 11
Or it is several.
4. Ao Gelieting according to claim 2 synthetic method, it is characterised in that the compound (2) and compound
(3) in reaction：One or several kinds of the catalysts in catalyst shown in following structure, compound (2) and catalysis
The mol ratio of agent is 200:1~20：
5. Ao Gelieting according to claim 2 synthetic method, it is characterised in that the intramolecular of the compound (4)
In ring closure reaction：Reaction dissolvent is selected from anhydrous DMA, dry DMF, anhydrous DMSO, anhydrous acetonitrile, anhydrous propanone, anhydrous tetrahydrochysene furan
Mutter and the one or several kinds in anhydrous 2- methyltetrahydrofurans；Reaction temperature is 20~80 DEG C；Alkali choosing used in reaction
From triethylamine (NEt3), diisopropylethylamine (DIPEA), DMA, DABCO, sodium acid carbonate, saleratus, carbon
One or several kinds in sour sodium, potassium carbonate, cesium carbonate and the carbon -7- alkene (DBU) of 1,8- diazabicylo 11；
Metallic catalyst used in reaction is selected from two (triphenylphosphine) palladium chlorides, tetrakis triphenylphosphine palladium, double (bis- Ya Benzyl
Benzylacetone) palladium, 1,1'- bis- (diphenylphosphoryl group) ferrocene palladium chloride, [RuCl2(C10H14)]2,RuCl3,RuClCp
(PPh3)2,[(3-F-Ph)3P]3RhCl, Rh (COD) BF4With the one or several kinds in Rh (COD) Cl；Compound (4) and catalysis
The mol ratio of agent is 100:1~10；
Part used in reaction is selected from triphenylphosphine, 1,1'- dinaphthalene -2,2'- diphenyl phosphine, MonoPhos, PipPhos,
JosiPhos, rev-JosiPhos, tri-butyl phosphine, tricyclohexyl phosphine and (3-F-Ph)3One or several kinds in P.
6. Ao Gelieting according to claim 2 synthetic method, it is characterised in that the oxidation of the compound (5) is anti-
Ying Zhong：Reaction dissolvent is selected from anhydrous methylene chloride, anhydrous propanone, absolute methanol, absolute ethyl alcohol, anhydrous isopropyl alcohol, anhydrous tetrahydrochysene
One or several kinds in furans and anhydrous 2- methyltetrahydrofurans；Reaction temperature is -78~20 DEG C；Oxygen used in reaction
Agent is selected from the one or several kinds in dimethyl ethylene oxide, ozone, metachloroperbenzoic acid and hydrogen peroxide.
7. Ao Gelieting according to claim 2 synthetic method, it is characterised in that the compound (6) and compound
(7) in addition reaction：Reaction dissolvent be selected from anhydrous DMSO, dry DMF, anhydrous DMA, anhydrous acetonitrile, anhydrous tetrahydro furan and
One or several kinds in anhydrous 2- methyltetrahydrofurans；Reaction temperature is -78~20 DEG C；Reducing agent choosing used in reaction
From sodium borohydride, potassium borohydride, lithium borohydride, lithium aluminium hydride reduction, one kind in Sodium triacetoxyborohydride and sodium cyanoborohydride
Or it is several.
8. Ao Gelieting according to claim 2 synthetic method, it is characterised in that the reduction of the compound (8) is anti-
Ying Zhong：Reaction dissolvent is selected from absolute methanol, absolute ethyl alcohol, anhydrous isopropyl alcohol, anhydrous normal propyl alcohol, anhydrous normal butyl alcohol and anhydrous 2- fourths
One or several kinds in alcohol；Reaction temperature is 0~40 DEG C.
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| CN107235983A (en) * | 2017-07-21 | 2017-10-10 | 苏州信恩医药科技有限公司 | A kind of Ao Gelieting synthetic method |
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| JO2870B1 (en) * | 2008-11-13 | 2015-03-15 | ميرك شارب اند دوهم كورب | Aminotetrahydropyrans as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes |
| US8895603B2 (en) * | 2011-06-29 | 2014-11-25 | Merck Sharp & Dohme Corp. | Crystalline forms of a dipeptidyl peptidase-IV inhibitor |
| WO2015139859A1 (en) * | 2014-03-20 | 2015-09-24 | F.I.S. - Fabbrica Italiana Sintetici S.P.A. | Process for the preparation of key intermediates of omarigliptin |
| TW201623286A (en) * | 2014-04-04 | 2016-07-01 | 賽諾菲公司 | Isoindolinone compounds as GPR119 modulators for the treatment of diabetes, obesity, dyslipidemia and related disorders |
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