CN107337664A - One koji Ge Lieting preparation method - Google Patents
One koji Ge Lieting preparation method Download PDFInfo
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- CN107337664A CN107337664A CN201610284601.9A CN201610284601A CN107337664A CN 107337664 A CN107337664 A CN 107337664A CN 201610284601 A CN201610284601 A CN 201610284601A CN 107337664 A CN107337664 A CN 107337664A
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- 0 CC[C@](C)[C@@](CC[C@](CC)C=*)F Chemical compound CC[C@](C)[C@@](CC[C@](CC)C=*)F 0.000 description 2
- GFJOBYHVMHPWGJ-VHSXEESVSA-N CC[C@H](C)[C@@](C)(C(C)=C)C#N Chemical compound CC[C@H](C)[C@@](C)(C(C)=C)C#N GFJOBYHVMHPWGJ-VHSXEESVSA-N 0.000 description 1
- LPDSKKSBKQPKDV-RYUDHWBXSA-N C[C@@H](CCC[F]C)C[C@H](CC#N)C=C Chemical compound C[C@@H](CCC[F]C)C[C@H](CC#N)C=C LPDSKKSBKQPKDV-RYUDHWBXSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention provides the preparation method of a koji Ge Lieting, the fluorobenzonitrile of 2 bromomethyl 4（Ⅰ）With the chlorouracil of 3 methyl 6（Ⅱ）In the basic conditions, reacted in alcohols solvent, reaction temperature is 80 ~ 120 DEG C, and after reaction completely, cooling crystallization obtains compound（Ⅲ）, compound（Ⅲ）With (R) 3 amino piperidine dihydrochloride（Ⅳ）Atmospheric pressure reflux reacts to obtain bent Ge Lieting in inorganic base, water absorbing agent and absolute ethyl alcohol（Ⅴ）.The present invention avoids the big solvent DMSO of higher boiling, polarity use in N alkylated reactions, and after reaction terminates, product directly separates out from solvent, and technical process is simply easily operated, and product yield and purity are very high（95%）.After adding water absorbing agent in substitution reaction, atmospheric pressure reflux can obtain bent Ge Lieting（Ⅴ）, the use of closed reactor is avoided, and the generation of byproduct of reaction is greatly reduced, technological operation is simple and easy, beneficial to industrialized production.
Description
Technical field
The invention belongs to medicinal chemistry art, be related to a koji Ge Lieting, specifically a koji Ge Lieting
Preparation method.
Background technology
Amber love song Ge Lieting be by Japanese Wu Tian companies research and develop new type II diabetes medicine, 2015 3
The moon lists in Japan.The medicine is weekly DPP IV (DPP-4) inhibitor, passes through selection
Property, continuation suppress DPP-4, control blood sugar level, its mechanism of action is unique, have do not produce hypoglycemia,
Do not cause the unique advantages such as increased weight, and Small side effects, cause the incidence of gastrointestinal side effect also very
It is low.
Bent Ge Lieting's is chemical entitled：2- ({ 6- [(3R) -3- amino piperidine -1- bases] -3- methyl -2,4- dioxos -3,4-
Dihydro -2H- pyrimidine -1- bases } methyl) -4- fluorobenzonitriles, its structural formula is：
Current bent Ge Lieting synthetic method mainly has：
The synthetic method of a koji Ge Lieting is disclosed in Chinese patent Authorization Notice No. CN101573351B,
The synthesis step is included using compound 2- bromomethyl -4- fluorobenzonitriles as raw material, with 3- methyl -6- chlorouracils in carbon
Heating response obtains compound (III) in sour potassium, DMSO, compound (III) and (R) -3- in closed reactor
Amino-piperadine dihydrochloride (IV) heating response in sodium acid carbonate, absolute ethyl alcohol obtains bent Ge Lieting.
The above method uses the big solvent DMSO of higher boiling, polarity in step 1, and solvent can not reclaim profit
It is low (60%) with, product yield, it is unfavorable for industrialized production；Step 2 is carried out in closed reactor, behaviour
Make it is cumbersome and generation accessory substance it is more, product purity is low.
The content of the invention
For above-mentioned technical problem of the prior art, the invention provides the preparation method of a koji Ge Lieting,
Described this koji Ge Lieting preparation method will solve the method technique of the prior art for preparing bent Ge Lieting
The complicated, technical problem that yield is low, accessory substance is more, product purity is low.
The invention provides the preparation method of a koji Ge Lieting, comprise the following steps：
1) 2- bromomethyls -4- fluorobenzonitriles (I) and 3- methyl -6- chlorouracils (II) in the basic conditions,
Reacted in alcohols solvent, described alkali is selected from triethylamine, DIPEA, 1,8- diazas
Any one in the carbon -7- alkene of two ring 11, described alcohols solvent be selected from normal propyl alcohol, isopropanol,
Any one in n-butanol, isobutanol, n-amyl alcohol or isoamyl alcohol, reaction temperature are 80~120 DEG C,
After reaction completely, cooling crystallization obtains compound (III),
2) compound (III) and (R) -3- amino-piperadines dihydrochloride (IV) are in inorganic base, water absorbing agent and organic
Atmospheric pressure reflux reacts to obtain bent Ge Lieting (V) in solvent, described water absorbing agent be anhydrous sodium sulfate,
Any one in anhydrous magnesium sulfate or molecular sieve, described organic solvent are absolute ethyl alcohol, positive third
Any one in alcohol or isopropanol,
Further, the alcohols solvent described in step 1) is n-butanol, isobutanol, n-amyl alcohol or isoamyl alcohol.
Further, the alcohols solvent described in step 1) is n-butanol, isobutanol.
Further, in step 1), 2- bromomethyl -4- fluorobenzonitriles (I), 3- methyl -6- chlorouracils (II),
The mol ratio of alkali and alcohols solvent is (1.05~1.5):1:(1.2~2.0):(10.0~60.0).
Further, in step 2), compound (III), (R) -3- amino-piperadines dihydrochloride (IV), nothing
The mol ratio of machine alkali, water absorbing agent and organic solvent is:1:(1.2~2.0):(3.0~5.0):(0.2~1.0):
(10.0~60.0).
Further, the inorganic base described in step 2) is sodium carbonate, potassium carbonate, sodium acid carbonate or carbon
Any one in potassium hydrogen phthalate.
The present invention for raw material, is sent out with 2- bromomethyl -4- fluorobenzonitriles (I) with 3- methyl -6- chlorouracils (II)
Raw N- alkylated reaction generation compounds (III), compound (III) and (R) -3- amino-piperadines dihydrochloride (IV)
Generation substitution reaction generates bent Ge Lieting (V).
The present invention avoids the big solvent DMSO of higher boiling, polarity use, reaction in N- alkylated reactions
After end, product directly separates out from solvent, and technical process is simply easily operated, and product yield and purity are very
High (95%).After adding water absorbing agent in substitution reaction, atmospheric pressure reflux can obtain bent Ge Lieting (V), avoid
The use of closed reactor, and greatly reduce the generation of byproduct of reaction, technological operation is simple and easy, profit
In industrialized production.
The present invention compares with prior art, and its technological progress is significant.The preparation method method raw material of the present invention
It is easy to get, operates that easy, high income, cost are low, purity is high, is adapted to industrialized production.
Embodiment
The embodiment of form by the following examples, the above of the present invention is remake further in detail
Describe in detail bright, but this should not be interpreted as to the scope of the present invention and be only limitted to following embodiment, it is all based on the present invention
The technology that the above is realized belongs to the scope of the present invention.
Embodiment 1
42.81g 2- bromomethyl -4- fluorobenzonitriles (I) are added into reaction bulb, 32.43g 3- methyl -6- chloridurias are phonetic
Pyridine (II), 31.02g DIPEAs, 187mL isopropanols, 90 DEG C of back flow reaction 3h.Stop
After reaction, Temperature fall is stirred, product separates out, and is directly filtrated to get crude product, then add drinking water 55mL to stir
Mashing is mixed, filters, 50 DEG C of dry 10h, obtains compound (III) 55.65g, yield 94.96%, purity
97.95%.
1H-NMR (400, DMSO-d6):δ=3.177 (s, 3H), δ=5.370 (s, 2H), δ=6.208 (s, 1H), δ
=7.440~7.396 (m, 2H), δ=8.024~7.989 (dd, 1H).
Embodiment 2
428.06g 2- bromomethyl -4- fluorobenzonitriles (I) are added into reaction bulb, 324.33g 3- methyl -6- chloridurias are phonetic
Pyridine (II), 310.20g DIPEAs, 1.87L n-butanols, 107 DEG C of reaction 2h.Stop reaction
Afterwards, Temperature fall is stirred, product separates out, and is directly filtrated to get crude product, then adds drinking water 550mL stirrings to beat
Slurry, filtering, 50 DEG C of dry 10h, obtains compound (III) 575.90g, yield 96.6%, purity 97.23%.
Embodiment 3
42.81g 2- bromomethyl -4- fluorobenzonitriles (I), 32.43g 3- methyl -6- chlorouracils are added into reaction bulb
(II), 24.40g triethylamines, 187mL isoamyl alcohol, 110 DEG C of reaction 2h.After stopping reaction, nature is stirred
Cooling, product separate out, and are directly filtrated to get crude product, then add drinking water 55mL stirring to pulps, filtering, and 50
DEG C dry 10h, obtain compound (III) 55.63g, yield 94.92%, purity 97.9%.
Embodiment 4
The addition 50.00g compounds (III) into reaction bulb, 35.31g (R) -3- amino-piperadines dihydrochloride (IV),
50.00g sodium acid carbonates, 10.00g anhydrous magnesium sulfates, 750mL absolute ethyl alcohols, atmospheric pressure reflux reaction 6h.Instead
Reaction solution heat filtering, filtrate stirring Temperature fall, product are separated out after should terminating, filtering, 50 DEG C of dry 10h,
Obtain bent Ge Lieting (V) 52.74g, yield 86.9%, purity 97.59%.
Embodiment 5
117.22g compounds (III), 83.08g (R) -3- amino-piperadine dihydrochlorides are added into reaction bulb
(IV), 117.62g sodium acid carbonates, 23.44g 3A molecular sieves, 1.56L absolute ethyl alcohols, atmospheric pressure reflux are anti-
Answer 4h.Reaction separates out reaction solution heat filtering, filtrate stirring Temperature fall, product after terminating, filtering, and 50
DEG C dry 10h, obtain bent Ge Lieting (V) 124.56g, yield 87.23%, purity 98.28%.
1H-NMR (400, DMSO-d6):δ=1.510~1.432 (m, 2H), δ=1.760 (m, 1H), δ=1.892
~1.873 (m, 1H), δ=2.701 (brs, 2H), δ=2.882 (m, 1H), δ=3.079 (s, 3H), δ=3.128 (brs,
1H), δ=3.193 (brd, 1H), δ=5.164 (dd, 2H), δ=5.382 (s, 1H), δ=7.162 (dd, 1H), δ
=7.355~7.307 (m, 1H), δ=7.500 (brs, 2H), δ=7.936 (dd, 1H).
Claims (6)
1. the preparation method of a koji Ge Lieting, it is characterised in that comprise the following steps：
1) 2- bromomethyls -4- fluorobenzonitriles (I) and 3- methyl -6- chlorouracils (II) in the basic conditions,
Reacted in alcohols solvent, described alkali is selected from triethylamine, DIPEA, 1,8- diazas
Any one in the carbon -7- alkene of two ring 11, described alcohols solvent be selected from normal propyl alcohol, isopropanol,
Any one in n-butanol, isobutanol, n-amyl alcohol or isoamyl alcohol, reaction temperature are 80~120 DEG C,
After reaction completely, cooling crystallization obtains compound (III),
2) compound (III) and (R) -3- amino-piperadines dihydrochloride (IV) are in inorganic base, water absorbing agent and organic
Atmospheric pressure reflux reacts to obtain bent Ge Lieting (V) in solvent, described water absorbing agent be anhydrous sodium sulfate,
Any one in anhydrous magnesium sulfate or molecular sieve, described organic solvent are absolute ethyl alcohol, positive third
Any one in alcohol or isopropanol,
2. koji Ge Lieting according to claim 1 preparation method, it is characterised in that：Step 1)
Described in alcohols solvent be n-butanol, isobutanol, n-amyl alcohol or isoamyl alcohol.
3. koji Ge Lieting according to claim 2 preparation method, it is characterised in that：Step 1)
Described in alcohols solvent for n-butanol, isobutanol.
4. koji Ge Lieting according to claim 1 preparation method, it is characterised in that：Step 1)
In, 2- bromomethyl -4- fluorobenzonitriles (I), 3- methyl -6- chlorouracils (II), alkali and alcohols solvent
Mol ratio be (1.05~1.5):1:(1.2~2.0):(10.0~60.0).
5. koji Ge Lieting according to claim 2 preparation method, it is characterised in that：Step 2)
In, compound (III), (R) -3- amino-piperadines dihydrochloride (IV), inorganic base, water absorbing agent and
Organic solvent mol ratio is:1:(1.2~2.0):(3.0~5.0):(0.2~1.0):(10.0~60.0).
6. koji Ge Lieting according to claim 1 preparation method, it is characterised in that：Step 2)
Described in inorganic base be sodium carbonate, potassium carbonate, sodium acid carbonate or saleratus in it is any
It is a kind of.
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| CN201610284601.9A CN107337664A (en) | 2016-05-03 | 2016-05-03 | One koji Ge Lieting preparation method |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109503551A (en) * | 2018-11-21 | 2019-03-22 | 安阳师范学院 | The preparation method of one koji Ge Lieting |
| CN109705089A (en) * | 2019-02-27 | 2019-05-03 | 浙江华贝药业有限责任公司 | The purification process of compound |
| CN109734673A (en) * | 2019-02-27 | 2019-05-10 | 浙江华贝药业有限责任公司 | A kind of purification process of compound |
| CN111349075A (en) * | 2018-12-21 | 2020-06-30 | 浙江万晟药业有限公司 | Preparation method of trelagliptin succinate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101360723A (en) * | 2005-09-16 | 2009-02-04 | 武田药品工业株式会社 | Process for the preparation of pyrimidinedione derivatives |
-
2016
- 2016-05-03 CN CN201610284601.9A patent/CN107337664A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101360723A (en) * | 2005-09-16 | 2009-02-04 | 武田药品工业株式会社 | Process for the preparation of pyrimidinedione derivatives |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109503551A (en) * | 2018-11-21 | 2019-03-22 | 安阳师范学院 | The preparation method of one koji Ge Lieting |
| CN111349075A (en) * | 2018-12-21 | 2020-06-30 | 浙江万晟药业有限公司 | Preparation method of trelagliptin succinate |
| CN109705089A (en) * | 2019-02-27 | 2019-05-03 | 浙江华贝药业有限责任公司 | The purification process of compound |
| CN109734673A (en) * | 2019-02-27 | 2019-05-10 | 浙江华贝药业有限责任公司 | A kind of purification process of compound |
| CN109705089B (en) * | 2019-02-27 | 2020-04-10 | 浙江华贝药业有限责任公司 | Method for purifying compound |
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