CN107602466A - A kind of preparation method of Nuo get Si Ta medicines - Google Patents
A kind of preparation method of Nuo get Si Ta medicines Download PDFInfo
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- CN107602466A CN107602466A CN201711157978.9A CN201711157978A CN107602466A CN 107602466 A CN107602466 A CN 107602466A CN 201711157978 A CN201711157978 A CN 201711157978A CN 107602466 A CN107602466 A CN 107602466A
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- isoquinolin
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Abstract
The invention discloses a kind of preparation method of Nuo get Si Ta medicines, the Nuo get Si Ta chemical names are N [(isoquinolin of 4 hydroxyl, 1 methyl, 7 phenoxy group 3) carbonyl] glycine；Preparation process of the present invention is succinct, and raw material is easy to get, economic and environment-friendly, is advantageously implemented industrialization, and the economic technology of Nuo get Si Ta bulk drugs can be promoted to develop, and reduces manufacturing cost, and yield is high, and environmental pollution is small, suitable for producing in enormous quantities.
Description
Art
The present invention relates to pharmaceutical technology field, more particularly to a kind of preparation method of Nuo get Si Ta medicines.
Background technology
Nuo get Si Ta (Roxadustat) is researched and developed by Fibrogen Inc of the U.S. (FibroGen), Astellas and A Si
A kind of micromolecular inhibitor of hypoxia inducible factor (HIF) prolyl hydroxylase that Li Kang obtains the arthorization, code name FG-
4592.Brand-new oral drugs are initiated as one kind, FG-4592 is currently in the III phase clinical trial stages, slow for treating
The property nephrosis anemia related to ESRD.Because the medicine does not have the Chinese translation of standard also, therefore the applicant is herein
It is " Nuo get Si Ta " by its transliteration.
The content of the invention
The invention provides Nuo get Si Ta preparation method；Preparation process of the present invention is succinct, and raw material is easy to get, economic ring
To protect, be advantageously implemented industrialization, the economic technology of Nuo get Si Ta bulk drugs can be promoted to develop, reduce manufacturing cost, yield is high,
Environmental pollution is small, suitable for producing in enormous quantities.
To achieve the above object, technical scheme is implemented as follows：
A kind of preparation method of Nuo get Si Ta medicines, the Nuo get Si Ta chemical names are N- [(4- hydroxyl -1- methyl -7- benzene oxygen
Base -3- isoquinolin) carbonyl] glycine, the preparation method that the Nuo get Si Ta is made comprises the following steps that：
（1）In 5- nitro-phenyls ethamine 1. middle addition monoxone and Sodamide, under catalyst and certain reaction temperature, occur
Cyclization, generation 7- nitro -4- isoquinolines are 2.；
（2）In step（1）7- nitro -4- isoquinolines 2. in sequentially add alkali accelerator and concentrated hydrochloric acid, generate 7- nitro -4- hydroxyls
The chloro- isoquinolin of base -3- is 3.；
（3）In step（2）The chloro- isoquinolin of 7- nitro -4- hydroxyls -3- of generation 3. middle addition chloromethanes, reacts, and generates 7-
Nitro -4- hydroxy-3-methyls-isoquinolin is 4.；
（4）In step（3）7- nitros -4- hydroxy-3-methyls-isoquinolin of generation is 4. middle to add potassium permanganate and the concentrated sulfuric acid, hair
Raw oxidation reaction, generates (7- nitro -4- hydroxyl -3- isoquinolin）Formic acid is 5.；
（5）In step（4）Generation（7- nitro -4- hydroxyl -3- isoquinolin）Formic acid 5. 6., in acid binding agent make by middle addition glycine
Under, acylation reaction occurs, glycine is 7. by generation N- [(7- nitro -4- hydroxyl -3- isoquinolin) carbonyl]；
（6）In step（5）N- [(7- nitro -4- hydroxyl -3- isoquinolin) carbonyl] glycine of generation is 7. middle to add bromine and nothing
Machine aqueous slkali, substitution reaction occurs, glycine is 8. by generation N- [(the bromo- 3- isoquinolin of 7- nitro -4- hydroxyls -1-) carbonyl]；
（7）In step（6）N- [(the bromo- 3- isoquinolin of 7- nitro -4- hydroxyls -1-) carbonyl] glycine of generation is 8. middle to add dense salt
Acid and chloromethanes, react, and glycine is 9. by generation N- [(7- amino-4-hydroxy -1- methyl -3- isoquinolin) carbonyl]；
（8）In step（7）N- [(7- nitro -4- hydroxyl -1- methyl -3- isoquinolin) carbonyl] glycine of generation 9. middle addition carbon
Acid sodium solution, and ammonia is passed through, reduction reaction, generation N- [(7- amino-4-hydroxy -1- methyl -3- isoquinolin) carbonyl] occurs
Glycine is 10.；
（9）In step（8）N- [(7- amino-4-hydroxy -1- methyl -3- isoquinolin) carbonyl] glycine of generation is 10. middle to add Asia
The aqueous solution of sodium sulphate, certain temperature is heated to, generates N- [(4,7- dihydroxy -1- methyl -3- isoquinolin) carbonyl] glycine
⑪；
（10）In step（9）Chlorine is added in N- [(4,7- dihydroxy -1- methyl -3- isoquinolin) carbonyl] glycine of generation
Benzene, and the mixed solution of potassium carbonate and KI is added, it is heated at 90-100 DEG C, condensation reaction occurs, generates N- [(4- hydroxyls
Base -7- methoxyl group -1- methyl -3- isoquinolin) carbonyl] glycine, as Nuo get Si Ta.
The step（1）Middle certain temperature is 120-150 DEG C.
The step（1）The catalyst of reaction is nickel.
The inorganic alkali solution is the mixture of one or both of sodium hydroxide, sodium carbonate, potassium carbonate.
The step（9）Middle certain temperature is 180-220 DEG C.
The step（10）Middle certain temperature is 90-100 DEG C.
Its chemical equation is：
The present invention compared with prior art, has the advantages that：
Preparation process of the present invention is succinct, and raw material is easy to get, economic and environment-friendly, is advantageously implemented industrialization, can promote Nuo get Si Ta
The economic technology development of bulk drug, reduces manufacturing cost, and yield is high, and environmental pollution is small, suitable for producing in enormous quantities.
Embodiment
The present invention is further elaborated with reference to specific embodiment.
Embodiment 1
Nuo get Si Ta preparation method, is comprised the following steps that：
（1）In 64.2g5- nitro-phenyls ethamine 1. middle addition monoxone 46g and Sodamide 25.3g, in catalyst nickel, it is heated to
120 DEG C, cyclization occurs, generates 7- nitro -4- isoquinolines 2. 66.5g；
（2）In step（1）2. 7- nitro -4- isoquinolines sequentially add alkali accelerator and concentrated hydrochloric acid 500ml in 62.3g, generate
The chloro- isoquinolin of 7- nitro -4- hydroxyls -3- 3. 59.3g；
（3）In step（2）3. the chloro- isoquinolin of 7- nitro -4- hydroxyls -3- of generation adds chloromethanes 26g in 53.1g, occur anti-
Should, generate 7- nitros -4- hydroxy-3-methyls-isoquinolin 4. 51.1g；
（4）In step（3）4. 7- nitros -4- hydroxy-3-methyls-isoquinolin of generation adds potassium permanganate and dense sulphur in 41.2g
Acid, oxidation reaction occurs, generate (7- nitro -4- hydroxyl -3- isoquinolin）Formic acid 5. 38.2g；
（5）In step（4）Generation（7- nitro -4- hydroxyl -3- isoquinolin）5. formic acid adds glycine 6. 16.2g in 35.2g,
Under acid binding agent effect, acylation reaction occurs, glycine is 7. by generation N- [(7- nitro -4- hydroxyl -3- isoquinolin) carbonyl]
31.2g；
（6）In step（5）7. N- [(7- nitro -4- hydroxyl -3- isoquinolin) carbonyl] glycine of generation adds bromine in 30.6g
46g and inorganic alkali solution sodium carbonate liquor 500ml, substitution reaction occurs, generate N- [(the bromo- 3- isoquinolines of 7- nitro -4- hydroxyls -1-
Quinoline) carbonyl] glycine 8. 29.8g；
（7）In step（6）8. N- [(the bromo- 3- isoquinolin of 7- nitro -4- hydroxyls -1-) carbonyl] glycine of generation is added in 28g
Concentrated hydrochloric acid 180ml and chloromethanes 46ml, reacts, generation N- [(7- amino-4-hydroxy -1- methyl -3- isoquinolin) carbonyl]
Glycine 9. 31.2g；
（8）In step（7）N- [(7- nitro -4- hydroxyl -1- methyl -3- isoquinolin) carbonyl] glycine of generation is 9. in 30.1g
Sodium carbonate liquor 500ml is added, and is passed through ammonia, reduction reaction occurs, [(7- amino-4-hydroxy -1- methyl -3- is different by generation N-
Quinoline) carbonyl] glycine 10. 28.6g；
（9）In step（8）N- [(7- amino-4-hydroxy -1- methyl -3- isoquinolin) carbonyl] glycine of generation is 10. in 24.3g
The aqueous solution 360ml of sodium sulfite is added, is heated to 180 DEG C of temperature, generation N- [(4,7- dihydroxy -1- methyl -3- isoquinolin)
Carbonyl] glycine 18.6g；
（10）In step（9）Added in N- [(4,7- dihydroxy -1- methyl -3- isoquinolin) carbonyl] glycine 18.2 of generation
Chlorobenzene 240ml, and the mixed solution 600ml of potassium carbonate and KI is added, it is heated at 95 DEG C, condensation reaction, generation occurs
N- [(4- hydroxyl -7- methoxyl group -1- methyl -3- isoquinolin) carbonyl] glycine 15.6g, as Nuo get Si Ta.
Its chemical equation is：
Embodiment 2
Nuo get Si Ta preparation method, is comprised the following steps that：
（1）Monoxone 360ml and Sodamide 46g is added in 5- nitro-phenyls ethamine 1. 77.3g, under the effect of catalyst nickel,
150 DEG C are heated to, cyclization occurs, generates 7- nitro -4- isoquinolines 2. 75.3g；
（2）In step（1）2. 7- nitro -4- isoquinolines sequentially add alkali accelerator and concentrated hydrochloric acid 260ml in 71.2g, generate
The chloro- isoquinolin of 7- nitro -4- hydroxyls -3- 3. 68.2g；
（3）In step（2）3. the chloro- isoquinolin of 7- nitro -4- hydroxyls -3- of generation adds chloromethanes 150ml in 65.3g, occur
Reaction, generate 7- nitros -4- hydroxy-3-methyls-isoquinolin 4. 61.2g；
（4）In step（3）4. 7- nitros -4- hydroxy-3-methyls-isoquinolin of generation adds potassium permanganate and dense sulphur in 59.3g
Sour 520ml, oxidation reaction occurs, generate (7- nitro -4- hydroxyl -3- isoquinolin）Formic acid 5. 55.4g；
（5）In step（4）Generation（7- nitro -4- hydroxyl -3- isoquinolin）5. formic acid adds glycine 6. 26.3g in 51.4g,
Under acid binding agent effect, acylation reaction occurs, glycine is 7. by generation N- [(7- nitro -4- hydroxyl -3- isoquinolin) carbonyl]
48.3g；
（6）In step（5）7. N- [(7- nitro -4- hydroxyl -3- isoquinolin) carbonyl] glycine of generation adds bromine in 41.2g
With inorganic base potassium carbonate and the mixed solution 800ml of sodium hydroxide, substitution reaction, generation N- [(7- nitro -4- hydroxyls -1- occurs
Bromo- 3- isoquinolin) carbonyl] glycine 8. 36.7g；
（7）In step（6）N- [(the bromo- 3- isoquinolin of 7- nitro -4- hydroxyls -1-) carbonyl] glycine of generation 8. in 33.1g plus
Enter concentrated hydrochloric acid 450ml and chloromethanes 46ml, react, generate N- [(7- amino-4-hydroxy -1- methyl -3- isoquinolin) carbonyls
Base] glycine 9. 27.4g；
（8）In step（7）N- [(7- nitro -4- hydroxyl -1- methyl -3- isoquinolin) carbonyl] glycine of generation is 9. in 26.8g
Sodium carbonate liquor 600ml is added, and is passed through ammonia, reduction reaction occurs, [(7- amino-4-hydroxy -1- methyl -3- is different by generation N-
Quinoline) carbonyl] glycine 10. 27.4g；
（9）In step（8）N- [(7- amino-4-hydroxy -1- methyl -3- isoquinolin) carbonyl] glycine of generation is 10. in 26.3g
The aqueous solution 650ml of sodium sulfite is added, is heated to 220 DEG C of temperature, generation N- [(4,7- dihydroxy -1- methyl -3- isoquinolin)
Carbonyl] glycine 23.2g；
（10）In step（9）Add in N- [(4,7- dihydroxy -1- methyl -3- isoquinolin) carbonyl] glycine 21.2g of generation
Enter chlorobenzene 55ml, and add the mixed solution 650ml of potassium carbonate and KI, be heated at 100 DEG C, condensation reaction occurs, it is raw
Into N- [(4- hydroxyl -7- methoxyl group -1- methyl -3- isoquinolin) carbonyl] glycine 18.9g, as Nuo get Si Ta.
Its chemical equation is as described in Example 1.
It is obvious to a person skilled in the art that the invention is not restricted to the details of above-mentioned one exemplary embodiment, Er Qie
In the case of without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of from which, embodiment all should be regarded as exemplary, and be nonrestrictive, the scope of the present invention is by appended right
It is required that rather than described above limit, it is intended that all changes in the implication and scope of the equivalency of claim will be fallen
Change is included in the present invention.Any mark in claim should not be considered as to the involved claim of limitation.
Based on the embodiment in the present invention, those of ordinary skill in the art are obtained under the premise of creative work is not made
The every other embodiment obtained, belongs to the scope of protection of the invention.
Claims (6)
1. a kind of preparation method of Nuo get Si Ta medicines, the Nuo get Si Ta chemical names are N- [(4- hydroxyl -1- methyl -7- benzene
Epoxide -3- isoquinolin) carbonyl] glycine, it is characterised in that：The preparation method that the Nuo get Si Ta is made walks including following technique
Suddenly：
（1）In 5- nitro-phenyls ethamine 1. middle addition monoxone and Sodamide, under catalyst and certain reaction temperature, occur
Cyclization, generation 7- nitro -4- isoquinolines are 2.；
（2）In step（1）7- nitro -4- isoquinolines 2. in sequentially add alkali accelerator and concentrated hydrochloric acid, generate 7- nitro -4- hydroxyls
The chloro- isoquinolin of base -3- is 3.；
（3）In step（2）The chloro- isoquinolin of 7- nitro -4- hydroxyls -3- of generation 3. middle addition chloromethanes, reacts, and generates 7-
Nitro -4- hydroxy-3-methyls-isoquinolin is 4.；
（4）In step（3）7- nitros -4- hydroxy-3-methyls-isoquinolin of generation is 4. middle to add potassium permanganate and the concentrated sulfuric acid, hair
Raw oxidation reaction, generates (7- nitro -4- hydroxyl -3- isoquinolin）Formic acid is 5.；
（5）In step（4）Generation（7- nitro -4- hydroxyl -3- isoquinolin）Formic acid 5. 6., in acid binding agent make by middle addition glycine
Under, acylation reaction occurs, glycine is 7. by generation N- [(7- nitro -4- hydroxyl -3- isoquinolin) carbonyl]；
（6）In step（5）N- [(7- nitro -4- hydroxyl -3- isoquinolin) carbonyl] glycine of generation is 7. middle to add bromine and nothing
Machine aqueous slkali, substitution reaction occurs, glycine is 8. by generation N- [(the bromo- 3- isoquinolin of 7- nitro -4- hydroxyls -1-) carbonyl]；
（7）In step（6）N- [(the bromo- 3- isoquinolin of 7- nitro -4- hydroxyls -1-) carbonyl] glycine of generation is 8. middle to add dense salt
Acid and chloromethanes, react, and glycine is 9. by generation N- [(7- amino-4-hydroxy -1- methyl -3- isoquinolin) carbonyl]；
（8）In step（7）N- [(7- nitro -4- hydroxyl -1- methyl -3- isoquinolin) carbonyl] glycine of generation 9. middle addition carbon
Acid sodium solution, and ammonia is passed through, reduction reaction, generation N- [(7- amino-4-hydroxy -1- methyl -3- isoquinolin) carbonyl] occurs
Glycine is 10.；
（9）In step（8）N- [(7- amino-4-hydroxy -1- methyl -3- isoquinolin) carbonyl] glycine of generation is 10. middle to add Asia
The aqueous solution of sodium sulphate, certain temperature is heated to, generates N- [(4,7- dihydroxy -1- methyl
- 3- isoquinolin) carbonyl] glycine；
（10）In step（9）Chlorine is added in N- [(4,7- dihydroxy -1- methyl -3- isoquinolin) carbonyl] glycine of generation
Benzene, and the mixed solution of potassium carbonate and KI is added, it is heated under certain temperature, condensation reaction occurs, generates N- [(4- hydroxyls
Base -7- methoxyl group -1- methyl -3- isoquinolin) carbonyl] glycine, as Nuo get Si Ta.
A kind of 2. preparation method of Nuo get Si Ta medicines according to claim 1, it is characterised in that：The step（1）In
Certain temperature is 120-150 DEG C.
A kind of 3. preparation method of Nuo get Si Ta medicines according to claim 1, it is characterised in that：The step（1）Instead
The catalyst answered is nickel.
A kind of 4. preparation method of Nuo get Si Ta medicines according to claim 1, it is characterised in that：The inorganic alkali solution
For the mixture of one or both of sodium hydroxide, sodium carbonate, potassium carbonate.
A kind of 5. preparation method of Nuo get Si Ta medicines according to claim 1, it is characterised in that：The step（9）In
Certain temperature is 180-220 DEG C.
A kind of 6. preparation method of Nuo get Si Ta medicines according to claim 1, it is characterised in that：The step（10）In
Certain temperature is 90-100 DEG C.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109956901A (en) * | 2019-04-25 | 2019-07-02 | 南京正大天晴制药有限公司 | The preparation method of compound of isobioquin group |
| RU2709493C1 (en) * | 2019-08-01 | 2019-12-18 | Марат Феликсович Фазылов | Method of producing roxadustat |
| CN112679430A (en) * | 2019-10-18 | 2021-04-20 | 上海迪赛诺化学制药有限公司 | Method for preparing isoquinolone compound |
| WO2021073623A1 (en) * | 2019-10-18 | 2021-04-22 | 上海迪赛诺化学制药有限公司 | Method for preparing isoquinolinone compounds |
-
2017
- 2017-11-20 CN CN201711157978.9A patent/CN107602466A/en not_active Withdrawn
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109956901A (en) * | 2019-04-25 | 2019-07-02 | 南京正大天晴制药有限公司 | The preparation method of compound of isobioquin group |
| CN109956901B (en) * | 2019-04-25 | 2022-09-06 | 南京正大天晴制药有限公司 | Preparation method of isoquinolone compound |
| RU2709493C1 (en) * | 2019-08-01 | 2019-12-18 | Марат Феликсович Фазылов | Method of producing roxadustat |
| WO2021020998A1 (en) * | 2019-08-01 | 2021-02-04 | Марат Феликсович ФАЗЫЛОВ | Method for producing roxadustat |
| CN112679430A (en) * | 2019-10-18 | 2021-04-20 | 上海迪赛诺化学制药有限公司 | Method for preparing isoquinolone compound |
| WO2021073623A1 (en) * | 2019-10-18 | 2021-04-22 | 上海迪赛诺化学制药有限公司 | Method for preparing isoquinolinone compounds |
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