WO2014187273A1 - 阿伐那非的制备方法 - Google Patents
阿伐那非的制备方法 Download PDFInfo
- Publication number
- WO2014187273A1 WO2014187273A1 PCT/CN2014/077632 CN2014077632W WO2014187273A1 WO 2014187273 A1 WO2014187273 A1 WO 2014187273A1 CN 2014077632 W CN2014077632 W CN 2014077632W WO 2014187273 A1 WO2014187273 A1 WO 2014187273A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- avervavir
- chloro
- reaction
- methoxybenzyl
- preparing
- Prior art date
Links
- 0 CCNCCC1[C@](*)C1 Chemical compound CCNCCC1[C@](*)C1 0.000 description 3
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
Definitions
- the invention belongs to the technical field of organic synthesis route design and preparation technology of raw materials and intermediates, and particularly relates to a preparation method of arvavir.
- Va afi is from japan
- Avastatin is an orally available, highly selective phosphodiesterase
- the -5 (PDE-5) inhibitor inhibits the metabolism of cyclic guanosine monophosphate in the body, thereby enhancing the relaxation of the smooth muscle and increasing the blood flow of the penis, thereby helping the erection.
- Avarnafil was marketed in the United States on April 27, 2012 with the approval of the US FDA under the trade name Stendrac, Avavira (Avanafij, I), and its chemical name is (S)- 4- [(3-chloro-4) -Methoxybenzyl)amino]-2-[2-(hydroxymethyl)- _-pyridinyl]-N-(2-P pyridinemethyl)-5-pyrimidinylamine.
- Avervafil is prepared by reacting VDI) with 2-methylamino acridine (IX).
- methylthio group (XI) and diethyl ethoxymethylidene malonate (XII) are cyclized to obtain a pyrimidine ring mother nucleus 4-hydroxy-2methylthioquinidine-5-carboxylate.
- the above original patent also discloses a method for preparing an analog using 2,4-dichloropyrimidine as a raw material; 2,4-dichloropyrimidine forms a carbanion under the action of n-butyllithium and diisopropylamine at 78 C Under the ultra-low temperature condition, a nucleophilic addition reaction with carbon dioxide or other pseudo-based compounds is carried out to form a 5-substituted-2,4-dichloropyrimidine derivative (XVII).
- the derivative (XVII) is further prepared by reacting with a side chain of 2 , ⁇ or 5-position to obtain a phthalic acid diesterase-5 (PDE) inhibitor similar in structure to the target compound (1).
- PDE phthalic acid diesterase-5
- the object of the present invention is to find a new preparation route, and to provide an improved preparation method of avervavir according to the atomic economic synthesis concept of green chemistry, which is a very inexpensive and readily available industrial raw material cytosine (Cytosine).
- the starting material is obtained by a process such as halogenation, condensation and substitution, and the preparation method has the advantages of simple process, economical and environmental protection, and favorable industrial production.
- a method for preparing avervavir the chemical name of the avervavir is (S)-4-[(3-chloro-4- Methoxybenzyl)amino]-2-[2-(hydroxypyryllyl)pyrrolidino]-N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide (1),
- the preparation method comprises the following steps: using cytosine as a raw material, the cytosine and 3-chloro-4-methoxybenzyl K (III) are substituted to form N-(3-chloro-4- Methoxybenzyl)cytosine (V); the N-(3-chloro-4-methoxybenzyl)cytosine (V) is condensed with S-hydroxymethylpyrrole(II) to obtain 4 - [(3-Chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidine: pyridine (VI), the 4-[(3 - Chlorooxybenzyl)amino 2-[2-(hydroxymethyl)pyrrolidinyl]pyrimidine (Vi:) undergoes halogenation reaction and occurs with the side chain ⁇ -(2-methylpyrimidine)carboxamide (W) The addition reaction produces avanafil (1).
- this main technical solution also includes the following technical solutions :
- the 3-chloro-4-methoxy halogen X is chlorine, bromine or a bowl.
- the acid binding agent for the substitution reaction is potassium carbonate, potassium hydroxide, potassium t-butoxide, sodium methoxide, sodium ethoxide, triethylamine isopropylamine, pyridine or sodium hydroxide, preferably guanylamine or pyridine.
- the condensation agent for the condensation reaction is ruthenium, osmium, dicyclohexylcarbodiimide (DCC; carbonyldiimidazole (CDI), ruthenium, ⁇ '. carbodiimide (DIC), 1-hydroxy-benzo Triazole ( ⁇ ), 0-benzotriazole-oxime, ⁇ , ⁇ ', ⁇ '-tetramethyluronium tetrafluoroborate (TBTU)., 0-0-azobenzotriazole 3 ⁇ 4 )- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethylurea hexafluorophosphate (HATU), benzotriazole- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyl hexafluorophosphate vinegar (HBTU Or benzotriazene sit-yloxytris(dimethylamino)phosphorus octafluorophosphate ( ⁇ ), preferably benzoxazole-oxime, ⁇ , ⁇ '
- the shuffling promoter is: triethylamine, pyridine, 2,6-dimethyl 3 ⁇ 4, 4-dimethylaminopyridine, N-methylmorpholine, N-ethylmorphine, diisopropyl Amine, 1,5-diazabicyclo[4.3.0]-non-5-ene, i, 8,
- the temperature of the condensation reaction is from 0 to 120 ° C, preferably from 50 to 60.
- the halogenating agent in the halogenation reaction is chlorine gas, liquid bromine or iodine, preferably liquid bromine or iodine.
- the catalyst for the addition reaction is palladium chloride, palladium acetate, tris(dibenzylidene propylene dipalladium, nickel chloride, nickel acetate, excellent
- the cocatalyst of the addition reaction is triphenylphosphine, tri-n-butylphosphine, tri-tert-butyl butyl, tricyclohexyl ketone, triethoxy phosphine, hydrazine: phenoxyphosphine, 1, fluorene-bis ( Diphenyl phenyl) ferrocene, 4,5-bisdiphenyl sulfonium-9,9-dimethyloxaxime or tris(2,4-di-tert-butyl)phenoxyl, preferably three (2) , 4-di-tert-butyl)phenoxyl.
- a method for preparing avervavir characterized by the steps of: using cytosine as a raw material, pyridine and 3-chloro-4-
- the methoxybenzyl halide (III) undergoes a substitution reaction to form ⁇ -(3-chloro-4-methoxybenzyl) cytidine (V); the ⁇ -(3-chloro-4-methoxy group Cytosine (V) undergoes a halogenation reaction and undergoes an addition reaction with the side chain ⁇ -(2-methylpyrimidine)formamide (IV) to form 6 (3-chloro)
- the halogen X in the 3-chloro-4-methoxybenzyl halide (III) is chlorine, bromine or iodine.
- the acid binding agent of the substitution reaction is potassium carbonate, potassium hydroxide, potassium t-butoxide, sodium methoxide, sodium ethoxide, triethylamine-isopropylamine, pyridine or sodium hydroxide, preferably triethylamine or pyridine.
- the halogenating agent in the halogenation reaction is chlorine gas, liquid bromine or iodine, preferably liquid bromine or iodine.
- the catalyst for the addition reaction is palladium chloride, palladium acetate, tris (dibenzylidene propylene dipalladium, nickel chloride, nickel acetate, preferably nickel acetate).
- the cocatalyst of the addition reaction is triphenylphosphine, tri-n-butylphosphine, tri-tert-butyl butyl, tricyclohexyl ketone, triethoxy phosphine, hydrazine: phenoxyphosphine, 1, fluorene-bis ( Diphenyl phenyl) ferrocene, 4,5-bisdiphenyl sulfonium-9,9-dimethyloxaxime or tris(2,4-di-tert-butyl)phenoxyl, preferably three (2) , 4-di-tert-butyl)phenoxyl.
- the condensation agent for the condensation reaction is ruthenium, osmium, -dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI) ruthenium, ⁇ '-diisopropylcarbodiimide (DIC; -benzotriazole (HOBt), 0-benzotriazole-oxime, oxime, ⁇ ', ⁇ '-tetramethylurea tetrafluoroborate (TBTU), 0-(7-azobenzo Triazole;- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyl hexafluorophosphate (HATU), benzo:: azole, ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethylurea Hexafluoro-acid ester (HBTU) or benzotriazide 3 ⁇ 4- 1-yloxytris(dimethylamino)phosphorus hexafluorophosphate ( ⁇ ), preferably benzo
- the base promoter of the condensation reaction is triethylamine, pyridine, 2,6-dimethylpyridinium, 4 dimethylaminopyridine, ⁇ -methylmorpholine, ⁇ -ethyl phenanthrene, diisopropyl Ethylamine, ], 5-diazabicyclo[4.3.0]-non-5-ene, 1,8-diazabicyclo[5.4.0]- eleven- 7 -ene or 1,4-di Azabicyclo[2.2.2]octyl, preferably tris(2,4-di-tert-butyl)phenoxyphosphine.
- the temperature of the condensation reaction is 0 - 20 ° C, preferably 60 - 70 ° (:.
- the preparation method of avervavir according to the present invention is based on the cheap and readily available industrial raw material cytosine, and is prepared by the steps of ii substitution, condensation and halogen addition.
- Afaunafil the advantages of the present invention are mainly that the raw materials are easy to obtain, the process is simple, economical and environmentally friendly, and is advantageous for industrial production.
- the technical solution of the present invention will be further described in detail below with reference to a few preferred embodiments.
- Embodiment 1 is a diagrammatic representation of Embodiment 1:
- Embodiment 2 is a diagrammatic representation of Embodiment 1:
- N (3-chloro-4-methoxybenzyl)cytosine (V) (2.65 g, lOnimol), benzotriazolyloxy (dimethylamino) was added to a three-necked flask.
- Phosphorus 3 ⁇ 4 hexafluorophosphate (BOP) (6.63 g, 15ramol) and acetonitrile 50 mL.
- BOP hexafluorophosphate
- DBU j-mono-7-ene
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14/948,387 US9453001B2 (en) | 2013-05-23 | 2015-11-23 | Avanafil preparation method |
US15/247,383 US9593101B2 (en) | 2013-05-23 | 2016-08-25 | Avanafil preparation method |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310195728.X | 2013-05-23 | ||
CN201310195728.XA CN103254179B (zh) | 2013-05-23 | 2013-05-23 | 阿伐那非的制备方法 |
CN201310195854.5A CN103265534B (zh) | 2013-05-23 | 2013-05-23 | 阿伐那非的制备方法 |
CN201310195854.5 | 2013-05-23 |
Related Child Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14948387 A-371-Of-International | 2014-05-16 | ||
US14/948,387 Continuation US9453001B2 (en) | 2013-05-23 | 2015-11-23 | Avanafil preparation method |
US15/247,383 Division US9593101B2 (en) | 2013-05-23 | 2016-08-25 | Avanafil preparation method |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2014187273A1 true WO2014187273A1 (zh) | 2014-11-27 |
Family
ID=51932845
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2014/077632 WO2014187273A1 (zh) | 2013-05-23 | 2014-05-16 | 阿伐那非的制备方法 |
Country Status (2)
Country | Link |
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US (2) | US9453001B2 (zh) |
WO (1) | WO2014187273A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108593805A (zh) * | 2018-06-01 | 2018-09-28 | 无锡富泽药业有限公司 | 3-氯-4-甲氧基苄胺盐酸盐同分异构体的分离方法及检测方法 |
CN114163380A (zh) * | 2021-12-06 | 2022-03-11 | 重庆医科大学 | 阿伐可泮中间体及其制备方法和用途 |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112661705A (zh) * | 2021-01-21 | 2021-04-16 | 山东省药学科学院 | 一种阿伐那非杂质的合成方法 |
CN114957332A (zh) * | 2022-05-30 | 2022-08-30 | 苏州正永生物医药有限公司 | 一种阿伐那非磷酸酯类化合物及其制备方法和应用 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001019802A1 (fr) * | 1999-09-16 | 2001-03-22 | Tanabe Seiyaku Co., Ltd. | Composes cycliques aromatiques azotes a six elements |
WO2001083460A1 (fr) * | 2000-04-28 | 2001-11-08 | Tanabe Seiyaku Co., Ltd. | Composes cycliques |
JP2002338466A (ja) * | 2001-03-15 | 2002-11-27 | Tanabe Seiyaku Co Ltd | 医薬組成物 |
CN103254179A (zh) * | 2013-05-23 | 2013-08-21 | 苏州明锐医药科技有限公司 | 阿伐那非的制备方法 |
CN103265534A (zh) * | 2013-05-23 | 2013-08-28 | 苏州明锐医药科技有限公司 | 阿伐那非的制备方法 |
-
2014
- 2014-05-16 WO PCT/CN2014/077632 patent/WO2014187273A1/zh active Application Filing
-
2015
- 2015-11-23 US US14/948,387 patent/US9453001B2/en not_active Expired - Fee Related
-
2016
- 2016-08-25 US US15/247,383 patent/US9593101B2/en not_active Expired - Fee Related
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001019802A1 (fr) * | 1999-09-16 | 2001-03-22 | Tanabe Seiyaku Co., Ltd. | Composes cycliques aromatiques azotes a six elements |
WO2001083460A1 (fr) * | 2000-04-28 | 2001-11-08 | Tanabe Seiyaku Co., Ltd. | Composes cycliques |
JP2002338466A (ja) * | 2001-03-15 | 2002-11-27 | Tanabe Seiyaku Co Ltd | 医薬組成物 |
CN103254179A (zh) * | 2013-05-23 | 2013-08-21 | 苏州明锐医药科技有限公司 | 阿伐那非的制备方法 |
CN103265534A (zh) * | 2013-05-23 | 2013-08-28 | 苏州明锐医药科技有限公司 | 阿伐那非的制备方法 |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108593805A (zh) * | 2018-06-01 | 2018-09-28 | 无锡富泽药业有限公司 | 3-氯-4-甲氧基苄胺盐酸盐同分异构体的分离方法及检测方法 |
CN114163380A (zh) * | 2021-12-06 | 2022-03-11 | 重庆医科大学 | 阿伐可泮中间体及其制备方法和用途 |
CN114163380B (zh) * | 2021-12-06 | 2023-11-07 | 重庆医科大学 | 阿伐可泮中间体及其制备方法和用途 |
Also Published As
Publication number | Publication date |
---|---|
US9593101B2 (en) | 2017-03-14 |
US20160362400A1 (en) | 2016-12-15 |
US20160075693A1 (en) | 2016-03-17 |
US9453001B2 (en) | 2016-09-27 |
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