CN109232542A - A method of preparing pharmaceutical compound avanaphil - Google Patents
A method of preparing pharmaceutical compound avanaphil Download PDFInfo
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- CN109232542A CN109232542A CN201811119905.5A CN201811119905A CN109232542A CN 109232542 A CN109232542 A CN 109232542A CN 201811119905 A CN201811119905 A CN 201811119905A CN 109232542 A CN109232542 A CN 109232542A
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Abstract
The invention discloses a kind of methods for preparing pharmaceutical compound avanaphil, belong to the technical field of the synthesis of medical compounds.Technical solution of the present invention main points are as follows: a method of prepare pharmaceutical compound avanaphil, synthetic route are as follows:
Description
Technical field
The invention belongs to the synthesis technical fields of medical compounds, and in particular to a kind of to prepare pharmaceutical compound avanaphil
Method.
Background technique
Avanaphil (Avanafil), Chinese chemical name are known as (S) -4- [(3- chloro-4-methoxy benzyl) amino] -2-
[2- (methylol) -1- pyrrolidinyl]-N- (2- pyrimidine methyl) -5- pyrimidine carboxamide, is by day Honda side Mitsubishi pharmacy strain formula
The drug for being used to treat male erectile dysfunction of authorization U.S. Virus company of commercial firm exploitation, in 27 Nikkei beauty April in 2012
State FDA approval lists in the U.S., trade name Stendra.The drug is a kind of to take orally quick-acting highly selective phosphodiesterases-
5- (PDE) inhibitor.The drug than silaenafil, cuts down Ta Nafei etc. with onset time short advantage since oral absorption is fast
And favored.
The method of synthesis avanaphil at present, synthetic route disclosed in international monopoly (WO 2001019802A1) is 3-
Chloro-4-methoxy benzylamine and the chloro- 2- methylthiopyrimidine -5- carboxylic acid, ethyl ester of 4- occur condensation reaction and obtain 4- (3- chloro-4-methoxy
Benzamido group) -2- methylthiopyrimidine -5- carboxylic acid, ethyl ester, then the compound is aoxidized to obtain 4- (3- with metachloroperbenzoic acid
Chloro-4-methoxy benzamido group) -2- methanesulfonyl pyrimidine -5- carboxylic acid, ethyl ester, the oxidation product and L- prolinol are (S) -2- hydroxyl first
Condensation, hydrolysis occur for base pyrrolidines, then carry out condensation reaction with 2- pyrimidine ethamine again and obtain avanaphil.Later many patents
(WO 2015177807A1, CN 105439964A, CN 103254179B, CN 104710411B, CN 104628709A etc.) is special
Benefit is improved on the basis of all original is ground herein, but reaction process methyl mercapto be all after the reaction the phase aoxidized, be then substituted,
In later period oxidation process, since intermediate contains nitrogen heteroatom, oxidation impurities are easy to produce, and oxidation can have sulfone and Asia
The state of sulfone will cause residual or influence to late phase reaction.Chinese patent CN 104650045B then use 5- uracil carboxylic acid or
Its ester is raw material, obtains avanaphil through chlorination, condensation amidation.But due to chlorinating step generate dichloride, further with
There is reaction selectivity when being condensed in amino intermediate.
In reported synthetic route, exists or react and use harsh reaction condition or reaction in the presence of selectivity
Relatively poor problem be easy to cause intermediate purity inadequate, and then influences the quality of final products.
Summary of the invention
The technical problem to be solved by the present invention is to provide a kind of method for preparing pharmaceutical compound avanaphil, this method tools
Have the advantages that high income, at low cost, economic and environment-friendly and to be suitable for industrialization, product purity high, is a kind of there is industrial production valence
The synthetic method of value.
The present invention adopts the following technical scheme that solve above-mentioned technical problem, a kind of pharmaceutical compound avanaphil for preparing
Method, it is characterised in that specific steps are as follows:
Step S1: compound 1 aoxidizes to obtain compound 2 through oxidant hydrogen peroxide；
Step S2: compound 2 is after phosphorus oxychloride chlorination with 3- chloro-4-methoxy benzyl amine in acid binding agent diisopropyl second
Reaction obtains compound 3 under the action of base amine；
Step S3: compound 3 and L- prolinol condensation reaction under the action of acid binding agent diisopropyl ethyl amine
Close object 4；
Step S4: compound 4 hydrolyzes under the action of sodium hydroxide and obtains compound 5；
Step S5: compound 5 and 2- amine methylpyrimidine are in dicyclohexylcarbodiimide (DCC) and 1- hydroxyl -1,2,3- benzene
And condensation reaction obtains 6 avanaphil of target compound under the action of triazine -4 (3H) -one；
Corresponding reaction equation in preparation process are as follows:
Preferably, reaction vessel used in step S1 is autoclave, and solvent used is water, oxidant used
The hydrogen peroxide for being 30% for mass fraction, reaction temperature are 120 DEG C.
Preferably, the detailed process of step S2 are as follows: compound 2, solvent toluene and chlorination reagent are added in the reaction vessel
Phosphorus oxychloride, is warming up to back flow reaction, is cooled to 0 DEG C after reaction and is washed with ice water, is added and contains after toluene is mutually dried
There is the toluene solution of the 3- chloro-4-methoxy benzyl amine of acid binding agent diisopropyl ethyl amine to be reacted, uses salt after reaction
Water washing, water washing are spin-dried for obtaining compound 3 after dry.
Preferably, the molar ratio of compound 2 described in step S2 and phosphorus oxychloride is 1:1.1-2.0；The toluene and change
The charge ratio for closing 2 is 2-5mL:1g；The molar ratio of the compound 2 and 3- chloro-4-methoxy benzyl amine is 1:1.01-
1.05；The molar ratio of the compound 2 and diisopropyl ethyl amine is 1:1.1.
Preferably, the detailed process of step S3 are as follows: compound 3, methylene chloride and diisopropyl are added in the reaction vessel
Dissolution is stirred at room temperature in ethylamine, adds L- prolinol and is stirred to react in 0-50 DEG C, is washed with brine after fully reacting, water
It washes, is spin-dried for obtaining compound 4 after dry.
Preferably, the charge ratio of methylene chloride described in step S3 and compound 3 is 10-15mL:1g；The compound
The molar ratio of 3 and L- prolinol is 1:1.2-1.5；The molar ratio of the acid binding agent diisopropyl ethyl amine and compound 3 is
1.03-1.2:1。
Preferably, the detailed process of step S4 are as follows: compound 4 and solvent DMF are added in the reaction vessel, after stirring and dissolving
Temperature of reaction system is controlled at 40 DEG C and is reacted hereinafter, the sodium hydroxide solution that mass fraction is 20% is added, reaction knot
Shu Houyong dilute hydrochloric acid adjusts the pH=7 of mixed system, adds water crystallization, compound 5 is obtained by filtration.
Preferably, the charge ratio of solvent DMF described in step S4 and compound 4 is 1.5-2.5mL:1g；The chemical combination
The molar ratio of object 4 and sodium hydroxide is 1:1.0-1.5.
Preferably, the detailed process of step S5 are as follows: anhydrous DMF, compound 5,2- amino methyl are added in the reaction vessel
Pyrimidine, dicyclohexylcarbodiimide and 1- hydroxyl -1,2,3- phentriazine -4 (3H) -one, are reacted in 0-30 DEG C, reaction knot
Filtered after beam, filtrate adds water, is extracted with chloroform, and organic phase washing is dry, filtrate be spin-dried for obtaining after silica gel column chromatography crude product Ah
It is non-to cut down that, crude product avanaphil obtains sterling avanaphil after refining methanol.
Preferably, the charge ratio of DMF described in step S5 and compound 4 is 10-15mL:1g；The compound 4 and 2-
The molar ratio of amino methylpyrimidine is 1:1.5.
Compared with the prior art, the present invention has the following advantages: reaction step is short, mild condition, high income, product purity
It is high and low in cost, it is suitable for industrialization production.
Specific embodiment
Above content of the invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below, and all technologies realized based on above content of the present invention belong to this hair
Bright range.
Compound 1 can be by method reported in the literature (European Journal of Medicinal in all embodiments
Chemistry, 2018,145:673-690.) it is prepared.
Embodiment 1
The preparation of compound 2
The preparation of compound 2
In 500mL autoclave, the hydrogen peroxide that compound 1 (214g, 1mol) and 200mL mass fraction are 30% is added,
It is gradually warming up to 120 DEG C to be reacted, after reaction, autoclave is cooled to room temperature, reaction solution is spin-dried for, and uses ethyl alcohol recrystallization
Obtain white solid, yield 95%, HPLC purity 98.5%.1H NMR(DMSO-d6):δ9.64(s,1H),8.37(d,2H),
4.07(q,2H),2.50(s,3H),1.20(t,3H).ESI-MS(m/z):247[M+1]+。
The preparation of compound 3
In reaction flask, compound 2 (246g, 1mol), toluene 492mL and diisopropyl ethyl amine 182mL, stirring is added
Under phosphorus oxychloride 94mL is slowly added dropwise, be warming up to back flow reaction, be cooled to 0 DEG C after reaction, ice water washing, toluene is mutually dried
The mixed liquor containing 3- chloro-4-methoxy benzyl amine 173g, diisopropylethylamine 182mL and toluene 492mL is instilled afterwards to carry out instead
It answers, is washed with brine after reaction, water washing is spin-dried for obtaining compound 3, yield 96.8%, HPLC purity after dry
98.8%.ESI-MS(m/z):400[M+1]+。
The preparation of compound 4
In reaction flask, compound 3 (400g, 1.0mol), methylene chloride 4000mL and diisopropyl ethyl amine is added
Dissolution is stirred at room temperature in 170mL, adds L- prolinol (121g, 1.2mol), is stirred to react in 0 DEG C, monitoring to compound 3
Fully reacting, salt water washing are washed, dry, and compound 4, yield 98.0%, purity 99.8% are obtained after being spin-dried for.ESI-
MS(m/z):422[M+1]+。
The preparation of compound 5
In reaction flask, compound 4 (421g, 1.0mol) and DMF 632mL, stirring and dissolving, by reaction system is added
Temperature control at 40 DEG C hereinafter, be slowly added dropwise mass fraction be 20% sodium hydroxide solution 200mL, after raw material react, use
It is 7.0 that dilute hydrochloric acid, which adjusts pH, is cooled to 0 DEG C of dropwise addition 500mL water, and solid is precipitated and filters, and washing obtains compound 5, yield is
98.9%, purity 98.7%.ESI-MS(m/z):394[M+1]+。
The preparation of avanaphil
In reaction flask, be added anhydrous DMF 3930mL, compound 5 (393g, 1.0mol), 2- aminopyrimidine (163.5g,
1.5mol), DCC (210g, 1.02mol) and 1- hydroxyl -1,2,3- phentriazine -4 (3H) -one (166g, 1.02mol), in 0 DEG C
It is stirred to react, monitoring to 5 fully reacting of compound, filtering, filtrate is added water, is extracted with chloroform, organic phase washing, dry, mistake
After the too short layer of silica gel of filtrate, obtain crude product avanaphil after being spin-dried for, crude product avanaphil through refining methanol obtain sterling Ah cutting down that
It is non-, yield 99.0%, purity 99.85%.1H NMR(DMSO-d6):δ9.16(s,1H),8.74(d,2H),8.54(s,
1H),7.32(t,1H),7.07(d,1H),4.56(s,2H),4.49(s,1H),4.12(s,1H),3.82(s,3H),3.51(m,
5H),1.93(m,4H).ESI-MS(m/z):484[M+1]+。
Embodiment 2
The preparation of compound 2
In 500mL autoclave, the hydrogen peroxide that compound 1 (214g, 1mol) and 200mL mass fraction are 30% is added,
It is gradually warming up to 120 DEG C to be reacted, after reaction, autoclave is cooled to room temperature, reaction solution is spin-dried for, and uses ethyl alcohol recrystallization
Obtain white solid, yield 95%, HPLC purity 98.5%.ESI-MS(m/z):247[M+1]+。
The preparation of compound 3
In reaction flask, compound 2 (246g, 1mol), toluene 1230mL and diisopropyl ethyl amine 364mL is added, stirs
It mixes down and phosphorus oxychloride 186mL is slowly added dropwise, be warming up to back flow reaction, be cooled to 0 DEG C after reaction, ice water washs, toluene phase
After drying instill the mixed liquor containing 3- chloro-4-methoxy benzyl amine 180g, diisopropylethylamine 182mL and toluene 492mL into
Row reaction, is washed with brine, water washing after reaction, is spin-dried for obtaining compound 3 after dry, yield 96.1%, HPLC is pure
Degree 98.7%.ESI-MS(m/z):400[M+1]+。
The preparation of compound 4
In reaction flask, compound 3 (400g, 1.0mol), methylene chloride 6000mL and diisopropyl ethyl amine is added
Dissolution is stirred at room temperature in 198mL, adds L- prolinol (151g, 1.5mol), is stirred to react in 50 DEG C, monitoring to compound 3
Fully reacting, salt water washing are washed, dry, and compound 4, yield 97.0%, purity 99.8% are obtained after being spin-dried for.ESI-
MS(m/z):422[M+1]+。
The preparation of compound 5
In reaction flask, compound 4 (421g, 1.0mol) and DMF 982mL, stirring and dissolving, by reaction system is added
Temperature control at 40 DEG C hereinafter, be slowly added dropwise mass fraction be 20% sodium hydroxide solution 300mL, after raw material react, use
It is 7.0 that dilute hydrochloric acid, which adjusts pH, is cooled to 0 DEG C of dropwise addition 800mL water, and solid is precipitated and filters, and washing obtains compound 5, yield is
98.5%, purity 98.1%.ESI-MS(m/z):394[M+1]+。
The preparation of avanaphil
In reaction flask, be added anhydrous DMF 5895mL, compound 5 (393g, 1.0mol), 2- aminopyrimidine (163.5g,
1.5mol), DCC (210g, 1.02mol) and 1- hydroxyl -1,2,3- phentriazine -4 (3H) -one (166g, 1.02mol), in 30
It DEG C being stirred to react, monitoring to 5 fully reacting of compound, filtering, filtrate is added water, is extracted with chloroform, organic phase washing, and it is dry,
After the too short layer of silica gel of filtered fluid, crude product avanaphil is obtained after being spin-dried for, crude product avanaphil obtains sterling Ah cutting down through refining methanol
That is non-, yield 98.0%, purity 99.8%.ESI-MS(m/z):484[M+1]+。
Embodiment 3
The preparation of compound 2
In 500mL autoclave, the hydrogen peroxide that compound 1 (214g, 1mol) and 200mL mass fraction are 30% is added,
It is gradually warming up to 120 DEG C to be reacted, after reaction, autoclave is cooled to room temperature, reaction solution is spin-dried for, and uses ethyl alcohol recrystallization
Obtain white solid, yield 95%, HPLC purity 98.5%.ESI-MS(m/z):247[M+1]+。
The preparation of compound 3
In reaction flask, compound 2 (246g, 1mol), toluene 1000mL and diisopropyl ethyl amine 250mL is added, stirs
It mixes down and phosphorus oxychloride 110mL is slowly added dropwise, be warming up to back flow reaction, be cooled to 0 DEG C after reaction, ice water washs, toluene phase
After drying instill the mixed liquor containing 3- chloro-4-methoxy benzyl amine 175g, diisopropylethylamine 182mL and toluene 492mL into
Row reaction, is washed with brine, water washing after reaction, is spin-dried for obtaining compound 3 after dry, yield 97.2%, HPLC is pure
Degree 98.9%.ESI-MS(m/z):400[M+1]+。
The preparation of compound 4
In reaction flask, compound 3 (400g, 1.0mol), methylene chloride 4500mL and diisopropyl ethyl amine is added
Dissolution is stirred at room temperature in 180mL, adds L- prolinol (128g, 1.27mol), and reaction, monitoring to compound is stirred at room temperature
3 fully reactings, salt water washing are washed, dry, and compound 4, yield 97.5%, purity 99.8% are obtained after being spin-dried for.ESI-
MS(m/z):422[M+1]+。
The preparation of compound 5
In reaction flask, compound 4 (421g, 1.0mol) and DMF 800mL, stirring and dissolving, by reaction system is added
Temperature control at 40 DEG C hereinafter, be slowly added dropwise mass fraction be 20% sodium hydroxide solution 250mL, after raw material react, use
It is 7.0 that dilute hydrochloric acid, which adjusts pH, is cooled to 0 DEG C of dropwise addition 500mL water, and solid is precipitated and filters, and washing obtains compound 5, yield is
98.9%, purity 98.7%.ESI-MS(m/z):394[M+1]+。
The preparation of avanaphil
In reaction flask, be added anhydrous DMF 4500mL, compound 5 (393g, 1.0mol), 2- aminopyrimidine (163.5g,
1.5mol), DCC (210g, 1.02mol) and 1- hydroxyl -1,2,3- phentriazine -4 (3H) -one (166g, 1.02mol), in room
Temperature is stirred to react, monitoring to 5 fully reacting of compound, filtering, and filtrate is added water, is extracted with chloroform, and organic phase washing is dry,
After the too short layer of silica gel of filtered fluid, crude product avanaphil is obtained after being spin-dried for, crude product avanaphil obtains sterling Ah cutting down through refining methanol
That is non-, yield 98.5%, purity 99.85%.ESI-MS(m/z):484[M+1]+。
Embodiment above describes basic principles and main features of the invention and advantage, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe originals of the invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (10)
1. a kind of method for preparing pharmaceutical compound avanaphil, it is characterised in that specific steps are as follows:
Step S1: compound 1 aoxidizes to obtain compound 2 through oxidant hydrogen peroxide；
Step S2: compound 2 is after phosphorus oxychloride chlorination with 3- chloro-4-methoxy benzyl amine in acid binding agent diisopropyl ethyl amine
Under the action of reaction obtain compound 3；
Step S3: compound 3 and condensation reaction under the action of acid binding agent diisopropyl ethyl amine of L- prolinol obtain compound
4；
Step S4: compound 4 hydrolyzes under the action of sodium hydroxide and obtains compound 5；
Step S5: compound 5 and 2- amine methylpyrimidine are in dicyclohexylcarbodiimide and 1- hydroxyl -1,2,3- phentriazine -4
Condensation reaction obtains 6 avanaphil of target compound under the action of (3H) -one；
Corresponding reaction equation in preparation process are as follows:
2. the method according to claim 1 for preparing pharmaceutical compound avanaphil, it is characterised in that: used in step S1
Reaction vessel be autoclave, solvent used be water, oxidant used is the hydrogen peroxide that mass fraction is 30%, instead
Answering temperature is 120 DEG C.
3. the method according to claim 1 for preparing pharmaceutical compound avanaphil, it is characterised in that: step S2's is specific
Process are as follows: compound 2, solvent toluene and chlorination reagent phosphorus oxychloride are added in the reaction vessel, is warming up to back flow reaction, reacts
After be cooled to 0 DEG C and washed with ice water, it is chloro- that the 3- containing acid binding agent diisopropyl ethyl amine is added after toluene is mutually dried
The toluene solution of 4- methoxy-benzyl amine is reacted, and is washed with brine after reaction, water washing, being spin-dried for after drying
Close object 3.
4. the method according to claim 3 for preparing pharmaceutical compound avanaphil, it is characterised in that: described in step S2
The molar ratio of compound 2 and phosphorus oxychloride is 1:1.1-2.0；The charge ratio of the toluene and chemical combination 2 is 2-5mL:1g；It is described
The molar ratio of compound 2 and 3- chloro-4-methoxy benzyl amine is 1:1.01-1.05；The compound 2 and diisopropyl ethyl amine
Molar ratio be 1:1.1.
5. the method according to claim 1 for preparing pharmaceutical compound avanaphil, it is characterised in that: step S3's is specific
Process are as follows: compound 3, methylene chloride and diisopropyl ethyl amine are added in the reaction vessel, dissolution is stirred at room temperature, adds
L- prolinol is stirred to react in 0-50 DEG C, is washed with brine after fully reacting, and washing is spin-dried for obtaining compound 4 after dry.
6. the method according to claim 5 for preparing pharmaceutical compound avanaphil, it is characterised in that: described in step S3
The charge ratio of methylene chloride and compound 3 is 10-15mL:1g；The molar ratio of the compound 3 and L- prolinol is 1:1.2-
1.5；The molar ratio of the acid binding agent diisopropyl ethyl amine and compound 3 is 1.03-1.2:1.
7. the method according to claim 1 for preparing pharmaceutical compound avanaphil, it is characterised in that: step S4's is specific
Process are as follows: be added compound 4 and solvent DMF in the reaction vessel, after stirring and dissolving by temperature of reaction system control 40 DEG C with
Under, the sodium hydroxide solution that mass fraction is 20% is added and is reacted, adjusts mixed system with dilute hydrochloric acid after reaction
PH=7 adds water crystallization, and compound 5 is obtained by filtration.
8. the method according to claim 7 for preparing pharmaceutical compound avanaphil, it is characterised in that: described in step S4
The charge ratio of solvent DMF and compound 4 is 1.5-2.5mL:1g；The molar ratio of the compound 4 and sodium hydroxide is 1:
1.0-1.5。
9. the method according to claim 1 for preparing pharmaceutical compound avanaphil, it is characterised in that: step S5's is specific
Process are as follows: anhydrous DMF, compound 5,2- amino methylpyrimidine, dicyclohexylcarbodiimide and 1- hydroxyl are added in the reaction vessel
Base -1,2,3- phentriazine -4 (3H) -one, is reacted in 0-30 DEG C, is filtered after reaction, filtrate adds water, is extracted with chloroform
It takes, organic phase washing, dry, filtrate is spin-dried for obtaining crude product avanaphil after silica gel column chromatography, and crude product avanaphil is through methanol
Sterling avanaphil is obtained after purification.
10. the method according to claim 9 for preparing pharmaceutical compound avanaphil, it is characterised in that: institute in step S5
The charge ratio for stating DMF and compound 4 is 10-15mL:1g；The molar ratio of the compound 4 and 2- amino methylpyrimidine is 1:
1.5。
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015001567A1 (en) * | 2013-07-01 | 2015-01-08 | Msn Laboratories Private Limited | Process for the preparation of (s)-4-[(3-chloro-4-methoxybenzyl)amino]-2-[2- (hydroxymethyl)-1-pyrrolidinyl]-n-(2-pyrimidinyl methyl-5-pyrimidine carboxamide |
| CN104530017A (en) * | 2015-01-05 | 2015-04-22 | 南京晓庄学院 | Avanafil preparation method |
| CN105439964A (en) * | 2015-12-09 | 2016-03-30 | 河北大学 | Preparation method of Avanafil intermediate |
-
2018
- 2018-09-25 CN CN201811119905.5A patent/CN109232542A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015001567A1 (en) * | 2013-07-01 | 2015-01-08 | Msn Laboratories Private Limited | Process for the preparation of (s)-4-[(3-chloro-4-methoxybenzyl)amino]-2-[2- (hydroxymethyl)-1-pyrrolidinyl]-n-(2-pyrimidinyl methyl-5-pyrimidine carboxamide |
| CN104530017A (en) * | 2015-01-05 | 2015-04-22 | 南京晓庄学院 | Avanafil preparation method |
| CN105439964A (en) * | 2015-12-09 | 2016-03-30 | 河北大学 | Preparation method of Avanafil intermediate |
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