CN106831601A - A kind of synthetic method of 2 amino methylpyrimidine hydrochloride and its derivative - Google Patents
A kind of synthetic method of 2 amino methylpyrimidine hydrochloride and its derivative Download PDFInfo
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- CN106831601A CN106831601A CN201710024025.9A CN201710024025A CN106831601A CN 106831601 A CN106831601 A CN 106831601A CN 201710024025 A CN201710024025 A CN 201710024025A CN 106831601 A CN106831601 A CN 106831601A
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- amino
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- methylpyrimidines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of preparation of pharmaceutical intermediate, the preparation method of more particularly to a kind of 2 amino methylpyrimidine hydrochloride and its derivative.The present invention is the improvement carried out after the shortcoming for overcoming the industrialized producing technology and laboratory process for commonly using now, is theed improvement is that:The method is initiation material with 2 cyanopyrimidines and its derivative, and it is protective agent to use Boc acid anhydrides, in the basic conditions, through reduction protection one pot reaction, is obtained by hydroperoxide deprotection.The method is reaction time short, and high conversion rate, product quality is excellent, and the 2 amino methylpyrimidine hydrochlorides and its derivative content produced are more than 99%, and operating procedure is simple, and required equipment is simple, and energy consumption is low.
Description
Technical field
The invention belongs to technical field of organic synthesis, it is related to the synthesis side of a kind of 2- substituted pyrimidines hydrochloride and its derivative
The synthetic method of method, more particularly to a kind of 2- amino methylpyrimidines hydrochloride and its derivative.
Technical background
Entitled (S) -4- [(3- chloro-4-methoxies benzyl) amino] -2- [2- (the hydroxyl first of avanaphil (Avanafil) chemistry
Base) -1- pyrrolidinyls]-N- (2- Pyrimidylmethyls) -5- pyrimidine carboxamides are by Japanese Tanabe Mitsubishi Pharmaceutical Co
Authorize the medicine for treating male erectile dysfunction of U.S. Wei Fusi (Vivus) drugmaker exploitation.Avanaphil is
A kind of oral quick-acting high selectivity phosphodiesterase -5 (PDE-5) inhibitor, can suppress cyclic guanosine monophosphate generation in vivo
Thank, so that the diastole effect of smooth muscle is enhanced, the CBF of penis increases, and then help is erected.Avanaphil in
The approval of the Nikkei U.S. FDA of April 27 in 2012 is in U.S.'s listing, trade name Stendra.Structure is as follows:
2- amino methylpyrimidine hydrochlorides are the intermediates for synthesizing avanaphil, prepare 2- amino methylpyrimidine hydrochlorides at present
Method is mainly:
1. chloroethene amidine is prepared by chloroacetonitrile, then with 1,1,3,3- tetramethoxy propane cyclization obtains 2- chloromethyl pyrimidines, finally leads to
Cross Dare guest reaction and obtain 2- amino methylpyrimidines.
The document report route yield has the yield of 60-70%, and contains ammonium chloride in product, is difficult to remove.
2., with 2- cyanopyrimidines as raw material, 2- first is obtained with ammoniacal liquor reaction under conditions of catalyst Raney's nickel and hydrogen
Amine pyrimidine, because 2- methylamine yl pyrimidines are unstable, therefore can add hydrochloric acid to obtain 2- methylamino pyrimidine hydrochlorides.Reaction equation
For:
The reaction yield is not equally high, it is necessary to the larger 10-20atm of Hydrogen Vapor Pressure, and impurity is more, predominantly for reduction is complete
Product, and the product that the amine being reduced into is coupled with unreacted cyano group again, after purification, yield also only has 40-50%, and color
It is deeper.Also have and replace what nickel was catalyzed using 10% palladium/carbon, impurity is equally more.
Impurity reaction is as follows:
The content of the invention
For deficiencies such as long, product yield is low, the synthesis difficulties of reaction time in the prior art, the invention provides a kind of work
The synthetic method of the 2- methylamino pyrimidine hydrochlorides that skill is simple, with short production cycle, high income, product purity are high, using 2- cyano group
Pyrimidine is initiation material, and 2- amino methylpyrimidine hydrochlorides are obtained by deprotection after reduction-protection reaction, is drawn simultaneously in reduction
Enter Boc protection groups, relative to the reduction reaction for being not added with protection group, impurity is reduced, and reduces post-processing difficulty, and improve product
Yield, while also being verified to its derivative, works well, and specific synthetic route is as follows:
Wherein R1 is located at 4 or 5, and R1 is hydrogen or methyl or ethyl.
It is concretely comprised the following steps:
Add organic solvent, water, Boc at room temperature in the reactor2O acid anhydrides and alkali, then at addition catalyst and 2- at room temperature
Cyanopyrimidine, being passed through hydrogen carries out reduction reaction, and reaction is passed through hydrogen chloride after terminating, and deprotection obtains product.
Room temperature of the present invention refers to 20-25 DEG C.
Specifically:
The derivative of the 2- amino methylpyrimidines hydrochloride is:2- amino methyl -4- methyl-pvrimidines hydrochloride,
2- amino methyl -4- ethyl-pyrimidines hydrochloride, 2- amino methyls -5- methylpyrimidines hydrochloride or 2- amino methyl -5- second
Yl pyrimidines hydrochloride.
The organic solvent is ethyl acetate;The alkali is NaOH, potassium hydroxide, sodium carbonate or potassium carbonate;It is described
Catalyst is 20% palladium dydroxide/carbon or 10% palladium/carbon;Each material mol ratio is in the reduction reaction:2- cyanopyrimidines or its
Derivative:Boc2O acid anhydrides:Alkali=1:1.0-1.3:1.0-1.7, volume ratio organic solvent:Water=5-30:2.5-15, wherein 2- cyanogen
Yl pyrimidines or derivatives thereof are 1 with the mass ratio of water:2.5-15
When catalyst is 20% palladium dydroxide/carbon or 10% palladium/carbon, mol ratio 2- cyanopyrimidines or derivatives thereof:Palladium dydroxide
Or palladium=1:0.005-0.05;
The temperature of the reduction reaction is 10-35 DEG C, and the reaction time is 8-24 hours, preferably 16 hours, is passed through the pressure of hydrogen
It is 0.5-5atm;
Mass ratio 2- cyanopyrimidines or derivatives thereof in the deprotection reaction:Hydrogen chloride=1:0.5-6, the temperature of deprotection reaction
It is 0-35 DEG C to spend, and the deprotection reaction time is 1-8 hours.
Further, present invention additionally comprises mashing purifying is carried out to product crude product the step of, mashing solvent is absolute ethyl alcohol.
Synthetic method reaction time of the present invention is short, and high conversion rate, product quality is excellent, the 2- amino methylpyrimidine salt produced
Hydrochlorate yield content more than 70% more than 99%, meets technical requirements of the market to 2- amino methylpyrimidine hydrochlorides, and
Operating procedure is simple, and required equipment is simple, and energy consumption is low.
Specific embodiment
The present invention is further illustrated with reference to embodiment, can make those skilled in the art that this hair is more completely understood
It is bright, but do not limit the invention in any way.
The 2- amino methylpyrimidine hydrochlorides of embodiment 1
100mL is added in hydrogenation bottle(20vol)Ethyl acetate, 50mL water(10vol)(Purified water), 2.28g NaOH
(0.0571mol, 1.2eq), 10.9gBoC2O acid anhydrides(0.05mol, 1.05eq), it is cooled to room temperature(20-25℃), add
0.5g20% palladium dydroxides/carbon(0.000712mol, 0.015eq), 5g 2- cyanopyrimidines(0.0476mol, 1.0eq), sealing
Good, nitrogen displacement 3 times, hydrogen is replaced 3 times, keeps Hydrogen Vapor Pressure 2atm, room temperature(20-25℃)Stirring 16 hours, TLC confirms nothing
Raw material, is filtered to remove insoluble matter, and point liquid, organic phase is washed once with 50mL saturated common salts, is cooled to 0-5 DEG C, is passed through hydrogen chloride
Gas about 15g, stirs 8 hours, and TLC confirms that reaction is complete, all takes off protection group.Crude product is filtered to obtain, 30mL ethanol is beaten,
Filtering, dries to obtain 5.3g hydrochlorides, yield 76.8%, purity 99.1%.
1H NMR(400MHz DMSO) δ:9.1(m, 2H) 8.8(s, 3H) 7.5(t, 1H) 4.2(s, 2H)。
2- amino methyl -4- methyl-pvrimidine the hydrochlorides of embodiment 2
25mL is added in hydrogenation bottle(5vol)Ethyl acetate, 25mL water(5vol)(Purified water), 2.59g potassium hydroxide
(0.0462mol, 1.1eq), 9.6gBoC2O acid anhydrides(0.0441mol, 1.05eq), it is cooled to room temperature(20-25℃), add
0.5g10% palladiums/carbon(0.00047mol, 0.011eq), 5g4- methyl -2- cyanopyrimidines(0.0420mol, 1.0eq), good seal,
Nitrogen displacement 3 times, hydrogen is replaced 3 times, keeps Hydrogen Vapor Pressure 0.5atm, room temperature(20-25℃)Stirring 24 hours, TLC confirms nothing
Raw material, is filtered to remove insoluble matter, and point liquid, organic phase is washed once with 50mL saturated common salts, is cooled to 0-5 DEG C, is passed through hydrogen chloride
Gas about 2.5g, stirs 3 hours, and TLC confirms that reaction is complete, all takes off protection group.Crude product is filtered to obtain, 30mL ethanol is beaten
Slurry, filtering, dries to obtain 4.74g hydrochlorides, yield 70.7%, purity 99.0%.
1H NMR(400MHz DMSO) δ:9.1(m, 1H) 8.8(s, 3H) 7.5(t, 1H) 4.2(s, 2H) 2.3
(s,3H)。
2- amino methyl -5- methylpyrimidine the hydrochlorides of embodiment 3
150mL is added in hydrogenation bottle(30vol)Ethyl acetate, 75mL water(15vol)(Purified water), 6.68g sodium carbonate
(0.063mol, 1.5eq), 11.0gBoC2O acid anhydrides(0.0504mol, 1.2eq), it is cooled to(30-35 DEG C, add 0.5g20% hydrogen
Palladium oxide/carbon(0.000712mol, 0.017eq), 5g5- methyl -2- cyanopyrimidines(0.042mol, 1.0eq), good seal, nitrogen
Gas is replaced 3 times, and hydrogen is replaced 3 times, keeps Hydrogen Vapor Pressure 5atm, and 30-35 DEG C is stirred 8 hours, and TLC confirms, without raw material, to cross and filter
Insoluble matter is removed, point liquid, organic phase is washed once with 50mL saturated common salts, is cooled to 0-5 DEG C, is passed through hydrogen chloride gas about 30g, risen
Warm to 30-35 DEG C is stirred 1 hour, and TLC confirms that reaction is complete, all takes off protection group.Crude product is filtered to obtain, 30mL ethanol is beaten
Slurry, filtering, dries to obtain 4.95g hydrochlorides, yield 73.9%, purity 99.1%.
1H NMR(400MHz DMSO) δ:9.1(m, 2H) 8.8(s, 3H) 4.2(s, 2H) 2.3(s,3H)。
2- amino methyl -4- ethyl-pyrimidine the hydrochlorides of embodiment 4
100mL is added in hydrogenation bottle(20vol)Ethyl acetate, 50mL water(10vol)(Purified water), 6.75g potassium carbonate
(0.0488mol, 1.3eq), 9.0gBoC2O acid anhydrides(0.0414mol, 1.1eq), be cooled to 10-15 DEG C, add 0.5g10% palladiums/
Carbon(0.00047mol, 0.013eq), 5g4- ethyl -2- cyanopyrimidines(0.0376mol, 1.0eq), good seal, nitrogen displacement 3
Secondary, hydrogen is replaced 3 times, keeps Hydrogen Vapor Pressure 2atm, and 10-15 DEG C is stirred 16 hours, and TLC is confirmed without raw material, is filtered to remove insoluble
Thing, point liquid, organic phase is washed once with 50mL saturated common salts, is cooled to 0-5 DEG C, is passed through hydrogen chloride gas about 15g, and stirring 3 is small
When, TLC confirms that reaction is complete, all takes off protection group.Crude product is filtered to obtain, 4.92g is dried to obtain in 30mL ethanol mashing, filtering
Hydrochloride, yield 75.4%, purity 99.2%.
1H NMR(400MHz DMSO) δ:9.1(m, 1H) 8.8(s, 3H) 7.5(t, 1H) 4.2(s, 2H) 3.0
(m, 2H) 1.3(t, 3H)。
2- amino methyl -5- ethyl-pyrimidine the hydrochlorides of embodiment 5
100mL is added in hydrogenation bottle(20vol)Ethyl acetate, 50mL water(10vol)(Purified water), 1.80g NaOH
(0.0451mol, 1.2eq), 8.62gBoC2O acid anhydrides(0.0395mol, 1.05eq), it is cooled to room temperature(20-25℃), add
0.5g20% palladium dydroxides/carbon(0.000712mol, 0.019eq), 5g5- ethyl -2- cyanopyrimidines(0.0376mol, 1.0eq),
Good seal, nitrogen displacement 3 times, hydrogen is replaced 3 times, keeps Hydrogen Vapor Pressure 2atm, and 30-35 DEG C is stirred 16 hours, and TLC is confirmed without original
Material, is filtered to remove insoluble matter, and point liquid, organic phase is washed once with 50mL saturated common salts, is cooled to 0-5 DEG C, is passed through hydrogen chloride gas
Body about 15g, stirs 3 hours, and TLC confirms that reaction is complete, all takes off protection group.Filter to obtain crude product, the mashing of 30mL ethanol, mistake
Filter, dries to obtain 4.96g hydrochlorides, yield 76.1%, purity 99.0%.
1H NMR(400MHz DMSO) δ:9.1(m, 2H) 8.8(s, 3H) 4.2(s, 2H) 3.0(m, 2H) 1.3
(t, 3H)。
Claims (10)
1. the synthetic method of a kind of 2- amino methylpyrimidines hydrochloride and its derivative, it is characterised in that its step is:In reaction
Organic solvent, water, Boc are added in device at room temperature2O acid anhydrides and alkali, then at add at room temperature catalyst and 2- cyanopyrimidines or
Its derivative, being passed through hydrogen carries out reduction reaction, and reduction reaction product is passed through hydrogen chloride, and deprotection obtains product 2- amino methyls
The hydrochloride of pyrimidine hydrochloride or its corresponding derivative.
2. method according to claim 1, it is characterised in that:The 2- amino methylpyrimidines hydrochloride and its derivative knot
Structure is:
Wherein R1 is located at 4 or 5, and R1 is hydrogen or methyl or ethyl.
3. method according to claim 1, it is characterised in that:The derivative choosing of the 2- amino methylpyrimidines hydrochloride
From:
2- amino methyl -4- methyl-pvrimidine hydrochlorides
2- amino methyl -4- ethyl-pyrimidine hydrochlorides
2- amino methyl -5- methylpyrimidine hydrochlorides
2- amino methyl -5- ethyl-pyrimidine hydrochlorides.
4. the synthetic method of 2- amino methylpyrimidines hydrochloride according to claim 1 and its derivative, it is characterised in that:
The organic solvent is ethyl acetate.
5. the synthetic method of 2- amino methylpyrimidines hydrochloride according to claim 1 and its derivative, it is characterised in that:
The alkali is NaOH, potassium hydroxide, sodium carbonate or potassium carbonate.
6. the synthetic method of 2- amino methylpyrimidines hydrochloride according to claim 1 and its derivative, it is characterised in that:
The catalyst is 20wt% palladium dydroxides/carbon or 10wt% palladiums/carbon.
7. the synthetic method of 2- amino methylpyrimidines hydrochloride according to claim 1 and its derivative, it is characterised in that:
Each material mol ratio is in the reduction reaction:2- cyanopyrimidines or derivatives thereof:Boc2O acid anhydrides:Alkali=1:1.0-1.3:1.0-
1.7, volume ratio organic solvent:Water=5-30:2.5-15, wherein 2- cyanopyrimidines or derivatives thereof are 1 with the mass ratio of water:
2.5-15;The temperature of the reduction reaction is 10-35 DEG C, and the reaction time is 8-24 hours, and the pressure for being passed through hydrogen is 0.5-
5atm。
8. the synthetic method of 2- amino methylpyrimidines hydrochloride according to claim 4 and its derivative, it is characterised in that:
In the reduction reaction, mol ratio 2- cyanopyrimidines or derivatives thereof:Palladium dydroxide or palladium=1:0.005-0.05.
9. the synthetic method of 2- amino methylpyrimidines hydrochloride according to claim 1 and its derivative, it is characterised in that:
Mass ratio 2- cyanopyrimidines or derivatives thereof in the deprotection reaction:Hydrogen chloride=1:0.5-6, the temperature of deprotection reaction is
0-35 DEG C, the deprotection reaction time is 1-8 hours.
10. the synthetic method of 2- amino methylpyrimidines hydrochloride according to claim 1 and its derivative, its feature exists
In:Mashing purifying is carried out to products obtained therefrom, mashing solvent is absolute ethyl alcohol.
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CN114890953A (en) * | 2022-07-15 | 2022-08-12 | 济南宣正药业有限公司 | Preparation method of 2-aminomethyl pyrimidine hydrochloride |
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