CN105924402A - Preparation method of 2-amido methylpyrimidine hydrochloride - Google Patents
Preparation method of 2-amido methylpyrimidine hydrochloride Download PDFInfo
- Publication number
- CN105924402A CN105924402A CN201610304245.2A CN201610304245A CN105924402A CN 105924402 A CN105924402 A CN 105924402A CN 201610304245 A CN201610304245 A CN 201610304245A CN 105924402 A CN105924402 A CN 105924402A
- Authority
- CN
- China
- Prior art keywords
- preparation
- amido
- feldalat
- aminomethyl pyrimidine
- hydrochloride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000001914 filtration Methods 0.000 claims abstract description 11
- 239000000706 filtrate Substances 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims abstract description 7
- 239000000047 product Substances 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 19
- RZNKMZKAXJTLQR-UHFFFAOYSA-N pyrimidin-2-ylmethanamine;hydrochloride Chemical compound Cl.NCC1=NC=CC=N1 RZNKMZKAXJTLQR-UHFFFAOYSA-N 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 12
- KPHYZXNSRFAWKM-UHFFFAOYSA-N methanesulfonic acid pyrimidin-2-ylmethanamine Chemical compound CS(O)(=O)=O.NCc1ncccn1 KPHYZXNSRFAWKM-UHFFFAOYSA-N 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 4
- 150000003230 pyrimidines Chemical class 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 230000003247 decreasing effect Effects 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 238000000967 suction filtration Methods 0.000 abstract 1
- 239000007789 gas Substances 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 208000010228 Erectile Dysfunction Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 201000001881 impotence Diseases 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- VTSWSQGDJQFXHB-UHFFFAOYSA-N 2,4,6-trichloro-5-methylpyrimidine Chemical compound CC1=C(Cl)N=C(Cl)N=C1Cl VTSWSQGDJQFXHB-UHFFFAOYSA-N 0.000 description 1
- -1 3-chloro-4-methoxy benzyl Chemical group 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- IIHQNAXFIODVDU-UHFFFAOYSA-N pyrimidine-2-carbonitrile Chemical compound N#CC1=NC=CC=N1 IIHQNAXFIODVDU-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a preparation method of 2-amido methylpyrimidine hydrochloride, and relates to the technical field of organic synthesis. The preparation method comprises the steps that 2-amido methylpyrimidine mesylate is taken as a raw material, sodium methylate is added at certain temperature, suction filtration is conducted after reacting is finished, the temperature of filtrate is decreased to certain temperature, an enough amount of hydrochloric acid gas is introduced, and stirring and filtering are conducted to obtain the product 2-amido methylpyrimidine hydrochloride. The 2-amido methylpyrimidine hydrochloride is simple in preparation technology, low in cost and simple in aftertreatment; in addition, the product purity reaches 99.5% or above, the yield reaches 85% or above, and the preparation method is suitable for industrialized production.
Description
Technical field:
The present invention relates to technical field of organic synthesis, be specifically related to the system of a kind of 2-aminomethyl pyrimidine hydrochloride
Preparation Method.
Background technology:
2-aminomethyl pyrimidine hydrochloride, CAS 372118-67-7, is the raw material of medicine avanaphil,
Avanaphil, No. CAS: 330784-47-9, Chinese another name: 4-[(3-chloro-4-methoxy benzyl) ammonia
Base]-2-[2-(methylol)-1-pyrrolidinyl]-N-(2-Pyrimidylmethyl)-5-pyrimidine Methanesulfomide is a kind of phosphoric acid
Diesterase 5 (PDE5) inhibitor, is used for treating male erectile dysfunction (ED).
WO2005/113553 2-cyanopyrimidine is raw material, under conditions of methanol, water, hydrogen chloride, uses
The method of palladium carbon catalytic hydrogenation, prepares 2-aminomethyl pyrimidine hydrochloride；US2004/142930 2-cyano group
Pyrimidine is raw material, under conditions of ethanol, hydrogen chloride, by the method for nickel catalytic hydrogenation, prepares 2-amido first
Yl pyrimidines hydrochlorate.There is the shortcoming that preparation cost is high, product purity is low in both approaches, is not suitable for work
Industry large-scale production.
Summary of the invention:
The technical problem to be solved is the 2-amido providing a kind of low cost, yield and purity high
The preparation method of methylpyrimidine hydrochlorate.
The technical problem to be solved uses following technical scheme to realize:
The preparation method of a kind of 2-aminomethyl pyrimidine hydrochloride, is former with 2-aminomethyl pyrimidine mesylate
Material, adds Feldalat NM at a certain temperature, and reaction terminates rear sucking filtration, gained filtrate is down to uniform temperature,
It is passed through enough HCl gas again, stirring, filter, obtain product 2-aminomethyl pyrimidine hydrochloride.
The addition temperature of described Feldalat NM is-10～10 DEG C.
Described Feldalat NM is solid or Feldalat NM/methanol solution.
The temperature that is passed through of described HCl gas is-10～10 DEG C.
The invention has the beneficial effects as follows: the present invention is with 2-aminomethyl pyrimidine mesylate as raw material, with methanol
After sodium reaction again with hydrochloric acid reaction, i.e. prepare 2-aminomethyl pyrimidine hydrochloride, preparation technology is simple, cost
Low, post processing is simple, and product purity reaches more than 99.5%, and yield reaches more than 85%, is suitable for industry
Metaplasia is produced.
Detailed description of the invention:
For the technological means making the present invention realize, creation characteristic, reach purpose and effect and be readily apparent from
Solve, below in conjunction with specific embodiment, the present invention is expanded on further.
Embodiment 1
Reaction bulb adds 2-aminomethyl pyrimidine mesylate, is cooled to-10 DEG C, is dividedly in some parts Feldalat NM
Solid, stirs 1h, and sucking filtration, filtrate again puts in reaction bulb, is cooled to-10 DEG C, is passed through enough salt
Acid gas, reacts 2h, sucking filtration, is dried, obtains 2-aminomethyl pyrimidine hydrochloride, and purity is more than 99.5%,
Yield 89%.
Embodiment 2
Reaction bulb adds 2-aminomethyl pyrimidine mesylate, is cooled to-10 DEG C, drip Feldalat NM/methanol
Liquid, stirs 1h, and sucking filtration, filtrate again puts in reaction bulb, is cooled to-10 DEG C, is passed through enough salt
Acid gas, reacts 2h, sucking filtration, is dried, obtains 2-aminomethyl pyrimidine hydrochloride, and purity is more than 99.5%,
Yield 86%.
Embodiment 3
Reaction bulb adds 2-aminomethyl pyrimidine mesylate, is cooled to 0 DEG C, be dividedly in some parts Feldalat NM solid
Body, stirs 1h, and sucking filtration, filtrate puts in reaction bulb again, is cooled to 0 DEG C, is passed through enough hydrogen chloride gas
Body, reacts 2h, sucking filtration, is dried, obtains 2-aminomethyl pyrimidine hydrochloride, and purity is more than 99.5%, receives
Rate 88.5%.
Embodiment 4
Reaction bulb adds 2-aminomethyl pyrimidine mesylate, is cooled to 0 DEG C, drip Feldalat NM/methanol solution
Body, stirs 1h, and sucking filtration, filtrate again puts in reaction bulb, is cooled to 0-5 DEG C, is passed through enough hydrochloric acid
Gas, reacts 2h, sucking filtration, is dried, obtains 2-aminomethyl pyrimidine hydrochloride, and purity is more than 99.5%,
Yield 86.5%.
The ultimate principle of the present invention and principal character and advantages of the present invention have more than been shown and described.One's own profession
Skilled person will appreciate that of industry, the present invention is not restricted to the described embodiments, above-described embodiment and explanation
The principle that the present invention is simply described described in book, without departing from the spirit and scope of the present invention,
The present invention also has various changes and modifications, and these changes and improvements both fall within claimed invention model
In enclosing.Claimed scope is defined by appending claims and equivalent thereof.
Claims (4)
1. the preparation method of a 2-aminomethyl pyrimidine hydrochloride, it is characterised in that: with 2-aminomethyl
Pyrimidine mesylate is raw material, adds Feldalat NM at a certain temperature, and reaction terminates rear sucking filtration, by gained
Filtrate is down to uniform temperature, then is passed through enough HCl gas, stirring, filters, obtains product 2-amido first
Yl pyrimidines hydrochlorate.
The preparation method of 2-aminomethyl pyrimidine hydrochloride the most according to claim 1, it is characterised in that:
The addition temperature of described Feldalat NM is-10～10 DEG C.
The preparation method of 2-aminomethyl pyrimidine hydrochloride the most according to claim 1, it is characterised in that:
Described Feldalat NM is solid or Feldalat NM/methanol solution.
The preparation method of 2-aminomethyl pyrimidine hydrochloride the most according to claim 1, it is characterised in that:
The temperature that is passed through of described HCl gas is-10～10 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610304245.2A CN105924402A (en) | 2016-05-06 | 2016-05-06 | Preparation method of 2-amido methylpyrimidine hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610304245.2A CN105924402A (en) | 2016-05-06 | 2016-05-06 | Preparation method of 2-amido methylpyrimidine hydrochloride |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105924402A true CN105924402A (en) | 2016-09-07 |
Family
ID=56834303
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610304245.2A Pending CN105924402A (en) | 2016-05-06 | 2016-05-06 | Preparation method of 2-amido methylpyrimidine hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105924402A (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004083495A (en) * | 2002-08-27 | 2004-03-18 | Koei Chem Co Ltd | Method for preparing 2-aminomethylpyrimidine and its salt |
| CN102584799A (en) * | 1999-09-16 | 2012-07-18 | 田边三菱制药株式会社 | Aromatic nitrogenous six-membered ring compounds |
| CN103254180A (en) * | 2013-05-23 | 2013-08-21 | 苏州明锐医药科技有限公司 | Preparation method of Avanafil |
| 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 |
| WO2015177807A1 (en) * | 2014-05-22 | 2015-11-26 | Wanbury Ltd. | A process for the preparation of avanafil and its novel intermediates |
| CN105229010A (en) * | 2013-01-29 | 2016-01-06 | 阿普廷伊克斯股份有限公司 | Spiral shell-lactan nmda receptor conditioning agent and uses thereof |
-
2016
- 2016-05-06 CN CN201610304245.2A patent/CN105924402A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584799A (en) * | 1999-09-16 | 2012-07-18 | 田边三菱制药株式会社 | Aromatic nitrogenous six-membered ring compounds |
| JP2004083495A (en) * | 2002-08-27 | 2004-03-18 | Koei Chem Co Ltd | Method for preparing 2-aminomethylpyrimidine and its salt |
| CN105229010A (en) * | 2013-01-29 | 2016-01-06 | 阿普廷伊克斯股份有限公司 | Spiral shell-lactan nmda receptor conditioning agent and uses thereof |
| CN103254180A (en) * | 2013-05-23 | 2013-08-21 | 苏州明锐医药科技有限公司 | Preparation method of Avanafil |
| 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 |
| WO2015177807A1 (en) * | 2014-05-22 | 2015-11-26 | Wanbury Ltd. | A process for the preparation of avanafil and its novel intermediates |
Non-Patent Citations (3)
| Title |
|---|
| 四川医学院: "《药物化学》", 31 January 1981 * |
| 田红潮，等: "阿伐那非的合成研究进展", 《山东化工》 * |
| 胡惟笑，等: "《有机化合物制备手册》", 31 March 1995 * |
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| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20160907 |