CN109503551A - The preparation method of one koji Ge Lieting - Google Patents
The preparation method of one koji Ge Lieting Download PDFInfo
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- CN109503551A CN109503551A CN201811412474.1A CN201811412474A CN109503551A CN 109503551 A CN109503551 A CN 109503551A CN 201811412474 A CN201811412474 A CN 201811412474A CN 109503551 A CN109503551 A CN 109503551A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention discloses the preparation methods of a koji Ge Lieting, methyl urea and diethyl malonate is used to prepare 3- methyl -6- chlorouracil for initial feed, it is simultaneously that initial feed prepares 2- chloromethyl -4- fluorobenzonitrile by 2- methylol -4- fluorobenzonitrile, bent Ge Lieting is prepared by 3- methyl -6- chlorouracil and 2- chloromethyl -4- fluorobenzonitrile again, the cost of material of use is low, preparation flow is easy to control, and is convenient for industrialized production.
Description
Technical field
The present invention relates to technical field of organic synthesis, the more particularly to preparation method of a koji Ge Lieting.
Background technique
Bent Ge Lieting succinate (Trelagliptinsuccinate), chemical name: (R) -2- ((6- (3- amino piperidine
- 1- base) -1 (2H)-yl of -3- methyl -2,4- dioxo -3,4- dihydro-pyrimidin) methyl) -4- fluorobenzonitrile succinate, be by
The novel DPP-IV inhibitors of Takeda Pharmaceutical Company Limited's research and development.On March 26th, 2015 is mainly used for long-term in Japan's approval listing
The treatment of type-2 diabetes mellitus, medication is primary weekly, can effectively improve conditions of patients, easy to use and improve patient's compliance,
Adverse reaction is few, therefore it is a kind of drug of novel, potential treatment type-2 diabetes mellitus.
But it is if usually former for starting with the fluoro- 2- halogen methyl cyanophenyl of 4- and 3- methyl -6- chlorouracil in the prior art
Material, be made intermediate 2- ((chloro- 3- methyl -2,4- dioxo -3, the 4- dihydro -2H- pyrimidine -1- methyl of 6-) -4- fluorobenzonitrile,
Aminolysis reaction is carried out with (R) -3- amino piperidine again, and song Ge Lieting is made.Wherein, 3- methyl -6- chlorouracil cost of material is high,
And the reaction for synthesizing 3- methyl -6- chlorouracil is generally cyclization and the halogenating reaction of diethyl malonate and methylurea, preparation
1- methylpyrimidine -2,4, in the reaction of 6- triketone, severe reaction conditions, the reaction time reaches 72h, and yield is lower；The fluoro- 2- halogen of 4-
The general synthetic method of methyl cyanophenyl is to first pass through cyaniding using the fluoro- 2 bromo toluene of 5- as raw material, using N-bromosuccinimide
(NBS) replace and be prepared, but wherein cyanation step uses highly toxic copper cyanider, is unfavorable for safety in production and environment is protected
Shield.
Therefore it provides the bent Ge Lieting preparation method that a kind of cost of material is low, production process is highly-safe is this field skill
The problem of art personnel's urgent need to resolve.
Summary of the invention
In view of this, the present invention provides the preparation methods of a koji Ge Lieting, using methyl urea and malonic acid diethyl
Ester is that initial feed prepares 3- methyl -6- chlorouracil, while preparing 2- chlorine by 2- methylol -4- fluorobenzonitrile for initial feed
Methyl -4- fluorobenzonitrile, then bent Ge Lieting is prepared by 3- methyl -6- chlorouracil and 2- chloromethyl -4- fluorobenzonitrile,
The cost of material of use is low, preparation flow is easy to control, and is convenient for industrialized production.
To achieve the goals above, the present invention adopts the following technical scheme:
The preparation method of one koji Ge Lieting, which is characterized in that specifically comprise the following steps:
(1) it prepares 3- methyl -6- chlorouracil: first being prepared under catalysts conditions by methyl urea and diethyl malonate
1- methylpyrimidine -2,4 is obtained, 6- triketone, using 1- methylpyrimidine -2,4,6- triketone and phosphorus oxychloride reaction obtain 3- first
Base -6- chlorouracil；
(2) it prepares 2- chloromethyl -4- fluorobenzonitrile: being prepared by 2- methylol -4- fluorobenzonitrile by chlorination reaction
2- chloromethyl -4- fluorobenzonitrile；
(3) song Ge Lieting: the 2- chlorine that the 3- methyl -6- chlorouracil and step (2) obtained by step (1) obtains is prepared
Methyl -4- fluorobenzonitrile first passes through substitution reaction, and bent Ge Lieting is prepared using aminating reaction.
Preferably, the step (1) specifically comprises the following steps:
(A) first methyl urea is dissolved in a solvent, is then slowly added into catalyst, obtain reaction solution；Then by third
Diethyl adipate dissolution, and be slowly dropped in reaction solution, while heating reaction solution to reflux and being reacted, finally pass through
1- methylpyrimidine -2,4,6- triketone can be obtained in purification, drying；
(B) first by the above-mentioned 1- methylpyrimidine -2,4 being prepared, 6- triketone is uniformly mixed with phosphorus oxychloride, then controls
Temperature is reacted, and 3- methyl -6- chlorouracil finally can be obtained by purification, drying.
Specific reaction equation is as follows:
Preferably, in the step (A) catalyst be metallic sodium, solvent include methanol, ethyl alcohol, propyl alcohol or isopropanol wherein
It is one or more, the molar ratio of the methyl urea, diethyl malonate and catalyst is 1: 1.2~2: 1~1.5, reflux
Under the conditions of react 18~20h.
Preferably, 0.6~0.8h of reaction is first controlled under the conditions of 0~5 DEG C in the step (B), then control 50~
1.2~1.5h is reacted under the conditions of 58 DEG C.
Preferably, the step (2) specifically: first by 2- methylol -4- fluorobenzonitrile and chlorination reagent according to weight ratio
It being uniformly mixed for 1: 4~5, then controls reaction temperature and carry out chlorination reaction, recycling excess chlorination reagent is concentrated into dripless,
Then it is added into organic solvent and dissolves to obtain 2- chloromethyl -4- fluorobenzonitrile solution for standby.
Specific reaction equation is as follows:
Preferably, the chlorination reagent includes thionyl chloride, phosphorus trichloride, phosphorus pentachloride, trim,ethylchlorosilane, N- phenyl
Saccharin chlorine, hexachloroacetone-triphenylphosphine, carbon tetrahalide-triphenyl phosphine, N- chlorosuccinimide-triphenylphosphine or
One of mesyl chloride is a variety of；
The condition of the chlorination reaction are as follows: 6~10h is reacted under the conditions of 30~65 DEG C；
The organic solvent include one of toluene, n,N-Dimethylformamide, benzene, chloroform or methyl tertiary butyl ether(MTBE) or
It is a variety of.
Preferably, the step (3) specifically comprises the following steps:
(a) the 3- methyl -6- chlorouracil that step (1) is prepared first is dissolved in n,N-diisopropylethylamine and N- first
3- methyl -6- chlorouracil solution is obtained in the mixture of base pyrrolidones；Then 3- methyl -6- chlorouracil solution is delayed
Slowly it is added dropwise in the 2- chloromethyl -4- fluorobenzonitrile solution that step (2) obtains, 2~5h is then reacted under the conditions of 40~58 DEG C,
2- [(chloro- -1 (the 2H)-pyrimidine radicals of 3,4- dihydro -3- methyl -2,4- dioxo of 6-) methyl] -4- fluorobenzonitrile is prepared；
(b) (R) -3- amino piperidine dihydrochloride and potassium carbonate are added in the mixed solvent and dissolve to obtain hybrid reaction
Liquid；
(c) 2- [(chloro- -1 (the 2H)-pyrimidine radicals of 3,4- dihydro -3- methyl -2,4- dioxo of the 6-) first obtained step (a)
Base] -4- fluorobenzonitrile be added step (b) mixed reaction solution in, then under the conditions of 66~69 DEG C react 8~10h.
Specific reaction equation is as follows:
Preferably, the molar ratio of 3- methyl -6- chlorouracil and 2- chloromethyl -4- fluorobenzonitrile is 1 in the step (a):
1.2~1.5；The n,N-diisopropylethylamine and N-Methyl pyrrolidone are mixed according to 3: 7 volume ratios.
Preferably, in the step (b) mixed solvent by isopropanol, methanol, ethyl alcohol, normal propyl alcohol, n-butanol or tetrahydro furan
It one of mutters or a variety of and water according to volume ratio is to be mixed to get at 18~20: 1；(R) -3- amino piperidine dihydrochloride and carbon
Sour potassium is mixed according to 1: 3.5 molar ratio.
Preferably, 2- [(chloro- -1 (the 2H)-pyrimidine radicals of 3,4- dihydro -3- methyl -2,4- dioxo of 6-) in the step (c)
Methyl] molar ratio of -4- fluorobenzonitrile and (R) -3- amino piperidine dihydrochloride is 1: 1.2~1.4.
It can be seen via above technical scheme that compared with prior art, the present disclosure provides a koji Ge Lieting's
Preparation method has the following beneficial effects:
(1) cost of material that synthetic method disclosed by the invention uses is low, and method overall simple, efficiently, can guarantee
Shorten the reaction time under the premise of product yield, improves product quality；
(2) present invention is in synthesis 1- methylpyrimidine -2,4, the reaction of 6- triketone, using methanol, ethyl alcohol, propyl alcohol or isopropyl
Alcohol will shorten within 20h as solvent, and greatly shorten the reaction time, improve production efficiency in the reaction time；
(3) present invention preparation 2- chloromethyl -4- fluorobenzonitrile is used as song Ge Lieting synthetic intermediate, is not only able to improve bent
The stability of Ge Lieting synthetic intermediate, and then the synthesis difficulty of song Ge Lieting is reduced, and 2- chloromethyl -4- fluorobenzonitrile
Itself is nontoxic, nonirritant, can be avoided the damage because of irritation present in synthetic intermediate to operator's health.
Specific embodiment
The technical scheme in the embodiments of the invention will be clearly and completely described below, it is clear that described implementation
Example is only a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, this field is common
Technical staff's every other embodiment obtained without making creative work belongs to the model that the present invention protects
It encloses.
The embodiment of the invention discloses the preparation methods of a koji Ge Lieting, specifically comprise the following steps:
(1) 3- methyl -6- chlorouracil is prepared
It (A) is that 1: 1.2~2: 1~1.5 mixing claim according to the molar ratio of methyl urea, diethyl malonate and catalyst
Take each raw material；Methyl urea is dissolved in a solvent first, is then slowly added into metallic sodium, obtains reaction solution；Then by the third two
Diethyl phthalate dissolution, and be slowly dropped in reaction solution, while heating 18~20h of reaction under reaction solution to counterflow condition,
1- methylpyrimidine -2,4,6- triketone finally can be obtained by purification, drying；Wherein solvent includes methanol, ethyl alcohol, propyl alcohol or different
Propyl alcohol is one such or a variety of；
(B) first by the above-mentioned 1- methylpyrimidine -2,4 being prepared, 6- triketone is uniformly mixed with phosphorus oxychloride, then controls
0.6~0.8h is reacted under the conditions of 0~5 DEG C, 1.2~1.5h of reaction under the conditions of 50~58 DEG C is then controlled, finally by mentioning
3- methyl -6- chlorouracil can be obtained in pure, drying.
(2) 2- chloromethyl -4- fluorobenzonitrile is prepared
First 2- methylol -4- fluorobenzonitrile is uniformly mixed with chlorination reagent according to weight ratio for 1: 4~5, is then controlled
6~10h is reacted under the conditions of 30~65 DEG C, recycling excess chlorination reagent is concentrated into dripless, is then added into organic solvent
Dissolve to obtain 2- chloromethyl -4- fluorobenzonitrile solution for standby；
Wherein, chlorination reagent includes thionyl chloride, phosphorus trichloride, phosphorus pentachloride, trim,ethylchlorosilane, N- phenyl benzene first
Acid imide chlorine, hexachloroacetone-triphenylphosphine, carbon tetrahalide-triphenyl phosphine, N- chlorosuccinimide-triphenylphosphine or methylsulphur
One of acyl chlorides is a variety of；
Wherein, organic solvent includes one of toluene, n,N-Dimethylformamide, benzene, chloroform or methyl tertiary butyl ether(MTBE)
Or it is a variety of.
(3) song Ge Lieting is prepared
(a) the 3- methyl -6- chlorouracil that step (1) is prepared first is dissolved in n,N-diisopropylethylamine and N- first
3- methyl -6- chlorouracil solution is obtained in the mixture of base pyrrolidones；Then according to 3- methyl -6- chlorouracil and 2-
3- methyl -6- chlorouracil solution is slowly added dropwise into step (2) for 1: 1.2~1.5 for the molar ratio of chloromethyl -4- fluorobenzonitrile
In obtained 2- chloromethyl -4- fluorobenzonitrile solution, 2~5h is then reacted under the conditions of 40~58 DEG C, 2- [(6- is prepared
Chloro- -1 (2H)-pyrimidine radicals of 3,4- dihydro -3- methyl -2,4- dioxo) methyl] -4- fluorobenzonitrile；Wherein N, N- diisopropyl
Ethamine and N-Methyl pyrrolidone are mixed according to 3: 7 volume ratios；
(b) (R) -3- amino piperidine dihydrochloride and potassium carbonate are added jointly according to 1: 3.5 molar ratio to mixed solvent
Middle dissolution obtains mixed reaction solution；Wherein mixed solvent is by isopropanol, methanol, ethyl alcohol, normal propyl alcohol, n-butanol or tetrahydrofuran
One or more and water according to volume ratio be to be mixed to get at 18~20: 1；
(c) according to 2- [(chloro- -1 (the 2H)-pyrimidine radicals of 3,4- dihydro -3- methyl -2,4- dioxo of 6-) methyl] -4- fluorobenzene
The molar ratio of formonitrile HCN and (R) -3- amino piperidine dihydrochloride is 1: 1.2~1.4 the 2- [(6- chloro- 3,4- for obtaining step (a)
- 1 (2H)-pyrimidine radicals of dihydro -3- methyl -2,4- dioxo) methyl] -4- fluorobenzonitrile be added step (b) mixed reaction solution
In, 8~10h is then reacted under the conditions of 66~69 DEG C.
Embodiment 1
The embodiment of the present invention 1 discloses the preparation method of a koji Ge Lieting, specifically comprises the following steps:
(1) 3- methyl -6- chlorouracil is prepared
It (A) is that 1: 1.2: 1 mixing weighs each raw material according to the molar ratio of methyl urea, diethyl malonate and catalyst；
Methyl urea is dissolved in methyl alcohol first, is then slowly added into metallic sodium, obtains reaction solution；Then diethyl malonate is molten
Solution, and be slowly dropped in reaction solution, while heating and reacting 18h under reaction solution to counterflow condition, finally by purifying, doing
It is dry that 1- methylpyrimidine -2,4,6- triketone can be obtained；
(B) first by the above-mentioned 1- methylpyrimidine -2,4 being prepared, 6- triketone is uniformly mixed with phosphorus oxychloride, then controls
0.8h is reacted under the conditions of 0 DEG C, then controls and reacts 1.5h under the conditions of 50 DEG C, 3- finally can be obtained by purification, drying
Methyl -6- chlorouracil.
(2) 2- chloromethyl -4- fluorobenzonitrile is prepared
First 2- methylol -4- fluorobenzonitrile is uniformly mixed with phosphorus trichloride according to weight ratio for 1: 4, is then controlled 30
10h is reacted under the conditions of DEG C, recycling excess chlorination reagent is concentrated into dripless, is then added and dissolves to obtain 2- chloromethyl -4- into benzene
Fluorobenzonitrile solution for standby, can be obtained final product.
(3) song Ge Lieting is prepared
(a) the 3- methyl -6- chlorouracil that step (1) is prepared first is dissolved in n,N-diisopropylethylamine and N- first
3- methyl -6- chlorouracil solution is obtained in the mixture of base pyrrolidones；Then according to 3- methyl -6- chlorouracil and 2-
3- methyl -6- chlorouracil solution is slowly added dropwise for 1: 1.2 and obtains into step (2) by the molar ratio of chloromethyl -4- fluorobenzonitrile
2- chloromethyl -4- fluorobenzonitrile solution in, then react 5h under the conditions of 40 DEG C, 2- [(chloro- 3, the 4- dihydro-of 6- be prepared
- 1 (2H)-pyrimidine radicals of 3- methyl -2,4- dioxo) methyl] -4- fluorobenzonitrile；Wherein n,N-diisopropylethylamine and N- methyl
Pyrrolidones is mixed according to 3: 7 volume ratios；
(b) (R) -3- amino piperidine dihydrochloride and potassium carbonate are added jointly according to 1: 3.5 molar ratio to mixed solvent
Middle dissolution obtains mixed reaction solution；Wherein mixed solvent is mixed to get by isopropanol and water according to volume ratio for 18~20: 1；
(c) according to 2- [(chloro- -1 (the 2H)-pyrimidine radicals of 3,4- dihydro -3- methyl -2,4- dioxo of 6-) methyl] -4- fluorobenzene
The molar ratio of formonitrile HCN and (R) -3- amino piperidine dihydrochloride is 1: 1.24 2- [(chloro- 3, the 4- bis- of 6- for obtaining step (a)
- 1 (2H)-pyrimidine radicals of hydrogen -3- methyl -2,4- dioxo) methyl] -4- fluorobenzonitrile be added step (b) mixed reaction solution in,
Then 10h is reacted under the conditions of 66 DEG C, final product can be obtained.
Mass Spectrometer Method and nuclear magnetic resonance spectroscopy detection are carried out to obtained product, as a result as follows:
ESI-MS(m/z)358.14[M+H]+；
1H-NMR (500MHz, CD3OD): δ 7.80-7.82 (m, 1H), 7.21-7.23 (t, J=6.0,2.0Hz, 1H),
7.09-7.11 (m, 1H), 5.41 (s, 1H), 5.27 (s, 2H), 3.30 (s, 3H), 3.18 (d, 1H), 3.03 (d, 1H), 2.84
(t, J=4.0Hz, 1H), 2.64 (s, 1H), 2.45 (s, 1H), 1.96 (d, 1H), 1.93 (d, 1H), 1.74-1.77 (m, 1H),
1.60 (d, 1H), 1.24 (d, 1H), 1.17 (m, 1H).
Product its structural formula that the present invention is prepared can be learnt by above-mentioned detection data are as follows:
Embodiment 2
The embodiment of the present invention 2 discloses the preparation method of a koji Ge Lieting, specifically comprises the following steps:
(1) 3- methyl -6- chlorouracil is prepared
It (A) is that 1: 2: 1.5 mixing weighs each raw material according to the molar ratio of methyl urea, diethyl malonate and catalyst；
Methyl urea is dissolved in propyl alcohol first, is then slowly added into metallic sodium, obtains reaction solution；Then diethyl malonate is molten
Solution, and be slowly dropped in reaction solution, while heating and reacting 20h under reaction solution to counterflow condition, finally by purifying, doing
It is dry that 1- methylpyrimidine -2,4,6- triketone can be obtained；
(B) first by the above-mentioned 1- methylpyrimidine -2,4 being prepared, 6- triketone is uniformly mixed with phosphorus oxychloride, then controls
0.6h is reacted under the conditions of 5 DEG C, then controls and reacts 1.5h under the conditions of 58 DEG C, 3- finally can be obtained by purification, drying
Methyl -6- chlorouracil.
(2) 2- chloromethyl -4- fluorobenzonitrile is prepared
First 2- methylol -4- fluorobenzonitrile is uniformly mixed with phosphorus pentachloride according to weight ratio for 1: 5, is then controlled 30
6~10h is reacted under the conditions of~65 DEG C, is recycled excessive phosphorus pentachloride, is concentrated into dripless, is then added to N, N- dimethyl formyl
2- chloromethyl -4- fluorobenzonitrile solution for standby is dissolved to obtain in amine.
(3) song Ge Lieting is prepared
(a) the 3- methyl -6- chlorouracil that step (1) is prepared first is dissolved in n,N-diisopropylethylamine and N- first
3- methyl -6- chlorouracil solution is obtained in the mixture of base pyrrolidones；Then according to 3- methyl -6- chlorouracil and 2-
3- methyl -6- chlorouracil solution is slowly added dropwise for 1: 1.5 and obtains into step (2) by the molar ratio of chloromethyl -4- fluorobenzonitrile
2- chloromethyl -4- fluorobenzonitrile solution in, then react 2h under the conditions of 58 DEG C, 2- [(chloro- 3, the 4- dihydro-of 6- be prepared
- 1 (2H)-pyrimidine radicals of 3- methyl -2,4- dioxo) methyl] -4- fluorobenzonitrile；Wherein n,N-diisopropylethylamine and N- methyl
Pyrrolidones is mixed according to 3: 7 volume ratios；
(b) (R) -3- amino piperidine dihydrochloride and potassium carbonate are added jointly according to 1: 3.5 molar ratio to mixed solvent
Middle dissolution obtains mixed reaction solution；Wherein mixed solvent is mixed to get by normal propyl alcohol and water according to volume ratio for 20: 1；
(c) according to 2- [(chloro- -1 (the 2H)-pyrimidine radicals of 3,4- dihydro -3- methyl -2,4- dioxo of 6-) methyl] -4- fluorobenzene
The molar ratio of formonitrile HCN and (R) -3- amino piperidine dihydrochloride is 1: 1.4 2- [(chloro- 3, the 4- dihydro-of 6- for obtaining step (a)
- 1 (2H)-pyrimidine radicals of 3- methyl -2,4- dioxo) methyl] -4- fluorobenzonitrile be added step (b) mixed reaction solution in, so
8h is reacted under the conditions of 69 DEG C afterwards, final product can be obtained.
Mass Spectrometer Method and nuclear magnetic resonance spectroscopy detection are carried out to obtained product, as a result as follows:
ESI-MS(m/z)358.16[M+H]+；
1H-NMR (500MHz, CD3OD): δ 7.80-7.82 (m, 1H), 7.21-7.23 (t, J=6.0,2.0Hz, 1H),
7.09-7.11 (m, 1H), 5.41 (s, 1H), 5.27 (s, 2H), 3.30 (s, 3H), 3.18 (d, 1H), 3.03 (d, 1H), 2.84
(t, J=4.0Hz, 1H), 2.64 (s, 1H), 2.45 (s, 1H), 1.96 (d, 1H), 1.93 (d, 1H), 1.74-1.77 (m, 1H),
1.60 (d, 1H), 1.24 (d, 1H), 1.17 (m, 1H).
Product its structural formula that the present invention is prepared can be learnt by above-mentioned detection data are as follows:
Embodiment 3
The embodiment of the present invention 3 discloses the preparation method of a koji Ge Lieting, specifically comprises the following steps:
(1) 3- methyl -6- chlorouracil is prepared
It (A) is that 1: 1.6: 1.3 mixing weighs each original according to the molar ratio of methyl urea, diethyl malonate and catalyst
Material；Methyl urea is dissolved in the in the mixed solvent of ethyl alcohol and isopropanol first, metallic sodium is then slowly added into, obtains reacting molten
Liquid；Then diethyl malonate is dissolved, and be slowly dropped in reaction solution, while heated under reaction solution to counterflow condition
19h is reacted, 1- methylpyrimidine -2,4,6- triketone finally can be obtained by purification, drying；
(B) first by the above-mentioned 1- methylpyrimidine -2,4 being prepared, 6- triketone is uniformly mixed with phosphorus oxychloride, then controls
0.7h is reacted under the conditions of 3 DEG C, then controls and reacts 1.4h under the conditions of 56 DEG C, 3- finally can be obtained by purification, drying
Methyl -6- chlorouracil.
(2) 2- chloromethyl -4- fluorobenzonitrile is prepared
First 2- methylol -4- fluorobenzonitrile is uniformly mixed with trim,ethylchlorosilane according to weight ratio for 1: 4.5, is then controlled
System reacts 8h under the conditions of 55 DEG C, recycles excessive trim,ethylchlorosilane, is concentrated into dripless, is then added and dissolves into chloroform
2- chloromethyl -4- fluorobenzonitrile solution for standby；
(3) song Ge Lieting is prepared
(a) the 3- methyl -6- chlorouracil that step (1) is prepared first is dissolved in n,N-diisopropylethylamine and N- first
3- methyl -6- chlorouracil solution is obtained in the mixture of base pyrrolidones；Then according to 3- methyl -6- chlorouracil and 2-
3- methyl -6- chlorouracil solution is slowly added dropwise for 1: 1.3 and obtains into step (2) by the molar ratio of chloromethyl -4- fluorobenzonitrile
2- chloromethyl -4- fluorobenzonitrile solution in, then react 4h under the conditions of 55 DEG C, 2- [(chloro- 3, the 4- dihydro-of 6- be prepared
- 1 (2H)-pyrimidine radicals of 3- methyl -2,4- dioxo) methyl] -4- fluorobenzonitrile；Wherein n,N-diisopropylethylamine and N- methyl
Pyrrolidones is mixed according to 3: 7 volume ratios；
(b) (R) -3- amino piperidine dihydrochloride and potassium carbonate are added jointly according to 1: 3.5 molar ratio to mixed solvent
Middle dissolution obtains mixed reaction solution；Wherein mixed solvent is mixed by isopropanol and tetrahydrofuran with water according to volume ratio for 19: 1
It arrives；
(c) according to 2- [(chloro- -1 (the 2H)-pyrimidine radicals of 3,4- dihydro -3- methyl -2,4- dioxo of 6-) methyl] -4- fluorobenzene
The molar ratio of formonitrile HCN and (R) -3- amino piperidine dihydrochloride is 1: 1.34 2- [(chloro- 3, the 4- bis- of 6- for obtaining step (a)
- 1 (2H)-pyrimidine radicals of hydrogen -3- methyl -2,4- dioxo) methyl] -4- fluorobenzonitrile be added step (b) mixed reaction solution in,
Then 9h is reacted under the conditions of 68 DEG C, final product can be obtained.
Mass Spectrometer Method and nuclear magnetic resonance spectroscopy detection are carried out to obtained product, as a result as follows:
ESI-MS(m/z)358.11[M+H]+；
1H-NMR (500MHz, CD3OD): δ 7.80-7.82 (m, 1H), 7.21-7.23 (t, J=6.0,2.0Hz, 1H),
7.09-7.11 (m, 1H), 5.41 (s, 1H), 5.27 (s, 2H), 3.30 (s, 3H), 3.18 (d, 1H), 3.03 (d, 1H), 2.84
(t, J=4.0Hz, 1H), 2.64 (s, 1H), 2.45 (s, 1H), 1.96 (d, 1H), 1.93 (d, 1H), 1.74-1.77 (m, 1H),
1.60 (d, 1H), 1.24 (d, 1H), 1.17 (m, 1H).
Product its structural formula that the present invention is prepared can be learnt by above-mentioned detection data are as follows:
Embodiment 4
The embodiment of the present invention 4 discloses the preparation method of a koji Ge Lieting, specifically comprises the following steps:
(1) 3- methyl -6- chlorouracil is prepared
It (A) is that 1: 2: 1.5 mixing weighs each raw material according to the molar ratio of methyl urea, diethyl malonate and catalyst；
Methyl urea is dissolved in dehydrated alcohol first, is then slowly added into metallic sodium, obtains reaction solution；Then by malonic acid diethyl
Ester dissolution, and be slowly dropped in reaction solution, while heating and reacting 20h under reaction solution to counterflow condition, finally by mentioning
1- methylpyrimidine -2,4,6- triketone can be obtained in pure, drying；
(B) first by the above-mentioned 1- methylpyrimidine -2,4 being prepared, 6- triketone is uniformly mixed with phosphorus oxychloride, then controls
0.8h is reacted under the conditions of 5 DEG C, then controls and reacts 1.5h under the conditions of 58 DEG C, 3- finally can be obtained by purification, drying
Methyl -6- chlorouracil.
(2) 2- chloromethyl -4- fluorobenzonitrile is prepared
First 2- methylol -4- fluorobenzonitrile is uniformly mixed with thionyl chloride according to weight ratio for 1: 5, is then controlled 65
10h is reacted under the conditions of DEG C, recycling excess thionyl chloride is concentrated into dripless, is then added and dissolves to obtain 2- chloromethyl-into toluene
4- fluorobenzonitrile solution for standby；
(3) song Ge Lieting is prepared
(a) the 3- methyl -6- chlorouracil that step (1) is prepared first is dissolved in n,N-diisopropylethylamine and N- first
3- methyl -6- chlorouracil solution is obtained in the mixture of base pyrrolidones；Then according to 3- methyl -6- chlorouracil and 2-
3- methyl -6- chlorouracil solution is slowly added dropwise for 1: 1.5 and obtains into step (2) by the molar ratio of chloromethyl -4- fluorobenzonitrile
2- chloromethyl -4- fluorobenzonitrile solution in, then react 5h under the conditions of 58 DEG C, 2- [(chloro- 3, the 4- dihydro-of 6- be prepared
- 1 (2H)-pyrimidine radicals of 3- methyl -2,4- dioxo) methyl] -4- fluorobenzonitrile；Wherein n,N-diisopropylethylamine and N- methyl
Pyrrolidones is mixed according to 3: 7 volume ratios；
(b) (R) -3- amino piperidine dihydrochloride and potassium carbonate are added jointly according to 1: 3.5 molar ratio to mixed solvent
Middle dissolution obtains mixed reaction solution；Wherein mixed solvent is mixed to get by tetrahydrofuran and water according to volume ratio for 20: 1；
(c) according to 2- [(chloro- -1 (the 2H)-pyrimidine radicals of 3,4- dihydro -3- methyl -2,4- dioxo of 6-) methyl] -4- fluorobenzene
The molar ratio of formonitrile HCN and (R) -3- amino piperidine dihydrochloride is 1: 1.3 2- [(chloro- 3, the 4- dihydro-of 6- for obtaining step (a)
- 1 (2H)-pyrimidine radicals of 3- methyl -2,4- dioxo) methyl] -4- fluorobenzonitrile be added step (b) mixed reaction solution in, so
10h is reacted under the conditions of 69 DEG C afterwards, final product can be obtained.
Mass Spectrometer Method and nuclear magnetic resonance spectroscopy detection are carried out to obtained product, as a result as follows:
ESI-MS(m/z)358.14[M+H]+；
1H-NMR (500MHz, CD3OD): δ 7.80-7.82 (m, 1H), 7.21-7.23 (t, J=6.0,2.0Hz, 1H),
7.09-7.11 (m, 1H), 5.41 (s, 1H), 5.27 (s, 2H), 3.30 (s, 3H), 3.18 (d, 1H), 3.03 (d, 1H), 2.84
(t, J=4.0Hz, 1H), 2.64 (s, 1H), 2.45 (s, 1H), 1.96 (d, 1H), 1.93 (d, 1H), 1.74-1.77 (m, 1H),
1.60 (d, 1H), 1.24 (d, 1H), 1.17 (m, 1H).
Product its structural formula that the present invention is prepared can be learnt by above-mentioned detection data are as follows:
Each embodiment in this specification is described in a progressive manner, the highlights of each of the examples are with other
The difference of embodiment, the same or similar parts in each embodiment may refer to each other.For device disclosed in embodiment
For, since it is corresponded to the methods disclosed in the examples, so being described relatively simple, related place is said referring to method part
It is bright.
The foregoing description of the disclosed embodiments enables those skilled in the art to implement or use the present invention.
Various modifications to these embodiments will be readily apparent to those skilled in the art, as defined herein
General Principle can be realized in other embodiments without departing from the spirit or scope of the present invention.Therefore, of the invention
It is not intended to be limited to the embodiments shown herein, and is to fit to and the principles and novel features disclosed herein phase one
The widest scope of cause.
Claims (10)
1. the preparation method of a koji Ge Lieting, which is characterized in that specifically comprise the following steps:
(1) it prepares 3- methyl -6- chlorouracil: being first prepared under catalysts conditions by methyl urea and diethyl malonate
1- methylpyrimidine -2,4,6- triketone, using 1- methylpyrimidine -2,4,6- triketone and phosphorus oxychloride reaction obtain 3- methyl -6-
Chlorouracil；
(2) it prepares 2- chloromethyl -4- fluorobenzonitrile: 2- chlorine is prepared by chlorination reaction by 2- methylol -4- fluorobenzonitrile
Methyl -4- fluorobenzonitrile；
(3) song Ge Lieting: the 2- chloromethyl-that the 3- methyl -6- chlorouracil and step (2) obtained by step (1) obtains is prepared
4- fluorobenzonitrile first passes through substitution reaction, and bent Ge Lieting is prepared using aminating reaction.
2. the preparation method of koji Ge Lieting according to claim 1, which is characterized in that the step (1) is specifically wrapped
Include following steps:
(A) first methyl urea is dissolved in a solvent, is then slowly added into catalyst, obtain reaction solution；Then by malonic acid
Diethylester dissolution, and be slowly dropped in reaction solution, while heating reaction solution to reflux and being reacted, finally by mentioning
1- methylpyrimidine -2,4,6- triketone can be obtained in pure, drying；
(B) first by the above-mentioned 1- methylpyrimidine -2,4 being prepared, 6- triketone is uniformly mixed with phosphorus oxychloride, then controls temperature
It is reacted, 3- methyl -6- chlorouracil finally can be obtained by purification, drying.
3. the preparation method of koji Ge Lieting according to claim 2, which is characterized in that catalysis in the step (A)
Agent is metallic sodium, and solvent includes that methanol, ethyl alcohol, propyl alcohol or isopropanol are one such or a variety of, the methyl urea, malonic acid
The molar ratio of diethylester and catalyst is 1: 1.2~2: 1~1.5, reacts 18~22h under counterflow condition.
4. the preparation method of koji Ge Lieting according to claim 2, which is characterized in that first controlled in the step (B)
System reacts 0.6~0.8h under the conditions of 0~5 DEG C, then controls 1.2~1.5h of reaction under the conditions of 50~58 DEG C.
5. the preparation method of koji Ge Lieting according to claim 1, which is characterized in that the step (2) specifically:
First 2- methylol -4- fluorobenzonitrile is uniformly mixed with chlorination reagent according to weight ratio for 1: 4~5, then controls reaction temperature
Chlorination reaction is carried out, recycling excess chlorination reagent is concentrated into dripless, is then added and dissolves to obtain 2- chloromethane into organic solvent
Base -4- fluorobenzonitrile solution for standby.
6. the preparation method of koji Ge Lieting according to claim 5, which is characterized in that
The chlorination reagent includes thionyl chloride, phosphorus trichloride, phosphorus pentachloride, trim,ethylchlorosilane, N- phenyl benzoyl imines
In chlorine, hexachloroacetone-triphenylphosphine, carbon tetrahalide-triphenyl phosphine, N- chlorosuccinimide-triphenylphosphine or mesyl chloride
It is one or more；
The condition of the chlorination reaction are as follows: 6~10h is reacted under the conditions of 30~65 DEG C；
The organic solvent includes one of toluene, n,N-Dimethylformamide, benzene, chloroform or methyl tertiary butyl ether(MTBE) or more
Kind.
7. the preparation method of koji Ge Lieting according to claim 1, which is characterized in that the step (3) is specifically wrapped
Include following steps:
(a) the 3- methyl -6- chlorouracil that step (1) is prepared first is dissolved in n,N-diisopropylethylamine and N- methyl pyrrole
3- methyl -6- chlorouracil solution is obtained in the mixture of pyrrolidone；Then 3- methyl -6- chlorouracil solution is slowly added dropwise
Enter in the 2- chloromethyl -4- fluorobenzonitrile solution that step (2) obtains, 2~5h is then reacted under the conditions of 40~58 DEG C, is prepared into
To 2- [(chloro- -1 (the 2H)-pyrimidine radicals of 3,4- dihydro -3- methyl -2,4- dioxo of 6-) methyl] -4- fluorobenzonitrile；
(b) (R) -3- amino piperidine dihydrochloride and potassium carbonate are added in the mixed solvent and dissolve to obtain mixed reaction solution；
(c) 2- [(chloro- -1 (the 2H)-pyrimidine radicals of 3,4- dihydro -3- methyl -2,4- dioxo of 6-) methyl]-obtained step (a)
4- fluorobenzonitrile is added in the mixed reaction solution of step (b), and 8~10h is then reacted under the conditions of 66~69 DEG C.
8. the preparation method of koji Ge Lieting according to claim 7, which is characterized in that 3- first in the step (a)
The molar ratio of base -6- chlorouracil and 2- chloromethyl -4- fluorobenzonitrile is 1: 1.2~1.5；The n,N-diisopropylethylamine and
N-Methyl pyrrolidone is mixed according to 3: 7 volume ratios.
9. the preparation method of koji Ge Lieting according to claim 7, which is characterized in that mixing in the step (b)
Solvent is according to volume ratio by one of isopropanol, methanol, ethyl alcohol, normal propyl alcohol, n-butanol or tetrahydrofuran or a variety of and water
Be mixed to get at 18~20: 1；(R) -3- amino piperidine dihydrochloride and potassium carbonate are mixed according to 1: 3.5 molar ratio.
10. the preparation method of koji Ge Lieting according to claim 7, which is characterized in that 2- in the step (c)
[(chloro- -1 (the 2H)-pyrimidine radicals of 3,4- dihydro -3- methyl -2,4- dioxo of 6-) methyl] -4- fluorobenzonitrile and (R) -3- amino piperazine
The molar ratio of pyridine dihydrochloride is 1: 1.2~1.4.
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| CN107337664A (en) * | 2016-05-03 | 2017-11-10 | 上海现代制药股份有限公司 | One koji Ge Lieting preparation method |
| CN107698560A (en) * | 2017-11-17 | 2018-02-16 | 石家庄度恩医药科技有限公司 | One koji Ge Lieting preparation method |
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| WO2008067465A1 (en) * | 2006-11-29 | 2008-06-05 | Takeda Pharmaceutical Company Limited | Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2h-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor |
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