A kind of synthetic method of the western croak intermediate of LeoTechnical field
The invention belongs to the field of chemical synthesis, and in particular to a kind of synthetic method of the western croak intermediate of Leo.
Background technology
The western croak of Leo（riociguat）It is for treating pulmonary hypertension (pulmonary hypertension, PH) medicineThing, mainly for chronic thromboembolic pulmonary hypertension (chronic throm-boembolic pulmonaryHypertension, CTEPH) and pulmonary hypertension (pulmonary arterial hypertension, PAH), its chemistryIt is entitled：N- [4,6- diaminourea -2- [1- [(2- fluorophenyls) methyl] -1H- pyrazolos [3,4-b] pyridine -3- bases] -5- pyrimidine radicals]-N- methylene dicarbamates, its structural formula is as follows.
In the synthetic method of the western croak of published Leo, mostly through intermediate 2- [1- (2- luorobenzyls) -1H- pyrazolos[3,4-b] pyridin-3-yl] -4,5,6- pyrimidine triamines（Compounds Ⅳ）To synthesize the western croak of Leo.
Made with two nitrogen-atoms on 1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridine -3- amitraz hydrochloridesFor double nucleophile, with phenylazo Cyanoacetyl-Cyacetazid, pyrimidine ring is directly synthesized under conditions of Feldalat NM makees alkali and obtains intermediate 3,Intermediate 3 palladium carbon or Raney's nickel do catalyst hydrogenation reduction and obtain triamine intermediate 4,（Referring to CN1665811A；US7173037B2）, its synthetic route is as follows.
But, find that the synthetic method has problems with actual building-up process according to said synthesis route：SecondCatalytic hydrogenation under high pressure is needed during step, danger coefficient is high, needs special high pressure reactor, no in industrialized productionBeneficial to industrialized great production, meanwhile, the step reactor product yield is low, and content is low, and impurity is more, and some impurity easily take final product toProduct, cause the newly-increased impurity of final products many, purification difficult；So that the step becomes the master for limiting the western croak industrialized great production of LeoWant factor.
Therefore, catalytic hydrogenation under a kind of normal pressure is developed, simply efficiently prepares the synthesis technique of high-purity intermediate IV,Become one of study hotspot and emphasis.Highly purified intermediate is provided further to prepare the western croak of Leo, so as to further expandThe industrial production scale of the western croak of Leo, reduces production cost.
The content of the invention
For the severe reaction conditions for overcoming prior art to exist, yield is low, the technical problem more than impurity, and inventor is carried outSubstantial amounts of research, so as to completing the present invention.
The present invention is achieved through the following technical solutions, in particular to a kind of synthetic method of the western croak intermediate of Leo,Comprise the following steps：
A, first by 1-（2- luorobenzyls）- 1H- pyrazolos [3,4-b] pyridine -3- amitraz hydrochlorides are compounds I, phenylpropyl alcoholAzo Cyanoacetyl-Cyacetazid is that compound ii and highly basic are added in reaction bulb, is subsequently adding DMF, be warming up to 100 ~ 120 DEG C reaction 10 ~15h, is down to 10 ~ 30 DEG C, post-treated to obtain compound III i.e. 2- [1-（2- luorobenzyls）- 1H- pyrazolos [3,4-b] pyridine -3-Base] -5- [（E）Phenyl-diazenyl] 4,6- thonzylamine,（The compound III refers to list of references WO2003095451A1）；
The mol ratio of described compounds I, compound ii and highly basic is 1:1~1.2:1~2；Described compounds I and solventTherebetween the ratio of addition is 1g：5~10ml；
The chemical equation of the step is as follows：
B, compound III, ammonium chloride and iron powder obtained by step a are added in reaction bulb, are subsequently adding ethanol/water mixingSolution, is heated to 6 ~ 10h of back flow reaction, is down to 10 ~ 30 DEG C, Jing process after obtain 2- [1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridin-3-yl] -4,5,6- pyrimidine triamines are compounds Ⅳ；
The mol ratio of described compound III, ammonium chloride and iron powder is 1:1~1.5:0.7~1.0；Described ethanol/water is mixedThe ratio for closing ethanol and water in solution is 6:4；Described compound III is 1g with ethanol/water mixed solution addition：10~15ml；
The chemical equation of the step is as follows：
。
According to a kind of synthetic method of the above-mentioned western croak intermediate of Leo, the highly basic described in step a is Feldalat NM, ethanolOne kind in sodium, sodium hydride.
According to a kind of synthetic method of the above-mentioned western croak intermediate of Leo, the reacted reactant liquor Jing described in step aPost processing obtains compound III, and the concrete operations of process are：Reacting liquid filtering, obtains solid, with dehydrated alcohol beating washing solid10 ~ 20 min, filter to obtain solid, repeat after above-mentioned washing step 2 times to obtain solid, do in being placed on 80 ~ 90 DEG C of drying bakerDry 4 ~ 6 h, obtains compound III.
According to a kind of synthetic method of the above-mentioned western croak intermediate of Leo, the temperature of the back flow reaction described in step b is75~85℃。
According to a kind of synthetic method of the above-mentioned western croak intermediate of Leo, the reacted reactant liquor Jing described in step bPost processing obtains compounds Ⅳ, and the concrete operations of process are：After completion of the reaction, filter, filtrate carries out vacuum distillation to no liquidSteam, vacuum：0.08 ~ 0.095 MPa, temperature：60 ~ 70 DEG C, in residue add water to stir 10 ~ 30 min, filter,Filter cake is placed in 80 ~ 90 DEG C of drying baker and is dried 4 ~ 6h, obtains compounds Ⅳ；
The ratio of the addition of the described residue removed under reduced pressure after solvent and water is 1g：2~3ml.
The positive beneficial effect of the present invention.
1. with 1-（2- luorobenzyls）- 1H- pyrazolos [3,4-b] pyridine -3- amitraz hydrochlorides are initiation material, by normal pressureCatalytic hydrogenation prepares the western croak key intermediate 2- of Leo [1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridin-3-yl] -4,5,6- pyrimidine triamines, it is to avoid Hydrogenation reaction, reduce requirement of the technique to equipment, greatly simplify technological operation, carryHigh reaction yield, is more beneficial for industrialized production.
2. synthesis under normal pressure, improves industrialized production safety, and the higher alcohols of safety in utilization is used as solvent, it is to avoid useThe big pyridine equal solvent of toxicity, reduces the harm to operating employee, and environmentally safe makes this technique more meet environmental protection reasonRead.
3. technique used catalyst is easy to get safely, and cost is far below the catalyst such as palladium carbon or Raney's nickel, can effectively reduce profitThe production cost of western croak difficult to understand.
4. the western croak intermediate 2- of the made Leo of this synthesis technique [1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridine -3-Base] -4,5,6- pyrimidine triamine purity up to more than 99%, can be directly used for synthesizing the subsequent step of the western croak of Leo, effectively preventImpurity is incorporated in the western croak finished product of Leo, improves the western croak end product quality of Leo.
4th, illustrate：
1 gained 2- of Fig. 1 embodiment of the present invention [1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridin-3-yl] -4,5,The relevant material pattern of 6- pyrimidine triamines；
1 gained 2- of Fig. 2 embodiment of the present invention [1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridin-3-yl] -4,5,The H-NMR collection of illustrative plates of 6- pyrimidine triamines.
5th, specific embodiment：
With reference to specific embodiment, the present invention is described in detail.Following examples will be helpful to the technology of this areaPersonnel further understand the present invention, but the invention is not limited in any way.It should be pointed out that the ordinary skill to this areaFor personnel, without departing from the inventive concept of the premise, some deformations and improvement can also be made.These belong to the present inventionProtection domain.
Embodiment 1：
A, add 50.0g in 500ml reaction bulbs（0.16mol）1-（2- luorobenzyls）- 1H- pyrazolos [3,4-b] pyrrolePyridine -3- amitraz hydrochlorides, 27.2 g（0.16mol）Phenylpropyl alcohol azo Cyanoacetyl-Cyacetazid, 8.6g（0.16mol）Feldalat NM and 350mlDMF, 12 h of stirring reaction at 110 DEG C, is cooled to 25 DEG C, filters to obtain solid, with 250ml ethanol agitator treatings solid 10Min, filters to obtain solid, repeats after above-mentioned washing step 2 times to obtain solid, after being dried 5 h in being placed on 85 DEG C of drying baker,60.7g compound IIIs are obtained, yield is 84.6%；
B, add 60.7g in 1 L reaction bulbs（0. 138mol）Compound III, 7.4 g（0. 138mol）Ammonium chloride and730ml ethanol/waters, stirring is lower to add 5.8g（0.1mol）Iron powder, after 8 h of stirring reaction at 79 DEG C, cools to 25DEG C, filtrate, vacuum distillation are obtained after filtration（Vacuum：0.090 MPa, temperature：65 ℃）Filtrate obtains residue, in residueAdd 120ml water to stir 30 min, filter to obtain solid, 5 h are dried in being placed on 85 DEG C of drying baker, obtain 33.8g compoundsIV, yield is 70.0%.Purity 99.4%.
Embodiment 2：
A, add 50.0g in 1L reaction bulbs（0.16mol）1-（2- luorobenzyls）- 1H- pyrazolos [3,4-b] pyridine -3-Amitraz hydrochloride, 29.9 g（0.176mol）Phenylpropyl alcohol azo Cyanoacetyl-Cyacetazid, 21.8g（0.32mol）Sodium ethylate and 500ml DMF, in15 h of stirring reaction at 120 DEG C, is cooled to 20 DEG C, filters to obtain solid, with 10 min of 250ml ethanol agitator treatings solid, mistakeSolid is filtered to obtain, and is repeated after above-mentioned washing step 2 times to obtain solid, after 5 h being dried in being placed on 80 DEG C of drying baker, is obtained57.4g compound IIIs, yield are 80.0%；
B, add 57.4g in 1L reaction bulbs（0. 13mol）Compound III, 8.3 g（0. 156mol）Ammonium chloride and860ml ethanol/waters, stirring is lower to add 6.6g（0.117mol）Iron powder, after 10 h of stirring reaction at 79 DEG C, cool to30 DEG C, after filtration, obtain filtrate, vacuum distillation（Vacuum：0.090 MPa, temperature：70 ℃）Filtrate obtains residue, to residueMiddle addition 120ml water stirs 30 min, filters to obtain solid, is dried 5 h, obtains 30.4g chemical combination in being placed on 85 DEG C of drying bakerThing IV, yield are 66.8%.Purity 99.1%.
Embodiment 3：
A, add 50.0g in 500ml reaction bulbs（0.16mol）1-（2- luorobenzyls）- 1H- pyrazolos [3,4-b] pyrrolePyridine -3- amitraz hydrochlorides, 33.4 g（0.196mol）Phenylpropyl alcohol azo Cyanoacetyl-Cyacetazid, 5.9g（0.245mol）Sodium hydride and 250mlDMF, 10 h of stirring reaction at 115 DEG C, is cooled to 30 DEG C, filters to obtain solid, with 250ml ethanol agitator treatings solid 10Min, filters to obtain solid, repeats after above-mentioned washing step 2 times to obtain solid, after being dried 5 h in being placed on 90 DEG C of drying baker,59.8g compound IIIs are obtained, yield is 83.4%；
B, add 59.8g in 1L reaction bulbs（0. 136mol）Compound III, 10.9 g（0. 2mol）Ammonium chloride and598ml medicinal alcohols/water, stirring is lower to add 7.6g（0.136mol）Iron powder, after stirring reaction 6h at 79 DEG C, coolsTo 20 DEG C, filtrate, vacuum distillation after filtration, are obtained（Vacuum：0.090 MPa, temperature：60 ℃）Filtrate obtains residue, to residueAdd 120ml water to stir 30 min in thing, filter to obtain solid, 5 h are dried in being placed on 80 DEG C of drying baker, obtain 32.5gizationCompound IV, yield are 68.3%.Purity 99.3%.