CN105461715A - Method for compounding riociguat intermediate - Google Patents
Method for compounding riociguat intermediate Download PDFInfo
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- CN105461715A CN105461715A CN201510927765.4A CN201510927765A CN105461715A CN 105461715 A CN105461715 A CN 105461715A CN 201510927765 A CN201510927765 A CN 201510927765A CN 105461715 A CN105461715 A CN 105461715A
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- leo
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- pyrazolo
- compound iii
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- 238000000034 method Methods 0.000 title claims abstract description 15
- KLMBASWITNCMTF-UHFFFAOYSA-N 2-phenyldiazenylpropanedinitrile Chemical compound N#CC(C#N)N=NC1=CC=CC=C1 KLMBASWITNCMTF-UHFFFAOYSA-N 0.000 title abstract description 5
- 238000013329 compounding Methods 0.000 title abstract 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 29
- 239000007787 solid Substances 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 20
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- 238000010189 synthetic method Methods 0.000 claims description 14
- 229960004756 ethanol Drugs 0.000 claims description 13
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 7
- 229960002587 amitraz Drugs 0.000 claims description 7
- 235000019270 ammonium chloride Nutrition 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- VAJVDSVGBWFCLW-UHFFFAOYSA-N 3-Phenyl-1-propanol Chemical compound OCCCC1=CC=CC=C1 VAJVDSVGBWFCLW-UHFFFAOYSA-N 0.000 claims description 5
- DYUQAZSOFZSPHD-UHFFFAOYSA-N Phenylpropyl alcohol Natural products CCC(O)C1=CC=CC=C1 DYUQAZSOFZSPHD-UHFFFAOYSA-N 0.000 claims description 5
- LQCYZZANGSLXDJ-UHFFFAOYSA-N dipropyldiazene Chemical compound CCCN=NCCC LQCYZZANGSLXDJ-UHFFFAOYSA-N 0.000 claims description 5
- 238000004821 distillation Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 238000010009 beating Methods 0.000 claims description 2
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 2
- 239000012065 filter cake Substances 0.000 claims description 2
- 238000010792 warming Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims 1
- MISVBCMQSJUHMH-UHFFFAOYSA-N pyrimidine-4,6-diamine Chemical class NC1=CC(N)=NC=N1 MISVBCMQSJUHMH-UHFFFAOYSA-N 0.000 claims 1
- 239000003054 catalyst Substances 0.000 abstract description 3
- 229910052731 fluorine Inorganic materials 0.000 abstract 2
- 239000011737 fluorine Substances 0.000 abstract 2
- OSRVIACMJANRFY-UHFFFAOYSA-N 2H-pyrazolo[3,4-b]pyridine-3-carboximidamide hydrochloride Chemical compound Cl.N1N=C(C=2C1=NC=CC2)C(=N)N OSRVIACMJANRFY-UHFFFAOYSA-N 0.000 abstract 1
- 238000010960 commercial process Methods 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 description 7
- 208000002815 pulmonary hypertension Diseases 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 208000026151 Chronic thromboembolic pulmonary hypertension Diseases 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 238000004904 shortening Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- WXXSNCNJFUAIDG-UHFFFAOYSA-N riociguat Chemical compound N1=C(N)C(N(C)C(=O)OC)=C(N)N=C1C(C1=CC=CN=C11)=NN1CC1=CC=CC=C1F WXXSNCNJFUAIDG-UHFFFAOYSA-N 0.000 description 1
- 229960000529 riociguat Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a method for compounding riociguat intermediate, firstly 1-(2-fluorine benzyl) 1H-pyrazolo [3, 4-b] pyridine-3-formamidine hydrochloride are used as starting materials, and 2-[1-(2-fluorine benzyl)-1 H- pyrazolo [3, 4-b] pyridine-3-yl]-4, 5, 6-pyrimidine triamine of the riociguat intermediate are prepared by catalyzing and hydrogenating in normal pressure through a catalyst. The method for compounding the riociguat intermediate is mild in reaction conditions, prevents using a high pressure reaction kettle, reduces process demands to equipment, enables product purity to be bigger than 99.0% at last, and is suitable for commercial process.
Description
Technical field
The invention belongs to the field of chemical synthesis, be specifically related to the synthetic method of the western croak intermediate of a kind of Leo.
Background technology
The western croak of Leo (riociguat) is used for the treatment of pulmonary hypertension (pulmonaryhypertension, PH) medicine, mainly for chronic thromboembolic pulmonary hypertension (chronicthrom-boembolicpulmonaryhypertension, and pulmonary hypertension (pulmonaryarterialhypertension CTEPH), PAH), its chemical name is: N-[4, 6-diamino-2-[1-[(2-fluorophenyl) methyl]-1H-pyrazolo [3, 4-b] pyridin-3-yl]-5-pyrimidyl]-N-methylene dicarbamate, its structural formula is as follows.
In the synthetic method of the western croak of published Leo, mostly synthesize the western croak of Leo through intermediate 2-[1-(2-luorobenzyl)-1H-pyrazolo [3,4-b] pyridin-3-yl]-4,5,6-pyrimidine triamines (compounds Ⅳ).
With 1-(2-luorobenzyl)-1H-pyrazolo [3,4-b] two nitrogen-atoms on pyridine-3-amitraz hydrochloride are as double nucleophile, with phenylazo propane dinitrile, directly synthesize pyrimidine ring make the condition of alkali at sodium methylate under and obtain intermediate 3, intermediate 3 does catalyst hydrogenation reduction with palladium carbon or Raney's nickel and obtains triamine intermediate 4, (see CN1665811A; US7173037B2), its synthetic route is as follows.
But finding in actual building-up process according to said synthesis route, there is following problem in this synthetic method: need under high pressure shortening in second step process, danger coefficient is high, need special high pressure reactor in suitability for industrialized production, be unfavorable for industrialized production, simultaneously, this step reactor product yield is low, content is low, and impurity is many, and some impurity easily takes the finished product to, the finished product are caused to increase impurity newly many, purification difficult; This step is made to become the principal element of the western croak industrialized production of restriction Leo.
Therefore, develop shortening under a kind of normal pressure, prepare the synthesis technique of high purity intermediate IV simply efficiently, become one of study hotspot and emphasis.There is provided highly purified intermediate for preparing the western croak of Leo further, thus expand the industrial production scale of the western croak of Leo further, reduce production cost.
Summary of the invention
In order to overcome the severe reaction conditions that prior art exists, the technical problem that yield is low, impurity is many, inventors performed large quantifier elimination, thus completes the present invention.
The present invention is achieved through the following technical solutions, and in particular to the synthetic method of the western croak intermediate of a kind of Leo, comprises the following steps:
A, first by 1-(2-luorobenzyl)-1H-pyrazolo [3,4-b] pyridine-3-amitraz hydrochloride and chemical compounds I, phenylpropyl alcohol azo propane dinitrile and compound ii and highly basic joins in reaction flask, then DMF is added, be warming up to 100 ~ 120 DEG C of reaction 10 ~ 15h, be down to 10 ~ 30 DEG C, through aftertreatment obtain compound III and 2-[1-(2-luorobenzyl)-1H-pyrazolo [3,4-b] pyridin-3-yl]-5-[(E) phenyl-diazenyl] 4,6-pyrimidinediamine, (this compound III refers to reference WO2003095451A1);
The mol ratio of described chemical compounds I, compound ii and highly basic is 1:1 ~ 1.2:1 ~ 2; The ratio of described chemical compounds I and solvent add-on is therebetween 1g:5 ~ 10ml;
The chemical equation of this step is as follows:
B, step a gained compound III, ammonium chloride and iron powder are joined in reaction flask, then ethanol/water mixing solutions is added, be heated to back flow reaction 6 ~ 10h, be down to 10 ~ 30 DEG C, obtain 2-[1-(2-luorobenzyl)-1H-pyrazolo [3 after treatment, 4-b] pyridin-3-yl]-4,5,6-pyrimidine triamine and compounds Ⅳs;
The mol ratio of described compound III, ammonium chloride and iron powder is 1:1 ~ 1.5:0.7 ~ 1.0; In described ethanol/water mixing solutions, the ratio of ethanol and water is 6:4; Described compound III and ethanol/water mixing solutions add-on are 1g:10 ~ 15ml;
The chemical equation of this step is as follows:
。
According to the synthetic method of the western croak intermediate of above-mentioned a kind of Leo, the highly basic described in step a is the one in sodium methylate, sodium ethylate, sodium hydride.
According to the synthetic method of the western croak intermediate of above-mentioned a kind of Leo, reacted reaction solution described in step a obtains compound III through aftertreatment, the concrete operations of process are: reacting liquid filtering, obtain solid, with dehydrated alcohol making beating washing solid 10 ~ 20min, filter to obtain solid, then to repeat after above-mentioned washing step 2 times to obtain solid, be placed on dry 4 ~ 6h in 80 ~ 90 DEG C of loft drier, obtain compound III.
According to the synthetic method of the western croak intermediate of above-mentioned a kind of Leo, the temperature of the back flow reaction described in step b is 75 ~ 85 DEG C.
According to the synthetic method of the western croak intermediate of above-mentioned a kind of Leo, reacted reaction solution described in step b obtains compounds Ⅳ through aftertreatment, the concrete operations of process are: after completion of the reaction, and filter, filtrate is carried out underpressure distillation and steamed to absence of liquid, vacuum tightness: 0.08 ~ 0.095MPa, temperature: 60 ~ 70 DEG C, adds water and stirs 10 ~ 30min, filter in residuum, filter cake is placed in the dry 4 ~ 6h of 80 ~ 90 DEG C of loft drier, obtains compounds Ⅳ;
Described remove solvent under reduced pressure after residuum and the ratio of add-on of water be 1g:2 ~ 3ml.
Positive beneficial effect of the present invention.
1. with 1-(2-luorobenzyl)-1H-pyrazolo [3,4-b] pyridine-3-amitraz hydrochloride is starting raw material, Leo western croak key intermediate 2-[1-(2-luorobenzyl)-1H-pyrazolo [3,4-b] pyridin-3-yl]-4,5 is prepared by normal pressure catalytic hydrogenation, 6-pyrimidine triamine, avoid Hydrogenation reaction, reduce the requirement of technique to equipment, very big Simplified flowsheet operation, improve reaction yield, be more conducive to suitability for industrialized production.
2. synthesis under normal pressure, improves suitability for industrialized production security, and the higher alcohols of safety in utilization, as solvent, is avoided the pyridine equal solvent using toxicity large, reduced the harm to operative employee, environmentally safe, make this technique more meet environmental protection theory.
3. technique used catalyst is easy to get safely, and cost, far below catalyzer such as palladium carbon or Raney's nickels, effectively can reduce the production cost of the western croak of Leo.
4. the made Leo of this synthesis technique western croak intermediate 2-[1-(2-luorobenzyl)-1H-pyrazolo [3,4-b] pyridin-3-yl]-4,5,6-pyrimidine triamine purity can reach more than 99%, the subsequent step of the western croak of synthesis Leo can be directly used in, effectively prevent impurity is incorporated in the western croak finished product of Leo, improves the western croak final product quality of Leo.
Four, accompanying drawing illustrates:
The related substance collection of illustrative plates of Fig. 1 embodiment of the present invention 1 gained 2-[1-(2-luorobenzyl)-1H-pyrazolo [3,4-b] pyridin-3-yl]-4,5,6-pyrimidine triamines;
The H-NMR collection of illustrative plates of Fig. 2 embodiment of the present invention 1 gained 2-[1-(2-luorobenzyl)-1H-pyrazolo [3,4-b] pyridin-3-yl]-4,5,6-pyrimidine triamines.
Five, embodiment:
Below in conjunction with specific embodiment, the present invention is described in detail.Following examples will contribute to those skilled in the art and understand the present invention further, but not limit the present invention in any form.It should be pointed out that to those skilled in the art, without departing from the inventive concept of the premise, some distortion and improvement can also be made.These all belong to protection scope of the present invention.
Embodiment 1:
A, in 500ml reaction flask, add 50.0g(0.16mol) 1-(2-luorobenzyl)-1H-pyrazolo [3,4-b] pyridine-3-amitraz hydrochloride, 27.2g(0.16mol) phenylpropyl alcohol azo propane dinitrile, 8.6g(0.16mol) sodium methylate and 350mlDMF, stirring reaction 12h at 110 DEG C, be cooled to 25 DEG C, filter to obtain solid, with 250ml ethanol agitator treating solid 10min, filter to obtain solid, to repeat after above-mentioned washing step 2 times to obtain solid again, to be placed in 85 DEG C of loft drier after dry 5h, obtain 60.7g compound III, yield is 84.6%;
B, in 1L reaction flask, add 60.7g(0.138mol) compound III, 7.4g(0.138mol) ammonium chloride and 730ml ethanol/water, 5.8g(0.1mol is added under stirring) iron powder, at 79 DEG C after stirring reaction 8h, cool to 25 DEG C, filtrate is obtained after filtration, underpressure distillation (vacuum tightness: 0.090MPa, temperature: 65 DEG C) filtrate obtains residuum, in residuum, add 120ml water stir 30min, filter to obtain solid, be placed on dry 5h in 85 DEG C of loft drier, obtain 33.8g compounds Ⅳ, yield is 70.0%.Purity 99.4%.
Embodiment 2:
A, in 1L reaction flask, add 50.0g(0.16mol) 1-(2-luorobenzyl)-1H-pyrazolo [3,4-b] pyridine-3-amitraz hydrochloride, 29.9g(0.176mol) phenylpropyl alcohol azo propane dinitrile, 21.8g(0.32mol) sodium ethylate and 500mlDMF, stirring reaction 15h at 120 DEG C, be cooled to 20 DEG C, filter to obtain solid, with 250ml ethanol agitator treating solid 10min, filter to obtain solid, to repeat after above-mentioned washing step 2 times to obtain solid again, to be placed in 80 DEG C of loft drier after dry 5h, obtain 57.4g compound III, yield is 80.0%;
B, in 1L reaction flask, add 57.4g(0.13mol) compound III, 8.3g(0.156mol) ammonium chloride and 860ml ethanol/water, 6.6g(0.117mol is added under stirring) iron powder, at 79 DEG C after stirring reaction 10h, cool to 30 DEG C, filtrate is obtained after filtration, underpressure distillation (vacuum tightness: 0.090MPa, temperature: 70 DEG C) filtrate obtains residuum, in residuum, add 120ml water stir 30min, filter to obtain solid, be placed on dry 5h in 85 DEG C of loft drier, obtain 30.4g compounds Ⅳ, yield is 66.8%.Purity 99.1%.
Embodiment 3:
A, in 500ml reaction flask, add 50.0g(0.16mol) 1-(2-luorobenzyl)-1H-pyrazolo [3,4-b] pyridine-3-amitraz hydrochloride, 33.4g(0.196mol) phenylpropyl alcohol azo propane dinitrile, 5.9g(0.245mol) sodium hydride and 250mlDMF, stirring reaction 10h at 115 DEG C, be cooled to 30 DEG C, filter to obtain solid, with 250ml ethanol agitator treating solid 10min, filter to obtain solid, to repeat after above-mentioned washing step 2 times to obtain solid again, to be placed in 90 DEG C of loft drier after dry 5h, obtain 59.8g compound III, yield is 83.4%;
B, in 1L reaction flask, add 59.8g(0.136mol) compound III, 10.9g(0.2mol) ammonium chloride and 598ml medicinal alcohol/water, 7.6g(0.136mol is added under stirring) iron powder, at 79 DEG C after stirring reaction 6h, cool to 20 DEG C, filtrate is obtained after filtration, underpressure distillation (vacuum tightness: 0.090MPa, temperature: 60 DEG C) filtrate obtains residuum, in residuum, add 120ml water stir 30min, filter to obtain solid, be placed on dry 5h in 80 DEG C of loft drier, obtain 32.5g compounds Ⅳ, yield is 68.3%.Purity 99.3%.
Claims (5)
1. a synthetic method for the western croak intermediate of Leo, it is characterized in that, described preparation method comprises the following steps:
A, first by 1-(2-luorobenzyl)-1H-pyrazolo [3,4-b] pyridine-3-amitraz hydrochloride and chemical compounds I, phenylpropyl alcohol azo propane dinitrile and compound ii and highly basic joins in reaction flask, then DMF is added, be warming up to 100 ~ 120 DEG C of reaction 10 ~ 15h, be down to 10 ~ 30 DEG C, compound III and 2-[1-(2-luorobenzyl)-1H-pyrazolo [3,4-b] pyridin-3-yl]-5-[(E) phenyl-diazenyl] 4,6-pyrimidinediamines are obtained through aftertreatment;
The mol ratio of described chemical compounds I, compound ii and highly basic is 1:1 ~ 1.2:1 ~ 2; The ratio of described chemical compounds I and solvent add-on is therebetween 1g:5 ~ 10ml;
B, step a gained compound III, ammonium chloride and iron powder are joined in reaction flask, then ethanol/water mixing solutions is added, be heated to back flow reaction 6 ~ 10h, be down to 10 ~ 30 DEG C, obtain 2-[1-(2-luorobenzyl)-1H-pyrazolo [3 after treatment, 4-b] pyridin-3-yl]-4,5,6-pyrimidine triamine and compounds Ⅳs;
The mol ratio of described compound III, ammonium chloride and iron powder is 1:1 ~ 1.5:0.7 ~ 1.0; In described ethanol/water mixing solutions, the ratio of ethanol and water is 6:4; Described compound III and ethanol/water mixing solutions add-on are 1g:10 ~ 15ml.
2. the synthetic method of the western croak intermediate of a kind of Leo according to claim 1, is characterized in that: the highly basic described in step a is the one in sodium methylate, sodium ethylate, sodium hydride.
3. the synthetic method of the western croak intermediate of a kind of Leo according to claim 1, it is characterized in that: the reacted reaction solution described in step a obtains compound III through aftertreatment, the concrete operations of process are: reacting liquid filtering, obtain solid, with dehydrated alcohol making beating washing solid 10 ~ 20min, filter to obtain solid, then to repeat after above-mentioned washing step 2 times to obtain solid, be placed on dry 4 ~ 6h in 80 ~ 90 DEG C of loft drier.
4. the synthetic method of the western croak intermediate of a kind of Leo according to claim 1, is characterized in that: the temperature of the back flow reaction described in step b is 75 ~ 85 DEG C.
5. the synthetic method of the western croak intermediate of a kind of Leo according to claim 1, it is characterized in that: the reacted reaction solution described in step b obtains compounds Ⅳ through aftertreatment, the concrete operations of process are: after completion of the reaction, and filter, filtrate is carried out underpressure distillation and steamed to absence of liquid, vacuum tightness: 0.08 ~ 0.095MPa, temperature: 60 ~ 70 DEG C, adds water and stirs 10 ~ 30min, filter in residuum, filter cake is placed in the dry 4 ~ 6h of 80 ~ 90 DEG C of loft drier, obtains compounds Ⅳ;
Described remove solvent under reduced pressure after residuum and the ratio of add-on of water be 1g:2 ~ 3ml.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003095451A1 (en) * | 2002-05-08 | 2003-11-20 | Bayer Healthcare Ag | Carbamate-substituted pyrazolopyridines |
| US20130237551A1 (en) * | 2010-05-26 | 2013-09-12 | Bayer Intellectual Property Gmbh | Substituted 5-fluoro-1H-pyrazolopyridines and their use |
| CN104530044A (en) * | 2014-12-31 | 2015-04-22 | 安徽联创生物医药股份有限公司 | Method for synthesizing riociguat |
-
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- 2015-12-15 CN CN201510927765.4A patent/CN105461715B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003095451A1 (en) * | 2002-05-08 | 2003-11-20 | Bayer Healthcare Ag | Carbamate-substituted pyrazolopyridines |
| US20130237551A1 (en) * | 2010-05-26 | 2013-09-12 | Bayer Intellectual Property Gmbh | Substituted 5-fluoro-1H-pyrazolopyridines and their use |
| CN104530044A (en) * | 2014-12-31 | 2015-04-22 | 安徽联创生物医药股份有限公司 | Method for synthesizing riociguat |
Non-Patent Citations (1)
| Title |
|---|
| JOACHIM MITTENDORF ET AL.: ""Discovery of Riociguat (BAY 63-2521): A Potent, Oral Stimulator of Soluble Guanylate Cyclase for the Treatment of Pulmonary Hypertension"", 《CHEMMEDCHEM》 * |
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