CN104650093A - Synthesis method of sildenafil analog - Google Patents
Synthesis method of sildenafil analog Download PDFInfo
- Publication number
- CN104650093A CN104650093A CN201510053662.XA CN201510053662A CN104650093A CN 104650093 A CN104650093 A CN 104650093A CN 201510053662 A CN201510053662 A CN 201510053662A CN 104650093 A CN104650093 A CN 104650093A
- Authority
- CN
- China
- Prior art keywords
- reaction
- compound
- reaction flask
- solid material
- virga
- 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.)
- Granted
Links
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical class CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 title abstract description 7
- 238000001308 synthesis method Methods 0.000 title abstract 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 136
- 150000001875 compounds Chemical class 0.000 claims description 54
- 239000000243 solution Substances 0.000 claims description 41
- 239000011343 solid material Substances 0.000 claims description 40
- 238000001816 cooling Methods 0.000 claims description 31
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 30
- 241000405119 Virga Species 0.000 claims description 23
- 238000002360 preparation method Methods 0.000 claims description 23
- 238000009413 insulation Methods 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- XYLFLTOUNVLVOX-UHFFFAOYSA-N 1-methyl-5-phenyl-3-propyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical class CCCC1=NN(C)C(C(N2)=O)=C1N=C2C1=CC=CC=C1 XYLFLTOUNVLVOX-UHFFFAOYSA-N 0.000 claims description 18
- 238000002425 crystallisation Methods 0.000 claims description 17
- 230000008025 crystallization Effects 0.000 claims description 17
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 15
- 238000010992 reflux Methods 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 238000010189 synthetic method Methods 0.000 claims description 14
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- 230000000630 rising effect Effects 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 claims description 9
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 5
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 5
- 239000012153 distilled water Substances 0.000 claims description 5
- 239000011259 mixed solution Substances 0.000 claims description 5
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- 238000007654 immersion Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000001035 drying Methods 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 201000001881 impotence Diseases 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 208000010228 Erectile Dysfunction Diseases 0.000 description 4
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- SECKRCOLJRRGGV-UHFFFAOYSA-N Vardenafil Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 SECKRCOLJRRGGV-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- DEIYFTQMQPDXOT-UHFFFAOYSA-N sildenafil citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 DEIYFTQMQPDXOT-UHFFFAOYSA-N 0.000 description 2
- 229960002381 vardenafil Drugs 0.000 description 2
- 229940094720 viagra Drugs 0.000 description 2
- -1 Chinese name: vigour Chemical compound 0.000 description 1
- 101001117086 Dictyostelium discoideum cAMP/cGMP-dependent 3',5'-cAMP/cGMP phosphodiesterase A Proteins 0.000 description 1
- 101100189582 Dictyostelium discoideum pdeD gene Proteins 0.000 description 1
- 241000234435 Lilium Species 0.000 description 1
- 101150098694 PDE5A gene Proteins 0.000 description 1
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 102000010989 Type 6 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 1
- 108010037638 Type 6 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 102100029175 cGMP-specific 3',5'-cyclic phosphodiesterase Human genes 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000002832 nitroso derivatives Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 206010036596 premature ejaculation Diseases 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229920002994 synthetic fiber Polymers 0.000 description 1
- 208000029257 vision disease Diseases 0.000 description 1
- 238000004073 vulcanization Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention provides a synthesis method of a sildenafil analog. The chemical name of the sildenafil analog is 5-[2-ethoxy-5-(4-methylpiperazine-1-yl-thiocarbonyl)]phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazol[4,3d]pyrimidine-7-thioketone; the sildenafil analog is prepared from 5-(2-ethoxy)phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazol[4,3-d]pyrimidine-7-one as a raw material through four steps of chemical reactions. The synthesis method of the sildenafil analog is simple in synthesis step operations, economic and environmentally friendly; the yield of each step is above 75% and the total yield is relatively high; the synthesis method is suitable for industrial production.
Description
Technical field
The present invention relates to organic compound preparation process amelioration, particularly a kind of synthetic method of Virga analogue.
Background technology
Virga (sidenafil, trade(brand)name viagra, Chinese name: vigour, viagra) chemistry 5-[2-oxyethyl group-5-(4-methylpiperazine-1-yl alkylsulfonyl) by name] phenyl-1-methyl-3-n-propyl-1, 6-dihydro-pyrazol also [4, 3-d] pyrimidin-7-ones, it is a phosphodiesterase inhibitor, by the development and production of U.S. Pfizer (Pfizer) company, first is specifically designed to the oral medicine for the treatment of male erectile dysfunction (ED) clinically, erection function is gone down and has the improvement of highly significant with premature ejaculation, in July, 2000 is in Discussion on Chinese Listed.The listing of Virga, has started a uncharted field to impotence treatment.The Vardenafil (vardenafil) that the treatment male erectile dysfunction medicine of current listing also has German Bayer and Glaxo smithkline company jointly to open and the Tadalafei that lily company of the U.S. cooperates out with Lcosilis company.According to the literature, this compounds has the effect of stronger Selective depression phosphodiesterase, and its research causes extensive concern, becomes new study hotspot.Chemists carry out a large amount of structural modifications to this compounds, to its active and to PDE5 selectivity can be improved, particularly reduce the activity to phosphodiesterase 1, phosphodiesterase 6, to reduce the sickness rate of visual disorder, flush and heating, and reduce in body and containing the reaction between nitro, nitroso compound.
Virga analogue becomes the focus of research at present, the optimal drug being used for the treatment of male erectile dysfunction that activity is higher to finding, selectivity is stronger, tolerance is better, effect is better, side effect is less.The invention provides a kind of Virga analogue, its chemical name is: 5-[2-oxyethyl group-5-(4-methylpiperazine-1-yl thiocarbonyl group)] phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3d] pyrimidine-7-thioketones, structural formula is as follows:
Document (Da Yuanfeng, Huang unravels silk synthetic fibre, Mo Wenjuan. a kind of research of Virga analogue synthesis technique) report the research of this compound synthesis technology, and chemical reaction mode is as follows:
This synthesis technique is with 5-[2-oxyethyl group-5-(4-methylpiperazine-1-yl carbonyl)] phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones for raw material, with P
2s
5obtain through a step vulcanization reaction, production cost is higher, and complicated operation, is not suitable for industry's enlarging production.
Summary of the invention
For above-mentioned the deficiencies in the prior art, the invention provides a kind of synthetic method of Virga analogue, the method production cost is low, and process is convenient, and the finished product impurity is few, is applicable to suitability for industrialized production.
Technical scheme of the present invention is achieved in that
A synthetic method for Virga analogue, comprises the following steps:
(1) preparation of compd B: drop into chloroacetyl chloride in reaction flask, is cooled to less than 20 DEG C, drops into aluminum trichloride (anhydrous) in less than 20 DEG C in batches, throws and finishes, stirring reaction; React complete, below frozen water cooling reaction solution to 20 DEG C, compd A is dropped into reaction flask in batches, throw and finish, heat up and carry out stirring reaction 2 ~ 4h, react complete, reaction solution is added in frozen water mixed solution, after solid material is separated out completely, filter, collect solid material and wash, filtering, dry, to obtain final product;
(2) preparation of Compound C: drop into DMF, pyridine and compd B in reaction flask, throws and finishes, insulation reaction 0.5 ~ 1h is carried out in intensification, reacts complete, below cooling reaction solution to 20 DEG C, crystallization, filters, collects to obtain solid material (I); Potassium hydroxide is put in dehydrated alcohol, then above-mentioned reaction gained solid material (I) is dropped in reaction flask, temperature rising reflux reaction 3 ~ 5h; React complete, cooling reaction solution, to room temperature, uses hydrochloric acid adjust pH, separates out mass crystallization, filters, and solid material is washed, and filters, dry Compound C;
(3) preparation of Compound D: drop into sulfur oxychloride in the reaction flask that reflux exchanger is housed, throw and finish, frozen water is cooled to less than 20 DEG C, Compound C is dropped into reaction flask in batches, throws and finishes, and heats up and carries out insulation reaction 1 ~ 3h; React complete, reclaim under reduced pressure sulfur oxychloride, to dry, reclaim complete, in reaction flask, adds tetrahydrofuran (THF), below cooling reaction solution to 20 DEG C, drop into N methyl piperazine in batches, throw and finish, temperature rising reflux reaction 2 ~ 4h, react complete, cooling reaction solution, to room temperature, filters, dry Compound D;
(4) preparation of compd E: drop into pyridine, thiophosphoric anhydride and Compound D in being equipped with in condenser reaction flask, throws and finishes, and heats up and carries out insulation reaction 1 ~ 3h, react complete, and reclaim under reduced pressure pyridine is to most Gao Neiwen 70 DEG C; Steamed, in reaction flask, add distilled water immersion slowly, crystallization, filter, dry yellow solid material, is Virga analogue;
Described compd A is 5-(2-oxyethyl group) phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones;
Described compd B is 5-[2-oxyethyl group-5-(chloromethyl-1-base carbonyl)] phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones;
Described Compound C is 5-[2-oxyethyl group-5-carboxyl] phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H pyrazolo [4,3-d] pyrimidin-7-ones;
Described Compound D is 5-[2-oxyethyl group-5-(4-methylpiperazine-1-yl carbonyl)] phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones;
Described Virga analogue is 5-[2-oxyethyl group-5-(4-methylpiperazine-1-yl thiocarbonyl group)] phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3d] pyrimidine-7-thioketones.
Its chemical equation is as follows:
Wherein, preferably, control the rate of feeding of compd A in described step (1), make temperature in reaction flask be no more than 20 DEG C; Compd A being dropped into the temperature of reaction after reaction flask is 40 ~ 50 DEG C.
Wherein, preferably, solid material after washing is collected in described step (1) to pH value 4-5.
Wherein, preferably, described step (2) middle preparation solid material (I) carries out the temperature of insulation reaction is 100-130 DEG C;
Wherein, preferably, described step is adjusted to pH value 2-3 with hydrochloric acid in (2), is washed to pH value 6-7.
Wherein, preferably, control the rate of feeding of Compound C in described step (3), make temperature in reaction flask remain on less than 20 DEG C; The temperature of carrying out insulation reaction is 70-75 DEG C.
Wherein, preferably, the temperature of carrying out insulation reaction in described step (4) is 80-85 DEG C, after crystallization, also comprises the step being adjusted to pH value 7-8 with sodium hydroxide solution.
Beneficial effect of the present invention:
1. the equal low price of most of source chemicals involved in invention synthesis, thus reduce total cost.
2. synthesis step of the present invention environmental protection simple to operate, economic, often walk yield more than 75%, total recovery is higher, be applicable to industrialized production.
Embodiment
Be clearly and completely described the technical scheme in the embodiment of the present invention below, obviously, described embodiment is only the present invention's part embodiment, instead of whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art, not making other embodiments all obtained under creative work prerequisite, belong to the scope of protection of the invention.
Embodiment 1
A synthetic method for Virga analogue, comprises the following steps:
(1) compound (B): 5-[2-oxyethyl group-5-(chloromethyl-1-base carbonyl)] preparation of phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones
In the 500ml reaction flask of drying, drop into 180g (1.592mol) chloroacetyl chloride, below cooling reaction solution to 20 DEG C, drop into 122.4g (0.9175mol) aluminum trichloride (anhydrous) in 20 DEG C below in batches, throw and finish, stirring 10min.React complete, below frozen water cooling reaction solution to 20 DEG C, 55.68g (0.1784mol) compound (A) is dropped into reaction flask in batches, control rate of feeding, make interior temperature be no more than 20 DEG C.Throw and finish, in 45-50 DEG C of stirring reaction 3h.React complete, add in frozen water mixed solution by counter for reaction solution, after solid material is separated out completely, filter, collect solid material and be washed to pH value 4-5. and filter, dry, obtain off-white color solid material 62g.Be compound (B).Yield: 89.3% (calculating with compd A).ESI(m/z)：388.5.mp＝177.1-177.4℃
(2) compound (C): 5-[2-oxyethyl group-5-carboxyl] preparation of phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H pyrazolo [4,3-d] pyrimidin-7-ones
In clean 500ml reaction flask, drop into 250g DMF, 10g pyridine and 62g (0.1595mol) compound (B), throw and finish, be warming up to 100-130 degree Celsius of insulation reaction 1h.React complete, below cooling reaction solution to 20 DEG C, crystallization, filter, solid material collects to obtain solid material (I).20g (0.3571mol) potassium hydroxide is put in 200g dehydrated alcohol, then above-mentioned reaction gained solid material (I) is dropped in reaction flask in the lump, temperature rising reflux reaction 4h.React complete, cooling reaction solution is to room temperature, and in less than 30 DEG C, adjust pH value 2-3 with 20% hydrochloric acid, separate out mass crystallization, filter, solid material is washed to PH to 6-7, filters, and dryly obtains compound (C) 45g.Yield: 79.3% (calculating with compd B), ESI (m/z): 356.mp=290.6-291.3 DEG C
(3) compound (D): 5-[2-oxyethyl group-5-(4-methylpiperazine-1-yl carbonyl)] preparation of phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones
100g sulfur oxychloride is dropped in the 500ml reaction flask of drying that reflux exchanger is housed, throw and finish, below frozen water cooling reaction solution to 20 DEG C, 45g (0.1264mol) compound (C) is dropped into reaction flask in batches, control rate of feeding, make interior temperature remain on less than 20 DEG C, throw and finish, in 70-75 DEG C of insulation reaction 2h.React complete, reclaim under reduced pressure sulfur oxychloride is to dry.Reclaim complete, in reaction flask, add 100g tetrahydrofuran (THF), below cooling reaction solution to 20 DEG C, drop into 23g (0.23mol) N methyl piperazine in batches, throw and finish, temperature rising reflux reaction 3h.React complete, cooling reaction solution, to room temperature, filters, dry off-white color solid 41.52g.Be compound (D).Yield: 75% (calculating with Compound C) ESI (m/z): 438.mp=195.8-196.4 DEG C
(4) compound (E): 5-[2-oxyethyl group-5-(4-methylpiperazine-1-yl thiocarbonyl group)] preparation of phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3d] pyrimidine-7-thioketones
In the 250ml reaction flask of drying that condenser is housed, drop into 100g pyridine, 16.63g (0.074mol) thiophosphoric anhydride and 41g (0.0936mol) compound (D), throw and finish, be warming up to 80-85 DEG C of insulation reaction 2h.React complete, reclaim under reduced pressure pyridine, to most Gao Neiwen 70 DEG C, has now steamed and has steamed to without cut.Steamed, in reaction flask, add 120g distilled water slowly fully soak, separate out mass crystallization, adjust pH value 7-8 with 20% sodium hydroxide solution, filter, dry must yellow solid material 40.998g.Be compound (E).Yield: 93.2% (calculating with Compound D) ESI (m/z): 470.Mp=219.3-221.7 DEG C
Embodiment 2
A synthetic method for Virga analogue, comprises the following steps:
(1) compound (B): 5-[2-oxyethyl group-5-(chloromethyl-1-base carbonyl)] preparation of phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones
In the 500ml reaction flask of drying, drop into 180g (1.592mol) chloroacetyl chloride, below cooling reaction solution to 20 DEG C, drop into 125g (0.9370mol) aluminum trichloride (anhydrous) in 20 DEG C below in batches, throw and finish, stirring 10min.React complete, below frozen water cooling reaction solution to 20 DEG C, 55.72g (0.1785mol) compound (A) is dropped into reaction flask in batches, control rate of feeding, make interior temperature be no more than 20 DEG C.Throw and finish, in 45-50 DEG C of stirring reaction 4h.React complete, add in frozen water mixed solution by counter for reaction solution, after solid material is separated out completely, filter, collect solid material and be washed to pH value 4-5. and filter, dry, obtain off-white color solid material 62.2g.Be compound (B).Yield: 89.6% (calculating with compd A).ESI(m/z)：388.5.mp＝177.2-177.4℃
(2) compound (C): 5-[2-oxyethyl group-5-carboxyl] preparation of phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H pyrazolo [4,3-d] pyrimidin-7-ones
In clean 500ml reaction flask, drop into 250g DMF, 10g pyridine and 61.8g (0.1590mol) compound (B), throw and finish, be warming up to 100-130 degree Celsius of insulation reaction 0.5h.React complete, below cooling reaction solution to 20 DEG C, crystallization, filter, solid material collects to obtain solid material (I).20g (0.3571mol) potassium hydroxide is put in 200g dehydrated alcohol, then above-mentioned reaction gained solid material (I) is dropped in reaction flask in the lump, temperature rising reflux reaction 5h.React complete, cooling reaction solution is to room temperature, and in less than 30 DEG C, adjust pH value 2-3 with 20% hydrochloric acid, separate out mass crystallization, filter, solid material is washed to PH to 6-7, filters, and dryly obtains compound (C) 44.6g.Yield: 78.8% (calculating with compd B), ESI (m/z): 356.mp=290.8-291.3 DEG C
(3) compound (D): 5-[2-oxyethyl group-5-(4-methylpiperazine-1-yl carbonyl)] preparation of phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones
100g sulfur oxychloride is dropped in the 500ml reaction flask of drying that reflux exchanger is housed, throw and finish, below frozen water cooling reaction solution to 20 DEG C, 45g (0.1264mol) compound (C) is dropped into reaction flask in batches, control rate of feeding, make interior temperature remain on less than 20 DEG C, throw and finish, in 70-75 DEG C of insulation reaction 1h.React complete, reclaim under reduced pressure sulfur oxychloride is to dry.Reclaim complete, in reaction flask, add 100g tetrahydrofuran (THF), below cooling reaction solution to 20 DEG C, drop into 23g (0.23mol) N methyl piperazine in batches, throw and finish, temperature rising reflux reaction 2h.React complete, cooling reaction solution, to room temperature, filters, dry off-white color solid 42.07g.Be compound (D).Yield: 76% (calculating with Compound C) ESI (m/z): 438.mp=195.9-196.3 DEG C
(4) compound (E): 5-[2-oxyethyl group-5-(4-methylpiperazine-1-yl thiocarbonyl group)] preparation of phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3d] pyrimidine-7-thioketones
100g pyridine, 16.75g (0.075mol) thiophosphoric anhydride and 40.8g (0.0931mol) compound (D) is dropped in the 250ml reaction flask of drying that condenser is housed, throw and finish, be warming up to 80-85 DEG C of insulation reaction 2h.React complete, reclaim under reduced pressure pyridine, to most Gao Neiwen 70 DEG C, has now steamed and has steamed to without cut.Steamed, in reaction flask, add 120g distilled water slowly fully soak, separate out mass crystallization, adjust pH value 7-8 with 20% sodium hydroxide solution, filter, dry must yellow solid material 41.634g.Be compound (E).Yield: 93.4% (calculating with Compound D) ESI (m/z): 470.Mp=219.4-221.7 DEG C.
Embodiment 3
A synthetic method for Virga analogue, comprises the following steps:
(1) compound (B): 5-[2-oxyethyl group-5-(chloromethyl-1-base carbonyl)] preparation of phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones
In the 500ml reaction flask of drying, drop into 180g (1.592mol) chloroacetyl chloride, below cooling reaction solution to 20 DEG C, drop into 124.3g (0.9317mol) aluminum trichloride (anhydrous) in 20 DEG C below in batches, throw and finish, stirring 10min.React complete, below frozen water cooling reaction solution to 20 DEG C, 55.86g (0.1789mol) compound (A) is dropped into reaction flask in batches, control rate of feeding, make interior temperature be no more than 20 DEG C.Throw and finish, in 45-50 DEG C of stirring reaction 2h.React complete, add in frozen water mixed solution by counter for reaction solution, after solid material is separated out completely, filter, collect solid material and be washed to pH value 4-5. and filter, dry, obtain off-white color solid material 61.9g.Be compound (B).Yield: 88.9% (calculating with compd A).ESI(m/z)：389.1.mp＝177.1-177.3℃
(2) compound (C): 5-[2-oxyethyl group-5-carboxyl] preparation of phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H pyrazolo [4,3-d] pyrimidin-7-ones
In clean 500ml reaction flask, drop into 248g DMF, 10g pyridine and 61.2g (0.1574mol) compound (B), throw and finish, be warming up to 100-130 degree Celsius of insulation reaction 1.5h.React complete, below cooling reaction solution to 20 DEG C, crystallization, filter, solid material collects to obtain solid material (I).20g (0.3571mol) potassium hydroxide is put in 196g dehydrated alcohol, then above-mentioned reaction gained solid material (I) is dropped in reaction flask in the lump, temperature rising reflux reaction 3h.React complete, cooling reaction solution is to room temperature, and in less than 30 DEG C, adjust pH value 2-3 with 20% hydrochloric acid, separate out mass crystallization, filter, solid material is washed to PH to 6-7, filters, and dryly obtains compound (C) 44.6g.Yield: 79.6% (calculating with compd B), ESI (m/z): 356.mp=290.7-291.2 DEG C
(3) compound (D): 5-[2-oxyethyl group-5-(4-methylpiperazine-1-yl carbonyl)] preparation of phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones
100g sulfur oxychloride is dropped in the 500ml reaction flask of drying that reflux exchanger is housed, throw and finish, below frozen water cooling reaction solution to 20 DEG C, 45g (0.1264mol) compound (C) is dropped into reaction flask in batches, control rate of feeding, make interior temperature remain on less than 20 DEG C, throw and finish, in 70-75 DEG C of insulation reaction 3h.React complete, reclaim under reduced pressure sulfur oxychloride is to dry.Reclaim complete, in reaction flask, add 100g tetrahydrofuran (THF), below cooling reaction solution to 20 DEG C, drop into 23g (0.23mol) N methyl piperazine in batches, throw and finish, temperature rising reflux reaction 4h.React complete, cooling reaction solution, to room temperature, filters, dry off-white color solid 41.68g.Be compound (D).Yield: 75.3% (calculating with Compound C) ESI (m/z): 438.mp=196.0-196.4 DEG C
(4) compound (E): 5-[2-oxyethyl group-5-(4-methylpiperazine-1-yl thiocarbonyl group)] preparation of phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3d] pyrimidine-7-thioketones
100g pyridine, 16.50g (0.073mol) thiophosphoric anhydride and 40.2g (0.0917mol) compound (D) is dropped in the 250ml reaction flask of drying that condenser is housed, throw and finish, be warming up to 80-85 DEG C of insulation reaction 2h.React complete, reclaim under reduced pressure pyridine, to most Gao Neiwen 70 DEG C, has now steamed and has steamed to without cut.Steamed, in reaction flask, add 120g distilled water slowly fully soak, separate out mass crystallization, adjust pH value 7-8 with 20% sodium hydroxide solution, filter, dry must yellow solid material 41.118g.Be compound (E).Yield: 93.1% (calculating with Compound D) ESI (m/z): 471.2Mp=219.3-221.6 DEG C.
Compound (B) proton nmr spectra that above-mentioned enforcement embodiment obtains, carbon-13 nmr spectra, mass spectrum are summarized as follows:
1H NMR(400MHz,CDCl
3):δ＝12.212(brs,1H),8.183(brs,1H)，8.142(d,1H，J＝8.4Hz),7.296(d,1H,J＝8.4Hz),5.191(s,2H)，4.230(m,2H)，4.182(s,3H),2.795(t,2H，J＝7.2Hz)，1.756(m,2H)，1.359(t,3H，J＝6.4Hz),0.971(t,3H，J＝6.8Hz).
13C NMR(400MHz,CDCl
3):δ＝190.33,161.11，154.25，149.14，145.42，138.33，133.08，131.50，127.16，124.81，123.81，113.08，65.21，47.67，38.31，27.61，22.19，14.74，14.29
IR(KBr):3293，2972，2874，2941，2841，3078，1579，1492，782，1698，1604cm
-1
Compound (C) proton nmr spectra that above-mentioned enforcement embodiment obtains, carbon-13 nmr spectra, mass spectrum are summarized as follows:
1H NMR(400MHz,CDCl
3):δ＝12.118(brs,1H),12.943(s,1H)，8.211(brs,1H),8.080(d,1H，J＝8.4Hz),7.253(d,1H,J＝8.4Hz),4.222(m,2H)，4.191(s,3H)，2.808(t,2H，J＝7.2Hz)，1.767(m,2H)，1.376(t,3H，J＝6.4Hz),0.964(t,3H，J＝7.2Hz).
13C NMR(400MHz,CDCl
3):δ＝167.06，160.34，154.17，149.29，145.40，138.38，133.61，132.36，124.76，123.26，123.23，112.99，65.02，38.27，27.61，22.19，14.77，14.27.
IR(KBr):3303，1704，3210，2984，2934，2872，3043，1563，1495，761，1682，1610cm
-1.
Compound (D) proton nmr spectra that above-mentioned enforcement embodiment obtains, carbon-13 nmr spectra, mass spectrum are summarized as follows:
1H NMR(400MHz,CDCl
3):δ＝12.034(brs,1H),7.706(brs,1H)，7.542(d,1H，J＝8.4Hz),7.204(d,1H,J＝8.4Hz),4.179(m,2H)，4.169(s,3H)，3.523(brs,4H))，2.802(t,2H，J＝7.2Hz)，
2.340(brs,4H)，2.204(s,3H),1.754(m,2H)，1.358(t,3H，J＝6.4Hz),0.966(t,3H，J＝7.2Hz)
13C NMR(400MHz,CDCl
3):δ＝168.66，157.78，154.13，149.30，145.39，138.38，131.40，130.25，128.08，127.74，122.92，113.00，64.87，54.96，47.44,42.43，46.04，38.27，27.61，22.19，14.77，14.27cm
-1
IR(KBr):3258，3018，1571，1497，810，2976，2869，2930，2840，1474，1607cm
-1.
Compound (E) proton nmr spectra that above-mentioned enforcement embodiment obtains, carbon-13 nmr spectra, mass spectrum are summarized as follows:
1H NMR(400MHz,CDCl
3):δ＝12.596(brs,1H),8.418(brs,1H)，7.563(d,1H，J＝8.0Hz),7.071(d,1H,J＝8.4Hz),4.525(s,3H)，4.372,4.370(brs,4H)，4.330(m,2H)，2.939(t,2H，J＝7.2Hz)，2.667,2.493(brs,4H)，2.378(s,3H),1.854(m,2H)，1.696(t,3H，J＝6.8Hz)，1.037(t,3H，J＝7.2Hz)
13C NMR(400MHz,CDCl
3):δ＝199.24，171.79，156.91，147.05，146.24，136.38，134.14，132.31，131.73，128.13，118.51，113.08，66.01，55.27,54.41，52.20,49.67，45.65，39.35，27.62，22.29，14.80，14.08.
IR(KBr):3257，3018，,1571，1497，810，2976，2870，2930,2840，1474，1607,1207，1193
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (7)
1. a synthetic method for Virga analogue, is characterized in that comprising the following steps:
(1) preparation of compd B: drop into chloroacetyl chloride in reaction flask, is cooled to less than 20 DEG C, drops into aluminum trichloride (anhydrous) in less than 20 DEG C in batches, throws and finishes, stirring reaction; React complete, below frozen water cooling reaction solution to 20 DEG C, compd A is dropped into reaction flask in batches, throw and finish, heat up and carry out stirring reaction 2 ~ 4h, react complete, reaction solution is added in frozen water mixed solution, after solid material is separated out completely, filter, collect solid material and wash, filtering, dry, to obtain final product;
(2) preparation of Compound C: drop into DMF, pyridine and compd B in reaction flask, throws and finishes, insulation reaction 0.5 ~ 1h is carried out in intensification, reacts complete, below cooling reaction solution to 20 DEG C, crystallization, filters, collects to obtain solid material (I); Potassium hydroxide is put in dehydrated alcohol, then above-mentioned reaction gained solid material (I) is dropped in reaction flask, temperature rising reflux reaction 3 ~ 5h; React complete, cooling reaction solution, to room temperature, uses hydrochloric acid adjust pH, separates out mass crystallization, filters, and solid material is washed, and filters, dry Compound C;
(3) preparation of Compound D: drop into sulfur oxychloride in the reaction flask that reflux exchanger is housed, throw and finish, frozen water is cooled to less than 20 DEG C, Compound C is dropped into reaction flask in batches, throws and finishes, and heats up and carries out insulation reaction 1 ~ 3h; React complete, reclaim under reduced pressure sulfur oxychloride, to dry, reclaim complete, in reaction flask, adds tetrahydrofuran (THF), below cooling reaction solution to 20 DEG C, drop into N methyl piperazine in batches, throw and finish, temperature rising reflux reaction 2 ~ 4h, react complete, cooling reaction solution, to room temperature, filters, dry Compound D;
(4) preparation of compd E: drop into pyridine, thiophosphoric anhydride and Compound D in being equipped with in condenser reaction flask, throws and finishes, and heats up and carries out insulation reaction 1 ~ 3h, react complete, and reclaim under reduced pressure pyridine is to most Gao Neiwen 70 DEG C; Steamed, in reaction flask, add distilled water immersion slowly, crystallization, filter, dry yellow solid material, is Virga analogue;
Described compd A is 5-(2-oxyethyl group) phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones;
Described compd B is 5-[2-oxyethyl group-5-(chloromethyl-1-base carbonyl)] phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones;
Described Compound C is 5-[2-oxyethyl group-5-carboxyl] phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H pyrazolo [4,3-d] pyrimidin-7-ones;
Described Compound D is 5-[2-oxyethyl group-5-(4-methylpiperazine-1-yl carbonyl)] phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones;
Described Virga analogue is 5-[2-oxyethyl group-5-(4-methylpiperazine-1-yl thiocarbonyl group)] phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3d] pyrimidine-7-thioketones.
2. the synthetic method of a kind of Virga analogue according to claim 1, is characterized in that: the rate of feeding controlling compd A in described step (1), makes temperature in reaction flask be no more than 20 DEG C; Compd A being dropped into the temperature of reaction after reaction flask is 40 ~ 50 DEG C.
3. the synthetic method of a kind of Virga analogue according to claim 1, is characterized in that: collect solid material after washing in described step (1) to pH value 4-5.
4. the synthetic method of a kind of Virga analogue according to claim 1, is characterized in that: in described step (2), the temperature of insulation reaction is carried out in preparation solid material (I) is 100-130 DEG C.
5. the synthetic method of a kind of Virga analogue according to claim 1, is characterized in that: described step is adjusted to pH value 2-3 with hydrochloric acid in (2), is washed to pH value 6-7.
6. the synthetic method of a kind of Virga analogue according to claim 1, is characterized in that: the rate of feeding controlling Compound C in described step (3), makes temperature in reaction flask remain on less than 20 DEG C; The temperature of carrying out insulation reaction is 70-75 DEG C.
7. the synthetic method of a kind of Virga analogue according to claim 1, it is characterized in that: the temperature of carrying out insulation reaction in described step (4) is 80-85 DEG C, after crystallization, also comprise the step being adjusted to pH value 7-8 with sodium hydroxide solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510053662.XA CN104650093B (en) | 2015-02-02 | 2015-02-02 | Synthesis method of sildenafil analog |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510053662.XA CN104650093B (en) | 2015-02-02 | 2015-02-02 | Synthesis method of sildenafil analog |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104650093A true CN104650093A (en) | 2015-05-27 |
| CN104650093B CN104650093B (en) | 2017-01-25 |
Family
ID=53241788
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510053662.XA Active CN104650093B (en) | 2015-02-02 | 2015-02-02 | Synthesis method of sildenafil analog |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104650093B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566330A (en) * | 2016-01-06 | 2016-05-11 | 王靖林 | Sildenafil analog and synthesis method thereof |
| CN107141294A (en) * | 2017-05-19 | 2017-09-08 | 王靖林 | A kind of mesylate polymorph of 5 type phosphodiesterase inhibitors and its preparation method and application |
| CN113603692A (en) * | 2021-06-24 | 2021-11-05 | 济南美鲁威生物科技有限公司 | Polymorph of phosphodiesterase type 5 inhibitor, preparation method and application thereof |
| CN115785101A (en) * | 2022-11-23 | 2023-03-14 | 西安市食品药品检验所 | Phenylpiperazine structure-containing nafil compound and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6200980B1 (en) * | 1995-06-07 | 2001-03-13 | Cell Pathways, Inc. | Method of treating a patient having precancerous lesions with phenyl purinone derivatives |
| CN1071118C (en) * | 1993-06-09 | 2001-09-19 | 辉瑞研究及发展公司 | Pyrazolopyrimidinones for the treatment of impotence |
-
2015
- 2015-02-02 CN CN201510053662.XA patent/CN104650093B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1071118C (en) * | 1993-06-09 | 2001-09-19 | 辉瑞研究及发展公司 | Pyrazolopyrimidinones for the treatment of impotence |
| US6200980B1 (en) * | 1995-06-07 | 2001-03-13 | Cell Pathways, Inc. | Method of treating a patient having precancerous lesions with phenyl purinone derivatives |
Non-Patent Citations (2)
| Title |
|---|
| VÉRONIQUE GILARDA等: "Detection, identification and quantification by1H NMR of adulterantsin 150 herbal dietary supplements marketed for improving sexual performance", 《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》 * |
| 笪远锋等: "一种西地那非类似物的合成工艺研究", 《中国当代医药》 * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566330A (en) * | 2016-01-06 | 2016-05-11 | 王靖林 | Sildenafil analog and synthesis method thereof |
| CN107141294A (en) * | 2017-05-19 | 2017-09-08 | 王靖林 | A kind of mesylate polymorph of 5 type phosphodiesterase inhibitors and its preparation method and application |
| CN107141294B (en) * | 2017-05-19 | 2018-04-17 | 王靖林 | A kind of mesylate polymorph of 5 type phosphodiesterase inhibitors and its preparation method and application |
| WO2018209809A1 (en) * | 2017-05-19 | 2018-11-22 | 王靖林 | Polycrystalline mesylate of phosphodiesterase type 5 inhibitor, preparation method therefor, and application thereof |
| TWI668222B (en) * | 2017-05-19 | 2019-08-11 | 王靖林 | Mesylate polymorph of type 5 phosphodiesterase inhibitor and preparation method and application thereof |
| US20190292192A1 (en) * | 2017-05-19 | 2019-09-26 | Jinglin WANG | Methanesulfonate polymorph of 5-type phosphodiesterase inhibitor and preparation method and applications thereof |
| US10654859B2 (en) * | 2017-05-19 | 2020-05-19 | Jinan Meiluwei Biotechnology Co., Ltd. | Methanesulfonate polymorph of 5-type phosphodiesterase inhibitor and preparation method and applications thereof |
| CN113603692A (en) * | 2021-06-24 | 2021-11-05 | 济南美鲁威生物科技有限公司 | Polymorph of phosphodiesterase type 5 inhibitor, preparation method and application thereof |
| CN115785101A (en) * | 2022-11-23 | 2023-03-14 | 西安市食品药品检验所 | Phenylpiperazine structure-containing nafil compound and preparation method thereof |
| CN115785101B (en) * | 2022-11-23 | 2023-10-13 | 西安市食品药品检验所 | Phenylpiperazine structure-containing nafil compound and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104650093B (en) | 2017-01-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104045637B (en) | A kind of preparation method of Eliquis | |
| CN102036983B (en) | Process for the preparation of 5-(2-amino-pyrimidin-4-yl)-2-aryl-1h-pyrrole-3-carboxamides | |
| CN103524440A (en) | Preparation method of gout curative medicine Lesinurad and midbody of Lesinurad | |
| CN103980253B (en) | Synthetic method for 5-chloro-6-(2-iminopyrrolidinyl-1-yl)methyl-2,4-(1H,3H)pyrimidinedione hydrochloride | |
| CN104650093A (en) | Synthesis method of sildenafil analog | |
| CN112321602A (en) | Preparation method of Ruogeli drug intermediate | |
| AU2018366342A1 (en) | Method for preparing Baricitinib | |
| JP2023027091A (en) | Improved process for preparing aminopyrimidine derivatives | |
| CN103896855A (en) | Method for synthesizing 4-(1-bromoethyl) -5-fluoro-6-chloropyrimidine | |
| CN106831768A (en) | A kind of synthetic method of 2,6 dichloropyridines [3,4 B] pyrazine | |
| WO2016192522A1 (en) | Ribociclib intermediate and preparation method therefor | |
| CN109694354B (en) | Synthesis method of 4-chloro-2-methylthiopyrimidine-5-ethyl formate | |
| CN103724358A (en) | Method for preparing (3aS, 6aR)-1, 3-dibenzyl-tetrahydro-4H-thieno [3, 4-d] imidazole-2, 4-(1H)-diketone | |
| CN109503568B (en) | Preparation method of dasatinib | |
| CN103319462A (en) | Preparation method of halosulfuron methyl | |
| CN112939893B (en) | Synthesis method of 4- (4-aminophenyl) -3-morpholinone | |
| CN103193666A (en) | Preparation method of 2-amino-3-chlorobenzoic methyl ester | |
| CN104557877A (en) | Avanafil intermediate as well as preparation method and application thereof | |
| CN107722007B (en) | Preparation method of apixaban impurity | |
| CN115385903A (en) | Preparation method of cyano-substituted benzoxazine-4-one derivative | |
| CN107245043B (en) | A kind of preparation method preparing 3 methylthiol propyl alcohol from 3- methylthiopropionaldehydes | |
| CN106866560B (en) | Lesinurad synthesis method | |
| CN105294697B (en) | The synthetic method of 2- amino -5,8- dimethoxy [1,2,4] triazol [1,5-c] pyrimidine | |
| WO2013178020A1 (en) | Etravirine preparing method and intermediate thereof | |
| CN107573345A (en) | A kind of Ai Dailalisi and its intermediate preparation method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20190731 Address after: 250101 Block 1718-01, No. 1 Building, Yaogu, Jinan, North Section of Gangxing No. 3 Road, Jinan High-tech Zone, Jinan City, Shandong Province Patentee after: Jinan Meiruwei Biotechnology Co.,Ltd. Address before: 250199 Jinan Overseas Students Pioneer Park C630, 19 Huaneng Road, Jinan City, Shandong Province Patentee before: Wang Jinglin |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20231226 Address after: 272000 No.88, Deyuan Road, high tech Zone, Jining City, Shandong Province Patentee after: Shandong Lukang Pharmaceutical Co.,Ltd. Address before: 250101 1718-01, block B, building 1, Jinan Yaogu, north section of Gangxing Third Road, high tech Zone, Jinan, Shandong Patentee before: Jinan Meiruwei Biotechnology Co.,Ltd. |