CN104650093B - Synthesis method of sildenafil analog - Google Patents
Synthesis method of sildenafil analog Download PDFInfo
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- CN104650093B CN104650093B CN201510053662.XA CN201510053662A CN104650093B CN 104650093 B CN104650093 B CN 104650093B CN 201510053662 A CN201510053662 A CN 201510053662A CN 104650093 B CN104650093 B CN 104650093B
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- silaenafil
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- 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 122
- 150000001875 compounds Chemical class 0.000 claims description 88
- 239000000376 reactant Substances 0.000 claims description 33
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 32
- 239000011343 solid material Substances 0.000 claims description 31
- 238000001816 cooling Methods 0.000 claims description 25
- -1 phenyl -1- methyl -3- n-propyl Chemical group 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 23
- 238000009413 insulation Methods 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 18
- 238000002425 crystallisation Methods 0.000 claims description 17
- 230000008025 crystallization Effects 0.000 claims description 17
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 238000010992 reflux Methods 0.000 claims description 13
- 238000010189 synthetic method Methods 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 239000000463 material Substances 0.000 claims description 9
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
- 230000000630 rising effect Effects 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 238000011084 recovery Methods 0.000 claims description 6
- 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 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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-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
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 5
- 239000012153 distilled water Substances 0.000 claims description 3
- 239000012467 final product Substances 0.000 claims description 2
- 238000007654 immersion Methods 0.000 claims description 2
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 150000003462 sulfoxides Chemical class 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 239000000126 substance Substances 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000001035 drying Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 4
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 201000001881 impotence Diseases 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 4
- 150000003217 pyrazoles Chemical class 0.000 description 4
- 208000010228 Erectile Dysfunction Diseases 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 238000005987 sulfurization reaction Methods 0.000 description 3
- 230000006837 decompression Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification 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
- 229940094720 viagra Drugs 0.000 description 2
- 229940126062 Compound A Drugs 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
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 241000234435 Lilium Species 0.000 description 1
- 101150098694 PDE5A gene Proteins 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 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
- 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 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
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005553 drilling Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000686 essence Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012535 impurity Substances 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
- 206010036596 premature ejaculation Diseases 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229920002994 synthetic fiber Polymers 0.000 description 1
- 229960002381 vardenafil Drugs 0.000 description 1
- 208000029257 vision disease Diseases 0.000 description 1
- 238000004073 vulcanization Methods 0.000 description 1
- 238000005406 washing 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[4,3-d]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 to a kind of synthesis side of silaenafil analog
Method.
Background technology
Chemical entitled 5- [the 2- ethoxy of silaenafil (sidenafil, trade name viagra, Chinese name: vigour, viagra)
Base -5- (4- methylpiperazine-1-yl sulfonyl)] phenyl -1- methyl -3- n-propyl -1,6- dihydro-pyrazol simultaneously [4,3-d] pyrimidine -
7- ketone, is a CD-840, is by the development and production of U.S. pfizer (Pfizer) company, clinically first special
For treating the oral medicine of male erectile dysfunction (ed), go down for erection function has the improvement of highly significant with premature ejaculation,
In July, 2000 is in Discussion on Chinese Listed.The listing of silaenafil, has started a uncharted field to impotence treatment.On at present
What the treatment male erectile dysfunction medicine in city also had that German bayer and glaxo smithkline company opens jointly cut down ground that
The Tadalafei that non-(vardenafil) and lily company of the U.S. cooperate out with lcosilis company.According to the literature, such
Compound has the effect of stronger Selective depression phosphodiesterase, and its research has caused extensive concern, becomes new grinding
Study carefully focus.Chemists carry out substantial amounts of structural modification to this kind of compound, to can improve its activity and to PDE5
Selectivity, particularly reduce the activity to phosphodiesterase 1, phosphodiesterase 6, to reduce vision disorder, flush and heating
The incidence of disease, and reduce internal and containing the reaction between nitro, nitroso compound.
Silaenafil analog becomes the focus of current research, and to finding, activity is higher, selectively higher, tolerance is more
The less optimal drug for treating male erectile dysfunction of good, better, side effect.The present invention provides a kind of west ground
That non-analog, its chemical name is: 5- [2- ethyoxyl -5- (4- methylpiperazine-1-yl thiocarbonyl group)] phenyl -1- methyl -3-
N-propyl -1,6- dihydro -7h- pyrazolo [4,3-d] pyrimidine -7- thioketones, structural formula is as follows:
Document (Da Yuanfeng, Huang unravels silk synthetic fibre, Mo Wenjuan. a kind of research of silaenafil analog synthesis technique) report this change
The research of compound synthesis technique, chemical reaction mode is as follows:
This synthesis technique with 5- [2- ethyoxyl -5- (4- methylpiperazine-1-yl carbonyl)] phenyl -1- methyl -3- n-propyl -
1,6- dihydro -7h- pyrazolo [4,3-d] pyrimidin-7-ones are raw material, with p2s5It is obtained through a step vulcanization reaction, production cost is relatively
Height, and complex operation, are not suitable for industry's enlarging production.
Content of the invention
For above-mentioned the deficiencies in the prior art, the present invention provides a kind of synthetic method of silaenafil analog, the method
Low production cost, it is convenient to process, and final products impurity is few, suitable industrialized production.
The technical scheme is that and be achieved in that:
A kind of synthetic method of silaenafil analog, comprises the following steps:
(1) preparation of compound b: put into chloracetyl chloride in reaction bulb, be cooled to less than 20 DEG C, in less than 20 DEG C in batches
Put into aluminum trichloride (anhydrous), throw and finish, stirring reaction；Reaction finishes, and frozen water cools down reactant liquor to less than 20 DEG C, in batches by compound
A puts into reaction bulb, throws and finishes, and heats up and is stirred reacting 2～4h, reaction finishes, and reactant liquor is added in frozen water mixed liquor, treats solid
After body material separates out completely, filter, collect solid material and wash, filter, be dried, obtain final product；
(2) preparation of compound c: put into n, n- dimethylformamide, pyridine and compound b in reaction bulb, throw and finish,
Intensification carries out insulation reaction 0.5～1h, and reaction finishes, and cooling reactant liquor, to less than 20 DEG C, separates out crystallization, filters, collects and must consolidate
Body material (i)；Potassium hydroxide is put in absolute ethyl alcohol, then puts into above-mentioned reaction gained solid material (i) in reaction bulb, rise
Warm back flow reaction 3～5h；Reaction finishes, cooling reactant liquor to room temperature, adjusts ph value with hydrochloric acid, separates out mass crystallization, filters, solid
Material washing, filters, dry compound c；
(3) preparation of compound d: put into thionyl chloride in the reaction bulb equipped with reflux condenser, throw and finish, frozen water cools down
To less than 20 DEG C, compound c is put into reaction bulb in batches, throw and finish, heat up and carry out insulation reaction 1～3h；Reaction finishes, and reduces pressure back
Receive thionyl chloride to doing, recovery finishes, add oxolane in reaction bulb, cooling reactant liquor, to less than 20 DEG C, puts in batches
N- methyl piperazine, throws and finishes, and temperature rising reflux reacts 2～4h, and reaction finishes, and cooling reactant liquor, to room temperature, filters, dry compound
d；
(4) preparation of compound e: put into pyridine, phosphorus pentasulfide and compound d in equipped with condenser reaction bulb,
Throw and finish, heat up and carry out insulation reaction 1～3h, reaction finishes, recovered under reduced pressure pyridine to 70 DEG C of highest interior temperature；Steamed, slowly to
Add distilled water immersion in reaction bulb, separate out crystallization, filter, dry yellow solid material, as silaenafil analog；
Described compound a is 5- (2- ethyoxyl) phenyl -1- methyl -3- n-propyl -1,6- dihydro -7h- pyrazolo [4,3-
D] pyrimidin-7-ones；
Described compound b is 5- [2- ethyoxyl -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- ethyoxyl -5- carboxyl] phenyl -1- methyl -3- n-propyl -1,6- dihydro -7h pyrazoles
And [4,3-d] pyrimidin-7-ones；
Described compound d is 5- [2- ethyoxyl -5- (4- methylpiperazine-1-yl carbonyl)] phenyl -1- methyl -3- positive third
Base -1,6- dihydro -7h- pyrazolo [4,3-d] pyrimidin-7-ones；
Described silaenafil analog is 5- [2- ethyoxyl -5- (4- methylpiperazine-1-yl thiocarbonyl group)] phenyl -1- first
Base -3- n-propyl -1,6- dihydro -7h- pyrazolo [4,3-d] pyrimidine -7- thioketones.
Its chemical equation is as follows:
Wherein it is preferred to, control the rate of feeding of compound a in described step (1), make temperature in reaction bulb be less than 20
℃；Compound a is put into the reaction temperature after reaction bulb and be 40～50 DEG C.
Wherein it is preferred to, it is washed to ph value 4-5 after collecting solid material in described step (1).
Wherein it is preferred to, the temperature that described step (2) middle preparation solid material (i) carries out insulation reaction is 100-130 DEG C；
Wherein it is preferred to, it is adjusted to ph value 2-3 with hydrochloric acid in described step (2), be washed to ph value 6-7.
Wherein it is preferred to, control the rate of feeding of compound c in described step (3), make reaction bulb keep internal temperature at 20 DEG C
Below；The temperature carrying out insulation reaction is 70-75 DEG C.
Wherein it is preferred to, the temperature carrying out insulation reaction in described step (4) is 80-85 DEG C, after separating out crystallization, also wraps
Include the step being adjusted to ph value 7-8 with sodium hydroxide solution.
Beneficial effects of the present invention:
1. the involved equal low price of most of source chemicals in invention synthesis, thus reduce totle drilling cost.
2. synthesis step of the present invention is simple to operate, economic and environment-friendly, often walk yield more than 75%, and total recovery is higher, is suitable for
Industrialized production.
Specific embodiment
Below the embodiment it is clear that described is clearly and completely described to the technical scheme in the embodiment of the present invention
It is only a part of embodiment of the present invention, rather than whole embodiments.Based on the embodiment in the present invention, the common skill in this area
All other embodiment that art personnel are obtained under the premise of not making creative work, broadly falls into the model of present invention protection
Enclose.
Embodiment 1
A kind of synthetic method of silaenafil analog, comprises the following steps:
(1) compound (b): 5- [2- ethyoxyl -5- (chloromethyl -1- base carbonyl)] phenyl -1- methyl -3- n-propyl -1,
The preparation of 6- dihydro -7h- pyrazolo [4,3-d] pyrimidin-7-ones
Put into 180g (1.592mol) chloracetyl chloride in the 500ml reaction bulb being dried, cool down reactant liquor to less than 20 DEG C,
Put into 122.4g (0.9175mol) aluminum trichloride (anhydrous) in less than 20 DEG C in batches, throw and finish, stir 10min.Reaction finishes, frozen water
55.68g (0.1784mol) compound (a), to less than 20 DEG C, is put into reaction bulb by cooling reactant liquor in batches, controls rate of feeding,
Interior temperature is made to be less than 20 DEG C.Throw and finish, in 45-50 DEG C of stirring reaction 3h.Reaction finishes, and adds to frozen water mixed liquor by counter for reactant liquor
In, after solid material separates out completely, filter, collect solid material and be washed to the filtration of ph value 4-5., be dried, obtain off-white powder material
62g.It is compound (b).Yield: 89.3% (being calculated with compound a).Esi (m/z): 388.5.mp=177.1-177.4 DEG C
(2) compound (c): 5- [2- ethyoxyl -5- carboxyl] phenyl -1- methyl -3- n-propyl -1,6- dihydro -7h pyrazoles
And the preparation of [4,3-d] pyrimidin-7-ones
250g n, n- dimethylformamide, 10g pyridine and 62g is put in clean 500ml reaction bulb
(0.1595mol) compound (b), throws and finishes, be warming up to 100-130 degree Celsius of insulation reaction 1h.Reaction finishes, and cooling reactant liquor is extremely
Less than 20 DEG C, separate out crystallization, filter, solid material collects to obtain solid material (i).20g (0.3571mol) potassium hydroxide is put into
In 200g absolute ethyl alcohol, then above-mentioned reaction gained solid material (i) is put in reaction bulb in the lump, temperature rising reflux reacts 4h.Instead
Should finish, cooling reactant liquor is to room temperature, and in less than 30 DEG C, adjusts ph value 2-3 with 20% hydrochloric acid, separates out mass crystallization, filters, Gu
Body material is washed to ph to 6-7, filters, dry compound (c) 45g.Yield: 79.3% (being calculated with compound b), esi (m/
Z): 356.mp=290.6-291.3 DEG C
(3) compound (d): 5- [2- ethyoxyl -5- (4- methylpiperazine-1-yl carbonyl)] phenyl -1- methyl -3- positive third
Base -1, the preparation of 6- dihydro -7h- pyrazolo [4,3-d] pyrimidin-7-ones
Put into 100g thionyl chloride in the 500ml reaction bulb of the drying equipped with reflux condenser, throw and finish, frozen water cooling is anti-
Answer liquid to less than 20 DEG C, 45g (0.1264mol) compound (c) is put into reaction bulb in batches, control rate of feeding, so that interior temperature is protected
Hold below 20 DEG C, throw and finish, in 70-75 DEG C of insulation reaction 2h.Reaction finishes, and recovered under reduced pressure thionyl chloride is extremely dry.Recovery finishes,
Add 100g oxolane in reaction bulb, cooling reactant liquor, to less than 20 DEG C, puts into 23g (0.23mol) n- methyl piperazine in batches
Piperazine, throws and finishes, and temperature rising reflux reacts 3h.Reaction finishes, and cooling reactant liquor to room temperature, filters, dry off-white powder 41.52g.
It is compound (d).Yield: 75% (being calculated with compound c) esi (m/z): 438.mp=195.8-196.4 DEG C
(4) compound (e): 5- [2- ethyoxyl -5- (4- methylpiperazine-1-yl thiocarbonyl group)] phenyl -1- methyl -3- positive third
Base -1, the preparation of 6- dihydro -7h- pyrazolo [4,3-d] pyrimidine -7- thioketones
100g pyridine, 16.63g (0.074mol) five sulfuration is put in the 250ml reaction bulb of the drying equipped with condenser
Two phosphorus and 41g (0.0936mol) compound (d), throw and finish, be warming up to 80-85 DEG C of insulation reaction 2h.Reaction finishes, and reduces pressure back
Receive pyridine to 70 DEG C of highest interior temperature, now steamed and steamed to no cut.Steamed, in reaction bulb, slowly add 120g distilled water
Fully soak, separate out mass crystallization, adjust ph value 7-8 with 20% sodium hydroxide solution, filtration, dry yellow solid material
40.998g.It is compound (e).Yield: 93.2% (being calculated with compound d) esi (m/z): 470.mp=219.3-221.7
℃
Embodiment 2
A kind of synthetic method of silaenafil analog, comprises the following steps:
(1) compound (b): 5- [2- ethyoxyl -5- (chloromethyl -1- base carbonyl)] phenyl -1- methyl -3- n-propyl -1,
The preparation of 6- dihydro -7h- pyrazolo [4,3-d] pyrimidin-7-ones
Put into 180g (1.592mol) chloracetyl chloride in the 500ml reaction bulb being dried, cool down reactant liquor to less than 20 DEG C,
Put into 125g (0.9370mol) aluminum trichloride (anhydrous) in less than 20 DEG C in batches, throw and finish, stir 10min.Reaction finishes, ice water cooling
But 55.72g (0.1785mol) compound (a), to less than 20 DEG C, is put into reaction bulb by reactant liquor in batches, controls rate of feeding, makes
Interior temperature is less than 20 DEG C.Throw and finish, in 45-50 DEG C of stirring reaction 4h.Reaction finishes, and adds in frozen water mixed liquor by counter for reactant liquor,
After solid material separates out completely, filter, collect solid material and be washed to the filtration of ph value 4-5., be dried, obtain off-white powder material
62.2g.It is compound (b).Yield: 89.6% (being calculated with compound a).Esi (m/z): 388.5.mp=177.2-177.4
℃
(2) compound (c): 5- [2- ethyoxyl -5- carboxyl] phenyl -1- methyl -3- n-propyl -1,6- dihydro -7h pyrazoles
And the preparation of [4,3-d] pyrimidin-7-ones
250g n, n- dimethylformamide, 10g pyridine and 61.8g is put in clean 500ml reaction bulb
(0.1590mol) compound (b), throws and finishes, be warming up to 100-130 degree Celsius of insulation reaction 0.5h.Reaction finishes, and cools down reactant liquor
To less than 20 DEG C, separate out crystallization, filter, solid material collects to obtain solid material (i).20g (0.3571mol) potassium hydroxide is put into
In 200g absolute ethyl alcohol, then above-mentioned reaction gained solid material (i) is put in reaction bulb in the lump, temperature rising reflux reacts 5h.Instead
Should finish, cooling reactant liquor is to room temperature, and in less than 30 DEG C, adjusts ph value 2-3 with 20% hydrochloric acid, separates out mass crystallization, filters, Gu
Body material is washed to ph to 6-7, filters, dry compound (c) 44.6g.Yield: 78.8% (being calculated with compound b), esi (m/
Z): 356.mp=290.8-291.3 DEG C
(3) compound (d): 5- [2- ethyoxyl -5- (4- methylpiperazine-1-yl carbonyl)] phenyl -1- methyl -3- positive third
Base -1, the preparation of 6- dihydro -7h- pyrazolo [4,3-d] pyrimidin-7-ones
Put into 100g thionyl chloride in the 500ml reaction bulb of the drying equipped with reflux condenser, throw and finish, frozen water cooling is anti-
Answer liquid to less than 20 DEG C, 45g (0.1264mol) compound (c) is put into reaction bulb in batches, control rate of feeding, so that interior temperature is protected
Hold below 20 DEG C, throw and finish, in 70-75 DEG C of insulation reaction 1h.Reaction finishes, and recovered under reduced pressure thionyl chloride is extremely dry.Recovery finishes,
Add 100g oxolane in reaction bulb, cooling reactant liquor, to less than 20 DEG C, puts into 23g (0.23mol) n- methyl piperazine in batches
Piperazine, throws and finishes, and temperature rising reflux reacts 2h.Reaction finishes, and cooling reactant liquor to room temperature, filters, dry off-white powder 42.07g.
It is compound (d).Yield: 76% (being calculated with compound c) esi (m/z): 438.mp=195.9-196.3 DEG C
(4) compound (e): 5- [2- ethyoxyl -5- (4- methylpiperazine-1-yl thiocarbonyl group)] phenyl -1- methyl -3- positive third
Base -1, the preparation of 6- dihydro -7h- pyrazolo [4,3-d] pyrimidine -7- thioketones
100g pyridine, 16.75g (0.075mol) five sulfuration is put in the 250ml reaction bulb of the drying equipped with condenser
Two phosphorus and 40.8g (0.0931mol) compound (d), throw and finish, be warming up to 80-85 DEG C of insulation reaction 2h.Reaction finishes, decompression
Reclaim pyridine to 70 DEG C of highest interior temperature, now steamed and steamed to no cut.Steamed, in reaction bulb, slowly add 120g distillation
Water fully soaks, and separates out mass crystallization, adjusts ph value 7-8, filtration, dry yellow solid material with 20% sodium hydroxide solution
41.634g.It is compound (e).Yield: 93.4% (being calculated with compound d) esi (m/z): 470.mp=219.4-221.7
℃.
Embodiment 3
A kind of synthetic method of silaenafil analog, comprises the following steps:
(1) compound (b): 5- [2- ethyoxyl -5- (chloromethyl -1- base carbonyl)] phenyl -1- methyl -3- n-propyl -1,
The preparation of 6- dihydro -7h- pyrazolo [4,3-d] pyrimidin-7-ones
Put into 180g (1.592mol) chloracetyl chloride in the 500ml reaction bulb being dried, cool down reactant liquor to less than 20 DEG C,
Put into 124.3g (0.9317mol) aluminum trichloride (anhydrous) in less than 20 DEG C in batches, throw and finish, stir 10min.Reaction finishes, frozen water
55.86g (0.1789mol) compound (a), to less than 20 DEG C, is put into reaction bulb by cooling reactant liquor in batches, controls rate of feeding,
Interior temperature is made to be less than 20 DEG C.Throw and finish, in 45-50 DEG C of stirring reaction 2h.Reaction finishes, and adds to frozen water mixed liquor by counter for reactant liquor
In, after solid material separates out completely, filter, collect solid material and be washed to the filtration of ph value 4-5., be dried, obtain off-white powder material
61.9g.It is compound (b).Yield: 88.9% (being calculated with compound a).Esi (m/z): 389.1.mp=177.1-177.3
℃
(2) compound (c): 5- [2- ethyoxyl -5- carboxyl] phenyl -1- methyl -3- n-propyl -1,6- dihydro -7h pyrazoles
And the preparation of [4,3-d] pyrimidin-7-ones
248g n, n- dimethylformamide, 10g pyridine and 61.2g is put in clean 500ml reaction bulb
(0.1574mol) compound (b), throws and finishes, be warming up to 100-130 degree Celsius of insulation reaction 1.5h.Reaction finishes, and cools down reactant liquor
To less than 20 DEG C, separate out crystallization, filter, solid material collects to obtain solid material (i).20g (0.3571mol) potassium hydroxide is put into
In 196g absolute ethyl alcohol, then above-mentioned reaction gained solid material (i) is put in reaction bulb in the lump, temperature rising reflux reacts 3h.Instead
Should finish, cooling reactant liquor is to room temperature, and in less than 30 DEG C, adjusts ph value 2-3 with 20% hydrochloric acid, separates out mass crystallization, filters, Gu
Body material is washed to ph to 6-7, filters, dry compound (c) 44.6g.Yield: 79.6% (being calculated with compound b), esi (m/
Z): 356.mp=290.7-291.2 DEG C
(3) compound (d): 5- [2- ethyoxyl -5- (4- methylpiperazine-1-yl carbonyl)] phenyl -1- methyl -3- positive third
Base -1, the preparation of 6- dihydro -7h- pyrazolo [4,3-d] pyrimidin-7-ones
Put into 100g thionyl chloride in the 500ml reaction bulb of the drying equipped with reflux condenser, throw and finish, frozen water cooling is anti-
Answer liquid to less than 20 DEG C, 45g (0.1264mol) compound (c) is put into reaction bulb in batches, control rate of feeding, so that interior temperature is protected
Hold below 20 DEG C, throw and finish, in 70-75 DEG C of insulation reaction 3h.Reaction finishes, and recovered under reduced pressure thionyl chloride is extremely dry.Recovery finishes,
Add 100g oxolane in reaction bulb, cooling reactant liquor, to less than 20 DEG C, puts into 23g (0.23mol) n- methyl piperazine in batches
Piperazine, throws and finishes, and temperature rising reflux reacts 4h.Reaction finishes, and cooling reactant liquor to room temperature, filters, dry off-white powder 41.68g.
It is compound (d).Yield: 75.3% (being calculated with compound c) esi (m/z): 438.mp=196.0-196.4 DEG C
(4) compound (e): 5- [2- ethyoxyl -5- (4- methylpiperazine-1-yl thiocarbonyl group)] phenyl -1- methyl -3- positive third
Base -1, the preparation of 6- dihydro -7h- pyrazolo [4,3-d] pyrimidine -7- thioketones
100g pyridine, 16.50g (0.073mol) five sulfuration is put in the 250ml reaction bulb of the drying equipped with condenser
Two phosphorus and 40.2g (0.0917mol) compound (d), throw and finish, be warming up to 80-85 DEG C of insulation reaction 2h.Reaction finishes, decompression
Reclaim pyridine to 70 DEG C of highest interior temperature, now steamed and steamed to no cut.Steamed, in reaction bulb, slowly add 120g distillation
Water fully soaks, and separates out mass crystallization, adjusts ph value 7-8, filtration, dry yellow solid material with 20% sodium hydroxide solution
41.118g.It is compound (e).Yield: 93.1% (being calculated with compound d) esi (m/z): 471.2mp=219.3-221.6
℃.
Prepared compound (b) proton nmr spectra of above-mentioned enforcement embodiment, carbon-13 nmr spectra, mass spectrum are summarized as follows:
1h nmr(400mhz,cdcl3): 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,cdcl3): 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
Prepared compound (c) proton nmr spectra of above-mentioned enforcement embodiment, carbon-13 nmr spectra, mass spectrum are summarized as follows:
1h nmr(400mhz,cdcl3): 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,cdcl3): 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.
Prepared compound (d) proton nmr spectra of above-mentioned enforcement embodiment, carbon-13 nmr spectra, mass spectrum are summarized as follows:
1h nmr(400mhz,cdcl3): 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,cdcl3): 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.
Prepared compound (e) proton nmr spectra of above-mentioned enforcement embodiment, carbon-13 nmr spectra, mass spectrum are summarized as follows:
1h nmr(400mhz,cdcl3): 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,cdcl3): 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 presently preferred embodiments of the present invention, not in order to limit the present invention, all essences in the present invention
Within god and principle, any modification, equivalent substitution and improvement made etc., should be included within the scope of the present invention.
Claims (7)
1. a kind of synthetic method of silaenafil analog is it is characterised in that comprise the following steps:
(1) preparation of compound b: put into chloracetyl chloride in reaction bulb, be cooled to less than 20 DEG C, put in less than 20 DEG C in batches
Aluminum trichloride (anhydrous), throws and finishes, stirring reaction；Reaction finishes, and compound a, to less than 20 DEG C, is thrown by frozen water cooling reactant liquor in batches
Enter reaction bulb, throw and finish, heat up and be stirred reacting 2～4h, reaction finishes, and reactant liquor is added in frozen water mixed liquor, treats solid
After material separates out completely, filter, collect solid material and wash, filter, be dried, obtain final product；
(2) preparation of compound c: put into n, n- dimethylformamide, pyridine and compound b in reaction bulb, throw and finish, heat up
Carry out insulation reaction 0.5～1h, reaction finishes, cooling reactant liquor, to less than 20 DEG C, separates out crystallization, filters, collects to obtain solid material
(i)；Potassium hydroxide is put in absolute ethyl alcohol, then puts into above-mentioned reaction gained solid material (i) in reaction bulb, heat up back
Stream reaction 3～5h；Reaction finishes, cooling reactant liquor to room temperature, adjusts ph value with hydrochloric acid, separates out mass crystallization, filters, solid material water
Wash, filter, dry compound c；
(3) preparation of compound d: put into thionyl chloride in the reaction bulb equipped with reflux condenser, throw and finish, frozen water is cooled to 20
Below DEG C, compound c is put into reaction bulb in batches, throw and finish, heat up and carry out insulation reaction 1～3h；Reaction finishes, recovered under reduced pressure chlorine
Change sulfoxide to doing, recovery finishes, add oxolane in reaction bulb, cooling reactant liquor, to less than 20 DEG C, puts into n- first in batches
Base piperazine, throws and finishes, and temperature rising reflux reacts 2～4h, and reaction finishes, and cooling reactant liquor, to room temperature, filters, dry compound d；
(4) preparation of compound e: put into pyridine, phosphorus pentasulfide and compound d in equipped with condenser reaction bulb, throw and finish,
Intensification carries out insulation reaction 1～3h, and reaction finishes, recovered under reduced pressure pyridine to 70 DEG C of highest interior temperature；Steamed, slowly to reaction bulb
Middle addition distilled water immersion, separates out crystallization, filters, dry yellow solid material, as silaenafil analog；
Described compound a is 5- (2- ethyoxyl) phenyl -1- methyl -3- n-propyl -1, and 6- dihydro -7h- pyrazolo [4,3-d] is phonetic
Pyridine -7- ketone；
Described compound b is 5- [2- ethyoxyl -5- (chloromethyl -1- base carbonyl)] phenyl -1- methyl -3- n-propyl -1,6- bis-
Hydrogen -7h- pyrazolo [4,3-d] pyrimidin-7-ones；
Described compound c is 5- [2- ethyoxyl -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- ethyoxyl -5- (4- methylpiperazine-1-yl carbonyl)] phenyl -1- methyl -3- n-propyl -1,
6- dihydro -7h- pyrazolo [4,3-d] pyrimidin-7-ones；
Described silaenafil analog is 5- [2- ethyoxyl -5- (4- methylpiperazine-1-yl thiocarbonyl group)] phenyl -1- methyl -3-
N-propyl -1,6- dihydro -7h- pyrazolo [4,3-d] pyrimidine -7- thioketones.
2. a kind of silaenafil analog according to claim 1 synthetic method it is characterised in that: described step (1)
The middle rate of feeding controlling compound a, makes temperature in reaction bulb be less than 20 DEG C；Compound a is put into the reaction after reaction bulb
Temperature is 40～50 DEG C.
3. a kind of silaenafil analog according to claim 1 synthetic method it is characterised in that: described step (1)
It is washed to ph value 4-5 after middle collection solid material.
4. a kind of silaenafil analog according to claim 1 synthetic method it is characterised in that: described step (2)
The temperature that middle preparation solid material (i) carries out insulation reaction is 100-130 DEG C；
5. a kind of silaenafil analog according to claim 1 synthetic method it is characterised in that: described step (2)
Middle hydrochloric acid is adjusted to ph value 2-3, is washed to ph value 6-7.
6. a kind of silaenafil analog according to claim 1 synthetic method it is characterised in that: described step (3)
The rate of feeding of middle control compound c, makes reaction bulb keep internal temperature at less than 20 DEG C；The temperature carrying out insulation reaction is 70-75
℃.
7. a kind of silaenafil analog according to claim 1 synthetic method it is characterised in that: described step (4)
In carry out insulation reaction temperature be 80-85 DEG C, separate out crystallization after, also include being adjusted to the step of ph value 7-8 with sodium hydroxide solution
Suddenly.
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| US6200980B1 (en) * | 1995-06-07 | 2001-03-13 | Cell Pathways, Inc. | Method of treating a patient having precancerous lesions with phenyl purinone derivatives |
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