CN1176081C - Intermediate for preparing sildenafic and preparing method thereof - Google Patents
Intermediate for preparing sildenafic and preparing method thereof Download PDFInfo
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- CN1176081C CN1176081C CNB021175217A CN02117521A CN1176081C CN 1176081 C CN1176081 C CN 1176081C CN B021175217 A CNB021175217 A CN B021175217A CN 02117521 A CN02117521 A CN 02117521A CN 1176081 C CN1176081 C CN 1176081C
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- 238000000034 method Methods 0.000 title claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- 150000001875 compounds Chemical class 0.000 claims abstract description 38
- 239000000203 mixture Substances 0.000 claims abstract description 8
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 10
- 230000035484 reaction time Effects 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 abstract description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 abstract description 12
- 239000002904 solvent Substances 0.000 abstract description 10
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 abstract description 7
- -1 1-methyl piperazine Chemical class 0.000 abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 abstract description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 abstract description 2
- 150000001350 alkyl halides Chemical class 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000000543 intermediate Substances 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 150000002576 ketones Chemical class 0.000 description 9
- 235000002639 sodium chloride Nutrition 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 229960000935 dehydrated alcohol Drugs 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 238000007363 ring formation reaction Methods 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000002262 Schiff base Substances 0.000 description 4
- 150000004753 Schiff bases Chemical class 0.000 description 4
- 229960001701 chloroform Drugs 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 3
- 239000010813 municipal solid waste Substances 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 235000017550 sodium carbonate Nutrition 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- DUVJMSPTZMCSTQ-UHFFFAOYSA-N 2-ethoxybenzaldehyde Chemical compound CCOC1=CC=CC=C1C=O DUVJMSPTZMCSTQ-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- NWFNSTOSIVLCJA-UHFFFAOYSA-L copper;diacetate;hydrate Chemical compound O.[Cu+2].CC([O-])=O.CC([O-])=O NWFNSTOSIVLCJA-UHFFFAOYSA-L 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229910000108 silver(I,III) oxide Inorganic materials 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- XYRPTPCAHTXXPI-UHFFFAOYSA-N 1-methyl-3-propyl-4,6-dihydro-2H-pyrido[4,3-d]pyrimidin-7-one Chemical class CN1CN(CC=2C1=CC(NC2)=O)CCC XYRPTPCAHTXXPI-UHFFFAOYSA-N 0.000 description 1
- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 description 1
- XDZMPRGFOOFSBL-UHFFFAOYSA-N 2-ethoxybenzoic acid Chemical compound CCOC1=CC=CC=C1C(O)=O XDZMPRGFOOFSBL-UHFFFAOYSA-N 0.000 description 1
- MDKAAWDKKBFSTK-UHFFFAOYSA-N 2-ethoxybenzoyl chloride Chemical compound CCOC1=CC=CC=C1C(Cl)=O MDKAAWDKKBFSTK-UHFFFAOYSA-N 0.000 description 1
- QWJUYOHCZUYXGC-UHFFFAOYSA-N 4-ethoxy-3-formylbenzenesulfonyl chloride Chemical compound CCOC1=CC=C(S(Cl)(=O)=O)C=C1C=O QWJUYOHCZUYXGC-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000003934 aromatic aldehydes Chemical class 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000013502 data validation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
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- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a novel intermediate compound in a structural formula (5) for preparing himbotome and a preparation method thereof. The method comprises the step that the intermediate in the structural formula (5) is prepared from a compound in a structural formula (3) and a compound, namely 1-methyl piperazine, in a structural formula (4) by reaction, wherein the reaction is carried out in solvent at-10 DEG C to 50 DEG C for 0.5 to 10 hours; the solvent is selected from low-grade alkyl halide, or low-grade aliphatic ketone, or tetrahydrofuran, or a mixture of acetone and water or a mixture of tetrahydrofuran and water. The present invention simplifies the reaction step, increases the total yield, easily controls the reaction condition in each step by the intermediate compound in the structural formula (5) for preparing the himbotome, and simultaneously, obviously reduces the cost by cheap and easily-acquired reagents.
Description
Technical field
The present invention relates to the vigorous ketone of preparation happiness, i.e. intermediate of the used following structural formula (5) of structural formula (1) compound and preparation method thereof:
The compound of structural formula (5) is the important intermediate of preparation structural formula (1) compound.The chemical name of the compound of structural formula (1) be 5-[2-oxyethyl group-5-(4-methylpiperazine-1-base alkylsulfonyl) phenyl-] 1-methyl-3-n-propyl-1,6-dihydro-7H-pyrido [4,3-d] pyrimidin-7-ones or abbreviate the vigorous ketone of happiness as.This compound can be used for many field of medicaments, finds that at first this compound can treat some cardiovascular diseasess, such as stenocardia, hypertension, heart failure etc.It is specially adapted to the treatment of male erectile dysfunction discovered in recent years.Preparation method of the present invention can obtain meeting the high purity of clinical quality standard and like vigorous ketone.
Specifically, the present invention relates to intermediate of new structural formula (5) and preparation method thereof, the chemical name of the intermediate of structural formula (5) is: 2-oxyethyl group-5-(4-methylpiperazine-1-base alkylsulfonyl) phenyl aldehyde.Adopt the compound of this intermediate preparation structural formula (1) to simplify reactions steps, each goes on foot easy control of reaction conditions, and the reagent of use cheaply is easy to get, and has improved overall yield simultaneously.
Background technology
Chinese patent application CN1168376A discloses a kind of method of liking vigorous ketone and used intermediate thereof of preparing; this method is to be starting raw material with the 2-ethoxybenzoic acid; through a plurality of intermediates is the diamide of 2-oxyethyl group-5-(4-methylpiperazine-1-base alkylsulfonyl) phenylformic acid and hydrochloric acid-triethylamine double salt and following structural formula (8); this reaction comprises that the diamide of following structural formula (8) is in alkalescence; cyclization under neutrality or the acidic conditions; in preferred embodiments; cyclization is in the presence of alkali; preferably in solvent; under the condition that optionally has hydrogen peroxide or peroxide salt, carry out, then neutralization reaction mixture immediately.Product can through conventional technical point from and purifying.This reaction is that starting raw material calculates with the benzoic acid derivative, according to used be a step or two step sulfonation methods, total recovery can reach 51.7% or 47.8% respectively.
Chinese patent application CN1057464A discloses the method that vigorous ketone compound is liked in another kind of preparation, and this method is at first utilized and the similar method preparation of CN1168376A following compound (9), carries out chlorosulphonation then, then generates the vigorous ketone of happiness with the N methyl piperazine reaction.When needing product changed into a kind of pharmaceutically useful salt.This method is calculated as starting raw material from the 2-ethoxy benzoyl chloride, and the total recovery of production compound (1) only is 2 7.6%.
The method that vigorous ketone is liked in the disclosed preparation of prior art still can not satisfy the needs of this area, and those skilled in the art are still constantly exploring better, more effective synthetic method of searching and used intermediate thereof.
Summary of the invention
The invention provides compound of a kind of new structural formula (5) and preparation method thereof:
This method comprises the compound with structural formula (3):
With the compound of structural formula (4), promptly the 1-methylpiperazine reacts the intermediate of generating structure formula (5):
Wherein this reaction is in solvent, carries out under-10 ℃-50 ℃, and the reaction times is 0.5-10 hour.
When the preparation the finished product are liked vigorous ketone, further comprise compound with the compound of structural formula (5) and the 4-amino of following structural formula (6)-1-methyl-3-n-propyl pyrazoles-5-formamide generating structure formula (1):
This is reflected under the oxygenizement of inorganic oxidizer and carries out.
The reaction of the compound of structural formula (5) and structural formula (6) is to carry out in lower aliphatic alcohols, preferably carries out in dehydrated alcohol.Inorganic oxidizer is FeCl preferably
3, neutralized verdigris or silver suboxide.
Particularly, according to the present invention, prepare structural formula (5) midbody compound and adopt its method for preparing structural formula (1) compound to realize by following reaction scheme:
Following according to above-mentioned reaction scheme, describe preparation method of the present invention in detail.
At structural formula (3) and structural formula (4) is in the reaction of 1-methylpiperazine, and in preferred embodiments, this is reflected in the solvent, carries out under-10-50 ℃, and the reaction times is 0.5-10 hour.Use saturated aqueous common salt then, saturated sodium carbonate washing is carried out drying with dewatering agent, and products therefrom obtains the intermediate of structural formula (5) with ethyl acetate and sherwood oil recrystallization.The structure of this intermediate can be passed through
1Data such as HNMR are confirmed.In this reaction, the consumption of 1-methylpiperazine can be the 1-5 equivalent, also can add mineral alkalis such as organic bases such as triethylamine or yellow soda ash, to reduce the consumption of 1-methylpiperazine.
Appropriate solvent can be selected from lower halogenated alkane such as methylene dichloride, chloroform or 1,2-ethylene dichloride etc.; Lower aliphatic ketone such as acetone etc., or ether solvent such as tetrahydrofuran (THF) etc., or the mixed solvent of acetone and water, tetrahydrofuran (THF) and water.
Suitable dewatering agent can be selected from anhydrous sodium sulphate, Calcium Chloride Powder Anhydrous, anhydrous magnesium sulfate etc., preferred anhydrous sodium sulphate.
The compound of structural formula (3) can pass through the compound of structural formula (2):
With the chlorsulfonic acid prepared in reaction.Generally (2) are dissolved in lower halogenated alkane solvents such as trichloromethane, the methylene dichloride or solvent-free also passable, to wherein dripping chlorsulfonic acid, temperature of reaction is-10-50 ℃, reaction times 1-10 hour.Or the compound of structural formula (3) also can pass through structural formula (7), for example compound of structural formula (7 '):
With the chlorsulfonic acid prepared in reaction.Generally the compound with structural formula (7 ') adds in the chlorsulfonic acid in batches, temperature of reaction is-10-50 ℃, reaction times is 2-24 hour, pour in the trash ice, use dichloromethane extraction, wash anhydrous sodium sulfate drying with saturated aqueous common salt, saturated sodium bicarbonate, saturated aqueous common salt successively, revolve and desolvate, promptly get product.Chlorsulfonic acid in this reaction is the mixture replacement of available chlorine sulfonic acid and thionyl chloride also.
Like in the reaction of vigorous ketone at the preparation the finished product, be in the reaction of the midbody compound of structural formula (5) and structural formula (6) 4-amino-1-methyl-3-n-propyl pyrazoles-5-formamide generating structure formula (1) product, this reaction is in dehydrated alcohol, with iron trichloride, neutralized verdigris or silver suboxide as oxygenant, under the reflux temperature of solvent, carry out reaction times 4-8 hour.It is 8-9 that reaction gained mixture is neutralized to pH with yellow soda ash, uses dichloromethane extraction, and anhydrous sodium sulfate drying revolves and desolvates, and uses the dehydrated alcohol recrystallization, promptly gets the product of structural formula (1).The structure of products therefrom by
1Data validation such as HNMR and ultimate analysis, the purity of this product is by efficient liquid phase chromatographic analysis, and purity is greater than 98.5%.Therefore, be that raw material calculating total recovery can reach 57-59% with the 2-ethoxy-benzaldehyde.The compound of the structural formula (6) that uses in this reaction is the commercially available prod that can buy, maybe can be by the preparation of the method described in the CN1168376A.
The product of structural formula (1) is when needs, can change into pharmaceutically useful salt according to a conventional method, such as Citrate trianion, acetate, fumarate, grape hydrochlorate, lactic acid salt, maleate, succinate, hydrochloride, vitriol or hydrosulfate, phosphoric acid salt or hydrophosphate.
The method that the present invention adopts the midbody compound of structural formula (5) to prepare and likes vigorous ketone is compared with the method for prior art, the formation of schiff bases and cyclization are finished in same reaction system, promptly adopt " one kettle way " reaction, simplified reaction scheme, the easy control of reaction conditions of each step, the while obtains meeting the material of clinical quality standard with high yield.Obviously, this method is compared more favourable with the prior art disclosed method.
Me in this specification structure formula represents methyl, and Et represents ethyl.
Embodiment
Specify preparation method of the present invention by following example, described in the text room temperature all refers to 20-25 ℃.
Preparation 1
5-chlorosulfonyl-2-ethoxy-benzaldehyde
Method 1
2g 2-ethoxy-benzaldehyde is dissolved in the 30ml chloroform, be cooled to 10 ℃, slowly to wherein splashing into the 5ml chlorsulfonic acid, at room temperature reacted then 1 hour, mixture is poured in the 150g trash ice, with chloroform extraction twice, merge organic phase, use the saturated aqueous common salt washed twice, the saturated sodium bicarbonate washing once, use the saturated common salt water washing more once, the organic phase anhydrous sodium sulfate drying revolves then and desolvates, obtain oily matter, solidify gradually, obtain subject compound, can be directly used in next step reaction without purifying.
Method 2:
The 5ml chlorsulfonic acid is cooled to add 2g compound 7 ' about-5 ℃ in batches, and room temperature reaction 6 hours is poured in the 150g trash ice, carries out aftertreatment by method 1, gets product 1.2g, productive rate 75.9%.
Preparation 2
2-oxyethyl group-5-(4-methylpiperazine-1-base alkylsulfonyl) phenyl aldehyde
The product 1g of preparation 1 is dissolved in the 30ml methylene dichloride, the ice-water bath cooling, splash into 3g 1-methylpiperazine, continue reaction 1-2 hour, use 20ml saturated aqueous common salt, 20ml saturated sodium carbonate, the water washing of 20ml saturated common salt successively, anhydrous sodium sulfate drying, revolving desolvates obtains product, with ethyl acetate and sherwood oil recrystallization, obtains subject compound 1.1g, fusing point 108-110 ℃, productive rate 88%.Molecular formula C
14H
20N
2O
4S, calculated value: C, 53.84; H, 6.46; N, 8.97.Measured value: C, 53.76; H, 6.50; N, 8.75.δ(ppm，CHCl
3)：10.49(s，1H)，8.18(s，1H)，7.91(d，1H)，7.10(d，1H)，4.25(q，2H)，3.03(br?s，4H)，2.48(br?s，4H)，2.27(s，3H)，1.54(t，3H)。
Preparation 3
5-[2-oxyethyl group-5-(4-methylpiperazine-1-base alkylsulfonyl) phenyl-1-methyl-3-n-propyl-1, the 6-dihydro-
7H-pyrido [4,3-d] pyrimidin-7-ones
The product of getting 0.5g preparation 2 is dissolved in the 10ml dehydrated alcohol, adds 0.35g4-amino-1-methyl-3-n-propyl pyrazoles-5-methane amide, reflux 3 hours, add the 0.6g FERRIC CHLORIDE ANHYDROUS again, continue to reflux 3 hours, mixture is poured in the 100ml cold water, be neutralized to pH value 8-9 with yellow soda ash, use dichloromethane extraction three times, united extraction liquid, anhydrous sodium sulfate drying, revolve and desolvate, use the dehydrated alcohol recrystallization, obtain the 0.65g subject compound, productive rate 85%, fusing point 188-189 ℃.Molecular formula C
22H
30N
6O
4S, calculated value: C, 55.69; H, 6.38; N, 17.70.Measured value: C, 55.58; H, 6.25; N, 17.56.δ(ppm，CHCl
3)：1.02(t，3H)，1.51(t，3H)，1.75(h，2H)，2.30(s，3H)，2.51(br?s，4H)，2.72(t，2H)，3.01(br?s，4H)，4.12(s，3H)，4.23(q，2H)，7.23(d，1H)，7.80(d，1H)，8.12(s，1H)，12.3(br?s，1H)。
The present invention adopts aromatic aldehyde and amine reaction to form schiff bases and then add oxygenant in same reaction system and carries out cyclization, this method and 97113261.5,91104162.1 middle disclosed method is compared, (1) saved one step of activation of carboxylic acid, reduced reactions steps, (2) formation of schiff bases and cyclization adopt " one kettle way " reaction, (3) when forming schiff bases, only in solvent, can react, need not to add other reagent, inorganic oxidizer iron trichlorides that the oxygenant employing cheaply is easy to get etc. help reducing cost.In a word, the present invention has simplified reactions steps, has improved overall yield, and each goes on foot easy control of reaction conditions, and the reagent of Shi Yonging cheaply is easy to get simultaneously, has obviously reduced cost.
Claims (2)
1. method for preparing structural formula (5) compound, this method comprise the compound reaction with the compound of structural formula (3) and structural formula (4):
It is characterized in that: wherein the compound of structural formula (3) is the compound by structural formula (7 '):
Prepare with the mixture reaction of chlorsulfonic acid or chlorsulfonic acid and thionyl chloride.
2. according to the process of claim 1 wherein that the temperature of reaction of mixture of the compound of structural formula (7) and chlorsulfonic acid or chlorsulfonic acid and thionyl chloride is-10-50 ℃, the reaction times is 2-24 hour.
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| CNB021175217A CN1176081C (en) | 2002-04-29 | 2002-04-29 | Intermediate for preparing sildenafic and preparing method thereof |
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| CN1176081C true CN1176081C (en) | 2004-11-17 |
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| CN101563348B (en) | 2006-12-21 | 2011-08-24 | 上海特化医药科技有限公司 | A process for the preparation of sildenafil and the intermediates thereof |
| KR101127814B1 (en) * | 2011-03-14 | 2012-03-23 | 에이치 엘 지노믹스(주) | Novel intermediate and process for preparing sildenafil or its salt using the same |
| CN104804003B (en) * | 2015-04-27 | 2017-07-28 | 广州同隽医药科技有限公司 | The synthesis technique of 5 aryl 1H pyrazolos [4,3 d] pyrimidine 7 (6H) ketone |
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