CN1208337C - Preparation of Xibo ketone - Google Patents
Preparation of Xibo ketone Download PDFInfo
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- CN1208337C CN1208337C CN 01131151 CN01131151A CN1208337C CN 1208337 C CN1208337 C CN 1208337C CN 01131151 CN01131151 CN 01131151 CN 01131151 A CN01131151 A CN 01131151A CN 1208337 C CN1208337 C CN 1208337C
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- 238000002360 preparation method Methods 0.000 title claims description 22
- 150000002576 ketones Chemical class 0.000 title description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- 238000000034 method Methods 0.000 claims abstract description 28
- 150000001875 compounds Chemical class 0.000 claims description 24
- -1 aliphatic alcohols Chemical class 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical group [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- 229940050410 gluconate Drugs 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 150000003016 phosphoric acids Chemical class 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 abstract description 6
- 239000002262 Schiff base Substances 0.000 abstract description 5
- 150000004753 Schiff bases Chemical class 0.000 abstract description 5
- 239000007800 oxidant agent Substances 0.000 abstract description 5
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical group Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 abstract 2
- PZMXDLWWQHYXGY-UHFFFAOYSA-N 4-amino-1-methyl-3-propylpyrazole-5-carboxamide Chemical compound CCCC1=NN(C)C(C(N)=O)=C1N PZMXDLWWQHYXGY-UHFFFAOYSA-N 0.000 abstract 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 abstract 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 abstract 1
- 238000005755 formation reaction Methods 0.000 abstract 1
- 238000005580 one pot reaction Methods 0.000 abstract 1
- 229910001923 silver oxide Inorganic materials 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 235000002639 sodium chloride Nutrition 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
- 239000002904 solvent Substances 0.000 description 7
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 229960001701 chloroform Drugs 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 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
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000010813 municipal solid waste Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000011084 recovery Methods 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
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 150000001350 alkyl halides Chemical class 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
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-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
- 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
- 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
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-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
- 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
- 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
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 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
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 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
- 239000000843 powder Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a preparing method of Xibotong. In the method, an intermediate in a structural formula (5) reacts with 4-amino-1-methyl-3-propylpyrazole-5-formamide in a structural formula (6) in the presence of an inorganic oxidizer, wherein the inorganic oxidizer is selected from FeCl3, copper acetate or silver oxide. In the method, the formation and cyclization reaction of schiff base are finished in the same reaction system, i.e., the reaction of a 'one pot method', and therefore, a reaction route is simplified.
Description
Technical field
The present invention relates to the preparation method of structural formula (1) compound:
The chemical name of this compound 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 be called the vigorous ketone of happiness.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 like the preparation method of vigorous ketone, this method has been simplified reactions steps, and 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 for preparing, this method comprises the cyclization of diamide under alkalescence, neutrality or acidic conditions of following structural formula (8), 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 27.6%.
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 the method that vigorous ketone is liked in better, more effective preparation of seeking.
Summary of the invention
The invention provides a kind of new following structural formula of preparation (1) and like the method for vigorous ketone compound,
This reaction comprises the compound with structural formula (3):
With structural formula (4) compound, i.e. the reaction of 1-methylpiperazine:
The intermediate of generating structure formula (5):
The method that vigorous ketone is liked in preparation of the present invention further comprises the 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 key of the present invention is the reaction of the compound and the structural formula (6) of structural formula (5), and this is reflected in the lower aliphatic alcohols and carries out, and preferably carries out in dehydrated alcohol.Inorganic oxidizer is FeCl preferably
3, neutralized verdigris or silver suboxide.
Particularly, according to the present invention, the method for preparing structural formula (1) compound can 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 haloalkane 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 haloalkane solvent 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.
In the reaction of key of the present invention, be in the reaction of structural formula (5) midbody compound 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 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, gluconate, lactic acid salt, maleate, succinate, hydrochloride, vitriol or hydrosulfate, phosphoric acid salt or hydrophosphate.
The inventive method 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, have 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.Simultaneously, the midbody compound of structural formula (5) has constituted a part of the present invention.
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 (5)
1. method for preparing structural formula (1) compound:
, described method comprises the reaction with the 4-amino of the compound of following structural formula (5) and following structural formula (6)-1-methyl-3-n-propyl pyrazoles-5-methane amide:
This reaction is at FeCl
3Oxygenizement under carry out.
2. according to the preparation method of claim 1, wherein this reaction is to carry out in lower aliphatic alcohols.
3. according to the preparation method of claim 2, described lower aliphatic alcohols is a dehydrated alcohol.
4. according to the preparation method of claim 1, this reaction is to carry out under the reflux temperature of lower aliphatic alcohols, and the reaction times is 4-8 hour.
5. according to the preparation method of claim 1, the product of structural formula (1) can be changed into pharmaceutically useful salt when needing, described salt is selected from Citrate trianion, acetate, fumarate, gluconate, lactic acid salt, maleate, succinate, hydrochloride, vitriol or hydrosulfate, phosphoric acid salt or hydrophosphate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 01131151 CN1208337C (en) | 2001-09-04 | 2001-09-04 | Preparation of Xibo ketone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 01131151 CN1208337C (en) | 2001-09-04 | 2001-09-04 | Preparation of Xibo ketone |
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| CN1406939A CN1406939A (en) | 2003-04-02 |
| CN1208337C true CN1208337C (en) | 2005-06-29 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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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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