CN104292174A - Method for preparing valsartan - Google Patents
Method for preparing valsartan Download PDFInfo
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- CN104292174A CN104292174A CN201410524268.5A CN201410524268A CN104292174A CN 104292174 A CN104292174 A CN 104292174A CN 201410524268 A CN201410524268 A CN 201410524268A CN 104292174 A CN104292174 A CN 104292174A
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- 0 CC=C(*)CCC(*)C(CCC=C1)=C1C1=NN=*C1 Chemical compound CC=C(*)CCC(*)C(CCC=C1)=C1C1=NN=*C1 0.000 description 2
- AGRQNHJIUBDYKZ-UHFFFAOYSA-O COc(cc1)ccc1C(CCC=C1)=C1C1=NN[NH2+]1 Chemical compound COc(cc1)ccc1C(CCC=C1)=C1C1=NN[NH2+]1 AGRQNHJIUBDYKZ-UHFFFAOYSA-O 0.000 description 1
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Abstract
The invention provides a method for preparing valsartan. The method comprises the following steps: firstly, reacting N-(triphenylmethyl)-5-(4'-formyl-biphenyl-2-yl) tetrazolium with sodium methoxide, secondly, adding dichlorodicyanobenzoquinone (DDQ) and oxidizing, thirdly, reacting with L-valine methyl ester, fourthly, alkylating with valeryl chloride, fifthly, removing triphenylmethyl group and sixthly removing ester group and acidifying to obtain the target product valsartan. According to the method, a novel method for preparing valsartan is provided by virtue of the Williamson ether synthesis step and DDQ oxidation step, since potassium dihydrogen phosphate is adopted as a buffering reagent in the triphenylmethyl group removal process and a 1.3mol/L sodium hydroxide solution is used in the hydrolysis process, the problem of racemization of the product generated caused by too strong alkaline is avoided and the method is of important significance in maintaining the optical purity of the valsartan product.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, specifically a kind of method preparing valsartan.
Background technology
Valsartan (chemistry is by name: N-(1-pentanoyl)-N-[4-2-(1H-tetrazole-5-base) phenyl] benzyl]-Valine) can be used for various types of hypertension, and have better protecting effect to heart and brain kidney.The hypertensive patients such as myocardial infarction, heart failure, proteinuria, diabetes can use as routine, can with diuretic(s) (as hydrochlorothiazide) conbined usage.The structural formula of valsartan is as follows:
Document about valsartan is quite abundant; especially concentrate in synthetic route; as Ivica with 2'-tetrazole base-4-formyl biphenyl (tetrazole base is protected) for raw material; secondary amine intermediate is prepared with the condensation of Valine methyl esters; again through positive pentanoyl; finally slough trityl-protecting group and the hydrolysising carboxy acid ester of tetrazole, obtain valsartan.And for example the people such as Donatienne is with 2'-tetrazole base-4-formyl biphenyl for raw material, with the condensation of Valine methyl esters, generates imine intermediate, then reduces to obtain secondary amine intermediate, carries out acylation reaction in the presence of a base, finally obtain valsartan with n-amyl chloride.
But, exist in current conventional synthesis process " making product generation racemization because alkalescence crosses strong ", therefore need to provide a kind of new synthetic method, to solve the problems of the technologies described above.
Summary of the invention
For solving the deficiencies in the prior art, the present invention proposes a kind of method preparing valsartan newly, and described method, by being oxidized to aldehyde by D.D.Q. after Williamson's method synthesis ether, provides new synthesis path.In the preparation process in accordance with the present invention, in Deprotection process, adopt biphosphate first as buffer reagent, avoid because alkalescence crosses strong and make product generation racemization.
In order to achieve the above object, the invention provides a kind of method preparing valsartan, described method comprises following steps:
1) take methyl alcohol as reaction solvent, make reactant I (N-(trityl group)-5-(4 '-formyl biphenyl-2-base) tetrazole) and sodium methylate room temperature reaction, obtain Compound II per,
Wherein, the molar ratio of reactant I and sodium methylate is 1:(1 ~ 5), the reaction times is 30 ~ 180 minutes; Preferably, the molar ratio of described reactant I and sodium methylate is 1:(1 ~ 3), the reaction times is 60 ~ 180 minutes;
2) after Compound II per being dissolved in methylene dichloride, add DDQ (2,3-Dichloro-5,6-dicyano-1,4-benzoquinone, No. CAS: 84-58-2) room temperature reaction, obtain compound III,
Wherein, the molar ratio of described Compound II per and DDQ is 1:(1 ~ 2), the reaction times is 30 ~ 240 minutes, preferably 60 ~ 180 minutes;
3) compound III and Valine methyl ester hydrochloride are joined in anhydrous conditions in methylene dichloride and stir after 10 ~ 60 minutes, then add sodium cyanoborohydride reaction in batches, obtain compound IV
Wherein, the molar ratio of chemicals III, Valine methyl ester hydrochloride and sodium cyanoborohydride is 1:(1 ~ 2): (1 ~ 3), adding the described sodium cyanoborohydride post-reacted reaction times is 30 ~ 180 minutes, preferably 30 ~ 120 minutes;
4) in toluene solvant, add compound IV, then, continue to add triethylamine, n-amyl chloride at 0 ~ 20 DEG C, react, obtain compound V,
Wherein, the molar ratio of described compound IV, triethylamine and n-amyl chloride is 1:(1 ~ 5): (1 ~ 3), temperature of reaction is preferably 0 ~ 5 DEG C, and the reaction times is 1 ~ 5 hour, preferably 1 ~ 2 hour;
5) in acetonitrile solvent, add potassium dihydrogen phosphate aqueous solution and compound V, back flow reaction obtains compound VI,
Wherein, the concentration of described potassium dihydrogen phosphate aqueous solution is preferably 0.05mol/L, and temperature of reaction is 20 ~ 100 DEG C, and the reaction times is 1 ~ 6 hour, and preferably, temperature of reaction is 80 DEG C, and the reaction times is 4 hours; And,
6) compound VI is dropped in toluene, then adds after aqueous sodium hydroxide solution reacted, after acidifying, obtain target product valsartan (compound VI I),
Wherein, the concentration of described aqueous sodium hydroxide solution is preferably 1.3mol/L, and the reaction times of compound VI and aqueous sodium hydroxide solution is 1 ~ 10 hour, temperature of reaction is 0 ~ 50 DEG C, and preferably, the reaction times of compound VI and aqueous sodium hydroxide solution is 8 hours, and temperature of reaction is 20 DEG C; Described acidifying refers to: after compound VI and aqueous sodium hydroxide solution have been reacted, and regulates pH value of reaction system to be 1 ~ 2, have solid to separate out at 5 DEG C, and namely filtration washing obtains target product valsartan (compound VI I) after drying.
In an embodiment of the present invention, described step 3) in sodium cyanoborohydride divide 3 ~ 5 times to add in reaction system.
In an embodiment of the present invention, described step 4) in n-amyl chloride feeding mode for drip.
All this area general purification step can be optionally comprised, such as: suction filtration, filtration, washing or oven dry etc., concrete example is as follows after those of skill in the art would appreciate that each step above-mentioned.
In an embodiment of the present invention,
In described step 1) and step 2) between can also comprise: 1.1) to step 1) reacted after reaction solution carry out after suction filtration is spin-dried for, add water and sodium hydrogen carbonate solution washing to bubble-free, after washing, decompression is spin-dried for again, obtains the Compound II per obtaining solid;
In described step 2) and step 3) between can also comprise: 2.1) to step 2) reacted after reaction solution filter after again decompression be spin-dried for, obtain the compound III of solid;
In described step 3) and step 4) between can also comprise: 3.1) to step 3) reacted after product carry out distilled water wash, then with anhydrous magnesium sulfate drying, obtain the compound IV of solid;
In described step 4) and step 5) between can also comprise: 4.1) to step 4) reacted after reaction solution carry out suction filtration, filtrate is washed with after saturated sodium bicarbonate washing again, use anhydrous magnesium sulfate drying again, after underpressure distillation, obtain the compound V of solid;
In described step 5) and step 6) between can also comprise: 5.1) by step 5) reacted after reaction solution be cooled to room temperature, suction filtration is carried out after separating out solid, in filtrate, add methylene dichloride carry out extraction and separatory, after organic phase anhydrous magnesium sulfate drying, filter, concentrate, add anhydrous diethyl ether again to separate out solid, after filtering, obtain solid chemical compound VI;
In step 6) after can also comprise: 6.1) filter the reaction solution obtained after acidifying, a small amount of cold water washing of filter cake, namely obtains target product valsartan after oven dry; 6.2) by step 6.1) valsartan that obtains carries out column chromatography for separation, and elutriant used is sherwood oil: ethyl acetate, and volume ratio is 20:1.
It should be noted that, if no special instructions, reagent involved in the present invention is commercial reagent, and described room temperature refers to 25 DEG C.
The present invention prepares in the method for valsartan, focus on being oxidized (step 2) route new for synthesizing Xieshatan provides by Williamson's ether synthesis (step 1) and DDQ, simultaneously, in the process of detritylation (step 5), adopt potassium primary phosphate as buffer reagent, in hydrolytic process, (step 6) uses the sodium hydroxide solution of 1.3mol/L, to avoid because alkalescence crosses racemization by force.
Compared with prior art, the present invention has following beneficial effect: the new preparation method being provided a kind of valsartan by Williamson's ether synthesis step and DDQ oxidation step, by adopting potassium primary phosphate as buffer reagent and the sodium hydroxide solution using 1.3mol/L in hydrolytic process in the process of detritylation, avoiding because alkalescence crosses the product racemization problem produced by force, having great importance for keeping the optical purity of valsartan product.
Embodiment
Be described in detail the present invention below in conjunction with embodiment, embodiment is intended to explain and non-limiting technical scheme of the present invention.
The invention provides a kind of novel method preparing valsartan, the synthesis path of the method is as follows.
Embodiment one
1. the preparation of valsartan
In 100mL flask, 20mL methyl alcohol, 5.56g N-(trityl)-5-(4'-bromomethylbiphenyl-2-base) tetrazole and 0.81g sodium methylate is added, room temperature reaction 180 minutes under room temperature.After completion of the reaction, reacting liquid filtering, adds 25mL methylene dichloride in reaction solution in TLC display, and with saturated sodium bicarbonate washing to bubble-free, washing, separatory, organic phase is dry with anhydrous sodium sulphate sodium, suction filtration, and decompression removing methylene dichloride, obtains the first step product.
Previous step product is dissolved in methylene dichloride, under room temperature, adds 2.27gD.D.Q. and stir 180 minutes.After question response is complete, by reacting liquid filtering, decompression is spin-dried for, and obtains second step product.
In anhydrous conditions, previous step product and 1.4g Valine methyl ester hydrochloride are placed in the there-necked flask of 50mL, then add 15mL methylene dichloride, stirring at room temperature 30 minutes, then add 0.55g sodium cyanoborohydride reaction 2h in five batches.Add 20mL methylene dichloride, then use the distilled water wash 3 times of 25mL, branch vibration layer, organic over anhydrous dried over mgso, obtains the 3rd step product.
In 50mL there-necked flask, previous step product is dissolved in 20mL toluene, adds 1.8mL triethylamine, under 0 DEG C of stirring, drip 1.2mL n-amyl chloride, drip and finish, reaction 2h.Suction filtration, filtrate washs 2 times with 25mL saturated sodium bicarbonate, and 20mL washes 2 times, anhydrous magnesium sulfate drying, removal of solvent under reduced pressure, obtains the 4th step product.
40mL acetonitrile, 25mL0.05molL-1 potassium dihydrogen phosphate aqueous solution and previous step product are put into 100mL there-necked flask, backflow 4h.Be cooled to 10 DEG C, separate out white solid, suction filtration, filtrate adds methylene dichloride, stirs, separatory, organic phase anhydrous magnesium sulfate drying, filters, concentrated, adds ether, has solid to separate out, and filters, obtains the 5th step product.
Previous step product and 20mL toluene are placed in 50mL single port flask, after stirring and dissolving, add the aqueous sodium hydroxide solution of 15mL1.3molL-1, room temperature reaction 8h.After question response, point remove organic layer, water layer 20mL toluene wash 2 times.At 5 DEG C, water layer dilute hydrochloric acid adjusts pH to 2, has off-white color solid to separate out, and to continue at maintenance 5 DEG C 30 minutes, filter, a small amount of cold water washing of filter cake, oven dry, obtains valsartan crude product.
2. valsartan is refined
Valsartan crude product is carried out column chromatography for separation, and elutriant used is sherwood oil: ethyl acetate volume ratio is 20:1.Through nuclear magnetic data checking,
1h-NMR (400MHz, CDCl
3) δ: 10.8 (s, 1H), 7.55 (d, J=11.8Hz, 2H), 7.37 (d, J=12.0Hz, 2H), 7.26 (m, 2H), 7.11 (d, J=12.0Hz, 2H), 5.50 (s, 1H), 4.50 (s, 2H), 4.42 (d, J=8.0Hz, 1H), 3.12 (m, 1H), 2.14 (t, J=12.6Hz, 2H), 1.48 (m, 2H), 1.29 (m, 2H), 1.03 (d, J=10.4Hz, 6H), 0.98 (t, J=9.8Hz, 3H).
Embodiment two
1. the preparation of valsartan
In 100mL flask, 20mL methyl alcohol, 5.56g N-(trityl)-5-(4'-bromomethylbiphenyl-2-base) tetrazole and 1.2g sodium methylate is added, room temperature reaction 180 minutes under room temperature.After completion of the reaction, reacting liquid filtering, adds 25mL methylene dichloride in reaction solution in TLC display, and with saturated sodium bicarbonate washing to bubble-free, washing, separatory, organic phase is dry with anhydrous sodium sulphate sodium, suction filtration, and decompression removing methylene dichloride, obtains the first step product.
Previous step product is dissolved in methylene dichloride, under room temperature, adds 2.27gD.D.Q. and stir 180 minutes.After question response is complete, by reacting liquid filtering, decompression is spin-dried for, and obtains second step product.
In anhydrous conditions, previous step product and 1.4g Valine methyl ester hydrochloride are placed in the there-necked flask of 50mL, then add 15mL methylene dichloride, stirring at room temperature 30 minutes, then add 0.55g sodium cyanoborohydride reaction 2h in five batches.Add 20mL methylene dichloride, then use the distilled water wash 3 times of 25mL, branch vibration layer, organic over anhydrous dried over mgso, obtains the 3rd step product.
In 50mL there-necked flask, previous step product is dissolved in 20mL toluene, adds 1.8mL triethylamine, under 5 DEG C of stirrings, drip 1.2mL n-amyl chloride, drip and finish, reaction 2h.Suction filtration, filtrate washs 2 times with 25mL saturated sodium bicarbonate, and 20mL washes 2 times, anhydrous magnesium sulfate drying, removal of solvent under reduced pressure, obtains the 4th step product.
40mL acetonitrile, 25mL0.1molL-1 potassium dihydrogen phosphate aqueous solution and previous step product are put into 100mL there-necked flask, backflow 4h.Be cooled to 10 DEG C, separate out white solid, suction filtration, filtrate adds methylene dichloride, stirs, separatory, organic phase anhydrous magnesium sulfate drying, filters, concentrated, adds ether, has solid to separate out, and filters, obtains the 5th step product.
Previous step product and 20mL toluene are placed in 50mL single port flask, after stirring and dissolving, add the aqueous sodium hydroxide solution of 15mL1.3molL-1, room temperature reaction 8h.After question response, point remove organic layer, water layer 20mL toluene wash 2 times.At 5 DEG C, water layer dilute hydrochloric acid adjusts pH to 2, has off-white color solid to separate out, and to continue at maintenance 5 DEG C 30 minutes, filter, a small amount of cold water washing of filter cake, oven dry, obtains valsartan crude product.
2. valsartan is refined
Valsartan crude product is carried out column chromatography for separation, and elutriant used is sherwood oil: ethyl acetate volume ratio is 20:1.Through nuclear magnetic data checking,
1h-NMR (400MHz, CDCl
3) δ: 10.8 (s, 1H), 7.55 (d, J=11.8Hz, 2H), 7.37 (d, J=12.0Hz, 2H), 7.26 (m, 2H), 7.11 (d, J=12.0Hz, 2H), 5.50 (s, 1H), 4.50 (s, 2H), 4.42 (d, J=8.0Hz, 1H), 3.12 (m, 1H), 2.14 (t, J=12.6Hz, 2H), 1.48 (m, 2H), 1.29 (m, 2H), 1.03 (d, J=10.4Hz, 6H), 0.98 (t, J=9.8Hz, 3H).
Embodiment three
1. the preparation of valsartan
In 100mL flask, 20mL methyl alcohol, 5.56g N-(trityl)-5-(4'-bromomethylbiphenyl-2-base) tetrazole and 0.81g sodium methylate is added, room temperature reaction 180 minutes under room temperature.After completion of the reaction, reacting liquid filtering, adds 25mL methylene dichloride in reaction solution in TLC display, and with saturated sodium bicarbonate washing to bubble-free, washing, separatory, organic phase is dry with anhydrous sodium sulphate sodium, suction filtration, and decompression removing methylene dichloride, obtains the first step product.
Previous step product is dissolved in methylene dichloride, under room temperature, adds 3.27gD.D.Q. and stir 120 minutes.After question response is complete, by reacting liquid filtering, decompression is spin-dried for, and obtains second step product.
In anhydrous conditions, previous step product and 1.4g Valine methyl ester hydrochloride are placed in the there-necked flask of 50mL, then add 15mL methylene dichloride, stirring at room temperature 30 minutes, then add 0.55g sodium cyanoborohydride reaction 2h in five batches.Add 20mL methylene dichloride, then use the distilled water wash 3 times of 25mL, branch vibration layer, organic over anhydrous dried over mgso, obtains the 3rd step product.
In 50mL there-necked flask, previous step product is dissolved in 20mL toluene, adds 1.8mL triethylamine, under 5 DEG C of stirrings, drip 1.2mL n-amyl chloride, drip and finish, reaction 2h.Suction filtration, filtrate washs 2 times with 25mL saturated sodium bicarbonate, and 20mL washes 2 times, anhydrous magnesium sulfate drying, removal of solvent under reduced pressure, obtains the 4th step product.
40mL acetonitrile, 25mL0.1molL-1 potassium dihydrogen phosphate aqueous solution and previous step product are put into 100mL there-necked flask, backflow 4h.Be cooled to 10 DEG C, separate out white solid, suction filtration, filtrate adds methylene dichloride, stirs, separatory, organic phase anhydrous magnesium sulfate drying, filters, concentrated, adds ether, has solid to separate out, and filters, obtains the 5th step product.
Previous step product and 20mL toluene are placed in 50mL single port flask, after stirring and dissolving, add the aqueous sodium hydroxide solution of 15mL0.5molL-1, room temperature reaction 8h.After question response, point remove organic layer, water layer 20mL toluene wash 2 times.At 5 DEG C, water layer dilute hydrochloric acid adjusts pH to 2, has off-white color solid to separate out, and to continue at maintenance 5 DEG C 30 minutes, filter, a small amount of cold water washing of filter cake, oven dry, obtains valsartan crude product.
2. valsartan is refined
Valsartan crude product is carried out column chromatography for separation, and elutriant used is sherwood oil: ethyl acetate volume ratio is 20:1.Through nuclear magnetic data checking,
1h-NMR (400MHz, CDCl
3) δ: 10.8 (s, 1H), 7.55 (d, J=11.8Hz, 2H), 7.37 (d, J=12.0Hz, 2H), 7.26 (m, 2H), 7.11 (d, J=12.0Hz, 2H), 5.50 (s, 1H), 4.50 (s, 2H), 4.42 (d, J=8.0Hz, 1H), 3.12 (m, 1H), 2.14 (t, J=12.6Hz, 2H), 1.48 (m, 2H), 1.29 (m, 2H), 1.03 (d, J=10.4Hz, 6H), 0.98 (t, J=9.8Hz, 3H).
Embodiment four
1. the preparation of valsartan
In 100mL flask, 20mL methyl alcohol, 5.56g N-(trityl)-5-(4'-bromomethylbiphenyl-2-base) tetrazole and 0.81g sodium methylate is added, room temperature reaction 180 minutes under room temperature.After completion of the reaction, reacting liquid filtering, adds 25mL methylene dichloride in reaction solution in TLC display, and with saturated sodium bicarbonate washing to bubble-free, washing, separatory, organic phase is dry with anhydrous sodium sulphate sodium, suction filtration, and decompression removing methylene dichloride, obtains the first step product.
Previous step product is dissolved in methylene dichloride, under room temperature, adds 3.5gD.D.Q. and stir 180 minutes.After question response is complete, by reacting liquid filtering, decompression is spin-dried for, and obtains second step product.
In anhydrous conditions, previous step product and 1.4g Valine methyl ester hydrochloride are placed in the there-necked flask of 50mL, then add 15mL methylene dichloride, stirring at room temperature 30 minutes, then add 0.55g sodium cyanoborohydride reaction 2h in five batches.Add 20mL methylene dichloride, then use the distilled water wash 3 times of 25mL, branch vibration layer, organic over anhydrous dried over mgso, obtains the 3rd step product.
In 50mL there-necked flask, previous step product is dissolved in 20mL toluene, adds 1.8mL triethylamine, under 5 DEG C of stirrings, drip 1.2mL n-amyl chloride, drip and finish, reaction 2h.Suction filtration, filtrate washs 2 times with 25mL saturated sodium bicarbonate, and 20mL washes 2 times, anhydrous magnesium sulfate drying, removal of solvent under reduced pressure, obtains the 4th step product.
40mL acetonitrile, 25mL0.1molL-1 potassium dihydrogen phosphate aqueous solution and previous step product are put into 100mL there-necked flask, backflow 4h.Be cooled to 10 DEG C, separate out white solid, suction filtration, filtrate adds methylene dichloride, stirs, separatory, organic phase anhydrous magnesium sulfate drying, filters, concentrated, adds ether, has solid to separate out, and filters, obtains the 5th step product.
Previous step product and 20mL toluene are placed in 50mL single port flask, after stirring and dissolving, add the aqueous sodium hydroxide solution of 15mL1.3molL-1, room temperature reaction 8h.After question response, point remove organic layer, water layer 20mL toluene wash 2 times.At 5 DEG C, water layer dilute hydrochloric acid adjusts pH to 2, has off-white color solid to separate out, and to continue at maintenance 5 DEG C 30 minutes, filter, a small amount of cold water washing of filter cake, oven dry, obtains valsartan crude product.
2. valsartan is refined
Valsartan crude product is carried out column chromatography for separation, and elutriant used is sherwood oil: ethyl acetate volume ratio is 20:1.Through nuclear magnetic data checking,
1h-NMR (400MHz, CDCl
3) δ: 10.8 (s, 1H), 7.55 (d, J=11.8Hz, 2H), 7.37 (d, J=12.0Hz, 2H), 7.26 (m, 2H), 7.11 (d, J=12.0Hz, 2H), 5.50 (s, 1H), 4.50 (s, 2H), 4.42 (d, J=8.0Hz, 1H), 3.12 (m, 1H), 2.14 (t, J=12.6Hz, 2H), 1.48 (m, 2H), 1.29 (m, 2H), 1.03 (d, J=10.4Hz, 6H), 0.98 (t, J=9.8Hz, 3H).
Embodiment five
1. the preparation of valsartan
In 100mL flask, 20mL methyl alcohol, 5.56g N-(trityl)-5-(4'-bromomethylbiphenyl-2-base) tetrazole and 0.81g sodium methylate is added, room temperature reaction 180 minutes under room temperature.After completion of the reaction, reacting liquid filtering, adds 25mL methylene dichloride in reaction solution in TLC display, and with saturated sodium bicarbonate washing to bubble-free, washing, separatory, organic phase is dry with anhydrous sodium sulphate sodium, suction filtration, and decompression removing methylene dichloride, obtains the first step product.
Previous step product is dissolved in methylene dichloride, under room temperature, adds 3.5gD.D.Q. and stir 120 minutes.After question response is complete, by reacting liquid filtering, decompression is spin-dried for, and obtains second step product.
In anhydrous conditions, previous step product and 1.4g Valine methyl ester hydrochloride are placed in the there-necked flask of 50mL, then add 15mL methylene dichloride, stirring at room temperature 30 minutes, then add 0.55g sodium cyanoborohydride reaction 2h in five batches.Add 20mL methylene dichloride, then use the distilled water wash 3 times of 25mL, branch vibration layer, organic over anhydrous dried over mgso, obtains the 3rd step product.
In 50mL there-necked flask, previous step product is dissolved in 20mL toluene, adds 1.8mL triethylamine, under 0 DEG C of stirring, drip 1.2mL n-amyl chloride, drip and finish, reaction 2h.Suction filtration, filtrate washs 2 times with 25mL saturated sodium bicarbonate, and 20mL washes 2 times, anhydrous magnesium sulfate drying, removal of solvent under reduced pressure, obtains the 4th step product.
40mL acetonitrile, 25mL0.1molL-1 potassium dihydrogen phosphate aqueous solution and previous step product are put into 100mL there-necked flask, backflow 4h.Be cooled to 10 DEG C, separate out white solid, suction filtration, filtrate adds methylene dichloride, stirs, separatory, organic phase anhydrous magnesium sulfate drying, filters, concentrated, adds ether, has solid to separate out, and filters, obtains the 5th step product.
Previous step product and 20mL toluene are placed in 50mL single port flask, after stirring and dissolving, add the aqueous sodium hydroxide solution of 15mL2.0molL-1, room temperature reaction 8h.After question response, point remove organic layer, water layer 20mL toluene wash 2 times.At 5 DEG C, water layer dilute hydrochloric acid adjusts pH to 2, has off-white color solid to separate out, and to continue at maintenance 5 DEG C 30 minutes, filter, a small amount of cold water washing of filter cake, oven dry, obtains valsartan crude product.
2. valsartan is refined
Valsartan crude product is carried out column chromatography for separation, and elutriant used is sherwood oil: ethyl acetate volume ratio is 20:1.Through nuclear magnetic data checking,
1h-NMR (400MHz, CDCl
3) δ: 10.8 (s, 1H), 7.55 (d, J=11.8Hz, 2H), 7.37 (d, J=12.0Hz, 2H), 7.26 (m, 2H), 7.11 (d, J=12.0Hz, 2H), 5.50 (s, 1H), 4.50 (s, 2H), 4.42 (d, J=8.0Hz, 1H), 3.12 (m, 1H), 2.14 (t, J=12.6Hz, 2H), 1.48 (m, 2H), 1.29 (m, 2H), 1.03 (d, J=10.4Hz, 6H), 0.98 (t, J=9.8Hz, 3H).
Embodiment six
1. the preparation of valsartan
In 100mL flask, 20mL methyl alcohol, 5.56g N-(trityl)-5-(4'-bromomethylbiphenyl-2-base) tetrazole and 0.81g sodium methylate is added, room temperature reaction 180 minutes under room temperature.After completion of the reaction, reacting liquid filtering, adds 25mL methylene dichloride in reaction solution in TLC display, and with saturated sodium bicarbonate washing to bubble-free, washing, separatory, organic phase is dry with anhydrous sodium sulphate sodium, suction filtration, and decompression removing methylene dichloride, obtains the first step product.
Previous step product is dissolved in methylene dichloride, under room temperature, adds 2.27gD.D.Q. and stir 180 minutes.After question response is complete, by reacting liquid filtering, decompression is spin-dried for, and obtains second step product.
In anhydrous conditions, previous step product and 1.4g Valine methyl ester hydrochloride are placed in the there-necked flask of 50mL, then add 15mL methylene dichloride, stirring at room temperature 30 minutes, then add 0.55g sodium cyanoborohydride reaction 2h in three batches.Add 20mL methylene dichloride, then use the distilled water wash 3 times of 25mL, branch vibration layer, organic over anhydrous dried over mgso, obtains the 3rd step product.
In 50mL there-necked flask, previous step product is dissolved in 20mL toluene, adds 1.8mL triethylamine, under 5 DEG C of stirrings, drip 1.2mL n-amyl chloride, drip and finish, reaction 2h.Suction filtration, filtrate washs 2 times with 25mL saturated sodium bicarbonate, and 20mL washes 2 times, anhydrous magnesium sulfate drying, removal of solvent under reduced pressure, obtains the 4th step product.
40mL acetonitrile, 25mL0.05molL-1 potassium dihydrogen phosphate aqueous solution and previous step product are put into 100mL there-necked flask, backflow 4h.Be cooled to 10 DEG C, separate out white solid, suction filtration, filtrate adds methylene dichloride, stirs, separatory, organic phase anhydrous magnesium sulfate drying, filters, concentrated, adds ether, has solid to separate out, and filters, obtains the 5th step product.
Previous step product and 20mL toluene are placed in 50mL single port flask, after stirring and dissolving, add the aqueous sodium hydroxide solution of 15mL2.0molL-1, room temperature reaction 8h.After question response, point remove organic layer, water layer 20mL toluene wash 2 times.At 5 DEG C, water layer dilute hydrochloric acid adjusts pH to 2, has off-white color solid to separate out, and to continue at maintenance 5 DEG C 30 minutes, filter, a small amount of cold water washing of filter cake, oven dry, obtains valsartan crude product.
2. valsartan is refined
Valsartan crude product is carried out column chromatography for separation, and elutriant used is sherwood oil: ethyl acetate volume ratio is 20:1.Through nuclear magnetic data checking,
1h-NMR (400MHz, CDCl
3) δ: 10.8 (s, 1H), 7.55 (d, J=11.8Hz, 2H), 7.37 (d, J=12.0Hz, 2H), 7.26 (m, 2H), 7.11 (d, J=12.0Hz, 2H), 5.50 (s, 1H), 4.50 (s, 2H), 4.42 (d, J=8.0Hz, 1H), 3.12 (m, 1H), 2.14 (t, J=12.6Hz, 2H), 1.48 (m, 2H), 1.29 (m, 2H), 1.03 (d, J=10.4Hz, 6H), 0.98 (t, J=9.8Hz, 3H).
Embodiment seven
1. the preparation of valsartan
In 100mL flask, 20mL methyl alcohol, 5.56g N-(trityl)-5-(4'-bromomethylbiphenyl-2-base) tetrazole and 0.81g sodium methylate is added, room temperature reaction 180 minutes under room temperature.After completion of the reaction, reacting liquid filtering, adds 25mL methylene dichloride in reaction solution in TLC display, and with saturated sodium bicarbonate washing to bubble-free, washing, separatory, organic phase is dry with anhydrous sodium sulphate sodium, suction filtration, and decompression removing methylene dichloride, obtains the first step product.
Previous step product is dissolved in methylene dichloride, under room temperature, adds 2.27gD.D.Q. and stir 180 minutes.After question response is complete, by reacting liquid filtering, decompression is spin-dried for, and obtains second step product.
In anhydrous conditions, previous step product and 1.4g Valine methyl ester hydrochloride are placed in the there-necked flask of 50mL, then add 15mL methylene dichloride, stirring at room temperature 30 minutes, then add 0.55g sodium cyanoborohydride reaction 2h in five batches.Add 20mL methylene dichloride, then use the distilled water wash 3 times of 25mL, branch vibration layer, organic over anhydrous dried over mgso, obtains the 3rd step product.
In 50mL there-necked flask, previous step product is dissolved in 20mL toluene, adds 1.8mL triethylamine, under 0 DEG C of stirring, drip 1.2mL n-amyl chloride, drip and finish, reaction 2h.Suction filtration, filtrate washs 2 times with 25mL saturated sodium bicarbonate, and 20mL washes 2 times, anhydrous magnesium sulfate drying, removal of solvent under reduced pressure, obtains the 4th step product.
40mL acetonitrile, 25mL0.1molL-1 potassium dihydrogen phosphate aqueous solution and previous step product are put into 100mL there-necked flask, backflow 4h.Be cooled to 10 DEG C, separate out white solid, suction filtration, filtrate adds methylene dichloride, stirs, separatory, organic phase anhydrous magnesium sulfate drying, filters, concentrated, adds ether, has solid to separate out, and filters, obtains the 5th step product.
Previous step product and 20mL toluene are placed in 50mL single port flask, after stirring and dissolving, add the aqueous sodium hydroxide solution of 15mL1.0molL-1, room temperature reaction 8h.After question response, point remove organic layer, water layer 20mL toluene wash 2 times.At 5 DEG C, water layer dilute hydrochloric acid adjusts pH to 2, has off-white color solid to separate out, and to continue at maintenance 5 DEG C 30 minutes, filter, a small amount of cold water washing of filter cake, oven dry, obtains valsartan crude product.
2. valsartan is refined
Valsartan crude product is carried out column chromatography for separation, and elutriant used is sherwood oil: ethyl acetate volume ratio is 20:1.
Compared with prior art, the present invention has following beneficial effect: the new preparation method being provided a kind of valsartan by Williamson's ether synthesis step and DDQ oxidation step, by adopting potassium primary phosphate as buffer reagent and the sodium hydroxide solution using 1.3mol/L in hydrolytic process in the process of detritylation, avoiding because alkalescence crosses the product racemization problem produced by force, having great importance for keeping the optical purity of valsartan product.
The present invention is described by above-mentioned related embodiment, but above-described embodiment is only enforcement example of the present invention.Must it is noted that published embodiment limit the scope of the invention.On the contrary, be contained in the spirit of claims and the amendment of scope and impartial setting to be included in scope of the present invention.
Claims (10)
1. prepare a method for valsartan, it is characterized in that, described method comprises following steps:
1) take methyl alcohol as reaction solvent, make reactant I and sodium methylate room temperature reaction, obtain Compound II per,
2) after Compound II per being dissolved in methylene dichloride, add DDQ room temperature reaction, obtain compound III,
3) compound III and Valine methyl ester hydrochloride are joined in anhydrous conditions in methylene dichloride and stir after 10 ~ 60 minutes, then add sodium cyanoborohydride reaction in batches, obtain compound IV,
4) in toluene solvant, add compound IV, then, continue to add triethylamine, n-amyl chloride at 0 ~ 20 DEG C, react, obtain compound V,
5) in acetonitrile solvent, add potassium dihydrogen phosphate aqueous solution and compound V, back flow reaction obtains compound VI,
And,
6) compound VI is dropped in toluene, then adds after aqueous sodium hydroxide solution reacted, after acidifying, obtain target product valsartan,
2. the method for claim 1, it is characterized in that, described step 6) in acidifying be after compound VI and aqueous sodium hydroxide solution have reacted, at 5 DEG C, regulate pH value of reaction system to be 1 ~ 2, separate out solid, described solid is target product valsartan.
3. the method for claim 1, is characterized in that, described step 1) in, the molar ratio of described reactant I and sodium methylate is 1:(1 ~ 5), the reaction times is 30 ~ 180 minutes; Preferably, the molar ratio of described reactant I and sodium methylate is 1:(1.2 ~ 1.5), the reaction times is 60 ~ 180 minutes.
4. the method for claim 1, is characterized in that, described step 2) in, the molar ratio of described Compound II per and DDQ is 1:(1 ~ 2), the reaction times is 30 ~ 240 minutes, preferably 60 ~ 180 minutes.
5. the method for claim 1, is characterized in that, described step 3) in, the molar ratio of described compound III, Valine methyl ester hydrochloride and sodium cyanoborohydride is 1:(1 ~ 2): (1 ~ 3); Described sodium cyanoborohydride divides 3 ~ 5 times to add in reaction system; Adding the described sodium cyanoborohydride post-reacted reaction times is 30 ~ 180 minutes, preferably 30 ~ 120 minutes.
6. the method for claim 1, is characterized in that, described step 4) in, the molar ratio of described compound IV, triethylamine and n-amyl chloride is 1:(1 ~ 5): (1 ~ 3); Prime number n-amyl chloride feeding mode is for dripping; Temperature of reaction is preferably 0 ~ 5 DEG C, and the reaction times is 1 ~ 5 hour, preferably 1 ~ 2 hour.
7. the method for claim 1, is characterized in that, described step 5) in, the concentration of described potassium dihydrogen phosphate aqueous solution is 0.05mol/L, and temperature of reaction is 20 ~ 100 DEG C, and the reaction times is 1 ~ 6 hour; And preferably, temperature of reaction is 80 DEG C, and the reaction times is 4 hours.
8. the method for claim 1, is characterized in that, described step 6) in, the concentration of described aqueous sodium hydroxide solution is 1.3mol/L, and the reaction times of compound VI and aqueous sodium hydroxide solution is 1 ~ 10 hour, and temperature of reaction is 0 ~ 50 DEG C; And preferably, the reaction times of compound VI and aqueous sodium hydroxide solution is 8 hours, and temperature of reaction is 20 DEG C.
9. the method for claim 1, is characterized in that, described step 3) in sodium cyanoborohydride divide 3 ~ 5 times to add in reaction system; Described step 4) in n-amyl chloride feeding mode for drip.
10. the method for claim 1, is characterized in that, at least one step during described method is further comprising the steps of:
In described step 1) and step 2) between also comprise: 1.1) to step 1) reacted after reaction solution carry out after suction filtration is spin-dried for, add water and sodium hydrogen carbonate solution washing to bubble-free, after washing, decompression is spin-dried for again, obtains the Compound II per obtaining solid;
In described step 2) and step 3) between also comprise: 2.1) to step 2) reacted after reaction solution filter after again decompression be spin-dried for, obtain the compound III of solid;
In described step 3) and step 4) between also comprise: 3.1) to step 3) reacted after product carry out distilled water wash, then with anhydrous magnesium sulfate drying, obtain the compound IV of solid;
In described step 4) and step 5) between also comprise: 4.1) to step 4) reacted after reaction solution carry out suction filtration, filtrate is washed with after saturated sodium bicarbonate washing again, use anhydrous magnesium sulfate drying again, after underpressure distillation, obtain the compound V of solid;
In described step 5) and step 6) between also comprise: 5.1) by step 5) reacted after reaction solution be cooled to room temperature, suction filtration is carried out after separating out solid, in filtrate, add methylene dichloride carry out extraction and separatory, after organic phase anhydrous magnesium sulfate drying, filter, concentrate, add anhydrous diethyl ether again to separate out solid, after filtering, obtain solid chemical compound VI; Or,
In step 6) after can also comprise: 6.1) filter the solid of separating out after acidifying, a small amount of cold water washing of filter cake, namely obtains target product valsartan after oven dry; 6.2) by step 6.1) valsartan that obtains carries out column chromatography for separation, and elutriant used is sherwood oil: ethyl acetate, and volume ratio is 20:1.
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