A kind of novel synthesis of valsartan
Technical field
The invention belongs to pharmaceutical chemistry and organic chemistry filed, particularly, the present invention relates to valsartan (Valsartan, 1) novel synthesis, and intermediate---N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-preparation method of L-Xie Ansuan (2).
Background technology
Valsartan (Valsartan) is a kind of non-peptide class Angiotensin II (ATII) receptor antagonist, the chemistry of valsartan is called N-(1-oxygen amyl group)-N-[[2 '-(1H-tetrazole-5-yl)-(1,1 '-phenylbenzene)-the 4-yl]-methyl]-the L-Xie Ansuan, the chemical structure of valsartan is as the formula (1).
Known valsartan and (or) synthetic method such as the patent US 5,399,578 of intermediate, US 5,965, and 592, WO 02/006253, and CN 1317485, and WO 04/026847, WO 04/111018, WO 05/049586, WO05/049587 and J.Med.Chem.1991,34 (8), 2525-2574, Bioorganic ﹠amp; Med.Lett.1994,4 (1), 29-34.
U.S. Pat 5; 399; the 578 valsartan synthetic methods of describing are shown in reaction formula (1); with 2 '-cyano group-4-formyl biphenyl (3) is raw material; with the tosilate (4) of L-Xie Ansuan benzyl ester through reductive amination process; positive valeryl reaction becomes tetrazole, go to protect valsartan (2).The shortcoming of this method is: one, adopts trialkyl azide tin and cyano group to react down at 120-140 ℃ and generate tetrazole, but trialkyl azide tin toxicity is big.1317485 pairs of tetrazole synthetic methods of patent CN are improved, the employing sodiumazide is a raw material, the polyoxyethylene glycol that trialkyl azide tin and terminal hydroxy group are silylated is a catalyzer, though reduced the consumption of trialkyl azide tin, sodiumazide danger is bigger.Its two, adopt the method for shortening to slough benzyl protecting group, need use hydrogenation unit.In addition, 04/111018 pair of method of sloughing benzyl of world patent WO is improved, and adopts hydrolysis under the alkaline condition, has avoided shortening; But the optical purity of valsartan crude product is not appeared in the newspapers, and yield is lower.
Reaction formula (1):
The valsartan synthetic method that world patent WO 04/026847 describes is shown in reaction formula (2); 2 '-tetrazole base-4-formyl biphenyl (4) with the protected mistake of tetrazole is a raw material; generate Schiff's base with L-Xie Ansuan or derivative (5) condensation; again through shortening or metal hydride reduction; gained secondary amine and n-amyl chloride carry out acylation reaction in the presence of water, obtain the valsartan (1) of high-optical-purity.The shortcoming of this method is: one, 2 '-tetrazole base-4-formyl biphenyl (or 2 '-tetrazole of the protected mistake of tetrazole base-4-formyl biphenyl) need preparation separately, cost height.Its two, need to adopt adopt shortening or metal hydride reduction Schiff's base.Its three, in the positive valeryl reaction, the existence of water can improve the optical activity of product valsartan on the one hand; But causing the n-amyl chloride partial hydrolysis simultaneously is positive valeric acid, influences the crystallization purifying of valsartan.
Reaction formula (2):
The valsartan synthetic method that existing patent WO 05/049586 describes is shown in reaction formula (3); 2 '-tetrazole base-4-bromomethylbiphenyl (7) with the protected mistake of tetrazole is a raw material; L-Xie Ansuan (6) condensation prepared secondary amine with the esterified protection of carboxyl; through positive valeryl reaction; slough the protecting group of tetrazole; and then, obtain valsartan (1) by the hydrolysis of ester group reaction.In this patent report, separating tetrazole protective group and hydrolysis of ester group reaction two rapid step by step yields is 50%, and the chiral purity of gained valsartan is not reported.
Reaction formula (3):
Summary of the invention
The novel method that the purpose of this invention is to provide a kind of preparation valsartan (1).Another object of the present invention has provided a kind of N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-preparation method of L-Xie Ansuan (2).
The inventor is through research, find a kind of effectively synthetic N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-the 4-yl]-methyl]-method of L-Xie Ansuan (2), and this method is applied to the preparation of valsartan (1), research and develop the variation route of a preparation valsartan, finished the present invention thus.
According to the present invention, it is characterized in that, among the present invention, valsartan (1) is through intermediate N (1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-the 4-yl]-methyl]-L-Xie Ansuan (2), by following steps preparations, shown in reaction formula (4).
Reaction formula (4):
According to the present invention, alkylated reaction described in the above-mentioned preparation process is meant 2 '-(N-trityl) tetrazole base-4-bromomethylbiphenyl (BBTT) and valine methyl ester (Val-OMe) (or its salt) synthetic N-[[2 '-(N-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl under alkaline condition]-methyl]-reaction of L-valine methyl ester (Val-1).
According to the present invention, described valine methyl ester salt is meant the inorganic acid salt of valine methyl ester, example hydrochloric acid salt, vitriol; Or organic acid salt, as tosilate.
Specifically, alkylated reaction of the present invention is in the presence of organic bases (for example triethylamine, diisopropylethylamine etc.), in organic solvent, nucleo philic substitution reaction obtains compound (Val-1) by 2 '-(N-trityl) tetrazole base-4-bromomethylbiphenyl (BBTT) and valine methyl ester (Val-OMe) or its salt.Wherein, temperature of reaction is in-20-80 ℃ temperature range; Reaction times is in 1-24 hours; Organic solvent is selected from THF, dioxane, methylene dichloride, ethylene dichloride, toluene, acetonitrile etc.
According to the present invention; acylation reaction described in the above-mentioned preparation process is meant N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1; 1 '-phenylbenzene)-the 4-yl]-methyl]-L-valine methyl ester (Val-1) and n-amyl chloride synthetic N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl under alkaline condition]-methyl]-reaction of L-valine methyl ester (Val-2).
Specifically; acylation reaction of the present invention is at organic bases (for example triethylamine, diisopropylethylamine etc.); perhaps mineral alkali (for example salt of wormwood, yellow soda ash) exists down, in organic solvent, obtains compound (Val-2) through acylation reaction by compound (Val-1) and n-amyl chloride.Wherein, temperature of reaction is in-20-80 ℃ temperature range; Organic solvent is selected from N, dinethylformamide, tetrahydrofuran (THF), dioxane, methylene dichloride, ethylene dichloride, toluene, acetonitrile etc.; Reaction times is in 1-24 hours.
According to the present invention, it is characterized in that, the reaction of alkaline hydrolysis described in the above-mentioned preparation process is meant N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-the 4-yl]-methyl]-L-valine methyl ester (Val-2) hydrolysis methyl esters under alkaline condition, obtain intermediate (Val-2 ').
According to the present invention, it is characterized in that described alkaline hydrolysis reaction is in the presence of excessive mineral alkali, carries out in the mixture of organic solvent and water.Wherein, organic solvent is selected from polar solvent, as lower aliphatic alcohols, and methyl alcohol, ethanol, propyl carbinol; Or aprotic polar solvent, as 1,4-dioxane, tetrahydrofuran (THF), N, dinethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO); Or the mixture of two or more solvents wherein.According to the difference of selecting organic solvent for use, the ratio of water and organic solvent changes in the scope of 1:1000 to 5:1, is preferably 1:10 to 5:1.The consumption of organic solvent is 1-100 times of compound (Val-2), is preferably 1-30 times.
According to the present invention, in the alkaline hydrolysis reaction, used alkali is selected from alkali metal hydroxide or alkaline earth metal hydroxides, as potassium hydroxide, sodium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide etc.
According to the present invention, in the alkaline hydrolysis reaction, the consumption of alkali is N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-5 to 1000 times (mol ratio) of L-valine methyl ester (Val-2), be preferably 10 to 100 times (mol ratio).
According to the present invention, can get compound (2) after the acidifying of above-mentioned alkaline hydrolysis reaction product; Wherein, the required acid of acidification reaction is preferably from organic acid, as acetate, formic acid, citric acid etc.
According to the present invention, prepared N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-optical purity of L-Xie Ansuan (2) is more than 95%.
According to the present invention, separate protective reaction in the described reaction formula (4), be meant the reaction of sloughing trityl-protecting group.Can be undertaken by known method of separating trityl.
Among the present invention, compound (Val-2) is earlier at alkaline condition hydrolysis ester group, and acidifying obtains compound (2) again, and compound (2) is sloughed trityl-protecting group at last and obtained valsartan (1), and total recovery is more than 67%, and chiral purity can reach more than 99%.And existing patent WO 05/049586 takes to slough earlier trityl-protecting group, uses the method for trimethyl silicane potassium alcoholate ester hydrolysis base again, and the yield of example 10 reports only is 50% in this patent, and the optical purity of this patented method products therefrom valsartan is not reported.Compare with WO 05/049586, this patent method yield is higher, and can obtain the valsartan of high-optical-purity.The present invention has also that raw material stable is easy to get, advantage such as industrialization operation easily.
Embodiment
Further specify the present invention below by embodiment.The preparation method who it should be understood that the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention; Under design prerequisite of the present invention, preparation method's of the present invention simple modifications is all belonged to the scope of protection of present invention.
In the following example, the optical purity of compound records with chirality HPLC.
Example 1.N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-preparation of L-valine methyl ester (Val-1)
Drying tube is being housed, and thermometer in the 1000mL four-hole bottle of dropping funnel and mechanical stirring slurry, adds valine methyl ester (Val-OMe, 24.3g, 0.185mol), and diisopropylethylamine (18.7g, 0.185mol), and methylene dichloride (300mL), stirring and dissolving, cooling.Under-10~0 ℃, drip N-trityl-2 '-tetrazole base-4-bromomethylbiphenyl (BBTT, 100g, 0.179mol) methylene dichloride (300mL) solution, finish, under 0~10 ℃, continue reaction 4 to 5 hours, TLC (developping agent, normal hexane: ethyl acetate=5: 1) show that raw material disappears substantially, the sodium bicarbonate aqueous solution washing of adding 5%, saturated brine washing, methylene dichloride is sloughed in the organic phase decompression, N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-the 4-yl]-methyl]-L-valine methyl ester crude product 110g (the HPLC analytical results shows that the content of Val-1 is 90% in the crude product).This crude product need not to be further purified, and directly carries out the next step.
Example 2.N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-preparation of L-valine methyl ester (Val-1)
Drying tube is being housed, thermometer, in the 100mL there-necked flask of dropping funnel, the adding valine methyl ester hydrochloride (the Val-OMe hydrochloride, 3.1g, 18.5mmol), diisopropylethylamine (3.74g, 37mmol), and methylene dichloride (30mL), stirring and dissolving, cooling.Under-10~0 ℃, drip N-trityl-2 '-tetrazole base-4-bromomethylbiphenyl (BBTT, 9.98g, 0.179mol) methylene dichloride (30mL) solution, finish, under 0~10 ℃, continue about 5 hours of reaction, TLC shows that raw material disappears substantially, adds 5% sodium bicarbonate aqueous solution washing, the saturated brine washing, methylene dichloride is sloughed in the organic phase decompression, N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-L-valine methyl ester crude product 12.1g, this crude product and example 1 products therefrom are identical.
Example 3.N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-preparation of L-valine methyl ester (Val-2)
Drying tube is being housed, thermometer, in dropping funnel and the churned mechanically 1000mL four-hole bottle, add example 1 gained crude product successively, ethyl acetate (500mL), and triethylamine (21.2g, 0.21mol) after the stirring and dissolving, be cooled to about-10 ℃, slowly drip n-amyl chloride (24.2g, 0.20mol).Finish, under this temperature, reacted 3 hours; Heat up then, continue reaction 5 hours at 35 ℃, TLC demonstration reaction is finished.Reaction solution is used saturated aqueous common salt, phosphoric acid buffer (pH=7), deionized water wash successively, anhydrous sodium sulfate drying, concentrating under reduced pressure, N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-the 4-yl]-methyl]-L-valine methyl ester crude product 110g (the HPLC analytical results shows that the content of Val-2 is 85.1% in the crude product).This crude product can directly carry out the next step.
Example 4.N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-preparation of L-Xie Ansuan (2)
In that being housed, temperature takes into account in the churned mechanically 1000mL there-necked flask, adding example 3 gained Val-2 crude products (110g, content 85.1%, 0.135mol), tetrahydrofuran (THF) (500ml), after the stirring and dissolving, and the adding lithium hydroxide aqueous solution (concentration 10%, 250ml), in 45 ℃ of following stirring reactions 12 hours, TLC (developping agent, normal hexane: ethyl acetate: acetate=63:35:2) show that raw material disappears, and divides the phase of anhydrating; It is 7-8 that the gained organic phase is regulated pH with Glacial acetic acid, is evaporated to small volume, adds ethyl acetate (1000ml), the saturated common salt water washing, and anhydrous sodium sulfate drying, concentrating under reduced pressure is separated out solid.Gained solid re-crystallizing in ethyl acetate, N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-L-Xie Ansuan (2) 68.2g, yield is 74.5% (in Val-2).Fusing point: 160-161 ℃, optical purity 97.1%.
Ultimate analysis:
Molecular formula: C43H43N5O3
Calculated value (%): C, 76.16; H, 6.35; N, 10.33
Measured value (%): C, 76.17; H, 6.47; N, 10.47
1H-NMR(400MHz,DMSO-d6)0.845(t,6H),0.969(d,J=6.4Hz,3H),1.288~1.230(m,2H),1.599~1.562(m,2H),2.345~2.279(m,2H),2.630~2.605(m,1H),3.791(d,J=10Hz,1H),4.470(dd,2H),7.017~6.948,7.448~7.225(m,18H),6.957(d,J=7.6Hz,2H),7.130(d,J=7.6Hz,2H),7.938(d,J=7.6Hz,1H),~11(brs,1H)ppm.
Example 5.N-(1-oxygen amyl group) N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-preparation of L-Xie Ansuan (2)
In that being housed, temperature takes into account in the churned mechanically 1000mL there-necked flask, add example 3 gained Val-2 crude product (110g, content 85.1%, 0.135mol), tetrahydrofuran (THF) (400ml), after the stirring and dissolving, add lithium hydroxide (26.4g, 1.1mol) and water (40ml), in 60 ℃ of following stirring reactions 24 hours, TLC shows that raw material disappears, and divides the phase of anhydrating; It is 7-8 that the gained organic phase is regulated pH with Glacial acetic acid, is evaporated to small volume, adds ethyl acetate (1000ml), the saturated common salt water washing, and anhydrous sodium sulfate drying, concentrating under reduced pressure is separated out solid.Gained solid re-crystallizing in ethyl acetate, N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-L-Xie Ansuan (2) 73.2g, yield is 79% (in Val-2).Fusing point: 160-161 ℃, optical purity 96.9%.
Example 6.N-(1-oxygen amyl group)-N-[[2 '-(1H-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-preparation of L-Xie Ansuan (valsartan, 1)
N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-the 4-yl]-methyl]-L-Xie Ansuan (2,67.8g, 0.1mol) be dissolved in the methylene dichloride (250ml), add hydrochloric acid (1N, 50ml), stirring reaction to raw material disappears under room temperature, divides the phase of anhydrating; Organic phase saturated common salt water washing adds entry (300ml) again, and the ice-water bath cooling is regulated pH=9 to 10, standing demix with aqueous sodium hydroxide solution (1N) down.Water intaking is placed in the 1000ml there-necked flask, adds methylene dichloride (300ml), stirs down, regulate pH=3 to 4 with hydrochloric acid (6N), tell organic phase after, water layer extracts twice with methylene dichloride (150ml), merge organic phase, anhydrous sodium sulfate drying, be evaporated to small volume after, add the ethyl acetate crystallization, get valsartan (1) 38.3g, yield 88.1%, fusing point 116.3-117.2 ℃, purity (HPLC) 99.1%.