PROCESS FOR THE OBTAINING OF TOLTERODINE TARTRATE
The present invention relates to a synthesis process for obtaining tolterodine tartrate, a compound that is used as an active ingredient in the treatment of urinary incontinence.
BACKGROUND OF THE INVENTION Tolterodine belongs to a class of drugs called antimuscarinic drugs, which are used in the treatment of urinary conditions. Tolterodine is used in the treatment of urinary incontinence because it acts to prevent contraction of the bladder and is known commercially as Detrusitol or Detrol LA. The chemical name of tolterodine base is N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine. Taking into account that in the structure of tolterodine a stereogenic center is present, studies of biological activity have been carried out which have shown that the active enantiomer is that of the R configuration. Furthermore, because tolterodine is an amine , stable salts are preferred for pharmaceutical use, so it is used as (+) - tartaric acid salt, that is, as (R) -tolterodine tartrate (Scheme
I):
Scheme I Since the approval by the United States Food and Drug Administration (FDA) of the use of tolterodine in the year of 1998, the synthesis of this compound in preparative scale has been carried out in different ways. The first method described for the preparation of tolterodine is presented in US Pat. No. 5,382,600, by N. A. Jónsson, B. A. Sparf, L.
Mikiver, P. Moses, L. Nilvebrant, G. Glas (Scheme I I).
(+) - tartaric acid, EtOH
Scheme II In the process described by N. A. Jonson et al. , the reaction of the benzopyranone (1) with methyl iodide and potassium carbonate gives the methyl ester (2), which is reduced to the alcohol (3) with lithium aluminum hydride. The alcohol thus obtained is esterified using tosyl chloride to give the compound (4), which is treated with diisopropylamine to convert it into the tertiary amine (5). The compound (5) is then treated with boron tribromide to give the amine (6) as a racemic mixture which is finally resolved via the formation of diastereomeric salts with (+) - tartaric acid. The process of N. A. Jonson et al. It has several drawbacks, such as long reaction times, low yields and the use of expensive and dangerous reagents, as well as making it unsuitable for commercial scale application. U.S. Patent No. 5,922,914 to J. R. Gage and J. E. Cabaj, provides an alternative process for the tolterodine preparation (Scheme III).
(+) - tartaric acid, EtOH
Scheme III In the process described by J. R. Gage et al. , the benzopyranone (1) is converted to the benzopyranol (7) by means of the reduction with diisobutyl aluminum hydride; the reductive alkylation of the diisopropylamine with the compound (7), by means of hydrogen and palladium on carbon, leads to the racemic tolterodine (6), which is resolved again with (+) - tartaric acid. The process of J. R. Gage et. to the. reduces the number of steps for obtaining tolterodine. However, the cost for the use of DIBAL is high, and this reagent is also dangerous. An alternate enantioselective synthesis is that described in patent EP 1496045 of P. G. Anderson and C. Hedberg (Scheme IV).
Scheme IV In the process of P. G. Anderson et al. , indenone (9), is reduced with borane using the Corey catalyst (8) to obtain the enantiomer (10), as a majority product. Subsequently, indenol is subjected to a sigmatropic rearrangement to give indenone (11), as the sole enantiomer, which undergoes an oxidation of Bayer-Villiger to form enantiomerically pure benzopyranone (1).
Other processes for the preparation of tolterodine found in the prior art, as in the international application WO 2005/061431 of G.P. Coca, Pablo Martín Pascual and Jorge Marin Juárez, or in the international application WO 03/014060 of Yatendra Kumar, Mohán Prasad and Satyananda Misra have a high number of steps for obtaining tolterodine. As can be seen, the processes described above have several disadvantages because the reaction times are long, the yields are low, expensive and dangerous reagents are used, in addition, in some cases, the scaling is complicated. From the above, there is a need to find alternatives that allow having an improved process, with which the aforementioned problems can be avoided, such as the process of obtaining tolterodine that is intended to be protected by the present invention.
DETAILED DESCRIPTION OF THE INVENTION The present invention describes an improved process for the preparation of tolterodine tartrate, with high yields and at a lower cost, thus being able to avoid the problems present in the prior art. The tolterodine tartrate preparation process of the present invention consists of four steps (Scheme V): 1.- 'Pr2NH CH3CN 2.- NaOH, MeOH 3.- HBr
Scheme V The benzopyranone (1) is subjected to a fairly simple reduction reaction, using sodium borohydride, methanol and toluene at a temperature between 5 and 15 ° C, preferably at 10 ° C, to obtain the alcohol (12) , with a high performance. Then, the two hydroxyl functions of the dialcohol (12) are protected using 2.0 to 3.0 equivalents of mesyl chloride, preferably 2.3 equivalents, in methylene chloride at a temperature between 10 and 20 ° C, preferably at 15 ° C, producing the compound dimesylated (13).
The previous step presents the advantages since mesyl chloride serves to introduce a good leaving group which is necessary for the substitution reaction with dilsopropylamine (14), which will give rise to tolterodine. The same reagent serves to protect the phenolic hydroxyl and in addition to that the subsequent deprotection is carried out easily under basic conditions.
Once the dimesylated compound (13) is obtained, it is first treated with diisopropylamine in acetonitrile by heating between 80 and 110 ° C, preferably at 100 ° C, under a pressure of 2 to 2.5 bar, preferably at 2.3 bar. Then, it is treated with sodium hydroxide in refluxing methanol to liberate the phenolic hydroxyl and, finally, the treatment of the reaction crude in ethyl acetate or methylene chloride, preferably ethyl acetate, with hydrobromic acid, allows for easy isolation of tolterodine in the form of the hydrobromide (14). Finally, tolterodine tartrate is obtained by treating the hydrobromide with sodium hydroxide to release the base and, subsequently, with (+) - tartaric acid to form the tartrate by fractional crystallization in ethanol. The benzopyranone of formula 1, starting material of the process of the present invention, is a known compound and can be prepared in a simple manner according to the procedure described in the Australian Journal of Chemistry, 26, 899-906 (1973), or in example 1 of document US 5,922,914. The following examples illustrate the process that is intended to be protected by the invention and should not be considered as limiting thereof. Example 1 2- (3-hydroxy-1-phenylpropyl) -4-methylphenol (12) Place in a 2L flask equipped with mechanical stirring and thermometer, 100 g of benzopyranone (1) (420 mmol), 28.6 g (757 g) mmol, 1.8 eq) of sodium borohydride and 300 ml of toluene and cooled to a temperature of 0 to 5 ° C. To the suspension is added 400 ml of MeOH previously cooled between 0 and 5 ° C, in a period of 2 to 3 hours, maintaining the temperature between 5 and 15 ° C during the addition. Stirring is continued at the same temperature until it is confirmed by HPLC that the reaction is complete (column: Nucleosil C18, mobile phase: acetonitrile-water 60:40, flow: 1.2 ml / min; ?: 214 nm; IR: dialcohol = 3.85 mm, benzopyranone = 8.02 mm). 150 ml of acetic acid are added. The solvent is evaporated in vacuo, 500 ml of water are added and the mixture is stirred for 30 minutes. The solid formed is filtered and dried at 60 ° C under vacuum to give 98.8 g of product (12), in a yield of 97%. PF: 1 18 - 1 19 ° C 1 H NMR (400 MHz, CDCl 3): d 2.17 (3 H, s, CH 3), 2.13 and 2.35 (2 H, m, CH 2), 2.68 (1 H, a, OH), 3.52 and 3.74 (2H, m, CH2), 4.57 (1 H, dd, J = 10.2, 6 Hz, CH), 6.70-6.85 (3H, m, Ph), 7.19.7.29 (5H, m, Ph). 13 C NMR (100 MHz, CDCl 3): d 20.7 (CH 3), 36.9 (CH 2), 38.6 (CH), 60.7 (CH 2), 1 1 5.9 (Short), 126.2 (Cpara). 1 27.9 (Cmeta). 1 28.2 (Cmeta). 1 28.4 (Short), 129.1 (Cmeta), 1 30.2 (Cipso), 1 34.4 (Cipso), 144.0 (CipSo), 1 51 .4 (Cipso). IR (cm "1): 3420, 2923, 1654, 1609, 1447, 1255, 1104, 1073, 1037, 901, 883, 812, 781, 698, 602, 499. Example 2 2- (3-methanesulfonyloxy) methansulfonate 1-phenylpropyl) -4-methylphenyl (13) 250 ml of methylene chloride, 50 g (20.83 mmol) of compound (12) and 69.81 g (68.75 mmol, 3.3 eq.) Of triethylamine are placed in a 1 L flask.; it is cooled to 0 ° C. 56.06 g (48.94 mmol, 2.35 eq.) Of mesyl chloride are added by means of an addition funnel, maintaining the temperature between 10 and 15 ° C. After the addition, stirring is continued for 1 hour at 15 ° C and the end of the reaction is verified by means of TLC (hexane-AcOEt-IPA 25: 5: 5). Once the reaction has ended, the temperature is allowed to rise to 25 ° C, 200 ml of water and 30% HCl are added until pH < 5. Stir for 15 minutes and let it rest. The organic phase is separated and washed with water (2 x 100 μl). The methylene chloride is evaporated to obtain 74 g of the product (13) as an oil in a 90% yield. 1 H NMR (300 MHz, CDCl 3): d 2.32 (3 H, s, CH 3), 2.47 (2 H, dd, J = 6.3, 14.2 Hz, CH 2), 2.92 (3 H, s, CH 3), 2.99 (3 H, s , CH3), 4.18 (2 H, m, CH2), 4.56 (1 H, dd, J = 7.8, 5.4 Hz, CH), 7.03-7.34 (8 H, m, Ph). 13 C NMR (75 MHz, CDCl 3): d 21 .1 (CH 3), 34.2 (CH 2), 37.1 (CH 3), 37.8 (CH 3), 39.7 (CH), 67.9 (CH 2), 121.4 (Short). 126.7 (Cpara), 127.8 (Short),
1 28.4 (Cmeta), 128.5 (Cmeta), 128.9 (Cmeta), 1 35.5 (Cpso), 137.1 (Cipso),
144. 8 (Cipso). IR (cnrf1): 3462, 3028, 2924, 1 620, 1490, 1454, 1 350, 1268, 1 1 96, 1 1 69, 1 103, 971, 920, 857, 824, 772, 736, 701, 526. EXAMPLE 3 2- (3- (Diisopropylamino) -1-phenylpropyl) -4-methylphenol Hydrobromide, (Tolterodine Hydrobromide) (14) Place in a Parr reactor, 50 g of the compound (13), 100 g of diisopropylamine and 50 ml of acetonitrile. The reaction mixture is heated to 100 ° C and 2.3 bar (34 psi) for 1 day. The remaining diisopropylamine and acetonitrile are evaporated under reduced pressure. The residue is dissolved in 150 ml of ethyl acetate and washed first with 100 ml of water, then with 75 ml of 10% HCl and then with 100 ml of water. The ethyl acetate is distilled off and the residue is dissolved in 150 ml of methanol. 78.1 g of 49% sodium hydroxide are added. The reaction mixture is heated to reflux for 2 to 4 hours. The methanol is distilled under reduced pressure until the separation of two phases is observed; the upper one contains the product. The lower phase is cooled to 5 to 10 ° C, 100 ml of cold water are added and washed with 50 ml of ethyl acetate. To the organic phase, 100 ml of ethyl acetate are added and washed twice with 75 ml of water. The organic phases are combined and 10.8 ml of hydrobromic acid are added. The suspension is cooled to 0 ° C and kept so for 1.5 hours. The solid is filtered and washed with ethyl acetate. After drying under reduced pressure at 60 ° C, 36.2 g of the compound (14) are obtained in a yield of 71%. MP: 210-21 1 ° C 1 H NMR (400 MHz, DMSO-d 6): d 1 .220 (12H, m, (CH 3) 2), 2.17 (3H, s, CH 3), 2.42 (2H, a, CH2), 2.91 (2H, a, CH2), 3.58 (2H, a, CH), 4.35 (1 H, t, J = 7.2 Hz, CH), 6.62-7.37 (8H, m, Ph), 8.66 (1 H, a, NH). 13 C NMR (100 MHz, DMSO-d 6): d 19.7 and 21.7 [(CH3) 2], 21.2 (CH3), 37.1 (CH2), 44.7 (CH), 48.4 (CH), 49.8 (CH) , 1 15.2 (Short), 126.3 (Cpara), 127.3 (Cmeta), 128.3 (Cmeta), 128.6 (Short), 129.9 (Cmeta), 132.4 (Cipso),
133. 02 (Cipso), 137.3 (CipSo), 148.7 (Cipso). IR (cm "1): 3213, 2938, 2661, 1717, 1608, 1508, 1458, 1397, 1260, 1210, 1 1 1 1, 1029, 935, 912, 827, 768, 755, 739, 700, 677, 636, 596, 531. EXAMPLE 4 (R) - Tolterodine Tartrate In a 1 L round flask, provided with mechanical stirring, 60 g (148 mmol) of the compound (14), 500 ml of methylene chloride and 250 ml are mixed. ml of water, stirring while adding 6 ml of 49% NaOH and 6 g of Na2CO3, the pH should be between 10 and 11. Stir for one hour and then let stand. Wash twice with 125 ml of water, distil the methylene chloride, dissolve the concentrate in 125 ml of ethanol and heat to 65 to 70 ° C. Add 33-30 g (222 mmol, 1.5 eq) of dissolved tartaric acid. in 333 ml of EtOH at 60 to 70 ° C, by means of an addition funnel for 45 minutes The suspension is refluxed for 1 hour, then cooled gradually to 0 ° C and maintained at that temperature for an additional 1 hour. The solid is filtered Ornate and wash 2 times with 100 ml of EtOH at 0 ° C. The compound obtained is dried under vacuum at 60 ° C overnight. The dried product is recrystallized with 2.15 L of ethanol, heating at 78 to 80 ° C for 30 minutes. The mixture is concentrated to half the volume, distilling 1.075 L of ethanol. Then, it cools to 20-25 ° C in one hour; then at 0 ° C and kept at that temperature for 1 hour. It is filtered and washed twice with 100 ml of ethanol. The product is dried under reduced pressure for 1 night and recrystallized once more in the same manner. 24 g of the compound are obtained in a yield of 34%. P.F. = 214 ° C. [a] 25D = +27.4 (c = 1, MeOH) 1 H NMR (400 MHz, DMSO-d6): d 1.10 (12H, d, J = 4.0 Hz, (CH3) 2), 2.15 (3H, s, CH3 ), 2.34 (2H, t, J = 7.6 Hz, CH2), 2.76 (2H, m, CH), 3.44 (2H, J = 6.4 Hz, CH2), 4.02 (2H, s, CH), 4.29 (11- 1, t, J = 7.6 Hz, CH), 6.67 (1H, d, J = 9.2 Hz, Ph), 6.78 (1H, dd, J = 2.0, 8.0 Hz, Ph), 7.01 (1H, s, Ph) , 7.14 (1H, t, J = 6.8 Hz, Ph), 7.28 (m, 4H, Ph). 13 C NMR (100 MHz, DMSO-d 6): d 17.9 and 17.8 [(CH 3) 2], 20.3 (CH 3), 32.4 (CH 2), 40.8 (CH), 45.1 (CH 2), 52.6 (CH), 71.8 (CH ), 115.1 (Short), 125.9 (CipSo), 127.3 (Cpara), 127.4 (Cmeta), 127.8 (Cmeta), 127.9 (Short), 128.2 (Cmeta), 129.9 (C¡pSo), 144.1 (Cipso), 152.4 (CipSo), 174.2 (C02H). IR (cm-1): 3572, 2923, 1704, 1590, 1500, 1403, 1265, 1125, 1069910, 817, 756, 736, 707, 599, 518, 475.