ES2291135B1 - PROCEDURE FOR THE PREPARATION OF TARTRATE OF (R) -TOLTERODINE. - Google Patents

Abstract

Process for the preparation of (R) -tolterodine tartrate comprising: reducing a benzopiranone, of formula 1, with sodium borohydride to form a dialcohol, of formula 12; reacting the hydroxyl groups of the dialcohol with mesyl chloride to introduce two methanesulfonyl groups and forming a dimesylated compound, of formula 13; reacting the dimesylated compound, with diisopropylamine under pressure, and then with sodium hydroxide to obtain tolterodine by isolating it as the corresponding hydrobromide, of formula 14; Release the tolterodine base from the hydrobromide, and then react the same with (+) - tartaric acid to prepare the (R) -tolterodine tartrate.

Description

Procedure for the preparation of tartrate (R) -tolterodine.

The present invention relates to a Synthesis procedure for the preparation of tartrate (R) -tolterodine, compound used as active ingredient in the treatment of incontinence urinary

Background of the invention

Tolterodine belongs to a class of medicines called antimuscarinics which are used in the treatment of urinary conditions. Tolterodine is used in the treatment of urinary incontinence because it acts preventing bladder contraction and it 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 the structure of tolterodine is a stereogenic center is present, they have been carried out biological activity studies that have shown that the Active enantiomer is that of the R configuration. In addition, due to that tolterodine is an amine, stable salts are preferred for pharmaceutical use, so it is used as acid salt (+) - tartaric, that is, as tartrate of (R) -tolterodine (Scheme I):

Scheme I

one

Since the approval by the Food and United States Drug Administration (FDA) of the use of Tolterodine in the year of 1998, the synthesis of this compound in Preparatory scale has been carried out in different ways.

The first method described for the preparation of Tolterodine is presented in US Patent No. 5,382,600, of N. A. Jönsson, B. A. Sparf, L. Mikiver, P. Moses, L. Nilvebrant, G. Glas (Scheme II).

Scheme II

2

In the procedure described by NA Jönsson et al ., The reaction of benzopiranone (1) with methyl iodide and potassium carbonate gives the methyl ester (2), which is reduced to 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 to the tertiary amine (5). The compound (5) is then treated with boron tribromide to give the amine (6) as a racemic mixture that is finally resolved via the formation of diastereoisomeric salts with (+) - tartaric acid.

The procedure of NA Jönsson et al . It suffers from 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 procedure for preparation tolterodine (Scheme III).

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Scheme III

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In the procedure described by JR Gage et al ., Benzopyranone (1) is converted to benzopyranol (7) by reduction with diisobutyl aluminum hydride; the reductive alkylation of diisopropylamine with the compound (7), by means of hydrogen and palladium on carbon, leads to racemic tolterodine (6), which is resolved again with (+) - tartaric acid.

The procedure of JR Gage et al reduces the number of stages for obtaining tolterodine. However, the cost for the use of DIBAL is high, in addition to the fact that this reagent is also dangerous.

An alternative enantioselective synthesis is the described in patent EP 1,496,045 of P. G. Anderson and C. Hedberg (Scheme IV).

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Scheme IV

4

In the procedure of PG Anderson et al ., Indenone (9), is reduced with borane using the Corey catalyst (8) to obtain the enantiomer (10), as the majority product. Subsequently, indenol undergoes a sigmatropic transposition to give indenone (11), as the sole enantiomer, which undergoes an oxidation of Bayer-Villiger to form enantiomerically pure benzopiranone (1).

Other procedures for the preparation of tolterodine found in the state of the art, as in the International application WO 2005/061431 of G.P. Coca, Pablo Martín Pascual and Jorge Marín Juárez, or in the international application WO 03/014060 by Yatendra Kumar, Mohan Prasad and Satyananda Misra they present a high number of stages to obtain tolterodine

As you can see, the procedures described above have several disadvantages because reaction times are long, yields are low, it they use expensive and dangerous reagents, in addition to that, in some cases, the Escalation is complicated. From the above, the need to find alternatives that allow for a process improved, with which the mentioned problems can be avoided how is the procedure for obtaining tolterodine that It is intended to protect by the present invention.

Detailed description of the invention

The present invention describes a process improved for the preparation of tolterodine tartrate, with high yields and at a lower cost, being able to avoid ase. the problems present in the prior art. He procedure for preparing tolterodine tartrate from the The present invention consists of four stages (Scheme V):

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Scheme V

5

Benzopyranone (1) undergoes a reaction of fairly simple reduction, using sodium borohydride, methanol and toluene at a temperature between 5 and 15 ° C, preferably at 10 ° C, to obtain the dialcohol (12), with a high performance.

Next, 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 at a temperature between 10 and 20 ° C, preferably at 15 ° C, producing the dimesylated compound (13).

The previous stage has the advantage that the mesyl chloride serves to introduce a good leaving group that it is necessary for the substitution reaction with diisopropylamine (14), which will give rise to tolterodine. Other advantages are that the same reagent serves to protect the phenolic hydroxyl and that the subsequent checkout is easily carried out under basic conditions

Once the dimesylated compound (13) is obtained, it is treated first with diisopropylamine in acetonitrile heating between 80 and 110 ° C, preferably at 100 ° C under a pressure from 2 to 2.5 bar, preferably at 2.3 bar. Then, it is treated with sodium hydroxide in methanol at reflux to release phenolic hydroxyl and, finally, the crude oil treatment of reaction in ethyl acetate or methylene chloride, preferably ethyl acetate, with hydrobromic acid, allows the easy isolation of tolterodine in the form of hydrobromide (14).

Finally, tolterodine tartrate is obtained by treating hydrobromide with sodium hydroxide to release the base and subsequently with acid (+) - tartaric to form tartrate by means of a fractional crystallization in ethanol.

The benzopiranone of formula 1, the 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 US Patent No. 5,922,914.

The following examples illustrate the procedure 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)

They are placed in a 2L flask equipped with mechanical agitation and thermometer, 100 g of benzopiranone (1) (420 mmol), 28.6 g (757 mmol, 1.8 eq) of sodium borohydride and 300 ml of toluene and cooled to a temperature of 0 to 5 ° C. Is added to the suspension 400 ml of MeOH previously cooled between 0 and 5 ° C, in a period of 2 to 3 hours, keeping the temperature between 5 and 15 ° C during the addition. Stirring continues temperature until confirmed by HPLC that the reaction has completed (column: Nucleosil C18; mobile phase: acetonitrile-water 60:40; flow: 1.2 ml / min; λ: 214 nm; t_R: dialcohol = 3.85 mm, benzopiranone = 8.02 mm). 150 ml of acetic acid are added. The solvent in vacuo, 500 ml of water are added and stirred for 30 minutes The solid formed is filtered and dried at 60 ° C with vacuum to give 98.8 g of product (12), in a yield of 97%

P.F .: 118-119 ° C.

1 H NMR (400 MHz, CDCl 3): δ 2.17 (3H, s, CH 3), 2.13 and 2.35 (2H, m, CH 2), 2.68 (1H, at OH), 3.52 and 3.74 (2H, m, CH2), 4.57 (1H, 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): δ 20.7 (CH 3), 36.9 (CH 2), 38.6 (CH), 60.7 (CH 2), 115.9. (C_ {ortho}), 126.2 (C_ {para}), 127.9 (C_ {meta}), 128.2 (C_ {meta}), 128.4 (C_ {ortho}), 129.1 (C_ {meta}), 130.2 (C_ {ipso}), 134.4 (C_ {ipso}), 144.0 (C_ {ipso}), 151.4 (C_ {ipso}).

R (cm -1): 3420, 2923, 1654, 1609, 1447, 1255, 1104, 1073, 1037, 901, 883, 812, 781, 698, 602, 499.

Example 2 Methanesulfonate 2- (3-methanesulfonyloxy-1-phenylpropyl) -4-methylphenyl (13)

250 ml of methylene chloride, 50 g (20.83 mmol) of the compound (12) are placed in a 1 L flask and
69.81 g (68.75 mmol, 3.3 eq.) Of triethylamine; 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. Once the addition is finished, it is kept under stirring 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 is over, the temperature is allowed to rise to 25 ° C, 200 ml of water and 30% HCl are added until pH <5. It is stirred for 15 minutes and allowed to stand. The organic phase is separated and washed with water (2 x 100 ml). The methylene chloride is evaporated to obtain 74 g of the product (13) as an oil in a yield of 90%.

1 H NMR (300 MHz, CDCl 3): δ 2.32 (3H, s, CH 3), 2.47 (2H, dd, J = 6.3, 14.2 Hz, CH 2), 2.92 (3H, s, CH 3), 2.99 (3H, s, CH 3), 4.18 (2 H, m, CH 2), 4.56 (1H, dd, J = 7.8, 5.4 Hz, CH), 7.03-7.34 (8 H, m, Ph).

13 C NMR (75 MHz, CDCl 3): δ 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 (C ort), 126.7 (C para), 127.8 (C_ {ortho}), 128.4 (C_ {meta}), 128.5 (C_ {meta}), 128.9 (C_ {meta}), 135.5 (C_ {ipso}), 137.1 (C_ {ipso}), 144.8 (C_ {ipso}).

IR (cm -1): 3462, 3028, 2924, 1620, 1490, 1454, 1350, 1268, 1196, 1169, 1103, 971, 920, 857, 824, 772, 736, 701, 526.

Example 3 Hydrobromide 2- (3- (diisopropylamino) -1-phenylpropyl) -4-methylphenol, (tolterodine hydrobromide) (14)

50 g of compound (13), 100 g of diisopropylamine and 50 ml of acetonitrile are placed in a Parr reactor. The reaction mixture is heated at 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 at reflux for 2 to 4 hours. The methanol is distilled under reduced pressure until the separation of two phases is observed; The top one contains the product. The lower phase is cooled to 5 to 10 ° C, 100 ml of cold water is 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 maintained 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 compound (14) are obtained in a yield of 71%.

P.F: 210-211 ° C.

1 H NMR (400 MHz, DMSO-d6): δ 1,220 (12H, m, (CH 3) 2), 2.17 (3H, s, CH 3), 2.42 (2H, a, CH 2), 2.91 (2H, a, CH 2), 3.58 (2H, a, CH), 4.35 (1H, t, J = 7.2 Hz, CH), 6.62-7.37 (8H, m, Ph), 8.66 (1H, a, NH).

13 C NMR (100 MHz, DMSO-d6): δ 19.7 and 21.7 [(CH 3) 2], 21.2 (CH 3), 37.1 (CH 2), 44.7 (CH), 48.4 (CH), 49.8 (CH), 115.2 (C ort), 126.3 (C_ {para}), 127.3 (C_ {meta}), 128.3 (C_ {meta}), 128.6 (C_ {ortho}), 129.9 (C_ {meta}), 132.4 (C_ {ipso}), 133.02 (C_ {ipso}), 137.3 (C_ {ipso}), 148.7 (C_ {ipso}).

IR (cm -1): 3213, 2938, 2661, 1717, 1608, 1508, 1458, 1397, 1260, 1210, 1111, 1029, 935, 912, 827, 768, 755, 739, 700, 677, 636, 596, 531.

Example 4 (R) -Tolterodine Tartrate

In a 1L round flask, provided with mechanical stirring, 60 g (148 mmol) of the compound (14) are mixed,
500 ml of methylene chloride and 250 ml of water. Stir while adding 6 ml of 49% NaOH and 6 g of Na2CO3, the pH should be between 10 and 11. It is stirred for one hour and then allowed to stand. The organic phase is separated and washed twice with 125 ml of water. The methylene chloride is distilled. The concentrate is dissolved in 125 ml of ethanol and heated to 65 to 70 ° C. 33.30 g (222 mmol, 1.5 eq) of tartaric acid dissolved in 333 ml of EtOH are added at 60 to 70 ° C, by means of an addition funnel for 45 minutes. The suspension is heated at reflux for 1 hour. Subsequently, it is gradually cooled to 0 ° C and maintained at that temperature for another hour. The solid formed is filtered and washed twice with 100 ml of EtOH at 0 ° C. The compound obtained is dried under vacuum at 60 ° C overnight. The already dried product is recrystallized with 2.15 L of ethanol, heating at 78 at 80 ° C for 30 minutes. The mixture is concentrated to half the volume, distilling 1,075 L of ethanol. Then, it is cooled to 20-25 ° C in one hour; It is then cooled to 0 ° C and maintained at that temperature for 1 hour. Filter and wash twice with 100 ml of ethanol. The product is dried under reduced pressure for 1 night and recrystallized once again in the same way. Are obtained
24 g of the compound in a yield of 34%.

P.F. = 214 ° C.

[α] 25 D = +27.4 (c = 1, MeOH).

1 H NMR (400 MHz, DMSO-d6): δ 1.10 (12H, d, J = 4.0 Hz, (CH 3) 2), 2.15 (3H, s, CH 3), 2.34 (2H, t, J = 7.6 Hz, CH 2), 2.76 (2H, m, CH), 3.44 (2H, J = 6.4 Hz, CH2), 4.02 (2H: s, CH), 4.29 (1H, 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-d6): δ 17.9 and 17.8 [(CH 3) 2], 20.3 (CH 3), 32.4 (CH2), 40.8 (CH). 45.1 (CH2), 52.6 (CH), 71.8 (CH), 115.1 (C_ {ortho}), 125.9 (C_ {ipso}), 127.3 (C_ {para}), 127.4 (C_ {meta}), 127.8 (C_ {meta}), 127.9 (C_ {ortho}), 128.2 (C_ {meta}), 129.9 (C_ {ipso}), 144.1 (C_ {ipso}), 152.4 (C_ ipso), 174.2 (CO 2 H).

IR (cm -1): 3572, 2923, 1704, 1590, 1500, 1403, 1265, 1125, 1069, 910, 817, 756, 736, 707, 599, 518, 475

Claims (7)

1. Procedure for the preparation of (R) -tolterodine tartrate characterized in that it comprises:

to)

reduce benzopiranone, of formula 1, with sodium borohydride to form, dialcohol, of formula 12;

b)

react the hydroxyl groups of dialcohol with mesyl chloride to introduce two groups of methanesulfonyl and form the dimesylated compound of formula 13;

C)

react the dimesylated compound, of formula 13, with diisopropylamine under pressure, and then with sodium hydroxide to obtain tolterodine, of formula 6, isolating it as the corresponding hydrobromide, of formula 14;

d)

release tolterodine base, of formula 6, from the hydrobromide, of formula 14 and then react with (+) - tartaric acid to prepare (R) -tolterodine tartrate.

2. Method according to claim 1, characterized in that the reduction step a) is carried out in a mixture of toluene and methanol. 3. Method according to claim 1, characterized in that in the reaction step b), the methanesulfonyl groups are introduced one as a protecting group of the phenolic hydroxyl, and the other as forming a leaving group for the subsequent replacement reaction with diisopropylamine. 4. Method according to claim 1, characterized in that in reaction step b), the two hydroxyl groups of the dialcohol of formula 12 are esterified using 2.0 to 3.0 equivalents of mesyl chloride. 5. Method according to claim 4, characterized in that 2.3 equivalents of mesyl chloride are preferably used. Method according to claim 4, characterized in that the reaction temperature is between 10 and 20 ° C, preferably at 15 ° C. Method according to claim 1, characterized in that the pressure during the reaction stage c) is between 2 and 2.5 bar, preferably at 2.3 bar.