Process for preparation of tamsulosin and its aralkylamine derivatives

The present invention discloses a new process for the synthesis of tamsulosin and its aralkylamine derivatives, especially (R)-(−)-5-{2-[2-(2-alkoxyphenoxy) ethylamino]propyl}-2-alkoxybenzenesulfonamides having the following formula 1 (where R1 and R2 represent C1-C4 alkyl groups) and their hydrochloride thereof, and other various pharmaceutical used salts.Tamsulosin hydrochloride (R1=Et, R2=Me, in its hydrochloride salt form) is an antagonist of α-A adrenoceptors in the prostate. Tamsulosin•HCl occurs as white crystals, which melt with decomposition at approximately 230° C. It is sparingly soluble in water and in methanol, slightly soluble in glacial acetic acid and in ethanol, and practically insoluble in ether.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention related to a new process for the preparation of the compounds of the formula 1 (where R1and R2represent C1-C4alkyl group) and their hydrochloride thereof, and other various pharmaceutical used salts. The process is more efficient than the reported processes in total yield and reaction steps for the synthesis of compounds having the formula 1. In the present invention, the use of optically pure starting material can provide the desired compound in more specific range to meet the pharmaceutical requirement. Furthermore, the shorter reaction steps will provide the desired drugs with limit scope of impurity profile.

2. Description of the Prior Art

It is described in the U.S. Pat. No. 5,447,958 that the compounds of the above formula 1 have excellent therapeutic effects against hypertension, congestive heart failure, angina pectoris or prostatic hypertrophy. In addition, the above patent disclosed a process for the preparation of compounds with the formula 1 by reacting following hydrochlorides of sulfonamide 2A with bromide 3:

Wherein, sulfonamide hydrochloride salt 2B (hydrochloride of formula 2A) can be synthesized from the Process 1 depicted below. The synthetic procedure of Process 1 involves phenylamine 4A as the starting material to produce the intermediates of acetamide 5A and (sulfo)acetamide 6A, and then to give sulfonamide hydrochloride salt 2B.

The synthesis of phenylamine 4A was disclosed in U.S. Pat. No. 4,000,197 andJ. Med. Chem.1973, 16, 480-483 by condensation of 4-methoxyphenylacetone with (R)-α-methylbenzylamine, followed by hydrogenation of the N═N double bond therein, and reductive debenzylation. The total yield for the preparation of phenylamine 4A is 25% with >99% enantiomeric purity.

Yamada et al. described a process for the synthesis of phenylamine 4A inSynth. Commun.1998, 28, 1935-1945 by using optically pure L-tyrosine as the starting material. The advantage of the current process is that the resultant product is optically pure. The preparation of intermediate 4B (hydrochloride of phenylamine 4A) involves overall 8 steps, and if extended to intermediate 5A, would be 9 steps. Yamada's procedure is depicted in Process 2 as below:

The synthetic procedure of Process 2 uses L-tyrosine 7 as the starting material to generate the intermediates of aminoester 8, (phenol)amidoester 9, (ether)amidoester 10, (hydroxy)ether amide 11, tosyl amide 12, iodide 13, ether amide 14, and finally to obtain hydrochloride of phenylamine 4B.

SUMMARY OF THE INVENTION

The present invention relates to a new process for the synthesis of sulfamoyl-substituted phenoethylamine derivatives and the acidic salts thereof, especially the tamsulosin derivatives having the following formula 1 (where R1and R2represent C1-C4alkyl group) or their hydrochloride thereof, and other various pharmaceutical used salts.

As mentioned before, the synthesis of tamsulosin 1 (R1=Et and R2=Me) involves a key intermediate, i.e. acetamide 5A. Herein, the invention discloses a new process, as shown in Process 3, for the preparation of the key intermediate 5A as depicted below, where comprises the new intermediates, such as (phenol)amido acid 15A, (phenol)amidoester 16A, (ether)amidoester 17A, hydroxy(ether)amide 18A.

The process is more efficient than the reported processes in total yield and reaction steps for the synthesis of compounds having the formula 1. Furthermore, in the invention, the use of optically pure starting material can provide the desired compound in more specific range to meet the pharmaceutical requirement. And the shorter reaction steps will provide the desired drugs with limit scope of impurity profile.

A new key intermediate (ether)benzoxy tosylate 21A, instead of bromide 3, for the preparation of formula 1 is also disclosed in the invention. It involves the use of 2-ethoxyphenol (19A) as the starting material. Sequential reaction of 19A with chloroethanol and toluenesulfonyl chloride will provide the key intermediate 21A via (ether)benzoxy alcohol 20A. The advantages associated with the use of (ether)benzoxy tosylate 21A instead of bromide 3 will simplify the manipulation of the reaction and, to a more important reason, avoid the pollution resulting from the hazardous halogenated wastes. The process for the preparation of (ether)benzoxy tosylate 21A is depicted as shown in Process 4.

The intermediate acetamide 5A was converted to (sulfo)acetamide 6A and then to sulfonamide hydrochloride salt 2B by the established methods. Sulfonamide hydrochloride salt 2B was allowed to react with (ether)benzoxy tosylate 21A to generate the desired tamsulosin (1, R1=Et, R2=Me). The synthesis of tamsulosin is depicted as shown in Process 5.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention relates to a new process for the synthesis of sulfamoyl-substituted phenoethylamine derivatives and the acidic salts thereof.

A process for the preparation of (phenol)amido acid 15 from starting material L-tyrosine 7 is shown in Process 6.

Additionally, an acylating agent and a solvent are used; the acylating agent is selected from RCOX, (RCO)2O and the combination thereof, wherein R is alkyl or aryl; X is a halide or a leaving group; the solvent is selected from alkanes, ethers, DMF, DMSO, ketones, urea and the combination thereof.

A process for the preparation of (phenol)amidoester 16 from (phenol)amido acid 15 is shown in Process 7.

Additionally, an acid chloride and a R′OH are used; the acid chloride is selected from the group of PCl3, PCl5, POCl5, SOCl2, oxalyl chloride and the combination thereof; the R and R′ groups are alkyl or aryl.

Furthermore, a process for the preparation of (ether)amidoester 17 from (phenol)amidoester 16 is shown in Process 8.

Additionally, an alkylating agent, a base and a solvent are used; the alkylating agent is selected from R2SO4, RI, RBr and the combination thereof; the base is selected from amines, carbonates, hydrogen carbonates, amides, alkoxides and the combination thereof; the solvent is selected from H2O, ketones, alkanes, ethers, DMF, DMSO, urea and the combination thereof.

A process for the preparation of hydroxy(ether)amide 18 from (ether)amidoester 17 is shown in Process 9.

Additionally, a reducing agent and a solvent are used; the reducing agent is selected from LiAlH4, DIBAL, K-selectride, L-selectride, BH3, NaBH4and the combination thereof; the solvent is selected from ethers, alcohols, H2O, alkanes, DMF, DMSO, urea and the combination thereof.

As shown in Process 10, acetamide 5 can be prepared from hydroxy(ether)amide 18.

Wherein, an acid halide, a solvent, an organic acid, MXn and M are used; the acid halide is selected from the group of TsCl, MsCl, SOCl2, SO2Cl2, PCl3, PCl5, POCl5, oxalyl chloride and the combination thereof; the solvent is selected from THF, ketones, alkanes, ethers, DMF, DMSO, CH2Cl2, CHCl3, CCl4, urea and the combination thereof, the organic acid is selected from oxalic acid (COOH)2, RCOOH and the combination thereof, where R is H, alkyl, or aryl; the M is selected from Li, Na, K, Mg, Ca, Zn, Pt, Pd, Cu, Co, Mn, Fe, Ni, or Cd; the X is Cl, Br, I, or OAc; the n value is 1-3 based on the valence of the metal.

As mentioned before, the synthesis of tamsulosin 1 involves a key intermediate acetamide 5. Herein, the invention could prepare tamsulosin 1 from acetamide 5.

The present invention can be further understood by the following examples, which are used to illustrate the present invention, but not to limit the scope thereof.

In the present invention a process for preparation of tamsulosin and its aralkylamine derivatives is disclosed. The steps for preparation of tamsulosin from starting material L-tyrosine are fewer and the yield is higher than that of the conventional method, meanwhile, the key intermediates 15A to 18A as synthesized during tamsulosin 1 preparation are also representative intermediates for the present invention.

Those embodiments described above are only to clarify the technical contents and characteristics of the present invention so that the persons skilled in the art can understand, make, and use the present invention but not intended to limit the scope of the present invention. Any equivalent modification and variation according to the spirit of the present invention is to be included within the scope of the present invention.