FI78075C - Process and intermediate for the preparation of 2-hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-tert.-butylaminoethyl) pyridine or pirbuterol - Google Patents

Description

! 78075

Process and intermediate for the preparation of 2-hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-tert-butylaminoethyl) pyridine, i.e. p-buterol 5 Separated from patent application 820396

This invention relates to a process for the preparation of pirbuterol of formula I

10 H0 \ HOCH ^ '^' N N 1

OH

15 and the intermediate used in this process.

Pirbuterol and its bronchodilator activity have been first described by Barth in a series of U.S. Patents (3,700,681, 3,763,173, 3,772,314 and 3,786,160). In this case, pirbuterol was synthesized as follows: C6H5CH2 ° ^ Tiir \ I 1. -f-NC, acetic acid 25 k. O - HOCH2 ^ 2. aq. HC1

B

30 C6H5CH2 ° O

OH

35 C6H5CH2 ° ^^ X

I Π H2 k X ~ - / r> (I) HOCH „N ^ N / ^ a / c

OH H

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Pirbuterol analogs in which the hydroxymethyl substituent of the pyridine ring is replaced by hydrogen, methyl, or methanesulfonylmethyl, and their bronchodilator activity, are described in U.S. Patent No. 3,952,101 to Jen and Kaiser in U.S. Patent No. 5,952,101. with.

Nakanishi has since described an alternative preferred process for preparing pirbuterol 10 (U.S. Patents 3,948,919; 4,031,108), which can be described as follows:

B

20 C

I I i. + nh2 25 _

C6H5N / ° 'VRN

νΛ JL \ X. -, i;

Alternatives and improvements to this process have also been described, such as the isolation of pirbuterol precursors as the maleate salt (Carroll et al., U.S. Patent 0,011,231) and hydrogenolysis instead of hydrolysis as a final step (Argentinian Patent 214005, 35 Luxembourgburg Patent 79564).

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The latter process has the disadvantage that toxic sulfide by-products are formed in the production of the epoxide. Even under the best conditions, traces of sulfur can remain in the process and increase the catalyst content when the protecting groups are removed by hydrogenolysis, which is the preferred method if desired, p-buterol as the free base. In addition, the epoxide is relatively unreactive to the tert-butylamine reagent even at elevated pressures and elevated temperatures, which requires a large excess of reagent and a relatively long reaction time.

A further disadvantage of the improved process is the polar nature of the aminoalcohol-intermediate, making it difficult to isolate this intermediate neat.

Pirbuterol has also recently been found to be useful in the treatment of congestive heart failure (Taylor, U.S. Patent 4,175,128).

The present invention provides an easy-to-implement method for synthesizing pirbuterol. The process according to the invention and the preparation of the starting material of the formula I used therein are summarized by means of the following reaction scheme 1.

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Reaction Scheme 1 ('635 (: Η20γί: ^

CH

^ OH H

(V, r1-benz- r2 = ch) ^ ^ hydrogenation w / o, '3 H0 ^ acetylation CH3 ΛΝΧ ^ \ Μ> <

OH H

v CH3COOy? ^ \

CH

3 φ ^ acetylation 0 0CO0CH3 ^ 0CH3

(VI) V

\ RC000H

N. T

x: k3coo./v.

(ch3CO) 20 ch3 ^ n ^ \ / \ n> \ 6 OCOCHj 0CH3 (VII)

T

ch3co ° OCOCH. t0CH3 J '' - ^^ liydrolysis

OH H

(I) 5 78075

The intermediates of formula VIII are also a subject of this invention.

This process also allows for the easy synthesis of pirbututerol from a commercially available compound; or alternatively utilizing an intermediate of formula V wherein R * is benz-2-yl and R is CH 1, which intermediate is prepared from readily available pyridine carbaldehyde (II; R is 2 benzyl, R is CH 2) according to Reaction Scheme 2 .

10

Reaction Scheme 2 r1 ° ® © rl * 3pch3j.

r2 JvV

(II) R10V ^ ~ V '' '

I RC000H

> (III) R10 ^ r ^ rVN —1— NH- 2 1 ^ ^ 2> o (IV)

t in H

(V) 6 78075

The carrying out of the process alternatives shown in Reaction Scheme 2 is described in more detail in Finnish Patent Application 820396, as is the hydrogenation of a compound of formula V to convert a benzyl group to a hydroxy group.

Acetylations to prepare compounds of formulas VI and VII are carried out under mild conditions using at least 2 or 3 molar equivalents of an acylating agent (e.g. acetyl chloride or acetic anhydride) in the presence of a tertiary amine such as triethylamine, usually at least a molar equivalent. The reaction is carried out in an inert solvent such as methylene chloride, ethyl acetate or the like. The temperature is not

15 casting critical. However, when acetylating compound V

12 (R is benzyl, R is methyl) are relatively low temperatures, e.g. 0-30 ° C, preferred to avoid or minimize N-oxide group side reactions.

The pyridine compound of formula VII is converted to the pyridine N-oxide of formula VI by treatment with at least two molar equivalents of peracid, preferably m-chloroperbenzoic acid, in a reaction inert solvent such as methylene chloride at 10-60 ° C, suitably at reflux with methylene chloride.

The key reaction in this series of reactions, the conversion of pyridine N-oxide VI to acetoxymethylpyridine VIII, is readily accomplished by heating with excess acetic anhydride. The temperature used is in the range of 120 to 160 ° C, suitably the reflux temperature of the reaction mixture (about 140 ° C), but preferably the reaction at elevated temperature, at or above the atmospheric boiling point of the reaction mixture avoids the need for condensation and reheating of acetic anhydride.

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The last step of the process, the hydrolysis of the compound of formula VIII to the desired compound of formula I is carried out in an alcoholic medium in the presence of an acid catalyst. A combination of methano-5 and hydrogen chloride is particularly suitable, from which the product is easily isolated as the hydrochloride salt. Temperature is not critical; for example, a temperature of 0 to 50 ° C or above may be used, but the reaction is suitably carried out at ambient temperature.

The invention is further illustrated by the following examples.

Example 1 3-Acetoxy-2-methyl-6- (1-acetoxy-2- (N-tert-butylacetamido) ethyl) pyridine To a suspension of 7.70 g (0.026 mol) of 2- (1-hydroxy) -2-tert-butylaminoethyl) -5-hydroxy-6-methylpyridine dihydrochloride in 300 ml of ethyl acetate and 7.7 ml of triethylamine, 10.8 ml of acetic anhydride were added and the solution was heated under reflux for 30 hours. An additional 5 mL of acetic anhydride was added to the reaction mixture and heating was continued for 24 hours, then allowed to cool to room temperature. The reaction mixture was poured into aqueous sodium bicarbonate solution (100 g NaHCO 3 in 700 ml water) and the resulting mixture was stirred for 1 hour. The ethyl acetate layer was separated, washed with aqueous sodium bicarbonate solution and then with water, and dried over magnesium sulfate. Evaporation of the dried ethyl acetate solution in vacuo gave 6.0 g (66%); mp. 124.5-127.5 ° C.

Analysis calculated for C 18 H 26 N 2 O 5: C 61.70 H 7.48 N 8.00 Found: C 61.93 H 7.39 N 8.44.

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Example 2 3-Acetoxy-2-methyl-6- [T-acetoxy-2- (N-tert-butylacetamido) ethyl] pyridine N-oxide A solution of 5.50 g (0.0157 mol) of 3- acetoxy-5 '-2-methyl-6- [1-acetoxy-2- (N-tert-butylacetamido) ethyl] pyridine and m-chloroperbenzoic acid (85% technical grade, 3.90 g, 0.0192 mol) ) In 150 ml of chloroform, heated at room temperature for 24 hours. After washing the reaction mixture with two 10 portions of aqueous sodium bicarbonate solution, the dried (MgSO 4) chloroform solution was evaporated to give 2.9 g (50%) of 3-acetoxy-2-methyl-6H-acetoxy-2- (N- tert-butyyliasetamido) ethyl ^ pyridine-n-oxide; mp. 113-116.5 ° C after crystallization from ether.

Analysis for C 18 H 26 N 2 O 6: Calculated: C, 59.00; H, 7.15; N, 7.65 Found: C, 59.25; H, 7.08; N, 8.14.

Example 3 3-Acetoxy-2-acetoxymethyl-6- [1-acetoxy-2-20 (N-tert-butylacetamido) ethyl] pyridine

A solution of 1.0 g (0.0027 mol) of 3-acetoxy-2-methyl-6- [1-acetoxy-2- (N-tert-butylacetamido) ethyl] pyridine N-oxide in 10 ml of vinegar -acid anhydride, heated at reflux for 2.5 hours, then allowed to cool to room temperature and stirred at this temperature overnight. The reaction mixture was poured into a 2-phase mixture of ethyl acetate and aqueous sodium bicarbonate and stirred for 1 hour. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and evaporated; in vacuo to give a brown oil which was purified by column chromatography on silica gel using 9,78075 ether as eluent to give 300 mg (27%) of the desired product; mp. 60-64 ° C.

Analysis for C20H28N2O7! Calculated: C, 58.81; N, 6.91; N, 6.86 Found: C, 59.02; H, 6.83; N, 7.30.

Example 4

Pirbuterol hydrochloride

A solution of 2.0 g (0.005 mol) of 2-acetoxy-roethyl-3-acetoxy-6- (1-acetoxy-2-N-acetyl-tert-10-butylaminoethyl) pyridine in 50 ml of methanol containing 1 ml of concentrated hydrochloric acid, was heated under reflux for 12 hours. The solvents were removed in vacuo and the residue was crystallized from ethyl acetate to give pirbuterol hydrochloride (900 mg, 58%); 15 colors 172-175 ° C (dec.), NMR and TLC using 6: 3: 1 EtOAz: CH 2 OH: Et 2 NH were identical to pirbuterol. Upon prolonged heating, 2-hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-aminoethyl) pyridine was obtained; mp. 184-186 ° C, dec.

Claims (6)

10 78075 A process for the preparation of 2-hydroxymethyl-3-hydroxy-6- (1-hydroxy-2-tert-butylaminoethyl) pyridine (pirbute-5-role) of the formula I HO ^ 1 10 hoch / ^ n N OH H known that a) heating the compound of formula VI 15 ^> <Γ VI CH, f1 \ 0 COCH- 20 v 13 o ococh3 in acetic anhydride to form a compound of formula VIII ch3coov ^ Tnn ^ CH-COO \ I VIII 3 COCH-OCOCH, and J b) the resulting compound of formula VIII is hydrolyzed in an alcoholic solvent in the presence of an acid catalyst to form pirbuterol. U 78075 2. A compound of formula VIII 5 CH3COO [mu] l / -. > <VIII N 'γ' X COCH3 OCOCH3 12 78075