CA2204028A1 - Process for preparation of 5-hydroxymethylthiazole - Google Patents

Abstract

A process for the preparation of 5-hydroxymethylthiazole comprises reacting a compound of formula (A) with a carboxylic acid salt (optimally in the presence of a quaternary ammonium salt) and hydrolyzing the resulting ester. Subsequent dechlorination gives 5-hydroxymethylthiazole.

Description

Wo 96/16050 PCr/uss5ll493o PROCF-ÇCi FOR PRFPARATION OF 5-HYDROXYMFTHYlTHlr701 F

Technical Field The present invention relates to a process and intermediate for the preparation of 5- hydroxymethylthiazole.

Rack~round of the Invention It has recently been determined that HIV protease inhibiting compounds are useful for illhibiting HIV protease in vitro and in vivo and are useful for inhibiting an HIV (human immunodeficiency virus) infection and are useful for treating AIDS(acquired immunoclefie ency syndrome).
It has also recently been determined that compounds of the formula l:

H3C~
~N CH3 R2 S~ ~NH~NH~O~

o R~ S~

wherein R1 is lower alkyl and R2 and R3 are phenyl are particularly useful as inhibitors of HIV-1 and HIV-2 protease and are useful for inhibiting HIV protease 20 in vitro and in vivo and are useful to inhibit HIV (human immunodeficiency virus) i"f~.;tions and, thus, are useful for the treatment of AIDS (acquired immunodeficiency syndrome).
In particular, the compound of formula ll, has been found to be especially effective as an inhibitor of HIV-1 and HIV-2 protease.

~N CH3 ~ H~o ~N

I I
The most prefer.ed compound of formula ll is (2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)-amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane (compound 111) The preparalion of compound lll and its use as an inhibitor of HIV protease are disclQsed in PCT Patent Application No. W094/14436, published July 7, 1994, which is hereby incorporated herein by reference.
The term "loweralkyl" as used herein refers to a straight or branched chain alkyl radical conlaining from 1 to 6 carbon atoms including, but not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.

A key intermediate in the preparation of compound lll is 5-hydroxy-methylthiazole.
Methods for the preparation of 5-hydroxymethylthiazole are disclosed in W094/14436 and include those shown in Scheme 1.

PCr/US95/14930 EtO2C

S +EtO~H ~ )~\N

LiAlH4 HO~

S~N

LiAlH4 EtO2C
~, S ~,~N

isoamylnitrite H2N~ NH2 ,~ EtO2C~

Cl S ~N

Wo 96/16050 PCr/uss5ll493o Neither of these methods is suited for large scale production of pure 5-hydroxymethylthiazole. Therefore, there is a continuing need for improved processes for the preparalion of 5-hydroxymethylthiazole.

5 Disclosure of the Invention The present invention relates to a process for the preparation of 5-hydroxymethylthiazole:

N~
~ ~ OH
S
5-hydroxymethylthiazole The process of this invention (see Scheme 2) comprises a first step of reacting 2-chloro-5-chloromethylthiazole with a carboxylic acid salt 15 (RCOO- X+ ~AI,erei" R is hydrogen, loweralkyl or phenyl and X is Na, K, Li or the like) at a temperature of from about 25C to about 120C to provide an ester of 2-chloro-5-hydroxymethylthiazole. Preferably, the carboxylic acid salt is a formic acid salt (for example, sodium formate, potassium formate or lithium formate and the like). This reaction mixture can further comprise a quaternary 20 d"""onium phase l,dn~ler catalyst. The reaction can be done in the absence ofsolvent or a solvent can be used. Suitable solvents include polar aprotic solvents such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile, 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidone and the like or hydrocarbon solvents such as heptane, octane, decane, benzene, toluene, xylene, 25 cumene and the like.
The ester of 2-chloro-5-hydroxymethylthiazole is hydrolyzed to provide 2-chloro-5-hydroxymethylthiazole. The hydrolysis can be accomplished by adding to the crude reaction mixture resulting from step 1 an ester hydrolyzing agent (for example, trimethylsilyl-OK/tetrahydrofuran and the like or an aqueous30 solution of a strong base and the like). A preferred ester hydrolyzing agent is an aqueous solution of a strong base (for example, NaOH, KOH or LiOH and the like).

Dechlorination of 2-chloro-5-hydroxymethylthiazole (for example, by catalytic hydrogenation, reaction with zinc/acetic acid or reaction with magnesium/methanol or magnesium/isopropanol and the like) provides 5 5-hydroxymethylthiazole.

':CHFME~

Cl--~ 1. carboxylicacid salt/ HO
~ quatemary ammonium ~
S N phase transfer catalyst (optional) S N
2. ester hydrolysis Cl Cl dech'~ i"dtion HO--~

S~N

Quaternary ammonium phase transfer catalysts useful in the process of the 10 present invention are disclosed in (1) "Phase -Transfer Catalysis, New chemistry, Catalysts and Applicationsn, ACS Symposium Series 326, American Chemical Society, Wash., D.C., 1987, Charles M. Starks (editor), (2) "Phase-Transfer Reactionsn, Fluka-Compendium, Volume 1, Georg Thieme Verlag, New York, 1986, Walter E. Keller (editor) and (3) "Phase-Transfer Reactions", Fluka-Compendium, Volume 2, Georg Thieme Verlag, New York, 1987, Walter E.
Keller (editor), all three of which are hereby incorporated herein by reference.Suitable quaternary ammonium phase transfer catalysts include, but are not inlended to be limited to, butylpyridinium bromide, benzyltriethylammonium bromide, benzyltriethylammonium chloride, benzyltrimethylammonium chloride, benzyltrimethylammonium fluoride, hexadecyltriethylammonium bromide, hexadecyltrimethylammonium bromide, hexadecyltrimethylammonium chloride, dibutyldimethylammonium chloride, decyltriethylammonium bromide, heptylpyridinium bromide, hexyltriethylammonium bromide, dodecylpyridinium bromide, dodecyltriethylammonium bromide, methyltrinonylammonium chloride, methyltriphenylammonium bromide, octyltriethylammonium bromide, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium hydroxide, tetraethylammonium chloride, tetramethylammonium bromide, tricaprylylmethyl ammonium chloride, trioctylmethylammonium chloride, trioctylpropylammonium chloride, tet,aprupylammonium bromide, or the like.
The starting material, 2-chloro-5-chloromethylthiazole, can be prepared as described in U.S. Patent No. 4,748,243.
In the p,ucess of the invention, the formic acid salt (or other like carboxylic acid salts) is used in an amount of from about 1.0 to about 5.0 mole equivalents (based on 2-chloro-5-chloromethylthiazole), preferably from about 2.5 to about 3.5 mole equivalents.
When present, the quaternary ammonium phase transfer catalyst is used in an amount from about 0.01 to about 0.1 mole equivalents (based on 2-chloro-5-chloromethylthiazole), preferably from about 0.01 to about 0.02 mole equivalents.
When ester hydrolysis is accomplished with aqueous strong base, the ~queous strong base comprises from about 1.0 to about 2.0 mole equivalents (based on 2-chloro-5-chloromethylthiazole) of the strong base (preferably, from about 1.0 to about 1.2 mole equivalents) at a concentration of from about 5% to about 50%, preferably from about 20% to about 30% (w/w).
Catalytic hydrogenation is a pre~:r-ed method for dechlorination. The catalytic hydrogenation of 2-chloro-5-hydroxymethylthiazole can be accomplished using hydrogen at a pressure of from about 1 dl",osphere to about 10 al",ospheres, and a hydrogenation catalyst (e.g., Pd/C, RaNi, and the like) in the amount of from about 1% to about 25% (by weight) in an inert solvent (e.g., methanol, ethanol, and the like).

The foregoing may be better understood by reference to the fc"Dw;ng examples which are provided for illustration and are not intended to limit the scope of the inventive concept.

Examele 1 A. Pre~r~tion of ~-chloro-5-hydroxymethylthi~7nle A 10.56 gram (gm) sample of 2-chloro-5-chloromethylthiazole (62.85 millimoles (mmol)) was placed in a 50 milliliter (mL) reaction flask. Added to fhe reaction flask were 12.82 gm (188 mmol) of sodium formate and 0.5 gm (1.2 mmol) of tricaprylylmethyl ammonium chloride and the mixture was heated and stirred at 80- C for 8.5 hours (hr). A magnetic stir bar was used to stir the 15 mixture and the sides of the reaction flask were uashed every 1.5 hr with 1-2 ml of diethyl ether. The top of the reaction flask was removed for about 1 minute to allow the ether to evapordte out of the mixture.
The reaction flask was cooled to 5- C and a 25% ~ueous solution of NaOH
(5.53 gm of a 50% NaOH solution diluted with 5.5 gm of ice) was added dropwise to 20 the reaction flask with stirring for approximately 15 minutes..
The reaction mixture was diluted with 70 mL of methyl-t-butyl-ether, 25 mL of water, and 5 mL of an aqueous saturated sodium chloride (NaCI) solution.
The diluted reaction mixture was l,ans~r-ed to a separatory funnel where it formed sepa~dle layers. The aqueous layer was sepdldled and washed with 25 mL of25 methyl-t-butyl ether, which was then recombined with the organic layer. The organic layer was dried over sodium sulfate (Na2SO4). Added to this was 1 gm of activated charcoal (Darco~ 60) and 2 gm of silica gel and swirled for 2 minutes.The resulting mixture was filtered through a cJiato",~!eous earth pad in a 30 mLcoarse s;"lered glass funnel. The diatomaceous earth pad was washed 5 times with30 10 mL of methyl-t-butyl ether to remove any final product from the pad. The resultant product was concenl,dled in a vacuum to yield 9.45 gm of 5-hydroxymethyl-2-chlorothiazole. 1H NMR (CDCI3)~7.41 (s, 1H), 4.81 (s,2H), 2.40 (bs, 1 H). MS(CI) m/e 150/152 (M+H)+, 167/169 (M+NH4)+.

Wo g6/16050 PCr/USs5/14930 B. Altern~tive Prep~r~tion of ?-chloro-5-hydroxymethylthi~7nle To a 3 necked 1 liter round bottom flask equipped with an overhead stirrer was charged 2-chloro-5-chloromethyl thiazole (100.0 9, 0.6 mole), sodium formate (121.5 9, 1.8 mole, 3 eq), tricaprylylmethyl ammonium chloride (4.81 9, 11.9 mmol, 0.02 eq.) and heptane (125 mL). The mixture which resulted was heated to 85C with slow stirring. The reaction was allowed to stir overnight after which time the mixture was cooled to room temperature and quenched with a 25%
aqueous solution of sodium hydroxide (100 9 of 50% aq. NaOH, 100 9 of ice), not - letting the internal temperature of the quenched mixture exceed 25C. The reaction mixture was then stirred for 30 minutes and then diluted with H2O (100 mL), 20% aq. NaCI (100 mL) and methyl t-butyl ether (200 mL). Stirring continued for an additional 15 minutes. After settling, the layers were separated and the lower aqueous layer was re-exlrdcted with methyl t-butyl ether (2 X 200 mL). The combined organic extracts were dried over sodium sulfate (75 g) and filtered. To this filtrate was charged Darco G-60 carbon (9.47 9) and silica gel230-400 mesh (18.9 9). This suspension was stirred at room temperature for 30 minutes and then filtered through a bed of diatomaceous earth. Methyl t-butylether (5 X 20 mL) was used as a flask and filter cake rinse. The combined filtrates were concentrated under reduced pressure (42C) until constant weight was achieved. 2-chloro-5-hydroxymethyl thiazole was thus isolated as a light yellow colored oil (84.0 9, 94.4 %). 13C NMR (CDCI3) (ppm) 57, 138, 141, 152.

C. PrP.p~r~ti(~n of 5-~lydroxymethylth~ le A 2.04 gm (13.64 mmol) sample of 5-hydroxymethyl-2-chlorothiazole was dissolv0d in 25 mL of l,letl,anol. The dissolved sample was placed in a Parrshaker which was charged with sodium acetate-3 H2O (1.1 mole equivalents) and 200 milligrams (mg) of 10% palladium/carbon. The system was charged with 4 al",ospheres of H2 gas and heated at 60- C with shaking for 18-24 hr. The shakerwas cooled, the reaction mixture was filtered and the filtrate was concenl,aled in a vacuum. The conce"l,dle was slurried with 50 mL of methyl-t-butyl ether and suhsequently dried over Na2SO4. The dried solution was concent,d~ed in a vacuum and 1.74 gm of a clear oil was obtained. 1.24 gm of the oil was chro",aloy,dphedonto 15 gm of silicon dioxide (SiO2). The oil was eluted with 100% ethylacetate.The eluates were combined and concent,alecJ under vacuum to provide 1.02 gm of Wo 96tlC050 PCr/USs5/14930 5-hydroxymethylthiazole as an oil. 1H NMR (CDCI3) ~ 8.76 (s, 1H), 7.75 (d,1H), 4.92 (s, 2H), 2.88 (bs, 1H). MS(CI) m/e 116 (M+H)+, 133 (M+NH4)+.

D. Altern~tive Prep~r~tion of 5-Hydroxymethylth~ le 2-Chloro-5-hydroxymethylthiazole (74.0 9, 495 mmol), was dissolved in methanol (925 mL) and charged into a Parr shaker. To this solution was charged sodium carbonate (26.76 9, 252.5 mmol, 0.51 eq) and 10% palladium on carbon (11.1 9). The system was heated (60 C) under 50 psi (3.40 atrn) of hydrogen 10 gas and agitated for 8 hours. (The reaction mixture can be vented periodically to release the buildup of carbon dioxide gas). The shaker was then cooled and the contents filtered through a bed of diatomaceous earth. The filtrate was then concentrated under reduced pressure (38 C) and the residue whic-h resulted was taken up in methyl t-butyl ether (600 mL) and dried over sodium sulfate (70 9).
15 This dried solution was then filtered and concentrated under reduced pressure (38 C) to provide 5-hydroxymethylthiazole 52.2 9, 91.6%.
The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed processes and reaction conditions. Variations which are obvious to one of ordinary skill in the art are intended to be included 20 within the scope and nature of the invention which are defined in the appended claims.

Claims (10)

We claim:

1. A process for preparing 5-hydroxymethylthiazole comprising:
(a) reacting 2-chloro-5-chloromethylthiazole with a carboxylic acid salt;
(b) reacting the resulting product of step (a) with an ester hydrolyzing agent; and (c) dechlorinating the product of step (b).

2. The process of Claim 1 further comprising in step (a) a quaternary ammonium phase transfer catalyst.

3. The process of Claim 1 wherein the dechlorination is accomplished by catalytic hydrogenation or reaction with zinc/acetic acid.

4. A process for preparing 5-hydroxymethylthiazole comprising:
(a) reacting 2-chloro-5-chloromethylthiazole with a formic acid salt in the presence of a quaternary ammonium phase transfer catalyst;
(b) reacting the resulting product of step (a) with an aqueous solution of strong base; and (c) dechlorinating the product of step (b).

5. The process of Claim 4 wherein the formic acid salt is sodium formate, potassium formate or lithium formate.

6. The process of Claim 4 wherein the quaternary ammonium phase transfer catalyst is tricaprylylmethyl ammonium chloride.

7. The process of Claim 4 wherein the dechlorination is accomplished by catalytic hydrogenation or reaction with zinc/acetic acid.

8. A process for preparing 5-hydroxymethylthiazole comprising (a) reacting 2-chloro-5-chloromethylthiazole with a formic acid salt in the presence of tricaprylylmethyl-ammonium chloride;
(b) reacting the resulting product of step (a) with aqueous sodium hydroxide; and (c) catalytic hydrogenation of the product of step (b).

9. A process for preparing 2-chloro-5-hydroxymethylthiazole comprising:
(a) reacting 2-chloro-5-chloromethylthiazole with a formic acid salt in the presence of a quaternary ammonium phase transfer catalyst; and (b) reacting the resulting product of step (a) with an aqueous solution of strong base.

10. The process of Claim 9 wherein the formic acid salt is sodium formate andthe quaternary ammonium phase transfer catalyst is tricaprylylmethyl ammonium chloride.