MXPA00010187A - Process for the preparation of methyl(2s)-2-[(3r)-3-(n-[tert -butyloxycarbonyl]- amino)-2-oxopyrrolidin-1-yl]propionate - Google Patents

Abstract

The invention concerns a novel chemical process for the manufacture of methyl (2S)-2-[3R)-3-(N-[tert- butyloxycarbonyl]amino)-2- oxopyrrolidin-1-yl]propionate.

Description

PROCESS FOR THE PREPARATION OF (2S) -2- [(3R) -3 (N- [TERT-BUTILOXICARBONILJAMINO) -2-QXOPIRROLIDIN-1-IL] METHYL PROPIONATE DESCRIPTION OF THE INVENTION The invention concerns a novel chemical process, and more particularly, concerns a novel chemical process for the manufacture of methyl (2SJ -2- [3R) -3- N- [tert-butyloxycarbonyl] -amino) -2-oxopyrrolidin-l-yl] propionate from the formula I.

Formula I which, for example, is useful in the manufacture of the compounds described in International Patent Application, Publication No. WO 97/31023 which processes pharmacologically useful properties for use in the treatment of autoimmune diseases or medical conditions, such as such as rheumatoid arthritis and other MHC Class II dependent T cell diseases. The compounds of Formula I have been previously prepared by the method described in Example 1 of WO 97/31023. In this method the compound of formula II Formula II which may be referred to as Boc- (D) -Met- (L) -Ala-OMe, is methylated using a broad excess (about equivalent LO) of methyl iodide in a mixture of N, N-dimethylformamide (DMF) and dichloromethane, followed by removal of the excess methyl iodide and cyclization of the sulfonyl salt formed, using sodium hydride, to form the lactam ring. The product was purified after preparation by chromatography. These are various disadvantages by carrying out this known process on a wide scale. For example, a disadvantage is the use of a broad excess of methyl iodide. This results in the production of unwanted byproducts and is environmentally undesirable. A further disadvantage, for example, is that the alkylation step and the cyclization step can not be summarized together without the above removal of the excess methyl iodide. At least all of the methyl iodides are removed before cyclization, take place under the methylation used of the firmly basic conditions of the amide nitrogen. Additional disadvantages for large-scale manufacturing are the use of DMF as a solvent and its elimination, and the use of chromatography to purify the product. The reaction of methyl iodide with the compound of the formula I is also reversible and in the excess removal of methyl iodide 5 from the reaction mixture of the partially reverted product for the initial material, the effect of which is enhanced on an increased scale. Such disadvantages make the process unoccupied for operation on the commercial scale. A process has now been described for the The manufacture of the compound of the formula I of Boc- (D) -Met (L) -Ala-OMe which overcomes one or more of the problems encountered with the known process. According to the invention, a process is provided for the manufacture of (2S) -2- [3R) -3- (N- [tei-15-butyloxycarbonyl] amino) -2-oxopyrrolidin-1-yl] propionate methyl ester ( formula I) comprising (1) methylation of the compound of formula II using trimethyloxonium tetrafluoroborate in a suitable solvent; followed by 20 (2) cilcization under basic conditions. In Step (1), a particular solvent that can be employed including, for example, an inert solvent such as dichloromethane, acetonitrile, tetrahydrofuran or sulfolane, or a mixture thereof. From this, a solvent Preferred is dichloromethane or acetonitrile, especially < i $ S ^ dichloromethane. Preferably, 0.95 to 1.3 equivalents, more preferably 1.0 to 1.25 equivalents (such as 1.13 to 1.23 equivalents), or trimethyloxonium tetrafluoroborto per equivalent of the compound of formula II are used in the reaction. Using less than 0.95 equivalents of trimethyloxonium tetrtafluoroborate results in significant amounts of the unreacted starting material and uses a large excess of trimethyloxonium tetrafluoroborate, significantly inhibiting the subsequent cyclization step when steps (1) and (2) SD? summarized. More preferably 1.17 equivalents of trimethyloxonium tetrafluoroborate is used. Preferably the addition of the trimethyloxonium tetrafluoroborate is carried out at a temperature in the range of -40 ° C to room temperature, for example, -40 ° C to + 20 ° C, and conveniently -10 to + 10 ° C, such as -5 to + 5 ° C. The reaction mixture can then conveniently be allowed to proceed to completion at or around room temperature, for example, + 10 ° C to + 30 ° C. It will be appreciated that the intermediates formed in step (1) is the sulfonium salt of formula III; and that this compound is an additional aspect of the present invention. In Step (2), a particular base that can be employed includes, for example, an alkali metal alkoxide (such as potassium tert-butoxide, lithium tert-butoxide, sodium tert-butoxide or sodium methoxide), an alkali metal hydride (such as sodium hydride), a dialkylamido (of alkali metal (such as lithium diisopropylamide) or an alkyl lithium (such as n-butyl lithium) A preferred base includes, example, potassium tert-butoxide Conveniently 0.8 to 1.1 equivalents (eg 0.85 to 1.05 equivalents, and more especially 0.9 to 1.0 equivalents) such base is used per equivalent of the compound of formula II, and preferably about 0.94 equivalents (to minimize epimerization) When such bases are used in Step (2), the reaction is preferably carried out at low temperature, for example, -50 ° C to 0 ° C, such as in the 40 ° range C. at -20 ° C, and preferably at or about -40 ° C, such a Thio -50 ° C to -30 ° C. Surprisingly it has also been found that an alkali metal carbonate, such as sodium or potassium carbonate, especially an alkali metal carbonate in a form having a high surface area, such as anhydrous potassium carbonate powder (for example. 325 meshes), can be used as the base in Stage (2). The additional excess of such a carbonate base can be used and the reaction can be carried out satisfactorily at temperatures between room temperature and + 90 ° C, for example 20 to 80 ° C. Preferably 1 to 4 equivalents of a base per equivalent of compound of the formula II is used, especially 2 to 4 equivalents, for example 3 equivalents. Advantages associated with the use of a carbonate base include, for example, that it is more convenient to use on a large scale, low temperatures that do not have to be employed for restricted epimerization as with a firm base, and the reaction can be carried out at high concentrations. A preferred aspect of the present invention is therefore the use of a carbonate base in Step 2. It will be appreciated that other inorganic bases, or mixtures of such bases, have a basicity similar to that of an alkali metal carbonate that could to be used in the reaction, preferably in a finely divided form. A solvent suitable for use in Step (2) includes, for example, any of those suitable for carrying out Step (1), or a mixture thereof. A preferred solvent includes, for example, acetonitrile and dichloromethane, especially the latter. The reaction is generally carried out for 6 to 18 hours, such as about 12 hours. When the anhydrous potassium carbonate is used in dichloromethane, it is preferable to carry out Step 2 at the reflux temperature of dichloromethane. Similarly, Step 2 can be carried out, for example, in THF at reflux, acetonitrile or at 80 ° C in sulfolane. An especially preferred aspect of the present invention comprises a process comprising (I) methylation of a compound of formula II using 0.95 to 1.05 equivalents of trimethyloxonium tetrafluoroborate per equivalent of the compound of formula II, followed by (2) cyclization under basic conditions using an alkali metal carbonate (preferably anhydrous potassium carbonate). In a further preferred aspect of the invention, Steps (1) and (2) are summarized, without prior isolation of the sulfonium salt formed in Step (1). This is particularly advantageous for large scale manufacturing. A summary procedure using a carbonate base in Step (2) is especially preferred. The reaction can be prepared by cooling, addition of water, filtration, separation of the ^^ .. ^^ - .. ^ »^ organic phase, washing of the organic phase with water and removal of volatile material by distillation. The product can be crystallized from a suitable solvent, such as a mixture of dichloromethane and isohexane, tetrahydrofuran and Solvent 30 Essochem, an ester such as ethyl, propyl or butyl acetate, or preferably a mixture of n-butyl acetate and isohexane. Alternatively the organic phase after washing can be concentrated and then diluted with a suitable solvent or solvents to induce crystallization, for example as described in the Examples. The starting material of formula II can be obtained by the process described in WO 97/31023. Alternatively, the compound of formula II can be obtained by (A) protection of the amino group of (D) -methionine with a butyloxycarbonyl group to give Boc- (D) -methionine; followed by (B) coupling of Boc- (D) -methionine with methyl ester of (L) -alanine to form Boc- (D) -Met- (L) -Ala-OMe. According to a further aspect of the invention is a process for preparing the compound of the formula I which comprises carrying out Steps (A) and (B), followed by the embodiment of the Steps (1) and (2) described in the above. Step (A) can be carried out using a reagent for tert-butoxycarbonylation, such as a di-tert-butyl dicarbonate, under basic conditions, for example using excess aqueous sodium hydroxide in tert-butanol. The reaction can be carried out at a temperature in the range of -10 ° C to + 25 ° C and conveniently at or about room temperature. The reagent for tert-butoxycarbonylation is preferably added at 0 to 5 ° C. Step (B) can be carried out using normal coupling conditions well known in Peptide Synthesis, for example, as described in WO 97/31023 and in the aforementioned Examples. The Steps (A), (B), (1) and (2) are summarized together, ie they are carried out without isolation and purification of the intermediates formed, as described in the aforementioned Examples. In this case, preferably 0.95 to 1.05 equivalents (more preferably 1 equivalent) of trimethyloxonium tetrafluoroborate per equivalent of Boc- (D) -methionine are used, although it will be appreciated that any of the preferred characteristics of Steps (1) and (2) referred to herein also applies to this 4-step process. The benefits of the summarized procedure are, for example, to avoid the problems associated with the use of a broad excess of methyl iodide, this reduces the number of evaporation and purification of required Stages, and the total yield based on the amount of (D) -methionine used significantly improved. Additionally, the use of potassium carbonate as a base in Step (2) is particularly advantageous. The invention will be illustrated by the following examples or limitations in which, unless stated otherwise: (i) the operations are carried out at room temperature, which is the range 18-26 ° C; (ii) the 1 H NMR spectrum was determined using tetramethylsilane (TMS) as an internal standard, and expressed as chemical change (delta values) in parts per million relative to TMS using conventional abbreviations by designation of major peaks: s, singlet; m, multiplet; t, triplet; b, broad; d, doublet. Example 1 Boc- (D) -Met- (L) -Ala-OMe (67.0 g, estimated to contain 0.17 mol)) was dissolved in acetonitrile (500 ml), cooled to 0-5 ° C and tetrafluoroborate was added. trimethyloxonium (29.6 g, 0.2 mol)) in portions maintaining the temperature at 0-5 ° C. The mixture was allowed to warm to 20 ° C for 30 minutes and was stirred for an additional 90 minutes. Additional acetonitrile (2000 mL) was added, the mixture was cooled to -40 ° C and a solution of 1M potassium tert-butoxide in tetrahydrofuran (160 mL) was added over 60 minutes, maintaining the temperature of the reaction mixture at - 40 ° C.

The mixture was allowed to warm to 20 ° C for 16 hours. The mixture was evaporated to dryness at 40 ° C under reduced pressure and the resulting oil was partitioned between brine (600 ml) and dichloromethane (400 ml). The organic phase was separated and the aqueous phase was extracted with dichloromethane (200 ml). The combined organic phase was washed with water (200 ml) and isohexane (1600 ml) was added. The solution was concentrated by distillation at atmospheric pressure at a main temperature of 53 ° C to remove the dichloromethane. The remaining solution was cooled to 40 ° C to initiate crystallization and additional isohexane (200 ml) was added. The mixture was heated to reflux and refluxed for 2 hours. The mixture was then allowed to cool to room temperature. The suspended crystalline product was collected by filtration, washed with cold isohexane and dried at 50 ° C in a vacuum oven. In this way methyl (2S) -2- [3R) -3- (N- [tert-butyloxycarbonyl] amino) -2-oxopyrrolidin-1-yl] propionate (28.4 g) was obtained; XH NMR (200 MHz, CDC13): 1.4 (s, 9H), 1.4 (d, 3H), 1.8 (m, 1H), 2.6 (m, 1H), 3.4 (m, 2H), 3.7 (s, 3H) , 4.2 (m, 1H), 4.9 (c, 1H), 5.2 (broad s, 1H). The starting material was obtained as follows: Boc (D) -methionine (50.0 g) was dissolved in dichloromethane (200 ml) and 1-hydroxybenzo-triazole hydrate (29.7 g) and (L) -alanine methyl ester hydrochloride was added. (31.0 g). The mixture was cooled to 0 ° C and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (43.0 g) was added in portions, maintaining the temperature of the mixture at 0-5 ° C. N-Methylmorpholine (42.2 g) was then added for 30 minutes, maintaining the temperature of the mixture at 0-5 ° C. The mixture was then stirred at 0 ° C for 5 hours. The reaction mixture was washed successively with water (2 x 100 ml), 10% aqueous citric acid solution (100 ml), saturated aqueous sodium bicarbonate solution (100 ml), water (100 ml) and evaporated to dryness at 40 ° C under reduced pressure to give Boc- (D) -Met- (L) -Ala-OMe (67.0 g estimated to contain 0.17 moles) as an oil. Example 2 (summary process) The sodium hydroxide solution (1.88M, 150 ml) was added for (D) -methionine (25.0 g, 0.166 mol) and tert-butanol (100 ml) was added. The mixture was cooled to 0-5 ° C and di-tert-butyl dicarbonate (41.1 g) was added in one portion. The reaction mixture was heated to 20 ° C and stirred for 4 hours. The mixture was cooled to 0-5 ° C and 2M aqueous citric acid solution (128 ml) was added, keeping the temperature below 5 ° C. Dichloromethane (250 ml) was added and the mixture was stirred at 20 ° C for 15 minutes. The upper aqueous phase was separated and the organic phase was retained. The aqueous phase was extracted with dichloromethane (125 ml) and the extract was combined with the remaining organic phase. The combined organic phase was washed with water (250 ml) and distilled at atmospheric pressure to a volume of 250 ml remaining. The solution (which contains Boc- (D) -methionine) was cooled to 0-5 ° C and (L) -alanine methyl ester hydrochloride (25.7 g), 1-hydroxybenzotriazole hydrate (24.6 g), hydrochloride l- (3-dimethylaminopropyl) -3-ethylcarbodiimide (35.6 g) and N-methyl-morpholine (35.6 g) maintaining the temperature of the mixture under 5 ° C. The mixture was then heated to 20 ° C and stirred at this temperature for 5 hours. The mixture was cooled to 0-5 ° C and water (100 ml) was added, keeping the temperature below 5 ° C, and the mixture was stirred for 15 minutes. The organic phase was separated and washed successively with water (150 mL), 2M aqueous citric acid solution (100 mL), 20% aqueous sodium bicarbonate solution (100 mL) and brine (100 mL). Dichloromethane (450 ml) was added to the organic phase and the distilled mixture was collected at atmospheric pressure to 100 ml of distillate. The mixture (which contains Boc- (D) -Met- (L) -Ala-OMe) was cooled to 0-5 ° C and trimethyloxonium tetrafluoroborate (25.1 g, 0.166 moles) was added in one portion keeping the temperature at 0 -5 ° C. The mixture was allowed to warm to 20 ° C for 30 minutes and then stirred for a further 4 hours. Powdered potassium carbonate (325 mesh, 71.9 g) was added and the mixture was refluxed for 12 hours. The mixture was cooled to 0-5 ° C and water (300 ml) was added. The mixture was stirred for 15 minutes at 20 ° C and filtered through a sintered funnel (porosity 3). The The lower organic phase of the filtrate was separated and washed with water (300 ml). The solution was distilled at atmospheric pressure to 320 ml of distillate, collected and n-butyl acetate (200 ml) was added. The solution was concentrated at 70-75 ° C under reduced pressure to 80 ml of remaining concentrate. The concentrate was cooled to 40 ° C and isohexane (80 ml) was added. The mixture was cooled to 20 ° C, then heated to 40 ° C and additional isohexane (320 ml) was added slowly over 1 hour. The mixture was stirred an additional 30 minutes at 40 ° C and then cooled to 0-5 ° C and stirred for 1 hour. The suspended crystalline solid was collected by filtration, washed with cold isohexane (2 x 50 ml), dried at 50 ° C in a vacuum oven for 8 hours. Methyl (2S) -2- [(3R) -3 (- [tert-butyloxycarbonyl] amino) -2-oxopyrrolidin-1-yl] propionate (36.5 g, 76% yield) was obtained; NMR with respect to Example 1. ^^? ^

Claims (11)

1. CLAIMS 1. A process for the manufacture of methyl (2S) -2 - [(3R) 3 (N- [tert-butyloxycarbonyl] amino) -2-oxopyrrolidin-l-yl] propionate of the formula I. comprising (1) methylation of the compound of the formula II using trimethyloxonium tetrafluoroborate in a suitable solvent; followed by (2) cyclization under basic conditions.
2. 2. The process in accordance with the claim 1, characterized in that the solvent used in step (1) comprises dichloromethane or acetonitrile and in step (2) comprises dichloromethane, acetonitrile, tetrahydrofuran or sulfolane.
3. 3. The process in accordance with the claim 1 or 2, characterized in that 0.95 to L.3 equivalents of trimethyloxonium tetrafluoroborate are used per equivalent of the compound of formula II.
4. 4. The process in accordance with the claim 1, 2 or 3, characterized in that in step (2) the base used is an alkali metal alkoxide, an alkali metal hydride, an alkali metal dialkylamide or an alkyl lithium
5. 5. The process according to claim 1 , 2 or 3, characterized in that in step (2) the base used is an alkali metal carbonate.
6. 6. The process in accordance with the claim 5, characterized in that step 2 is carried out at a temperature between room temperature and 90 ° C.
7. The process according to claim 5 or 6, characterized in that 1 to 4 equivalents of powdered potassium carbonate are used.
8. The process according to any of the preceding claims, characterized in that the compound of the formula I is isolated by crystallization from a solvent mixture comprising n-butyl acetate and isohexane or dichloromethane and isohexane.
9. 9. A process for the manufacture of the compound of the formula I characterized in that it comprises the steps of: (i) protecting the amino group of (D) -methionine with a butyloxycarbonyl group to give Boc- (D) -methionine: (ii) Boc- (D) -methionine coupling with (L) -alanine methyl ester to form Boc- (D) -Met- (L) -Ala-OMe; (iii) methylation of Boc- (D) -Met- (L) -Ala-OMe with trimethyloxonium tetrafluoroborate in a suitable solvent; and (iv) cyclization under basic conditions.
10. 10. The process according to any preceding claim characterized in that all stages are summarized.
11. 11. The compound