ITUB20152779A1 - PROCESS FOR THE SYNTHESIS OF 4-PROTECTED CHETO PROLINA - Google Patents

Description

SUMMARY

"PROCESS FOR THE SYNTHESIS OF PROTECTED 4-KETO PROLINA"

A process for the synthesis of 4-keto proline-N-protected (1), starting from the corresponding protected 4-hydroxy-proline, in the presence of the oxidizing system PsOg / dimethyl sulfoxide (DMSO) is described:

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PG

4-c lu · fa »- ji rwl ina jir ulLfta

to"

This process can also be applied in the presence of a chiral center in the position carrying the carboxylic acid (position 3) without significant epimerization of the latter center.

This process is particularly advantageous from an environmental point of view, yields, productivity and purity of the product obtained, as it does not employ the use of chromium-based oxidants, metals such as ruthenium or oxidizing system precursors of genotoxic impurities.

"PROCESS FOR THE SYNTHESIS OF PROTECTED 4-KETO PROLINA"

The invention relates to the preparation process of N-protected 4-keto proline by oxidation of the corresponding N-protected 4-hydroxy-prolins.

BACKGROUND OF THE INVENTION

The 4-keto prolin derivatives are important intermediates for the preparation, among other things, of ACE inhibitors, used for the treatment of hypertension and cardiovascular diseases.

As reported in the literature (JACS 1957, 79, 185-92), 4-keto prolin derivatives are unstable, especially in basic conditions, where they can give aldol condensation or ring opening with the generation of by-products and impurities.

The synthesis of 4-keto proline intermediates by oxidation from the corresponding hydroxyl derivatives is described in several patents and articles.

DD283626A5 describes the oxidation of N-benzyloxy-4-hydroxy proline via the pyridine-SOs complex. Although the oxidation described is in the absence of metals, the main disadvantage lies in the use of highly toxic pyridine.

Traditional methods of oxidation using the Jones reagent, based on chromium, are also reported. As known, these chromium-containing oxidative systems are highly toxic (US4296113, JOC2001, 66, 3593; J0C2 002, 67,71 62),

In Organic Process Research & Development, 19 (1), 270-283; 2015, the oxidation of hydroxy proline N-BOC is described using TEMPO / hypochlorite as an oxidizing system, which, as known, can generate genotoxic impurities.

US 8618310 describes a homogeneous aqueous phase oxidation in the presence of Ru02 and NaI04 in accordance with the following scheme:

RuO-i / NalO

PG \ PG

The resulting product precipitates, thus preserving further oxidation and degradation reactions. Even if from a toxicological and environmental point of view, said oxidation has a lower impact than the previously described literature, however, there is the use of Ruthenium which, in addition to having a certain economic impact, also requires strict control in the isolated product to limit it. heavy metal contamination.

DESCRIPTION OF THE INVENTION

An advantageous oxidation process of 4-hydroxy proline derivatives has now been found in which oxidation is obtained using the oxidizing system P2Q5 / DMSO in basic conditions, with subsequent isolation under controlled conditions in order to prevent degradation known in the literature.

The process of the invention is shown in the following diagram:

PG

in which PG is a protective group of the amino group (as described in the book: "Protective Groups in Organic Synthesis, Third Edition. T.W. Greene") which includes a carbonyl function and is linked through this function to the amino nitrogen. One of the most common groups is tert-butyloxycarbonyl (BOC).

The process consists of a single oxidation stage which is followed by the isolation of the product. The product can be purified as an organic or inorganic base salt and then isolated again as carboxylic acid.

Oxidation occurs in a mixture of organic solvents, for example a mixture of dichloromethane and dimethyl sulfoxide or in pure dimethyl sulfoxide.

Oxidation occurs by consecutive additions of sulfuric anhydride (P2O5) and an organic base such as diisopropylethylamine or triethylamine.

Upon completion of the conversion, the reaction mixture is quenched and extracted in organic solvent.

The reaction product is then precipitated from the fine workup concentrated organic solution in salified form, for example as a phenylethylamine, naphthylamine or dicyclohexylamine salt.

The subsequent desalting in an organic solvent such as methyltertbutyl ether and subsequent precipitation by acetonitrile provides the desired oxidation product in high purity.

According to a preferred version of the invention, the process is performed as follows:

1 mole of N-protected hydroxy proline is basified with 1.0-1.1 mole of organic base, preferably diisopropylamine in dimethyl sulfoxide. 5-25 volumes of solvent are used, preferably 14 ÷ 16 volumes with respect to the quantity of N-protected hydroxy proline, or mixtures of dimethylsulfoxide / methylene chloride. At a temperature lower than 25 ° C, preferably at a temperature between 15 ° C-18 ° C, the organic base, preferably diisopropylamine, is added in portions in aliquots of 0.25-0.65 moles at a time, preferably 0.4-0. 5 moles, for a total of 7 ÷ 18 portions, preferably 9 ÷ 11 portions, and, in rapid succession, portions of phosphoric anhydride, in aliquots of 0.08-0.21 moles at a time, preferably 0.14-0.17 moles, for a total of 7 ÷ 18 portions, preferably 9 ÷ 11 portions at a temperature below 25 ° C, preferably at a temperature between 15 ° C-20 ° C.

The reaction is controlled by UPLC analysis using an ACQUITY BEH C18 column and water / acetonitrile / 0.1% trifluoroacetic as the eluent phase.

At the end of the reaction it is acidified to a pH of between 2.0-4.0, preferably 2. 5-3. 5 with hydrochloric acid.

It is then extracted with an organic solvent, preferably methylene chloride by counter-extracting the aqueous phase to recover product with the same solvent. After concentration, an oil is obtained which can be used directly in the subsequent salification stage.

The oil obtained is dissolved in organic solvent, preferably ethyl acetate. 5-8 volumes of solvent are used, preferably 6 ÷ 7 volumes with respect to the initial quantity of N-protected hydroxy proline. To the solution obtained, at a temperature below 25 ° C, preferably between 20 ° C-25 ° C, 1.5-2 is added. 5 moles of organic base, phenylethylamine or naphthylamine or dicyclohexylamine. These moles refer to the N-protected proline hydroxy content present in the titrated starting oil.

The suspension thus obtained is filtered. The solid thus obtained, if necessary, can be further purified by recrystallization or pulping from ethyl acetate or other known solvents.

The acid salt of the N-protected 4-keto proline is then dissolved in 3-5 volumes of water and 4-6 volumes of organic solvent, preferably methyltertbutyl ether. The suspension obtained is acidified with inorganic acids, preferably phosphoric acid, and the organic phase evaporated to dryness. The oil obtained is then dissolved in 3-5 volumes with respect to the starting salt in organic solvent, preferably ethyl acetate.

The filtered solid is dried under vacuum at a temperature of 45 ° C-55 ° C to obtain N-protected 4-keto proline.

The solid thus obtained, if necessary, can be further purified by recrystallization or pulping from ethyl acetate or other organic solvents known in the literature.

The process of the invention is particularly advantageous since, unlike known processes, it is conducted without the use of oxidizing systems containing harmful or toxic species, and in the absence of metals whose use should be strictly monitored in the isolated product. Also from the economic point of view, said oxidation has the advantage of using reagents with a low cost impact and whose by-products are easily removable in the aqueous phase.

Finally, said process is also safe from the calorimetric point of view and is therefore scalable in an industrial plant.

The invention is illustrated in detail in the following examples.

Example 1: synthesis of N-BOC-4-keto proline naphthylamine salt To a solution of N-BOC hydroxy proline (25 g, 0.108 moles) in dimethyl sulfoxide (350 ml) diisopropylamine (14.0 g, 0.108 moles) is added . The solution obtained is then cooled to 16-1 7 ° C and approximately 10 portions of diisopropylamine aliquots (6.28 g, 0.0486 moles) are added followed by corresponding aliquots of phosphoric anhydride (4.60g, 0.0162 moles). ).

The reaction is then controlled by UPLC. At the end of the reaction, the reaction mixture is slowly dropped into a mixture of methylene chloride (250 ml) and water (30 ml) at pH 3.0 ± 0.5, at a temperature between 0-5 ° C and keeping the pH constant between 3.0 ± 0.5 by simultaneous addition of hydrochloric acid (about 40 ml).

After separating the phases, the aqueous phase is counter-extracted with dichloromethane (150 ml) and the combined organic phases washed with water (2X100 ml).

It is then concentrated in oil by drying with ethyl acetate.

The oil obtained is dissolved in ethyl acetate (162 ml). To the solution obtained, at a temperature between 20 ° C-25 ° C, naphthylamine (18.6 g, 0.13 moles) is added. The obtained product is filtered and washed with ethyl acetate (41 ml).

The isolated solid is dried under reduced pressure at 50 ° C to obtain N-BOC-4-keto proline naphthylamine salt (24.2 g, 0.065 mol) as a white solid. Molar yield from N-BOC-hydroxy proline: 60%.

Example 2: synthesis of N-BOC-4-keto proline from N-BOC-4-keto proline naphthylamine salt

23.2 g of N-protected 4-keto proline naphthylamine salt (93%, 0.058 mol) are suspended in a mixture of 100 ml of water and 250 ml of methyl tertbutyl ether. 85% phosphoric acid is added to the suspension up to pH 2 ± 0.5. The phases are separated and the aqueous phase is countered with methyl tert-butyl ether (125 ml). The combined organic phases are then washed with water (50 ml) and evaporated to dryness, anhydrifying with ethyl acetate (3X50 ml). Ethyl acetate (25 ml) is added to the oily residue obtained and stirred at 25 ± 5 ° C for 1H. The solid is then filtered by washing with ethyl acetate (10 ml). The product obtained is then dried under reduced pressure at a temperature of 50 ° C to obtain N-protected 4-keto proline (12.2 g, 0.053 mol) as a white solid. HPLC purity: 99.5%

Molar yield from N-BOC-keto proline naphthylamine salt: 91%.

The solid thus obtained, if necessary, can be further purified by recrystallization or pulping from ethyl acetate or other known organic solvents.

UPLC-MS [M + H +] = 228

1H NMR (400 MHz, DMSO)

δ 12.85 (s, IH), 4.54 (m, IH), 3.86-3.78 (m, IH), 3.69-3.64 (m, IH), 3.16-3.06 (m, IH), 2.53-2.45 (m, IH DMSO ), 1.42 and 1.40 (2 x s, 9H).

Example 3: synthesis of N-BOC-4-keto proline dicyclohexylamine salt

Diisopropylamine (21.0 g, 0.162 mol) is added to a solution of N-BOC hydroxy proline (37.5 g, 0.162 mol) in dimethyl sulfoxide (530 ml). The solution obtained is then cooled to 16-17 ° C and approximately 10 portions of diisopropylamine aliquots (9.42 g, 0.0729 moles) are added followed by corresponding aliquots of phosphoric anhydride (6.90 g, 0.0243 moles). ).

The reaction is then controlled by UPLC. At the end of the reaction, the reaction mixture is slowly dropped into a mixture of methylene chloride (400 ml) and water (45 ml) at pH 3.0 ± 0.5, at a temperature between 0-5 ° C and keeping the pH constant between 3.0 ± 0.5 by simultaneous addition of hydrochloric acid (about 60 ml).

After separating the phases, the aqueous phase is counter-extracted with dichloromethane (230 ml) and the combined organic phases washed with water (2X150 ml).

It is then concentrated in oil by drying with ethyl acetate.

The oil obtained is dissolved in ethyl acetate (250 ml). To the solution obtained, diclohexylamine (35.3 g, 0.2 moles) is added at a temperature between 20 ° C-25 ° C. The obtained product is filtered and washed with ethyl acetate (60 ml).

The isolated solid is dried under reduced pressure at 50 ° C to obtain N-BOC-4-keto proline salt of dicyclohexylamine (45.2 g, 0.11 mol) as a white solid.

Molar yield from N-BOC-hydroxy proline: 68%.

Example 4: synthesis of N-BOC-4-keto proline from N-BOC-4-keto proline dicyclohexylamine salt

40 g of N-protected 4-keto proline dicyclohexylamine salt (93%, 0.09 mol) are suspended in a mixture of 155 ml of water and 390 ml of methyl tertbutyl ether. 85% phosphoric acid is added to the suspension up to pH 2 ± 0.5. The phases are separated and the aqueous phase is counter-extracted with methyl tert-butyl ether (200 ml). The combined organic phases are then washed with water (80 ml) and evaporated to dryness, anhydrifying with ethyl acetate (3X80 ml). Ethyl acetate (31 ml) is added to the oily residue obtained and stirred at 25 ± 5 ° C for 1H. The solid is then filtered by washing with ethyl acetate (15 ml). The product obtained is then dried under reduced pressure at a temperature of 50 ° C to obtain N-protected 4-keto proline (19 g, 0.083 mol) as a white solid. HPLC purity: 99.6%.

Molar yield from N-BOC-keto proline dicyclohexylamine salt: 92%. The solid thus obtained, if necessary, can be further purified by recrystallization or pulping from ethyl acetate or other known organic solvents.

UPLC-MS [M + H +] = 228

1H NMR (400 MHz, DMSO)

δ 12.85 (s, IH), 4.54 (m, IH), 3.86-3.78 (m, IH), 3.69-3.64 (m, IH), 3.16-3.06 (m, IH), 2.53-2.45 (m, IH DMSO ), 1.42 and 1.40 (2 x s, 9H).

Claims (1)

CLAIMS 1. A process for the preparation of N-protected 4-keto prolins which includes Γ oxidation of the corresponding N-protected 4-hydroxy-prolins by means of P205 / dimethyl sulfoxide (DMSO) under basic conditions, 2. Process according to claim 1 wherein the oxidation takes place in a mixture of dichloromethane and dimethyl sulfoxide or in pure dimethyl sulfoxide. 3. Process according to claim 2 in which oxidation occurs by consecutive additions of sulfuric anhydride (P2O5) and an organic base. 4. Process according to claim 3 wherein the organic base is diisopropylethylamine or triethylamine. 5. Process according to one or more of claims 1 to 4 wherein the N-protected 4-keto proline and the N-BOC 4-keto-proline and the N-protected 4-hydroxy-proline is N-BOC-4- hydroxy-proline. Process according to one or more of claims 1 to 5 wherein the product is purified as an organic or inorganic base salt and then isolated again as carboxylic acid. Milan, 3 August 2015