HK1039111B - Method for producing enantiomer-free n-methyl-n-[(1s)-1-phenyl-2-((3s)-3-hydroxypyrrolidine-1-yl)ethyl]-2,2-diphenyl acetamide - Google Patents

Description

Process for the preparation of enantiomerically pure N-methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-yl) ethyl ] -2, 2-diphenylacetamide

The present invention relates to a novel process for the preparation of N-methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-yl) ethyl ] -2, 2-diphenylacetamide or N-methyl-N- [ (1R) -1-phenyl-2- ((3R) -3-hydroxypyrrolidin-1-yl) ethyl ] -2, 2-diphenylacetamide, and N-methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-yl) ethane ] and N-methyl-N- [ (1R) -1-phenyl-2- ((3R) - 3-hydroxypyrrolidin-1-yl) ethane ].

The compound N-methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-yl) ethyl ] -2, 2-diphenylacetamide and its pharmaceutically acceptable salts have valuable pharmacological properties, such as analgesic, anti-inflammatory and aquaretic actions, as described by Barber et al (B.J. Pharmacol. (1994), 133, 1317-.

As described in patent application DE19523502 or EP752246, it was found that this compound is a particularly effective compound, which is suitable for use as a medicament for the treatment of inflammatory bowel diseases in a very specific manner. The compound is particularly useful and effective in this indication because it simultaneously alleviates the pain associated with the disease and in the acute cases of ileus or resulting pain due to inflammatory bowel disease, restores normal or begins a motor response of the moving bowel without significant side effects. Furthermore, the compounds are useful in non-inflammatory bowel diseases such as IBS (irritable bowel syndrome).

Patent applications DE4034785A1 and DE4215213A1 or EP569802A1 describe the preparation of N-methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-yl) ethyl ] -2, 2-diphenylacetamide by reacting (2S) -2-N-carboxyethyl-2-phenylglycine-N, N- [ (3S) -3-hydroxytetramethylamide with diphenylacetyl chloride, as described in DE4215213, starting from the starting compound (2S) -2-N-carboxyethyl-2-phenylglycine-N, N- [ (3S) -3-hydroxytetramethyleneamide, also known as (1S) - [ 1-N-methylamino-1-phenyl-2- ((3S) -3- Hydroxypyrrolidine) ethane can be prepared by reacting (1S) -1-amino-1-phenyl-2-chloroethane with (3S) -3-hydroxypyrrolidine, followed by methyl iodomethylation. However, this preparation method has problems in solubility of the starting product and the resulting racemic product mixture contaminated with by-products has to be laboriously separated after the synthesis process. The hitherto known processes for preparing N-methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-yl) ethyl ] -2, 2-diphenylacetamide are laborious and expensive and give low yields based on the starting compounds.

It is therefore an object of the present invention to utilize a simple and economical process for the preparation of N-methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-yl) ethyl ] -2, 2-diphenylacetamide, or when using enantiomeric starting materials, can be carried out in a simple manner and economically, starting from economical, readily soluble starting materials, to give products which are as enantiomerically pure as possible and can therefore be isolated and purified in a simple manner.

The object of the invention is achieved by the process as claimed in claim 1, the previously unknown compound N-methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-yl) ethane ] being used as a novel intermediate for the preparation of N-methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-yl) ethyl ] -2, 2-diphenylacetamide or N-methyl-N- [ (1R) -1-phenyl-2- ((3R) -3-hydroxypyrrolidin-1-yl) ethane ] being used as an intermediate for the preparation of N-methyl-N- [ (1R) -1-phenyl-2- ((3R) -3- Novel intermediates of hydroxypyrrolidin-1-yl) ethyl ] -2, 2-diphenylacetamide.

We have found that the compounds of formula (III) below can be prepared in high yield and in enantiomerically pure form:

wherein R and R²Has the following meanings and has the following meanings,

r is H, OR¹Or SR¹’

R¹Is A, aryl, heteroaryl, Si (R)³)₃Or C (O) R³，

R²Is H, A, aryl, heteroaryl, Si (R)³)₃Or C (O) R³，

R³Is H, A, an aryl or heteroaryl group,

a is a straight or branched alkyl group containing 1 to 6 carbon atoms,

which comprises amide coupling of (3S) -3-hydroxypyrrolidine or (3R) -3-hydroxypyrrolidine of the following formula (II) or their reaction with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid or their mixtures, depending on the desired end product

Salts formed with suitable organic acids:

wherein

R²Is H, A, aryl, heteroaryl, Si (R)³)₃Or C (O) R³，

R³Is H, A, an aryl or heteroaryl group,

and N-substituted phenylglycine of the formula (I) below

Formula (II):

wherein

R is H, OR¹Or SR¹，

R¹Is A, aryl, heteroaryl, Si (R)³)₃Or C (O) R³，

R³Is H, A, an aryl or heteroaryl group,

m is H or a cation selected from alkali metal, alkaline earth metal, ammonium or alkylammonium.

The alkyl group contains 1 to 6, preferably 1, 2, 3 or 4 carbon atoms. Alkyl is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore pentyl, 1-, 2-or 3-methylbutyl, 1-, 1, 2-or 2, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3-or 4-methylpentyl, 1-, 1, 2-, 1, 3-, 2, 2-, 2, 3-or 3, 3-dimethylbutyl, 1-or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 2-or 1, 2, 2-trimethylpropyl.

Aryl is preferably unsubstituted phenyl or phenyl which is mono-or disubstituted by halogen, OA or alkyl, furthermore, for example biphenyl or naphthyl.

Heteroaryl is preferably, for example, furyl, thienyl, pyridyl, pyrrolyl or thiazolyl.

Si(R³)₃Preferably, for example, Si (CH)³)₃。

C(O)R³Preference is given to acetyl or benzoyl, for example.

R is particularly preferably, for example, methoxy or ethoxy.

R¹In particular, for example, methyl, ethyl, propyl, butyl, phenyl, Si (CH)₃)₃Or an acetyl group.

R²In particular, for example, H, tert-butyl, Si (CH)₃)₃Acetyl, benzyl or benzoyl, with H being particularly preferred.

The amides of the formula (III) prepared can, if desired, be converted in a simple manner by reductive removal of the protective group for the hydroxyl group of pyrrolidine in N-methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-yl) ethane ] or N-methyl-N- [ (1R) -1-phenyl-2- ((3R) -3-hydroxypyrrolidin-1-yl) ethane ] of the formula (IV).

By reaction with an activated carboxylic acid of the formula (V):

wherein R is⁴Is F, Cl, Br, I, OA or O-CO-A,

can be prepared from the free base of a compound of formula (IV) or a salt thereof with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid or a suitable organic acid:

the enantiomeric compound of the following formula (VI) is obtained in pure form:

these compounds are preferably prepared as hydrochloride salts, the compound N-methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-yl) ethyl ] -2, 2-diphenylacetamide being the known form EMD 61753; but the corresponding salts with the above-mentioned acids can likewise be prepared analogously.

In particular, N-methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-yl) ethyl ] -2, 2-diphenylacetamide can be prepared by the final reaction with diphenylacetyl chloride.

Compounds of formula (IV) which are synthesized as intermediates are generally obtainable by reacting a compound of formula (I), preferably used in a reaction of formula (I) with a compound of formula (II), wherein R has OR¹Definitions in which R¹Is A, aryl, heteroaryl, Si (R)³)₃Or COR²And R²Is H, alkyl, aryl or heteroalkyl, having the preferred meanings as set forth above. Unexpectedly, in contrast to the use of the corresponding formyl compounds, enantiomerically pure reaction products of the formula (III) are obtained. In this process, the resolution of the racemate can advantageously be dispensed with.

The reaction of compounds (I) and (II) can be carried out in any desired aprotic solvent. Particularly suitable solvents are polar aprotic solvents selected from the group consisting of diethyl ether, petroleum ether, acetone, nitrobenzene, dimethylformamide, dimethyl sulfoxide or other corresponding solvents. In this regard, the starting materials are dissolved in sufficient solvent to provide a 10-30% solution, preferably with the reaction being carried out in tetrahydrofuran as the solvent.

The reaction of compounds (I) and (II) is carried out under suitable conditions at a temperature of from 0 to 50 ℃ however, particularly good results are obtained at room temperature at from 20 to 30 ℃ at normal pressure.

To activate the starting material, the presence of an auxiliary reagent is required. These may be adjuvants which may also be used as peptide coupling reagents. Suitable compounds are, for example, phosphorus oxychloride, phosphorus halides of the valences III and V, phosgene, dicyclohexylcarbodiimide, tributylammonium salt of pyridine, phenyl dichlorophosphate, 2-chloro-1, 2, 3-trinitrobenzene, phosphoric acid esters, chlorosulfonyl isocyanate, CH₃SO₂Cl-(C₂H₅)₃N、(C₆H₅)₃P-CCl₄-(C₂H₅)₃N, N, N' -carbonyldiimidazole, N- (alkylcarbonyl) imidazole, acid anhydrides or acid chlorides, especially alkyl chloroformates, for example ethyl chloroformate. Other suitable auxiliary agents are described in various references, for example, in the C.Ferri "organic synthesisFormation reaction "; comprehensive organic synthesis of R.C.Larock "; introduction to the preparation of functional groups ", Verlag Chemie, 1989.

Furthermore, the presence of a base is desirable. Suitable bases are likewise deduced from the above-mentioned references. Such bases are, for example, tertiary amines, such as triethylamine, however, inorganic bases may also be added, suitable inorganic bases being, in particular, carbonates. When using alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide, particular attention should be paid to the exact addition, since otherwise undesirable side reactions occur. However, to simplify processing, it is also possible to employ an excess of hydroxypyrrolidine, which thus acts as a base per se.

The work-up of the reaction product (III) obtained can be carried out with the filtrate after filtering off the precipitate obtained with customary laboratory methods. For example, common and suitable methods include distilling off the solvent, redissolving the crude product in an organic solvent, extracting the resulting solution several times with water, redistilling the solvent and recrystallizing the resulting product by recrystallization from a suitable solvent, e.g., methanol. However, other processing methods known to the person skilled in the art are also possible, for example methods additionally comprising chromatographic purification.

Depending on the reaction conditions, the reaction product (III) is obtained from aqueous solvent mixtures as the free base or as an acid addition salt with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid or suitable organic acids, in which case the isolation can be carried out after phase separation according to customary experimental methods.

Suitable organic carboxylic acids which may be used are, in particular, aliphatic, cycloaliphatic, araliphatic, aromatic or heterocyclic mono-or polycarboxylic acids, sulfonic acids or sulfuric acids, for example formic acid, acetic acid, propionic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene-mono-and disulfonic acids, lauryl sulfuric acid.

A compound of the formula (III)In a protective atmosphere, for example in a nitrogen atmosphere in the presence of a hydride transfer reagent. Suitable hydride transfer agents are selected from the group consisting of metal aluminum hydrides, preferably lithium aluminum hydride, metal alkoxyaluminum hydrides, such as lithium aluminum triethoxide hydride, metal borohydrides, preferably NaBH₄Or borane, the additional presence of a lewis acid being required, for example boron trifluoride.

The reduction is preferably carried out in a polar aprotic and hydride-inert solvent. Suitable solvents are the same as described above, particularly suitable solvents are, for example, diethyl ether or tetrahydrofuran.

For the hydrogenation, the compound of the formula (III) is dissolved in a suitable solvent and added to the solution containing the hydride transfer reagent in equimolar amounts or in a slight excess with warming. However, it is also possible to add the starting compounds to be hydrogenated and the hydrogenation reagent in suitable amounts in a suitable manner so that the starting compounds have a concentration in the resulting reaction mixture of from 10 to 25% by weight, based on the solvent. To complete the reaction, the reaction mixture was stirred under reflux for several hours. The reaction solution is then processed according to methods known to those skilled in the art, for example by decomposing excess hydride transfer reagent by adding a solvent mixture of protic and aprotic solvents, and liberating the reaction product. Suitable proton-generating solvents are, for example, water or alcohols, such as ethanol or methanol. Suitable aprotic solvents are all the polar aprotic solvents mentioned above, in particular tetrahydrofuran, the latter being preferably used since it is commercially available as an anhydrous product.

The product work-up can be carried out after phase separation according to customary experimental methods. The crude product obtained can be worked up by crystallization or, for work-up, it is dissolved, for example, in an organic water-immiscible solvent and treated with an excess of a mineral acid, preferably hydrochloric acid, and the salt formed by this process can subsequently be isolated in crystalline form.

Further reaction of N-methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-yl) ethane ] or its dihydrochloride with a suitable diphenylacetic acid derivative, preferably the acid chloride, gives the desired end product N-methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-yl) ethyl ] -2, 2-diphenylacetamide (formula VI, EMD 61753) according to the process described in DE-A1-4034785 and DE-A1-4215213 or EP0569802A 1.

The following examples serve to illustrate the invention but are not intended to limit the scope thereof, since different variants of the examples are possible, yielding the desired product N-methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-yl) ethane ] [ formula (IV) ], which is useful as an intermediate for the preparation of N-methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-yl) ethyl ] -2, 2-diphenylacetamide.

Examples

From (2S) -phenylglycine of the formula I, N-substituted (2S) -2-phenylglycine-N, N- [ (3S) -3-hydroxytetramethyleneamides of the formula III

Example 1

(2S) -N-formyl-2-phenylglycine-N, N- [ (3S) -3-hydroxytetramethyleneamide

Obtained from (2S) -N-formyl-2-phenylglycine (e.g. from Huszthy, Peter; Oue, Masatoshi; Bradshaw, Jerald S.; Zhu, Cheng Y.; Wang, Tingmin et al, J.Org.Chem., EN, 57(20) [1992] 5383. 5394 from (S) - (+) -alpha-aminophenylacetic acid and acetic anhydride/formic acid) and (3S) -3-hydroxypyrrolidine (obtained from Bhat, Krishna L.; Flanagan, Denisem.; Joullie, Madelein M., Synth.Commun., EN, 15(7) [1985] 587. clan 598 or Naylor, Alan; Judd, Duncan B.; Scopes, David I.C.Hayes., Ann G., Ph J.J.J.J.2148., benzyl J.3-2134.) (S.) -2138.):

4.8ml of ethyl chloroformate in 10ml of tetrahydrofuran are added under nitrogen at-15 ℃ with stirring to 9g of (2S) -N-formyl-2-phenylglycine and 5.5ml of N-methylmorpholine in 250ml of THF, after 10 minutes to a solution of 6.2g of (3S) -3-hydroxypyrrolidine hydrochloride in 50ml of dimethylformamide and 7ml of triethylamine. After stirring for 18 hours, the resulting precipitate was separated off and the resulting (2S) -N-formyl-2-phenylglycine-N, N- [ (3S) -3-hydroxytetramethyleneamide was isolated from the filtrate by concentration using customary experimental methods and subsequently purified by chromatography.

1H-NMR：D₆-DMSO；3.0-3.8(m)，4.25(d)，5.0(s，br)，5.7(dd)，7.4(ArH)，8.0(ArH)，8.8(CHO)：

MS-FAB：(M+1)⁺221，205；

Crystallization m.p.: 97-101 ℃;

[α]D²⁰+208 °, c-1 methanol.

Example 2

(2S) -N-carboxybenzyl-2-phenylglycine-N, N- [ (3S) -3-hydroxytetramethyleneamide

From (2S) -N-carboxybenzyl-2-phenylglycine (e.g. (S) - (+) -alpha-aminophenylacetic acid and benzyl chloride carbonate according to Hones, Raymon dCF; Turner, Ian; Howard, Kevin J., Tetrahedron Lett., 34(39) [1993] 6329-) -9332) and (3S) -3-hydroxypyrrolidine (obtained from Bhat, Krishna L.; Flanagan, Denisem.; Joullie, Madelein M., Synth. Commun., EN, 15(7) [1985]587- -598 or Naylor, Alan; Judd, Duncan B.; Scopes, David I.C.Hayes, Ann G.; Birch, PhilJ.Chem, 37. 14.; S.2148.; benzyl alcohol (S-1994) 3S-2134):

14.3g of (2S) -N-carboxybenzyl-2-phenylglycine in 100ml of tetrahydrofuran are treated with cooling under a nitrogen atmosphere with a solution of 5.5ml of 4-methylmorpholine and 4.8ml of ethyl chloroformate and 10ml of THF, and are subsequently stirred for 30 minutes. Subsequently, 4.36g of (3S) -3-hydroxypyrrolidine and 10ml of tetrahydrofuran solution were added, and after stirring for 18 hours, the resulting precipitate was separated, and the resulting (2S) -N-carboxybenzyl-2-phenylglycine-N, N- [ (3S) -3-hydroxytetramethyleneamide was isolated from the filtrate by concentration using a usual experimental method, dissolved in an organic solvent, washed with an aqueous phase, concentrated again and crystallized.

1H-NMR：D₆-DMSO+TFA；5.1(s)，PhCH₂R；

FAB-MS：355(M+1)⁺，311，196，176；

Consistency: an oil;

[α]D²⁰+108 °, c-1 methanol.

Example 3

(2S) -N-carboxyethyl-2-phenylglycine-N, N- [ (3S) -3-hydroxytetramethyleneamide 3.a)

From (2S) -N-carboxyethyl-2-phenylglycine (obtained, for example, from (S) - (+) -alpha-aminophenylacetic acid and ethyl chlorocarbonate according to Bodurow, C.C.; Boyer, B.D.; Brennan, J.; C.A.; Burks, J.E.; et al tetrahedron Lett., 30(18) [1989] 2321-)) and (3S) -3-hydroxypyrrolidine (obtained from (Bhat, Krishna L.; Flanagan, Denisem.; Joullie, Madelein M., Synth.Commun., EN, 15(7) [1985] 587-; 598 or Naylor, Alman; Judd, Duncan B., Scopes, David I.C.Hayes., Ann.G.; Birch, Philip., J.J.J.J.2148.; Med.; S-3-2134) (benzyl alcohol) (see, J.3, J.7.):

16.7g of (2S) -N-carboxyethyl-2-phenylglycine are treated with a solution of 8.3ml of 4-methylmorpholine and 7.1ml of ethyl chloroformate and 20ml of THF under a nitrogen atmosphere with cooling and subsequent stirring for 60 minutes. Subsequently, 6.5g of (3S) -3-hydroxypyrrolidine and 30ml of tetrahydrofuran solution were added, and after stirring for 18 hours, the resulting precipitate was separated, and the resulting (2S) -N-carboxyethyl-2-phenylglycine-N, N- [ (3S) -3-hydroxytetramethyleneamide was isolated from the filtrate by concentration using a usual experimental method, dissolved in an organic solvent, washed with an aqueous phase, concentrated again and crystallized.

3.b)

From (2S) -N-carboxyethyl-2-phenylglycine (see above) and (3S) -3-hydroxypyrrolidine hydrochloride (commercially available): a mixture of 24g of (2S) -N-carboxyethyl-2-phenylglycine and 10g of methylmorpholine in 100ml of THF is added at about-10 ℃ to 11g of ethyl chloroformate in 100ml of THF. After stirring, a mixture of 12g of (3S) -3-hydroxypyrrolidine hydrochloride in 10ml of deionized water and a mixture of 10g of methylmorpholine in 20ml were added. After stirring for a few hours, the phases are separated and (2S) -N-carboxyethyl-2-phenylglycine-N, N- [ (3S) -3-hydroxytetramethyleneamide is isolated by customary experimental methods by concentration, dissolution in an organic solvent, washing with the aqueous phase, reconcentration and crystallization.

The analytical data for variants 3a and 3b are as follows:

1H-NMR：D₆-DMSO；1.2(t)，3-3.8(m，br)，4.05(q)，4.25(s，br)，7.25-7.45(m)；

MS：293(M+1)⁺，247，178，106；

crystallization m.p.: 124-126 ℃;

[α]D²⁰1 at 137 deg.c, methanol.

N-methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-yl) ethane of formula IV

Example 4

N-methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-yl) ethane ═ 1- [ (3S) -3-hydroxypyrrolidin-1-yl ] - (2S) -2-methylamino-2-phenylethane

2200ml of a 1.08mol lithium aluminum hydride-tetrahydrofuran solution are slowly warmed up under a nitrogen atmosphere and a solution of 264g of (2S) -N-carboxyethyl-2-phenylglycine-N, N- [ (3S) -3-hydroxytetramethyleneamide ] and 1400ml of tetrahydrofuran is added with stirring. After the addition was complete, the mixture was refluxed for 3 hours and the cooled reaction solution was hydrolyzed with a water/tetrahydrofuran mixture. After the sodium carbonate treatment and removal of the inorganic components, the product is separated from the filtrate by customary experimental methods. The oily crude product forms a solid after purification by crystallization or chromatography.

1H-NMR：D₆-DMSO；2.1-3.1(m)，3.6(dd)，4.3(m)，7.15-7.35(m)；

MS：220(M⁺)，205，120，100，91；

Appearance: a yellow oil crystallized from batch to batch;

[α]D²⁰+66.8 °; c-0.0938 g in 10ml methanol.

Example 5

N-methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-yl) ethane dihydrochloride

Salt ═ salt

1- [ (3S) -3-hydroxypyrrolidin-1-yl ] - (2S) -2-methylamino-2-phenylethane dihydrochloride

2200ml of a 1.08mol lithium aluminum hydride-tetrahydrofuran solution are slowly warmed up under a nitrogen atmosphere and a solution of 264g of (2S) -N-carboxyethyl-2-phenylglycine-N, N- [ (3S) -3-hydroxytetramethyleneamide ] and 1400ml of tetrahydrofuran is added with stirring. After the addition was complete, the mixture was refluxed for 3 hours, then cooled and the reaction solution was hydrolyzed with 80ml of water/400 ml of tetrahydrofuran mixture. After the sodium carbonate treatment and removal of the inorganic components, the product is separated from the filtrate by customary experimental methods. The oily crude product is dissolved in an organic, water-immiscible solvent and treated with an excess of hydrochloric acid. The crystalline product is isolated and dried.

1H-NMR：D₆-DMSO；3.4(m)，3.8(m)，4.2(m)，4.4(m)，4.9(m)，7.5 and 7.8(ArH)；

m.p.：240-242℃；

[α]D²⁰-22.4 °; c 1 in water.

Claims (12)

1. Process for the alternative preparation of N-methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-yl) ethyl ] -2, 2-diphenylacetamide or N-methyl-N- [ (1R) -1-phenyl-2- ((3R) -3-hydroxypyrrolidin-1-yl) ethyl ] -2, 2-diphenylacetamide, characterized in that

a) An N-substituted phenylglycine derivative of the following formula (I):

wherein

R isOR¹Or SR¹，

R¹Is A, aryl, heteroaryl, Si (R)³)₃、C(O)R³Or a benzyl group, or a mixture of benzyl groups,

R³is H, A, an aryl or heteroaryl group,

a is a straight or branched alkyl group containing 1 to 6 carbon atoms,

m is H or a cation selected from alkali metal, alkaline earth metal, ammonium or alkylammonium,

with a compound of formula (II) or a salt thereof with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid or an organic carboxylic acid:

wherein

R²Is H, A, aryl, heteroaryl, Si (R)³)₃Or C (O) R³，

R³Is H, A, an aryl or heteroaryl group,

in the formulae (I) and (II), the alkyl group has 1 to 6 carbon atoms, the aryl group is unsubstituted phenyl or phenyl which is mono-or disubstituted by halogen, OA or alkyl, or biphenyl or naphthyl, the heteroaryl group is furyl, thienyl, pyridyl, pyrrolyl or thiazolyl,

to obtain a compound of formula III:

wherein R and R²Has the definition as described above, and the definition,

b) and subsequently reduced to a compound of the following formula (IV):

it is optionally converted into the corresponding acid addition salts of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid or into salts of organic carboxylic acids, and

c) the compound of formula (IV) thus obtained is reacted with an activated carboxylic acid of formula (V) as follows:

wherein R is⁴Is F, Cl, Br, I, OA or O-CO-A,

to obtain a compound of the following formula (VI):

it is optionally converted into the corresponding acid addition salt with an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, orthophosphoric acid, or with an organic acid, the starting materials used in step a) depending on the desired enantiomer of the final product.

2. The process as claimed in claim 1, characterized in that compounds of the formula (I) are used in which R has OR¹Definitions in which R¹Is A, aryl, heteroaryl, Si (R)³)₃Or C (O) R³And R³H, A, aryl or heteroaryl.

3. Process according to claim 1 or 2, characterized in that the reaction of formulae (I) and (II) is carried out in an aprotic solvent at a temperature of 0 to 50 ℃.

4. A process according to claim 3, characterized in that the reaction is carried out in a polar aprotic solvent at a temperature of 20-30 ℃.

5. The process according to claim 1, characterized in that the reaction of compounds (I) and (II) is carried out in a solvent selected from the group consisting of diethyl ether, petroleum ether, acetone, nitrobenzene, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, the starting materials being present in the solvent in a concentration of 10 to 30%.

6. The process as claimed in claim 1, characterized in that the compounds (I) and (II)) Is carried out in the presence of an auxiliary agent selected from the group consisting of phosphorus oxychloride, phosphorus halides of the valences III and V, phosgene, dicyclohexylcarbodiimide, tributylammonium salt of pyridine, phenyl dichlorophosphate, 2-chloro-1, 2, 3-trinitrobenzene, phosphate esters, chlorosulfonyl isocyanate, CH₃SO₂Cl-(C₂H₅)₃N、(C₆H₅)₃P-CCl₄-(C₂H₅)₃N, N, N' -carbonyldiimidazole, N- (alkylcarbonyl) imidazole, acetic anhydride, acetyl chloride and ethyl chloroformate and organic or inorganic bases.

7. Process according to claim 1, characterized in that the reaction of compounds (I) and (II) is carried out in the presence of a base selected from triethylamine, sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide.

8. The process according to claim 1, characterized in that the reduction of the compound of formula (III) is carried out in the presence of a hydride transfer reagent selected from metal alanates, metal alkoxyalanates, metal borohydrides or boranes, in a polar aprotic solvent selected from diethyl ether, petroleum ether, acetone, nitrobenzene, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran.

9. The method of claim 8, characterized in that the metal aluminum hydride is lithium aluminum hydride, the metal alkoxyaluminum hydride is lithium aluminum triethoxy hydride, and the metal borohydride is NaBH₄。

10. Process according to claim 8 or 9, characterized in that the reduction of the compound of formula (III) is carried out in the presence of a lewis acid.

11. A process according to claim 10, characterised in that the lewis acid is boron trifluoride.

12. The process as claimed in claim 1 or 8, characterized in that the compound of the formula (III) is used as starting material dissolved in a solvent in a concentration of 10 to 25%, the hydrogenation product being liberated by addition of a mixture of a protic solvent and an aprotic solvent.