HK1099301A - Method for the production of 3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol derivatives - Google Patents

Description

Process for producing 3-amino-5- (hydroxymethyl) cyclopentane-1, 2-diol derivative

no marking

The subject of the invention is a process for the production of acetals and ketals of 3-amino-5- (hydroxymethyl) cyclopentane-1, 2-diol and their derivatives and organic acid salts, e.g. 2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentane-1-amine hydrogen oxalate, from 2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one of formula II.

And/or mirroring

Enantiomerically pure compounds are hereinafter referred to as enantiomeric mixtures with an enantiomeric excess (ee) of at least 90%.

C_1-6Alkyl means hereinafter a straight-chain or branched aliphatic alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl.

C_3-8Cycloalkyl means in the following an alicyclic alkyl group having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

Alcoholic solutions or suspensions refer hereinafter to solutions or suspensions of at least one organic compound in any mixture of ethanol, methanol, propanol, isopropanol, n-butanol, isobutanol and/or tert-butanol, which may be mixed with water and/or other solvents, solubilizers or other auxiliaries.

Depending on the composition of the starting materials, the process is likewise suitable for preparing enantiomerically pure compounds or enantiomeric mixtures of any composition. In each case, an enantiomer not depicted is intended to be included in the description of the structural formulae by the addition of "and/or mirror image" or mirror image "or like supplementary indications.

Substituted cyclopentylamines, such as (1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-amin-e hydrochloride, are intermediates for the preparation of pharmaceutically active adenosine derivatives which are useful, inter aliA, in the treatment of coronary perfusion injury, heart failure and hypertension (US-A-5364862 and WO-A-95/28160).

In one known process for the preparation of (1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-amine hydrochloride (WO-A-98/01426 and WO-A-00/23447) (-) -5, 6-isopropylidenedioxy-2-azabicyclo [2.2.1] heptan-3-one is converted into the corresponding protected N-BOC derivative using the very expensive and hydrolytically sensitive di-tert-butyl dicarbonate. WO-A-95/28160 discloses the synthesis of precursors (compounds of the general formulA vi) starting from 5, 6-dihydroxy-2-azabicyclo [2.2.1] heptan-3-one. After cleavage of the lactam, if appropriate, the newly formed hydroxyl group is subsequently methylated and the BOC protecting group is removed using HCl gas. The hydrochloride salts are obtained in this process, but their purity, yield or physicochemical properties are not described. The material obtained was used directly in the next synthesis step without further work-up.

The processes disclosed in the prior art for preparing (1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-amine hydrochloride have disadvantages which prevent the industrial implementation of the process. It is therefore an object of the present invention to provide an economical process for the preparation of acetals and ketals of 3-amino-5- (hydroxymethyl) cyclopentane-1, 2-diol, and their derivatives and salts of organic acids which can be carried out industrially.

The object of the invention is achieved in a process according to claim 1 starting from 2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one.

The process according to the invention makes it possible in particular to prepare enantiomerically pure hydrogen oxalates of (1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-1-amine and of (1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-amine.

The process of the invention may be carried out with (-) -2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one or (+) -2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one, and mixtures thereof.

The compound 2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one is disclosed in WO-A-00/03032 as A mixture of enantiomers and (-) -2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one in enantiomerically pure form.

By using acetylated lactams, the process of the invention is sufficiently simple to use conventional, low-cost protecting group technology. The advantage of using acetyl protecting groups in the process of the invention is the simplification of the operation, in particular compared to the BOC protecting groups used in the prior art.

Acetyl groups can easily be removed again in the alkaline hydrolysis step, however the process in WO-A-98/01426 requires the use of HCl gas to remove the protecting groups. The method of the present invention represents A substantial improvement over the method of WO-A-98/01426, which generates large amounts of NaCl waste and requires significant expense to protect the system and lines from corrosion.

It has been found that the cyclic acetals and ketals of dihydroxycyclopentylamine of formula I prepared by the process of the present invention can be advantageously precipitated as the hydrogen oxalate salt, which is a substantial improvement in operation (filtration, centrifugation) over the hydrochloride salts previously disclosed.

And/or mirroring

The salts prepared by the process of the invention, for example (1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-aminehydroxyhydrogen oxalate, can in principle be obtained from the corresponding hydrochloride salts by ion exchange and reprecipitation. However, the above salts are not obtained as direct hydrolysis products of the N-BOC compounds mentioned in WO-A00/23447, since the BOC protecting group must first be removed with a strong acid. Furthermore, it is disadvantageous to reprecipitate the HCl-acid salt with an organic acid.

A process for preparing the compound of formula I is described below

And/or mirroring

Wherein R is¹Is hydrogen, C_1-6Alkyl radical, C_3-8-cycloalkyl or benzyl, and wherein i) R²Is methyl and R³Is an ethyl group; ii) R²Is hydrogen, and R³Is C_1-6-alkyl or phenyl or iii) R²And R³Together are of the formula- (CH)₂)_n-wherein n-4-6 and is present in the form of a free amine or a salt of a di-or tri-basic organic acid.

For this purpose, in a first reaction step, the 2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one of the formula II is converted by cis-hydroxylation of the double bond into 2-acetyl-5, 6-dihydroxy-2-azabicyclo [2.2.1] hept-3-one of the formula III

And/or mirroring

And/or mirroring.

In a second reaction step by reaction with a compound of the formula R²-CO-R³Or with 2, 2-dimethoxypropane or 2, 2-dimethoxybutane to convert the compound of formula III into an acetal or ketal of formula IV,

and/or mirroring

In the formula, R²And R³Have the meaning indicated.

In a subsequent reaction step, the compound of the formula IV is converted into a compound of the formula V by reductive ring opening,

and/or mirroring

In the formula, R²And R³Have the meaning indicated.

In a subsequent optional reaction step, by reaction with an alkylating agent, for example dimethyl sulfate (DMS), benzyl chloride or compounds of the formula R¹Halide of-X (wherein R is¹Having the stated meaning other than hydrogen, X is bromine or iodine) to convert the alcohols of the formula V or their alcoholates, if appropriate, into ethers of the formula VI, R in the formula V²And R³Has the meaning as indicated above and which is,

and/or mirroring

In the formula, R²And R³Have the meaning indicated.

In a further reaction step, one of the compounds obtained in the first two reaction steps is converted into a compound of the formula I by alkaline hydrolysis

And/or mirroring

In the formula, R¹、R²And R³Have the meaning indicated.

In the following optional final reaction stepIn the process, the compounds of the general formula I are reacted with binary or ternary organic acids to give the corresponding salts, in which R is¹、R²And R³Have the meaning indicated.

In order to increase the conversion and to save oxidizing agents before cis-hydroxylation, preference is given to using 2-acetyl-2-azabicyclo [2.2.1] compounds from the reaction mixture by extraction]The interfering compounds are advantageously removed in the synthesis of hept-5-en-3-one. For example, the common impurity 4-Dimethylaminopyridine (DMAP) can be obtained by treatment with dilute aqueous acid, such as dilute HCl or H₂SO₄Acid extraction is performed to remove.

In a preferred embodiment, the cis hydroxylation of the double bond is carried out using an inorganic oxidizing agent, for example osmium tetraoxide, potassium osmate or potassium permanganate.

Because of the toxicity and volatility of osmium tetroxide, in a more preferred embodiment, hydroxylation is carried out using 2-10% aqueous solutions of osmium tetroxide or osmium tetroxide immobilized on an organic or inorganic support.

In a particularly preferred embodiment, osmium tetroxide is used in an amount of from 0.1 to 2 mol%, more preferably from 0.2 to 0.9 mol%, based on the amount of 2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one.

Osmium tetroxide can advantageously be regenerated in the reaction in the presence of at least one organic N-oxide, for example N-4-methylmorpholine N-4-oxide, and/or a secondary or tertiary amine, and at least one inorganic oxidizing agent, for example hydrogen peroxide. Suitable as co-oxidants for the regeneration of osmium tetroxide in the course of the reaction are sterically bulky N-oxides, such as N-4-methylmorpholine N-4-oxide, di-and trialkylamine N-oxides, such as trimethylamine N-oxide, or mixtures of the described secondary and tertiary amines with organic or inorganic oxidants, such as tert-butyl hydroperoxide, magnesium monoperoxyphthalate, 3-chloroperbenzoic acid, hydrogen peroxide, sodium and/or potassium perchlorate, periodate, permanganate. Particular preference is given to using N-oxides and mixtures of the amines with hydrogen peroxide.

In a particularly preferred process, enantiomerically pure (-) -2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one is converted by cis-hydroxylation with osmium tetroxide into (1R, 4S, 5R, 6S) -2-acetyl-5, 6-dihydroxy-2-azabicyclo [2.2.1] hept-3-one of the general formula III

In another preferred method, the formation of acetals or ketals is carried out with acid catalysis.

In another particularly preferred process, sulfuric acid and/or p-toluenesulfonic acid is used for acid catalysis.

In a preferred process, 2-acetyl-5, 6-dihydroxy-2-azabicyclo [2.2.1] of the formula III is reacted by reaction with acetone or 2, 2-dimethoxypropane]Conversion of hept-3-one to 8-acetyl-4, 4-dimethyl-3, 5-dioxa-8-azatricyclo [5.2.1.0 ] of formula IVa^2，6]Decan-9-ones

And/or mirroring.

In a particularly preferred variant of the process, (1R, 4S, 5R, 6S) -2-acetyl-5, 6-dihydroxy-2-azabicyclo [2.2.1] by reaction with acetone or 2, 2-dimethoxypropane]Conversion of hept-3-one to (1S, 2R, 6S, 7R) -8-acetyl-4, 4-dimethyl-3, 5-dioxa-8-azatricyclo [5.2.1.0^2，6]Decan-9-one (IVa).

In another preferred method, coordination (complex) metal hydrides, such as LiBH, are used₄、NaBH₄、NaAlH₂(OCH₂CH₂OCH₃)₂Or LiAlH₄Preferably with NaBH₄And (4) carrying out reduction ring opening.

In another preferred method, byReaction of complex metal hydride with (1S, 2R, 6S, 7R) -8-acetyl-4, 4-dimethyl-3, 5-dioxa-8-azatricyclo [5.2.1.0 ]^2，6]Conversion of decan-9-one to (1R, 2S, 3R, 4R) -N- [2, 3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-1-yl radical of the formula Va]Acetamide

In a preferred variant of the process, the ethers of the formula VI (in which R is¹Is methyl) is carried out in the presence of strong bases, such as NaOH and/or KOH, with DMS in acetone, particularly preferably with a water content of less than 1%, based on the solvent.

In another preferred variant of the process, C is used_1-6-alkyl or C_3-8-cycloalkyl halides in the presence of AgOH for ether formation.

In a particularly preferred process (1R, 2S, 3R, 4R) -N- [2, 3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-1-yl ] acetamide is converted into (1R, 2S, 3R, 4R) -N- [2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-yl ] acetamide by reaction with DMS or methyl iodide

In a preferred variant of the process, at least one compound selected from the group consisting of LiOH, NaOH, KOH, Mg (OH) is used₂、Ca(OH)₂And Ba (OH)₂Is subjected to alkaline hydrolysis in aqueous and/or alcoholic solution or suspension of alkali metal or alkaline earth metal hydroxide.

In a preferred variant of the process, the alkaline hydrolysis is carried out at a pressure of from 1 to 10 bar, particularly preferably from 1 to 2 bar, and a temperature of from 50 to 150 ℃, particularly preferably from 80 to 100 ℃.

In a particularly preferred variant of the process, the alkaline hydrolysis is carried out with a solution of NaOH and/or KOH in methanol and/or ethanol at a pressure of 1 to 2 bar and a temperature of 80 to 100 ℃.

In a preferred process, the alkaline hydrolysis is carried out using a methanol and/or ethanol solution of NaOH and/or KOH, preferably at a pressure of 1 to 2 bar and a temperature of 80 to 100 ℃,

conversion of i) (1R, 2S, 3R, 4R) -N- [2, 3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-1-yl ] acetamide into (1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-1-amine or

Ii) (1R, 2S, 3R, 4R) -N- [2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-yl ] acetamide to (1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-amine

In a preferred variant of the process, the formation of the salt in the optional last reaction step is carried out using an organic acid selected from oxalic acid free of or containing water of crystallization, (+) -, (-) -or meso-tartaric acid, (+) -or (-) -malic acid, tartronic acid, pyruvoic acid and oxaloacetic acid.

In a further particularly preferred variant of the process, the compounds (1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-1-amine or (1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-amine are converted into the corresponding hydrogen oxalate.

The invention also relates to compounds of the formula III

Or mirror image.

Similarly, the invention also includes compounds of formula IV

Or mirror image

Wherein R is²And R³Have the meaning indicated above.

The invention also includes compounds of formula VI

Or mirror image

Wherein R is¹Have the stated meaning, including hydrogen, and R²And R³Have the meaning indicated above.

The invention also includes salts of dibasic and tribasic organic acids of the compounds of formula I

Or mirror image

In the formula, R¹、R²And R³Have the meaning indicated above.

Examples

Although the invention is fully disclosed by the exemplified examples 1-18, many other examples are possible, as the parameters of the process of the invention may vary. The embodiments that carry out these variations, as defined in the description and in the claims, are considered to be embodiments of the invention and to fall within the scope of protection of the present patent application.

Example 1

(1R, 4S, 5R, 6S) -2-acetyl-5, 6-dihydroxy-2-azabicyclo [2.2.1] heptan-3-one (general formula III)

132.1g (0.87mol) (-) -2-acetyl-2-azabicyclo [2.2.1]Hept-5-en-3-one and 118.1g (0.87mol) N-4-methylmorpholine N-4-oxide H₂O was added to 750ml acetone, 224ml deionized water and 75ml t-butanol. The reaction mixture was warmed to 30 ℃. A solution of 2.0g (7.9mmol) of osmium tetroxide in 10ml of acetone is added dropwise over 15 minutes, and the reaction mixture is stirred for 2 hours at 30 ℃. The reaction solution was then cooled to 10 ℃ and 180.1g (0.69mol) of a 40% sodium hydrogensulfite solution were then added over a period of 1 hour to remove excess N-4-methylmorpholine N-4-oxide and osmium tetroxide. The reaction mixture was then adjusted to pH7 with 35.1g of concentrated sulfuric acid. The resulting suspension was filtered and the material on the filter was washed with 20ml of acetone. The filtrate was concentrated to 350-400ml under vacuum (40-400 mbar) at 40 ℃. The reaction solution was cooled to 20 ℃. The aqueous phase was adjusted to pH 2 with 12.9g of concentrated sulfuric acid, and after separation, it was extracted with ethyl acetate (5X 400 ml). The combined organic phases were evaporated to dryness. The resulting residue was dried under high vacuum overnight.

Yield: 81.6g (0.44mol) of (1R, 4S, 5R, 6S) -2-acetyl-5, 6-dihydroxy-2-azabicyclo [2.2.1] hept-3-one, about 50% based on (-) -2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one.

¹H-NMR (300MHz) in CDCl₃The method comprises the following steps: δ 4.89(2H, s (broad peak); 4.57(1H, m); 4.17(1H, m); 4.01(1H, m); 2.83(1H, m); 2.39(3H, s); 2.14(1H, m); 1.92(1H, m).

Example 2

(1S, 2R, 6S, 7R) -8-acetyl-4, 4-dimethyl-3, 5-dioxa-8-azatricyclo [5.2.1.0^2，6]Decan-9-ones (formula IVa ═ formula IV, where R is²＝R³Armenine methyl

72.2g (0.39mol) of (1R, 4S, 5R, 6S) -2-acetyl-5, 6-dihydroxy-2-azabicyclo [2.2.1] heptan-3-one, 49.8g (0.47mmol) of 2, 2-dimethoxypropane and 1.48g (7.8mmol) of p-toluenesulfonic acid were added to 145ml of ethanol. The clear brown solution was heated to 50 ℃ and stirred at 50 ℃ for 2 hours, cooled to 0 ℃ over 30 minutes and then mixed with 50ml of methanol. The brown suspension was stirred at 0 ℃ for 1 hour. The precipitated crystals were filtered off and washed with 25ml of ethanol. The moist product was dried under vacuum at 40 ℃.

Yield: 53.0g (0.24mol) (1S, 2R, 6S, 7R) -8-acetyl-4, 4-dimethyl-3, 5-dioxa-8-azatricyclo [5.2.1.0^2，6]Decan-9-one, about 56% as (1R, 4S, 5R, 6S) -2-acetyl-5, 6-dihydroxy-2-azabicyclo [2.2.1]]Hept-3-one meter.

¹H-NMR (300MHz) in CDCl₃The method comprises the following steps: δ 4.74(1H, m); 4.56(1H, m); 4.43(1H, m); 2.94(1H, m); 2.41(3H, s); 2.16(1H, m); 1.95(1H, m); 1.49(3H, s); 1.34(3H, s).

Example 3

(1R, 2S, 3R, 4R) -N- [2, 3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentyl]Acetamide (formula Va ═ formula V, where R²＝R³Armenine methyl

18.0g (0.08mol) of (1S, 2R, 6S, 7R) -8-acetyl-4, 4-dimethyl-3, 5-dioxa-8-azatricyclo [5.2.1.0^2，6]Decan-9-one was added to 250ml methanol and the clear colorless solution was cooled to 0 ℃. 6.6g (0.17mol) of sodium borohydride are added in portions over a period of 1 hour, so as to maintain the temperature below 5 ℃.

The reaction mixture was then warmed to 20 ℃ over 30 minutes and stirred at 20 ℃ for 15 hours. Next, 17.5g of acetic acid was added dropwise over 10 minutes, and the reaction mixture was stirred for another 10 minutes and then evaporated to dryness. The residue (44.8g) was dissolved in 100ml of ethyl acetate and stirred for about 10 minutes. The crystals precipitated were filtered off and washed with ethyl acetate (2X 20 ml). The filtrate was evaporated and dried under high vacuum. The crude product (21.3g) was purified by column chromatography on silica gel (mobile phase ethyl acetate/methanol (5: 1)).

Yield: 18.4g (0.08mmol) (1R, 2S, 3R, 4R) -N- [2, 3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-1-yl)Acetamide, about 100%, with [1S, 2R, 6S, 7R ]]-8-acetyl-4, 4-dimethyl-3, 5-dioxa-8-azatricyclo [5.2.1.0^2，6]Decyl-9-one meter.

¹H-NMR (300MHz) in CDCl₃The method comprises the following steps: δ 7.51(1H, d); 4.60(1H, m); 4.37(1H, m); 4.34(1H, m); 4.0(1H, s, broad); 3.86(1H, dd); 3.67(1H, dd); 2.52(1H, m); 2.33(1H, m); 1.94(3H, s); 1.49(1H, m); 1.46(3H, s); 1.28(3H, s).

Example 4

(1R, 2S, 3R, 4R) -N- [2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-yl) acetamide (formula IVa ═ formula IV, wherein R is¹＝R²＝R³Armenine methyl

31.2g (0.14mol) of (1R, 2S, 3R, 4R) -N- [2, 3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-1-yl ] acetamide and 5.4g of sodium hydroxide solution (40% strength) are added to 250ml of acetone and heated to 50 ℃. In parallel, 20.2g (0.16mol) of dimethyl sulfate and 5.7g of sodium hydroxide solution (40% strength) were added dropwise at 50 ℃ over 90 minutes. The reaction mixture was stirred at 50 ℃ for a further 3 hours and then concentrated in vacuo to a volume of about 90 ml. The residue was mixed with 54ml of water and 100ml of ethyl acetate and stirred for 30 minutes. The phases were separated and the aqueous phase was extracted with ethyl acetate (2X 70 ml). The combined organic phases were evaporated to dryness.

The crude product (31.5g) was purified by distillation (bp 120-.

Yield: 16.9g (0.07mol) of (1R, 2S, 3R, 4R) -N- [2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-yl ] acetamide, about 51% based on (1R, 2S, 3R, 4R) -N- [2, 3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-1-yl ] acetamide.

¹H-NMR (300MHz) in CDCl₃The method comprises the following steps: δ 6.83(1H, d); 4.52(1H, m); 4.37(1H, m); 4.34(1H, m); 3.55(1H, dd); 3.42(1H, dd); 3.41(3H, s); 2.53(1H, m); 2.34(1H, m); 1.93(3H, s); 1.45(3H, s); 1.42(1H, m); 1.27(3H, s).

Example 5

(1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-amine (formula Ia ═ formula I, where R is¹＝R²＝R³Armenine methyl

2.34g (0.01mol) of (1R, 2S, 3R, 4R) -N- [2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-yl]Acetamide and 1.5ml Ba (OH)₂·H₂A suspension of 0 (30% strength in water) in 1.2ml of water is stirred at reflux for 22 hours at 100 ℃. The suspension is cooled to 20 ℃, mixed with 50ml of toluene and filtered. The phases were separated and the aqueous phase was extracted with toluene (2X 50 ml). The combined organic phases were evaporated to dryness.

Yield: 1.5g (7.5mmol) of (1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-ylamine, as a yellow liquid, are approximately 75% based on (1R, 2S, 3R, 4R) -N- [2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-yl ] acetamide.

¹H-NMR (300MHz) in CDCl₃The method comprises the following steps: δ 4.48(1H, dd); 4.19(1H, dd); 3.43(2H, d); 3.37(1H, m); 3.36(3H, s); 2.30(1H, m); 2.24(1H, m); 1.47(3H, s); 1.43(2H, s, broad); 1.33(1H, m); 1.29(3H, s).

Example 6

(1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-amin-e hydrogen oxalate (salts of compounds of the general formula I, wherein R¹＝R²＝R³Armenine methyl

17.0g of anhydrous oxalic acid (0.19mol) are added in portions to a solution of 42.1g (0.21mol) of (1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-amine in 107ml of ethanol at 25 ℃. The reaction solution was stirred at 25 ℃ for 30 minutes. 430ml of acetone and 55ml of heptane are then added in succession, followed by cooling to 0 ℃ and stirring for a further 60 minutes at 0 ℃. The crystals which separated out were filtered off and washed with 110ml of heptane. The residue on the filter was dried under vacuum at 40 ℃.

Yield: 42.7g (0.15mol) of (1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-amin-e hydrogen oxalate, about 70% based on (1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-amine.

¹H-NMR(300MHz)in DMSO-d₆: δ 8.73(4H, s, broad); 4.50(1H, m); 4.40(1H, m); 3.36(3H, m); 3.27(3H, s); 2.23(2H, m); 1.57(1H, m); 1.42(3H, s); 1.23(3H, s).

Example 7

(1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-1-amine (formula Ia ═ formula I, where R is¹＝H，R²＝R³Armenine methyl

A solution of 3.5g (15.3mmol) (1R, 2S, 3R, 4R) -N- [2, 3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-1-yl ] acetamide in 25ml ethanol and 7.8g of 50% strength sodium hydroxide solution are heated in a reaction vessel at 100 ℃ and 2 bar for 15.5 hours. The reaction mixture was cooled to room temperature. The orange suspension is then dissolved in 30ml of ethanol and evaporated to dryness under vacuum. The residue was mixed with 10ml of water and evaporated to dryness under vacuum. The residue was then extracted with methyl tert-butyl ether (MTBE) (2X 10ml) and the combined organic phases were evaporated to dryness in vacuo.

Yield: 2.2g (11.7mmol) of (1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-1-ylamine, approx.76%, based on (1R, 2S, 3R, 4R) -N- [2, 3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-1-yl ] acetamide.

¹H-NMR (300MHz) in CDCl₃The method comprises the following steps: δ 4.78(1H, d); 4.22, (1H, d); 3.72(1H, dd); 3.55(1H, dd); 3.53(1H, m); 2.44(2H, m); 1.44(3H, s); 1.30(1H, m); 1.29(3H, s).

Example 8

(1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentane-1-Amine hydrogen oxalate (salts of compounds of formula I, wherein R¹＝H，R²＝R³Armenine methyl

0.48g (5.3mmol) of oxalic acid and ethanol (2X 3ml) are added portionwise, with stirring, to a solution of 1.0g (5.3mmol) of (1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-1-amine in 3ml of ethanol. The white precipitate was filtered off and dried under vacuum at room temperature.

Yield: 1.0g (3.7mmol) of (1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-1-amin-e hydrogen oxalate, about 70% based on (1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-1-amine.

¹H-NMR(300MHz)in DMSO-d₆: δ 6.95(5H, s, broad); 4.46(2H, m); 3.52(1H, dd); 3.20(2H, m); 2.26(1H, m); 2.17(1H, m); 1.57(1H, m); 1.40(3H, s); 1.23(3H, s).

Example 9

(1SR, 2RS, 6SR, 7RS) -8-acetyl-4, 4-dimethyl-3, 5-dioxa-8-azatricyclo [5.2.1.0^2，6]Decan-9-ones (formula IVa ═ formula IV, where R is²＝R³Armenine methyl

A mixture of 72.2g (0.39mol) (1SR, 4SR, 5RS, 6SR) -2-acetyl-5, 6-dihydroxy-2-azabicyclo [2.2.1] heptan-3-one and 49.8h (0.47mol)2, 2-dimethoxypropane and 1.48g (7.8mmol) 4-toluenesulfonic acid monohydrate in 145ml ethanol was heated at 50 ℃ for 90 minutes. The reaction mixture was then cooled to 0 ℃ over 30 minutes and stirred for a further 75 minutes. The precipitated crystals were filtered off, washed with 25ml of ethanol and dried at 40 ℃ and 30 mbar.

Yield: 53.0g (0.24mol) (1SR, 2RS, 6SR, 7RS) -8-acetyl-4, 4-dimethyl-3, 5-dioxa-8-azatricyclo [5.2.1.0^2，6]Decan-9-one, about 60% (1SR, 4SR, 5RS, 6SR) -2-acetyl-5, 6-dihydroxy-2-azabicyclo [2.2.1]]A group of heptan-3-ones,¹H-NMR(CDCl₃) And (5) the consistency is achieved.

Example 10

(1RS, 2SR, 3RS, 4RS) -N- [2, 3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-1-yl]Acetamide (formula Va ═ formula V, where R²＝R³Armenine methyl

17.7g (79mmol) (1SR, 2RS, 6SR, 7RS) -8-acetyl-4, 4-dimethyl-3, 5-dioxa-8-azatricyclo [5.2.1.0^2，6]Solution of decan-9-one in 250ml methanol in N₂Cooling to about 0 ℃ under an atmosphere. 6.6g (175mmol) of sodium borohydride were added portionwise over a period of 1 hour, so that the temperature was kept below 5 ℃. The reaction mixture is stirred at room temperature overnight, mixed with a solution of 17.5g of acetic acid in 20ml of methanol and dried under vacuum at 30-35 ℃. The residue was dissolved in 100ml of ethyl acetate and the white suspension was stirred for 10 minutes and then filtered. The residue on the filter was washed with ethyl acetate (2X 20 ml). The combined filtrates were evaporated to dryness and then dried under high vacuum. (yield: 21.3g of crude product as a viscous yellow oil). 15.0g of the crude product are chromatographed on silica gel 60 with ethyl acetate/methanol (5: 1, vol.: vol.).

Yield: 18g (1RS, 2SR, 3RS, 4RS) -N- [2, 3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-1-yl]Acetamide (79mmol) as a viscous yellow oil, ca.100% as (1SR, 2RS, 6SR, 7RS) -8-acetyl-4, 4-dimethyl-3, 5-dioxa-8-azatricyclo [5.2.1.0^2，6]The content of the decyl-9-ketone is measured,¹H-NMR(CDCl₃) And (5) the consistency is achieved.

Example 11

(1RS, 2SR, 3RS, 4RS) -N- [2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-yl ] acetamide

(formula VIa ═ formula VI where R¹＝R²＝R³Armenine methyl

11.5g (50mmol) (1RS, 2SR, 3RS, 4RS) -N- [2, 3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-1-yl ] acetamide in 150ml acetone and 2.1g 40% strength sodium hydroxide solution are heated to about 50 ℃. 7.7g (61mmol) of dimethyl sulfate and 9.9g of 40% strength sodium hydroxide solution are added in parallel at 50 ℃ over the course of 90 minutes. The reaction mixture was stirred at 50 ℃ for a further 3.5 hours and then concentrated under vacuum to about 30 ml. After cooling to about 20 ℃ 20ml of water and 40ml of MTBE were added. The phases were separated and the aqueous phase was extracted with MTBE (2X 25 ml). The combined organic phases were evaporated to dryness to give 11.5g of crude product.

Yield: 11.5g (47mmol) (1RS, 2SR, 3RS, 4RS) -N- [2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-yl]Acetamide as a reddish brown oil (about 94% as (1RS, 2SR, 3RS, 4RS) -N- [2, 3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-1-yl)]An acetamide meter),¹H-NMR(CDCl₃) And (5) the consistency is achieved.

Example 12

Pre-purification: extraction of (-) -2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one (general formula II)

30l of water are introduced into a 630l stirring apparatus (enameled steel) and 8.35kg of hydrochloric acid (technical grade, 32% strength) are added. 3.7kg of sodium chloride and 150kg of (-) -2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one (89% purity) are then added to the reactor. The mixture was gently stirred at room temperature (experience shows that if the stirring speed is too fast an emulsion will form). After 30 minutes, the stirrer was switched off and after a further 30 minutes the phases were easily separated. The resulting, purified (-) -2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one is used immediately after extraction for the preparation of (1R, 4S, 5R, 6S) -2-acetyl-5, 6-dihydroxy-2-azabicyclo [2.2.1] hept-3-one.

Yield: about 133kg of (-) -2-acetyl-2-azabicyclo [2.2.1]Hept-5-en-3-one (about 100%,¹H-NMR(CDCl₃) And (5) the consistency is achieved.

Example 13

(1R, 4S, 5R, 6S) -2-acetyl-5, 6-dihydroxy-2-azabicyclo [2.2.1] heptan-3-one (general formula III)

250kg of an aqueous solution (50% strength) of N-4-methylmorpholine N-4-oxide, 132l of water and 68kg of tert-butanol are introduced into a 2500l stirring apparatus (stainless steel) and 830l of acetone are added. To this mixture was added 20kg of an 4% strength aqueous osmium tetroxide solution at room temperature. 150kg of (-) -2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one are then added within 1 hour, so that the vessel temperature does not exceed 30 ℃ to 35 ℃ and stirring is continued for 1 hour. The residual (-) -2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one content is less than 0.2%, 58kg of aqueous sodium bisulfite solution (40% strength) are added within 1 hour at 10-50 ℃. The reaction solution was then adjusted to pH 5 with sulfuric acid (20% strength) at a temperature of 10-18 ℃.

The residue was centrifuged and washed with acetone (2X 20 l). The mother liquor and the washings were combined and concentrated by distilling off acetone, tert-butanol and water at 200-300 mbar and a temperature below 45 ℃. The reaction mixture was cooled to 20 ℃ and adjusted to pH 2 with sulfuric acid (20% strength) at 12-20 ℃. It is then extracted with ethyl acetate (4X 670l) and the combined organic phases are concentrated at from 30 to 200 mbar and a temperature below 45 ℃. The distillation was stopped when the internal temperature was above 45 ℃ at 30-50 mbar and the residue was mixed with 620 l of methanol. At 200 mbar and an internal temperature of 30 ℃ ethyl acetate and methanol were distilled until the total volume was 400 l. The reaction solution was cooled to room temperature and then used directly for the next step for the preparation of [1S, 2R, 6S, 7R ]]-8-acetyl-4, 4-dimethyl-3, 5-dioxa-8-azatricyclo [5.2.1.0^2，6]Decan-9-one.

Yield about 59% (1R, 4S, 5R, 6S) -2-acetyl-5, 6-dihydroxy-2-azabicyclo [2.2.1]A group of heptan-3-ones,¹H-NMR(CDCl₃) And (5) the consistency is achieved.

Example 14

(1S, 2R, 6S, 7R) -8-acetyl-4, 4-dimethyl-3, 5-dioxa-8-azatricyclo [5.2.1.0^2，6]Decan-9-ones (formula IVa ═ formula IV, where R is²＝R³Armenine methyl

21kg of toluene-4-sulfonic acid monohydrate are introduced into a 2500l stirring apparatus (stainless steel), and 1240kg of (1R, 4S, 5R, 6S) -2-acetyl-5, 6-dihydroxy-2-azabicyclo [2.2.1] are added at room temperature]Heptan-3-one solution (ca. 19% concentrated)Degree) and 250kg2, 2-dimethoxypropane. The reaction solution was heated at 50 ℃ for 1 hour, then cooled to 35 ℃ and 1200l of methanol was added. After addition of methanol, (1S, 2R, 6S, 7R) -8-acetyl-4, 4-dimethyl-3, 5-dioxa-8-azatricyclo [5.2.1.0 ] is measured^2，6]Content of decan-9-one, pouring the solution into a container, and diluting with methanol for preparing (1R, 2S, 3R, 4R) -N- [2, 3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-1-yl]An acetamide.

Yield: 195kg (1S, 2R, 6S, 7R) -8-acetyl-4, 4-dimethyl-3, 5-dioxa-8-azatricyclo [5.2.1.0^2，6]Decan-9-one (about 68% as (1R, 4S, 5R, 6S) -2-acetyl-5, 6-dihydroxy-2-azabicyclo [2.2.1]]The content of the hepta-3-ketone is measured,¹H-NMR(CDCl₃) And (5) the consistency is achieved.

Example 15

(1R, 2S, 3R, 4R) -N- [2, 3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-1-yl]Acetamide (formula Va ═ formula V, where R²＝R³Methyl group) without isolation

1323kg of (1S, 2R, 6S, 7R) -8-acetyl-4, 4-dimethyl-3, 5-dioxa-8-azatricyclo [ 5.2.1.0)^2，6]The methanolic solution of decan-9-one (about 5.3%) was added to a 2500l stirring apparatus (stainless steel) and cooled to about 5 ℃.46 kg of sodium borohydride, 3 to 5kg each, were added in 12 portions over about 4 hours so that the internal temperature of the stirrer did not exceed 10 ℃. After the addition was complete, the reaction mixture was warmed to about 20 ℃ and stirred for 1 hour, then 53l NaOH (30% strength) was added. Methanol was repeatedly distilled off under vacuum, and deionized water was added thereto. 780l of acetone were then added to the aqueous solution. After removal of the aqueous phase, (1R, 2S, 3R, 4R) -N- [2, 3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-1-yl]The acetamide solution is used for preparing (1R, 2S, 3R, 4R) -N- [2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-yl without isolation]An acetamide.

Example 16

(1R, 2S, 3R, 4R) -N- [2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-yl]Acetyl groupAmines (formula VIa ═ formula VI, where R is¹＝R²＝R³Methyl group) without isolation

70kg of sodium hydroxide were added to 484kg of a solution of (1R, 2S, 3R, 4R) -N- [2, 3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-1-yl ] acetamide in acetone (ca. 15% strength), and the mixture was stirred at 25 ℃ for 30 minutes. After 30 minutes of phase settling, the aqueous phase was removed. After a further 30kg of 30% strength sodium hydroxide solution were added, the mixture was heated to 50 ℃ and then 123kg of dimethyl sulfate (DMS) and 30% strength sodium hydroxide solution were added in parallel within 75 minutes, so that the pH was maintained at 11-13 at an internal temperature of 50 ℃. The reaction solution was then stirred for 15 minutes and then cooled to room temperature. After 30 minutes of phase settling, the aqueous phase was removed. The acetone was distilled off under vacuum until the residual amount was 500l and the (1R, 2S, 3R, 4R) -N- [2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-yl ] acetamide solution was cooled to 25 ℃ and directly reacted further to give (1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-amine.

The yield was not determined and the solution was used directly for the preparation of (1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-amine.¹H-NMR(CDCl₃) And (5) the consistency is achieved.

Example 17

(1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-amine (formula Ia ═ formula I, where R is¹＝R²＝R³Armenine methyl

460kg of (1R, 2S, 3R, 4R) -N- [2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-yl]An acetone solution of acetamide (ca. 13.6% strength) was added to a 630l stirring apparatus (stainless steel). Acetone was distilled off at 30-300 mbar and a temperature below 45 ℃ until the acetone content was below 0.1%, 400l of ethanol were added to the reaction mixture. Then, 126kg of sodium hydroxide solution (50% strength) were added at room temperature and the hydrolysis was carried out for 8 hours at about 100 ℃ and 2 bar. The reaction solution was cooled to room temperature and distilled off at 100 mbar and a temperature below 45 ℃And (4) removing ethanol. The residue was mixed with 180l of water and the remaining amount of ethanol was distilled off. After distillation, about 270l of reaction mixture were present in the reactor, mixed with 140l of water and then extracted with MTBE (2X 145 l). The combined organic phases were used directly for the preparation of (1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-amin-e hydrogen oxalate. (1R, 2S, 3R, 4R) -N- [2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-yl]The conversion of acetamide to (1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-amine was > 96.5%.¹H-NMR(CDCl₃) And (5) the consistency is achieved.

Example 18

(1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-amin-e hydrogen oxalate (salt of compound of general formula I, wherein R is¹＝R²＝R³Armenine methyl

The (1S, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-amine solution described in example 5 was added over the course of 30 minutes to 23.3kg of oxalic acid and 210 l of ethanol in a 630l stirring apparatus (enameled steel). After 60% addition, a small amount of (1R, 2S, 3R, 4R) -2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-amin-e hydrogen oxalate was added to seed the solution. The precipitated product was separated by centrifugation and washed with MTBE/ethanol (60: 40) (2X 120 l).

Yield: 56kg (1R, 2S 3R 4R) -2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-amin-e hydrogen oxalate (about 78% in the form of (1R, 2S, 3R, 4R) -N- [2, 3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-yl]An acetamide meter),¹H-NMR(CDCl₃) And (5) the consistency is achieved.

Claims (18)

1. A process for the preparation of a compound of formula I

And/or mirroring

Wherein R is¹Is hydrogen, C_1-6Alkyl radical, C_3-8-cycloalkyl or benzyl, and wherein i) R²Is methyl and R³Is an ethyl group; ii) R²Is hydrogen, and R³Is C_1-6-alkyl or phenyl or iii) R²And R³Together are of the formula- (CH)₂)_n-wherein n-4-6 and is present in the form of a free amine or a salt of a di-or tri-basic organic acid, characterized in that 2-acetyl-2-azabicyclo [2.2.1] of formula II is hydroxylated by cis-hydroxylation of the double bond]Conversion of hept-5-en-3-one to 2-acetyl-5, 6-dihydroxy-2-azabicyclo [2.2.1] of formula III]A group of heptan-3-ones,

and/or mirroring

And/or a mirror image of the image,

then by reaction with a compound of the formula R²-CO-R³Or with 2, 2-dimethoxypropane or 2, 2-dimethoxybutane to convert the compound of the formula III into the ketone or acetal of the formula IV,

and/or mirroring

In the formula, R²And R³Have the meaning indicated;

followed by reductive ring opening to convert the compound of formula IV to a compound of formula V,

and/or mirroring

In the formula, R²And R³Has the meaning as indicated above and which is,

and optionally by reaction with dimethyl sulfate, benzyl chloride or a compound of formula R¹The halide reaction of X converts the alcohol of the formula V or its alcoholate into the ether of the formula VI, where R¹Having the stated meaning other than hydrogen, X is bromine or iodine,

and/or mirroring

In the formula, R²And R³Have the meaning indicated.

Wherein a compound of formula V or VI is converted to a compound of formula I by basic hydrolysis,

and/or mirroring

In the formula, R¹、R²And R³Having the stated meaning, and finally optionally converted into the corresponding salts by addition of dibasic or tribasic organic acids, where R¹、R²And R³Have the meaning indicated.

2. The method of claim 1, wherein the cis hydroxylation of the double bond is performed using osmium tetroxide.

3. A method as claimed in claim 2, characterized in that osmium tetroxide is used in an amount of 0.1 to 2.0 mol%, preferably 0.2 to 0.9 mol%, based on the compound of the general formula II, and that osmium tetroxide can be regenerated during the reaction.

4. A method as claimed in claim 3, wherein said osmium tetroxide is regenerated by adding a sterically hindered N-oxide or a mixture of a sterically hindered amine and hydrogen peroxide.

5. The method according to at least one of claims 1 to 4, characterized in that the formation of the ketal or acetal is carried out acid-catalyzed.

6. The process of claim 5, wherein sulfuric acid and/or p-toluenesulfonic acid is used for acid catalysis.

7. The process according to at least one of claims 1 to 6, characterized in that acetone or 2, 2-dimethoxypropane is used for the formation of the ketal or acetal.

8. The process according to at least one of claims 1 to 7, characterized in that the reductive ring opening uses a complex metal hydride, preferably NaBH₄The method is carried out.

9. The process according to at least one of claims 1 to 8, characterized in that the alcohol of the formula V is converted into the methyl ether with dimethyl sulfate.

10. The process according to at least one of claims 1 to 8, characterized in that the alcohol of the formula V is converted into a methyl ether with methyl iodide.

11. The process according to at least one of claims 1 to 10, characterized in that at least one of the components selected from the group consisting of LiOH, NaOH, KOH, Ca (OH)₂And Ba (OH)₂Is subjected to alkaline hydrolysis in aqueous and/or alcoholic solution or suspension of alkali metal or alkaline earth metal hydroxide.

12. The process as claimed in claim 11, characterized in that the alkaline hydrolysis is carried out at a pressure of 1 to 10 bar, particularly preferably 1 to 2 bar, and a temperature of 50 to 150 ℃, particularly preferably 80 to 100 ℃.

13. The process according to at least one of the claims 1 to 12, characterized in that the organic acid is selected from oxalic acid free of and/or containing water of crystallization, (+) -, (-) -or meso-tartaric acid, (+) -or (-) -malic acid, tartronic acid, pyruvoic acid and oxaloacetic acid.

14. The method according to claim 13, wherein oxalic acid free of water of crystallization and/or oxalic acid containing water of crystallization is used as the salt-forming organic acid.

15. A compound of the formula I, wherein,

or mirror image.

16. A compound of the formula IV,

or mirror image

Wherein R is²And R³Have the meaning stated in claim 1.

17. A compound of the formula VI having the formula,

or mirror image

In the formula, R¹、R²And R³Have the meaning stated in claim 1.

18. Salts of dibasic or tribasic organic acids of the compounds of formula I,

or mirror image

In the formula, R¹、R²And R³Have the meaning stated in claim 1.