EP1771434A2

EP1771434A2 - Method for the production of 3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol derivatives

Info

Publication number: EP1771434A2
Application number: EP05706975A
Authority: EP
Inventors: Gareth-John Griffiths; Silvia Lange; Walter Brieden
Original assignee: Lonza AG
Current assignee: Lonza AG
Priority date: 2004-01-30
Filing date: 2005-01-24
Publication date: 2007-04-11
Also published as: US7417153B2; CN1922166A; JP2007538001A; WO2005073213A3; EP1574508A1; WO2005073213A2; US20070043225A1

Abstract

The invention relates to a method for the production of acetals and ketals of 3-amino-5-(hydroxymethyl)cyclopentane-1,2-diols of formula (I) (and/or the enantiomer), where Rl = H, C1-6 alkyl, C3-8 cycloalkyl or benzyl and i) R2 = methyl and R3 = ethyl, ii) R2 = H and R3 = C1-6 alkyl or phenyl or iii) R2 and R3 together form a group of formula -(CH2)n- with n = 4 to 6, present as free amines or as salts of di- or tri-basic organic acids, starting from 2-acetyl-2-aza-bicyclo[2.2.1]hept-5-en-3-one of formula (II) (and/or the enantiomer). The method is equally useful, depending on the starting material, for the production of enantiomerically-pure compounds, or mixtures with arbitrary enantiomeric content.

Description

Process for the preparation of 3-amino-5- (hydroxymethyl) cyclopentane-1,2-diol derivatives

The invention relates to a process for the preparation of acetals and ketals of 3-amino-5- (hydroxymethyl) cyclopentane-1,2-diols, and their derivatives and salts of organic acids such as 2,3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-amine hydrogen oxalate, starting from 2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one of the formula

and / or mirror image

In the following, enantiomerically pure compounds are understood to mean mixtures of enantiomers with an enantiomeric excess (ee) of at least 90%.

Ci -e-alkyl is understood below to mean a linear or branched aliphatic alkyl group having 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl.

C _3-8 cycloalkyl is an alicyclic alkyl group with 3 to 8

Understand carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

In the following, a solution or suspension of at least one organic compound in any mixture is made from an alcoholic solution or suspension

Ethanol, methanol, propanol, isopropyl alcohol, n-butanol, isobutanol and / or tert-butanol, optionally in a mixture with water and / or other solvents, solubilizers or other auxiliaries, understood.

Depending on the composition of the starting material, the process is equally suitable for producing enantiomerically pure compounds or mixtures of any enantiomer composition. The enantiomer, not shown in each case, is said to be in the Structural formula representations can also be included by adding “and / or mirror image” or “or mirror image”.

Substituted cyclopentylamines, such as (1R, 2S, 3R, 4R) -2,3-isopropylidendioxy- 4- (methoxymethyl) cyclopentan-l-amine hydrochloride, are intermediates for the production of pharmaceutically active adenosine datenates, which among other things for the treatment of coronary arteries Circulatory disorders, heart failure and high blood pressure can be used (US-A-5364862 and WO-A-95/28160).

In a known process for the preparation of (1R, 2S, 3R, 4R) -2,3-isopropylidenedioxy- 4- (methoxymethyl) cyclopentane-1-amine hydrochloride (WO-A-98/01426 and

WO-A-00/23447) turns (-) - 5,6-isopropylidenedioxy-2-azabicyclo [2.2.1] heptan-3-one into a correspondingly protected product using the very expensive and hydrolysis-sensitive compound di-tert-butyl dicarbonate Implemented N-BOC derivative. The synthesis of the starting material (compound of the formula vi) starting from 5,6-dihydroxy-2-azabicyclo- [2.2.1] heptan-3-one is disclosed in WO-A-95/28160. After the lactam has been cleaved, optionally followed by methylation of the newly formed hydroxyl group, the BOC protective group is cleaved off using HCl gas. In this process, hydrochlorides are obtained which, however, are not specified in terms of purity, yield or chemical-physical properties. The substances obtained are used directly in the next synthesis stages without further processing.

The process disclosed in the prior art for the preparation of (1R, 2S, 3R, 4R) -2,3-isopropylidenedioxy-4- (methoxymethyl) cyclopentane-1-amine hydrochloride has disadvantages which require a large-scale implementation of the process prevent. It was therefore an object of the present invention to provide an economically feasible process for the preparation of acetals and ketals of 3-amino-5- (hydroxymethyl) cyclopentane-1, 2-diols, and also their derivatives and salts of organic acids.

This object was achieved in the process according to claim 1, starting from 2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one.

According to the process of the invention, enantiomerically pure hydrogen oxalates of (1R, 2S, 3R, 4R) -2,3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentane 1-amine and the (1R, 2S, 3R, 4R) -2,3-isopropylidenedioxy-4- (methoxymethyl) cyclopentane-1-amine.

The process according to the invention can be carried out using (-) - 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 any mixture thereof.

The compound 2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one as an enantiomer mixture, and the enantiomerically pure form (-) - 2-acetyl-2-azabicyclo [2.2.1] hept-5- en-3-ones are disclosed in WO-A-00/03032.

Thanks to the use of acetylated lactams, the process uses conventional and inexpensive protective group technology. Compared to the BOC protective group used in the prior art, the use of the acetyl protective group in the process according to the invention is characterized by easier handling.

Furthermore, the acetyl group can easily be removed again in an alkaline hydrolysis step, while the process from WO-A-98/01426 relies on the use of HCl gas for the elimination of the BOC protective group. Compared to the method from WO-A-98/01426, in which NaCl waste is produced in considerable quantities and which requires a great deal of effort to protect systems and lines against corrosion, the method according to the invention represents a significant step forward.

It was found that cyclic acetals and ketals of dihydroxycyclopentylamines of the formula prepared by the process according to the invention

and / or mirror image can advantageously be precipitated as hydrogen oxalates, which have significant advantages in handling (filtration, centrifugation) compared to the already known hydrochlorides.

The salts which can be prepared by the process according to the invention, such as, for example, (1R, 2S, 3R, 4R) -2,3-isopropylidenedioxy-4- (methoxymethyl) cyclopentane-1-amine-hydroxy-hydrogen oxalate, can in principle be obtained from the anion exchange and reprecipitation corresponding hydrochlorides can be obtained. However, they are not available as a direct hydrolysis product from the N-BOC compound mentioned in WO-A 00/23447, since the BOC protective group must first be split off with a strong acid. Furthermore, the reprecipitation of an HCl acid salt with an organic acid is not favored.

A process for the preparation of compounds of the formula is described

and / or mirror image wherein R ^{1 is} hydrogen, Ci ^ - alkyl, C ₃ . ₈ -cycloalkyl or benzyl and in which i) R ^{2 is} methyl and R ^{3 is} ethyl, ii) R ^{2 is} hydrogen and R ^{3 is} Ci ^ - alkyl or phenyl or iii) R ² and R ^{3 are} together a group of the formula - (CH ₂ ) _n - with n = 4 to 6, and which are present as free amines or as salts of dibasic or triphasic organic acids.

For this purpose, a 2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one of the formula is used in a first reaction step

and / or mirror image by c j-hydroxylation of the double bond in a 2-acetyl-5,6-dihydroxy-2-azabicyclo- [2.2.1] heptan-3-one of the formula

HO OH and / or mirror image transferred.

In a second reaction step, a compound of the formula III is converted into a ketal or acetal by reaction with a ketone or an aldehyde of the formula R ² -CO-R ³ or by reaction with 2,2-dimethoxypropane or 2,2-dimethoxybutane of the formula

and / or mirror image in which R ² and R ^{3 have} the meanings given.

In the following reaction step, a compound of the formula IV is converted into a compound of the formula by reducing the ring opening

^V > and / or mirror image where R ² and R ^{3 have} the meanings mentioned.

In an optionally subsequent reaction step, an alcohol of the formula V, or optionally an alcoholate thereof, where R ² and R ^{3 have} the meanings mentioned, by reaction with an alkylating agent such as, for example, dimethyl sulfate (DMS), Benzyl chloride or a halide of the formula R -X, in which R has the meaning given except hydrogen and X = bromine or iodine, in an ether of the formula

and / or mirror image where R and R have the meanings mentioned.

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

and / or mirror image in which R ¹ , R ² and R ^{3 have} the meanings given.

In a possibly subsequent final reaction step, compounds of

Formula I reacted with a two- or three-base organic acid to give the corresponding salts, in which R, R and R have the meanings mentioned.

To increase sales and save the oxidizing agent before the hydroxylation, disruptive compounds from the synthesis of 2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one are advantageously removed by extraction. The most common impurity 4-dimethylaminopyridine (DMAP) can be removed, for example, by acidic extraction with a dilute aqueous acid, such as dilute HCl or H ₂ SO ₄ .

In a preferred embodiment, the cw-hydroxylation of the double bond is carried out using an inorganic oxidizing agent such as, for example, osmium tetraoxide, potassium osmate or potassium permanganate. Because of the toxicity and volatility of osmium tetraoxide, the hydroxylation is carried out in a further preferred embodiment using a 2 to 10% aqueous solution of osmium tetraoxide or with osmium tetraoxide fixed on an organic or inorganic support. In a particularly preferred embodiment, osmium tetraoxide is used in an amount of 0.1 to 2 mol% with respect to 2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one, preferably in an amount of 0.2 up to 0.9 mol%.

The osmium tetraoxide can advantageously be regenerated during the reaction in the presence of at least one organic N-oxide such as N-4-methylmorpholine-N-4-oxide and / or a secondary or tertiary amine and at least one inorganic oxidizing agent such as hydrogen peroxide. Suitable co-oxidants for the regeneration of osmium tetraoxide during the reaction are sterically demanding N-oxides such as N-4-methylmorpholine-N-4-oxide, di- and trialkylamine N-oxides such as trimethylamine-N-oxide, or mixtures of the above secondary and tertiary amines with organic or inorganic oxidizing agents such as tert-butyl hydroperoxide, magnesium monoperoxyphthalate, 3-chloroperbenzoic acid, hydrogen peroxide, sodium and / or potassium perchlorate, periodate or permanganate. The use of N-oxides and mixtures of the amines mentioned with hydrogen peroxide is particularly preferred.

In a particularly preferred process, enantiomerically pure (-) - 2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one is obtained by cw-hydroxylation with osmium tetraoxide in (1R, 4S, 5R, 6S) -2 acetyl-5,6-dihydroxy-2-azabicyclo [2.2. l] heptan-3-one of the formula

converted.

In a preferred process variant, the acetal or ketal formation is carried out with acid catalysis. In a particularly preferred process variant, sulfuric acid and / or p-toluenesulfonic acid are used for acid catalysis.

In a preferred process, 2-acetyl-5,6-dihydroxy-2-azabicyclo [2.2.1] heptan- 3-one of the formula III is reacted with acetone or 2,2-dimethoxypropane in 8-acetyl-4,4- dimethyl-3,5-dioxa-8-azatricyclo [5.2.1.0 ² ' ⁶ ] decan-9-one of the formula

and / or mirror image transferred.

In a particularly preferred process variant, the (1 R, 4S, 5R, 6S) -2-acetyl-5,6-di-hydroxy-2-azabicyclo [2.2.1] heptan-3-one is reacted with acetone or 2, 2-Dimethoxypropane in the (IS, 2R, 6S, 7R) -8-acetyl-4,4-dimethyl-3,5-dioxa-8-azatricyclo [5.2.1.0 ^2,6 ] decan-9-one ( IVa) transferred.

In a preferred process, the reducing ring opening is carried out with a complex metal hydride such as LiBH ₄ , NaBH ₄ , NaAlH ₂ (OCH ₂ CH ₂ OCH ₃ ) ₂ or LiAlIL, preferably with NaBFL ;.

In a further preferred method, the (IS, 2R, 6S, 7R) -8-acetyl-4,4-dimethyl-3,5-dioxa-8-azatricyclo [5.2.1.0 '] decan-9-one, by reaction with a complex metal hydride in the (lR, 2S, 3R, 4R) -N- [2,3-isopropylidendioxy-4- (hydroxymethyl) cyopentan-l-yl] acetic acid amide of the formula

In a preferred process variant, the formation of the ether of the formula VI with R methyl with DMS in acetone is carried out in the presence of a strong base, for example NaOH and / or KOH, particularly preferably with a water content of less than 1%, based on the solvent ,

In a further preferred process variant, the ether formation is carried out with a C _I - _O - alkyl or C ₃ - cycloalkyl halide in the presence of AgOH.

In a particularly preferred process, the (IR, 2S, 3R, 4R) -N- [2,3-isopropylidene-dioxy-4- (hydroxymethyl) cyclopentan-1-yl] acetic acid amide is reacted with DMS or methyl iodide in the (IR , 2S, 3R, 4R) -N- [2,3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-yl] acetic acid amide

converted.

In a preferred process variant, the alkaline hydrolysis is carried out with at least one alkali metal or alkaline earth metal hydroxide, selected from the group consisting of LiOH, ΝaOH, KOH, Mg (OH) ₂ , Ca (OH) and Ba (OH) ₂ , in aqueous and / or alcoholic solution or suspension.

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

In a particularly preferred process variant, the alkaline hydrolysis is carried out with ΝaOH and / or KOH in methanolic and / or ethanolic solution, at a pressure of 1 to 2 bar and at a temperature of 80 to 100 ° C. In a preferred process, alkaline hydrolysis with NaOH and / or KOH in methanolic and / or ethanolic solution, preferably under a pressure of 1 to 2 bar and temperatures of 80 to 100 ° C., i) the (IR, 2S, 3R, 4R) -N- [2,3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-l-yl] acetic acid amide into the (IR, 2S, 3R, 4R) -2,3-isopropylidenedioxy-4- (hydroxymethyl) cyclo- pentan-1-amine or

ii) the (IR, 2S, 3R, 4R) -N- [2,3-isopropylidenedioxy-4- (methoxymethyl) cyclopentanl-yl] acetic amide into the (IR, 2S, 3R, 4R) -2,3-isopropylidenedioxy -4- (methoxymethyl) cyclopentan-1-amine

converted.

In a preferred process variant, the salt formation in the optional final reaction step with an organic acid selected from the group consisting of crystal water-free or crystal water-containing oxalic acid, (+) -, (-) - or meso-tartaric acid, (+) - or (-) - Malic acid, tartronic acid, mesoxalic acid and oxaloacetic acid are carried out.

In a particularly preferred process variant, salt formation is carried out with oxalic acid which is free of water of crystallization or contains water of crystallization, (+) -, (-) - or meso-tartaric acid, (+) - or (-) - malic acid.

In a further particularly preferred process variant, the compounds (1 R, 2S, 3R, 4R) -2,3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentane-1-amine or (1R, 2S, 3R, 4R) -2.3 -Isopropylidendioxy-4- (methoxymethyl) cyclopentan-l-amine converted into the corresponding hydrogen oxalates. The invention also relates to compounds of the formula

HO OH or mirror image.

The invention also includes compounds of the formula

or mirror image in which R ² and R ^{3 have} the meanings given above.

The invention also includes compounds of the formula

or mirror image in which R ^{1 has} the abovementioned meaning including hydrogen and R ² and R ^{3 have} the abovementioned meanings. In addition, the invention also includes salts of dibasic and triphasic organic acids of compounds of the formula

or mirror image 1 9 ^ wherein R, R and R have the meanings given above.

Examples

Although the present invention is fully disclosed by the examples 1 to 18 according to the invention, numerous further examples according to the invention can be carried out due to the claimed variations in the process parameters. Examples which are carried out by implementing these, within the variations defined in the description and in the claims, are to be considered as examples according to the invention and fall within the scope of protection of this patent application.

example 1

(IR, 4S, 5R, 65) -2-acetyl-5,6-dihydroxy-2-azabicyclo [2.2.1] heptan-3-one (Formula III) 132.1 g (0.87 mol) (-) -2-Acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one and 118.1 g (0.87 mol) of N-4-methylmorpholine-N-4-oxide ^• H ₂ 0 were in 750 mL acetone, 224 mL demineralized water (demineralized water) and 75 mL tert-butanol. The reaction solution was warmed to 30 ° C. A solution of 2.0 g (7.9 mmol) of osmium tetraoxide in 10 ml of acetone was added dropwise over 15 minutes and the reaction mixture was stirred at 30 ° C. for 2 hours. The reaction solution was then cooled to 10 ° C. and, in order to reduce excess N-4-methylmorpholine-N-4-oxide and osmium tetraoxide, over a period of 1 hour with 180.1 g (0.69 mol) of 40% sodium hydrogen sulfite solution added. The reaction mixture was then concentrated with 35.1 g. Sulfuric acid adjusted to pH 7. The resulting suspension was filtered and the filter material was washed with 20 mL acetone. The filtrate was under vacuum (40 to 400 mbar) at a temperature of 40 ° C

Concentrated 350 to 400 mL. The reaction solution was cooled to 20 ° C. The aqueous phase was concentrated with 12.9 g. Adjusted sulfuric acid to pH 2 and extracted with ethyl acetate (5 x 400 mL). The combined organic phases were evaporated to dryness. The residue obtained was dried under high vacuum overnight. Yield: 81.6 g (0.44 mol) (IR, 4S, 5R, 6S) -2-acetyl-5,6-dihydroxy-2-azabicyclo [2.2.1] - heptan-3-one, approx. 50% based on (-) - 2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one 1H-NMR (300 MHz) in CDC1 ₃ : δ 4.89 (2H, s (broad); 4.57 (1H, m); 4.17 (1H, m) 4.01 (1H, m); 2.83 (1H, m); 2.39 (3H, s); 2.14 (lH, m); 1.92 (1H, m). Example 2

(IS, 2R, 6S, 7R -8-acetyl-4,4-dimethyl-3,5-dioxa-8-azatricyclo [5.2.1.0 ² ' ⁶ ] decan-9-one

(Formula IVa = Formula IV with R ² = R ³ = methyl)

72.2 g (0.39 mol) (IR, 4S, 5R, 6S) -2-acetyl-5,6-dihydroxy-2-azabicyclo [2.2.1] heptan-3-one, 49.8 g (0 , 47 mmol) of 2,2-dimethoxypropane and 1.48 g (7.8 mmol) of p-toluenesulfonic acid were placed in 145 ml of ethanol. The brown, clear solution was heated to 50 ° C., stirred at 50 ° C. for 2 hours, cooled to 0 ° C. within 30 minutes and then mixed with 50 ml of ethanol. The brown suspension was stirred at 0 ° C for 1 hour. The precipitated crystals were filtered off and washed with 25 ml of ethanol. The moist product was dried at 40 ° C under vacuum.

Yield: 53.0 g (0.24 mol) (IS, 2R, 6S, 7R) -8-acetyl-4,4-dimethyl-3,5-dioxa-8-azatricycle-

[5.2.1.0 ^2,6 ] decan-9-one, approx. 56% based on (IR, 4S, 5R, 6S) -2-acetyl-5,6-dihydroxy-2-azabicyclo [2.2.1] heptane-3-one.

Η NMR (300 MHz) in CDC1 ₃ : 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

(IR, 2S, 3 ^ _» 4R) -N- [2 -isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-yI] acetic acid amide (formula Va = formula V with R ² = R ³ = methyl) 18.0 g ( 0.08 mol) (IS, 2R, 6S, 7R) -8-acetyl-4,4-dimethyl-3,5-dioxa-8-azatricyclo [5.2.1.0 ² ' ⁶ ] - decan-9-one were found in 250 ml of methanol are introduced and the clear colorless solution is cooled to 0.degree. 6.6 g (0.17 mol) of sodium borohydride were added in portions in the course of 1 hour in such a way that the temperature was kept below 5 ° C. The reaction mixture was then heated to 20 ° C. in the course of 30 minutes and stirred at 20 ° C. for 15 hours. 17.5 g of acetic acid were then added dropwise in 10 minutes, the reaction mixture was stirred for a further 10 minutes and then evaporated to dryness. The residue (44.8 g) was taken up in 100 ml of ethyl acetate and stirred for about 10 minutes. The precipitated crystals were filtered off and washed with ethyl acetate (2 × 20 mL). The filtrate was evaporated and dried under high vacuum. The crude product (21.3 g) was purified by column chromatography on silica gel (eluent: ethyl acetate / methanol (5: 1)). Yield: 18.4 g (0.08 mmol) (IR, 2S, 3R, 4R) -N- [2,3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-l-yl] acetic acid amide, based on approx. 100% on [IS, 2R, 6S, 7R] -8-acetyl-

4,4-dimethyl-3,5-dioxa-8-azatricyclo [5.2.

1H-ΝMR (300 MHz) in CDC1 ₃ : δ 7.51 (IH, d); 4.60 (IH, m); 4.37 (IH, m); 4.34 (IH, m); 4.0 (IH, s, broad); 3.86 (IH, dd); 3.67 (IH, dd); 2.52 (IH, m); 2.33 (IH, m); 1.94 (3H, s); 1.49 (IH, m); 1.46 (3H, s); 1.28 (3H, s).

Example 4

(IR, 2S, 3R _» 4R) -N- [2,3-isopropylidenedioxy-4- (methoxymethyl) yclopentan-l-yl] acetic acid amide (formula IVa = formula IV with R ¹ = R ² = R ³ = methyl )

31.2 g (0.14 mol) (IR, 2S, 3R, 4R) -N- [2,3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-l-yl] acetic acid amide and 5.4 g sodium hydroxide solution (40% -ig) were placed in 250 mL acetone and heated to 50 ° C. 20.2 g (0.16 mol) of dimethyl sulfate and 5.7 g of sodium hydroxide solution (40%) were added dropwise at 50 ° C. over 90 minutes. The reaction mixture was stirred for a further 3 hours at 50 ° C. and then concentrated in vacuo to a volume of approximately 90 ml. 54 ml of water and 100 ml of ethyl acetate were added to the residue and the mixture was stirred for 30 minutes. The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 70 mL). The combined organic phases were evaporated to dryness. The crude product (31.5 g) was purified by distillation (bp 120 to 130 ° C at 0.15 mbar).

Yield: 16.9 g (0.07 mol) (IR, 2S, 3R, 4R) -N- [2,3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-l-yl] acetic acid amide, based on approx. 51% to (IR, 2S, 3R, 4R) -N- [2,3-isopropylidene-dioxy-4- (hydroxymethyl) cyclopentan-1-yl] acetic acid amide. 1H-ΝMR (300 MHz) in CDC1 ₃ : δ 6.83 (IH, d); 4.52 (IH, m); 4.37 (IH, m); 4.34 (IH, m);

3.55 (IH, dd); 3.42 (IH, dd); 3.41 (3H, s); 2.53 (IH, m); 2.34 (IH, m); 1.93 (3H, s); 1.45 (3H, s); 1.42 (1H, m); 1.27 (3H, s).

Example 5 (IR, 2S, 3R, 4R) -2,3-isopropylidenedioxy-4- (methoxymethyl) cyclopentane-l-amine

(Formula Ia = Formula I with R ¹ = R ² = R ³ = methyl)

A suspension of 2.34 g (0.01 mol) of (IR, 2S, 3R, 4R) -N- [2,3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-l-yl] acetic acid amide and 1.5 mL Ba (OH) ₂ Η ₂ 0 (30% Suspension in water) in 1.2 ml of water was stirred under reflux at 100 ° C. for 22 hours. The suspension was cooled to 20 ° C., 50 ml of toluene were added and the mixture was filtered. The phases were separated and the aqueous phase was extracted with toluene (2 x 50 mL). The combined organic phases were evaporated to dryness. Yield: 1.5 g (7.5 mmol) (IR, 2S, 3R, 4R) -2,3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-amine as a yellow liquid, approx. 75% based on (IR , 2S, 3R, 4R) -N- [2,3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan- 1 -yl] acetic acid amide. 1H-ΝMR (300 MHz) in CDC1 ₃ : δ 4.48 (IH, dd); 4.19 (IH, dd); 3.43 (2H, d); 3.37 (IH, m); 3.36 (3H, s); 2.30 (IH, m); 2.24 (IH, m); 1.47 (3H, s); 1.43 (2H, s, broad); 1.33 (IH, m); 1.29 (3H, s).

Example 6

(IR, 2S Λj4R) -2-isopropylidenedioxy-4- (methoxymethyl) cyclopentane-l-amine hydrogen oxalate (salt of the compound of formula I with R ¹ = R ² = R ³ = methyl) To a solution of 42.1 g (0.21 mol) (lR, 2S, 3R, 4R) -2,3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-l-amine in 107 mL ethanol were treated with 17.0 g of anhydrous oxalic acid at 25 ° C ( 0.19 mol) added in portions. The reaction solution was stirred at 25 ° C for 30 minutes. Subsequently, 430 ml of acetone and 55 ml of heptane were added in succession, then cooled to 0 ° C. and stirred for a further 60 minutes at 0 ° C. The precipitated crystals were filtered off and washed with 110 ml of heptane. The filter residue was dried under vacuum at 40 ° C. Yield: 42.7 g (0.15 mol) (IR, 2S, 3R, 4R) -2,3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-1-amine hydrogen oxalate, approx. 70% based on ( IR, 2S, 3R, 4R) -2,3-isopropylidenedioxy- 4- (methoxymethyl) cyclopentane-1-amine. 1H-NMR (300 MHz) in DMSO-d ₆ : δ 8.73 (4H, s, broad); 4.50 (IH, m); 4.40 (IH, m); 3.36 (3H, m); 3.27 (3H, s); 2.23 (2H, m); 1.57 (IH, m); 1.42 (3H, s); 1.23 (3H, s).

Example 7 (IR, 2S, 3R.4R) -2,3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentane-l-amine (Formula Ia = Formula I with R ¹ = H, R ² = R ³ = methyl)

A solution of 3.5 g (15.3 mmol) (IR, 2S, 3R, 4R) -N- [2,3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-l-yl] acetic acid amide in 25 mL ethanol and 7.8 g of 50% sodium hydroxide solution were heated in an autoclave at 100 ° C. and 2 bar for 15.5 hours. The The reaction mixture was cooled to room temperature. Then the orange suspension was dissolved in 30 mL ethanol and evaporated to dryness in vacuo. The residue was mixed with 10 mL water and evaporated to dryness in vacuo. The residue was then extracted with methyl tert-butyl ether (MTBE) (2 × 10 mL) and the combined organic phases were evaporated to dryness in vacuo.

Yield: 2.2 g (11.7 mmol) (1R, 2S, 3R, 4R) -2,3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-1-amine, approx. 76% based on (LÄ, 2S, 3R, 4R) -N- [2,3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-1-ylacetic acid amide.

1H-ΝMR (300 MHz) in CDC1 ₃ : δ 4.78 (IH, d); 4.22 (IH, d); 3.72 (IH, dd); 3.55 (IH, dd); 3.53 (IH, m); 2.44 (2H, m); 1.44 (3H, s); 1.30 (IH, m); 1.29 (3H, s).

Example 8

(IR, 2S R _» 4R) -2-isopropylidenedioxy-4- (hydroxymethyl) cyclopentane-l-amine hydrogen oxalate (salt of the compound of formula I with R ¹ = H, R ² = R ³ = methyl) To a solution of 1.08 g (5.3 mmol) (1R, 2S, 3R, 4R) -2,3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-l-amine in 3 mL ethanol were added in portions with 0.48 g

(5.3 mmol) oxalic acid and ethanol (2 3 mL) added. The white precipitate was filtered off and dried in vacuo at room temperature.

Yield: 1.0 g (3.7 mmol) (IR, 2S, 3R, 4R) -2,3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentane-1-amine hydrogen oxalate, approx. 70% based on ( 1 R, 2S, 3R, 4R) -2,3 -isopropylidenedioxy-

4- (hydroxymethyl) cyclopentane-1 amine.

1H NMR (300 MHz) in DMSO-d ₆ : δ 6.95 (5H, s, broad); 4.46 (2H, m); 3.52 (IH, dd);

3.20 (2H, m); 2.26 (IH, m); 2.17 (IH, m); 1.57 (IH, m); 1.40 (3H, s); 1.23 (3H, s).

Example 9

(ISR, 2RS, 6SR, 7RS) -8-AcetyI-4,4-dimethyl-3,5-dioxa-8-azatricyclo [5.2.1.0 ² ' ⁶ ] decan-9-one (formula IVa = formula IV with R. ² = R ³ = methyl)

A mixture of 72.2 g (0.39 mol) (ISR, 4SR, 5RS6SR) -2-acetyl-5,6-dihydroxy-2-azabicyclo- [2.2.1] heptan-3-one, 49.8 g (0.47 mol) 2,2-dimethoxypropane and 1.48 g (7.8 mmol) 4-toluenesulfonic acid monohydrate in 145 ml ethanol was heated to 50 ° C. over 90 minutes.

The reaction mixture was then cooled to 0 ° C. over 30 minutes and stirring continued for 75 minutes. The precipitated crystals were filtered off, washed with 25 ml of ethanol and dried at 40 ° C. and 30 mbar. Yield: 53.0 g (0.24 mol) (\ SR, 2RS, 6SR, 7RS) -8-acetyl-4,4-dimethyl-3,5-dioxa-8-aza-tricyclo [5.2.1.0 ^{2> 6} ] decan-9-one, approx. 60% based on (ISR, 4SR, 5RS, 6SR) -2-acetyl-5,6-dihydroxy-2-azabicyclo [2.2.1] heptan-3-one, 1H- NMR (CDC1 ₃ ) corresponds.

Example 10

(lRS, 2SR, 3RS, 4RS) -N- [2,3-isopropylidendioxy-4- (hydroxymethyl) cyclopentan-l-yl] acetic acid amide (formula Va = formula V with R ² = R ³ = methyl)

A solution of 17.7 g (79 mmol) (\ SR, 2RS, 6SR, 7RS) -8-acetyl-4,4-dimethyl-3,5-dioxa-

8-aza-tricyclo [5.2. in 250 ml of methanol was cooled to about 0 ° C. under an N ₂ atmosphere. 6.6 g (175 mmol) sodium borohydride were added portionwise over 1 hour so that the temperature was kept below 5 ° C. The reaction mixture was stirred at room temperature overnight, a solution of 17.5 g of acetic acid in 20 ml of methanol was added and the mixture was brought to dryness in vacuo at 30 to 35 ° C. The residue was taken up in 100 ml of ethyl acetate and the white suspension was filtered after stirring for 10 minutes. The filter residue was washed with ethyl acetate (2 x 20 mL). The combined filtrates were evaporated to dryness and then dried under high vacuum. (Yield: 21.3 g of crude product as a yellow viscous oil). 15.0 g of the crude product were chromatographed on silica gel 60 with ethyl acetate / methanol (5: 1, v: v). Yield: 18 g (lRS, 2SR, 3RS, 4RS) -N- [2,3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan- 1-yl] acetic acid amide (79 mmol) as a yellow viscous oil, approx. 100% related to

(ISR, 2RS, 6SR, 7RS) -8-acetyl-4,4-dimethyl-3,5-dioxa-8-azatricyclo [5.2.1.0 ^{2> 6} ] decan-9-one, 1H-ΝMR (CDC1 ₃ ) equivalent.

Example 11 (l tS, 2SR ÄS ^, 4RS) -N- [2 -isopropylidendioxy-4- (methoxymethyl) cyclopentan-l-yl] acetic acid amide (formula Via = formula VI with R ¹ = R ² = R ³ = methyl )

11.5 g (50 mmol) (IR, 2SR, 3RS, 4RS) -N- [2,3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan- 1-yl] acetic acid amide were dissolved in 150 mL acetone and 2.1 g 40% sodium hydroxide solution heated to approx. 50 ° C. 7.7 g (61 mmol) of dimethyl sulfate and 9.9 g of 40% sodium hydroxide solution were metered in parallel at 50 ° C. within 90 minutes. The reaction mixture was stirred for a further 3.5 hours at 50 ° C. and then concentrated in vacuo to about 30 ml. After cooling to about 20 ° C, 20 mL water and 40 mL MTBE were added. The Phases were separated and the aqueous phase was extracted with MTBE (2 x 25 mL). Concentration of the combined organic phases to dryness gave 11.5 g of crude product. Yield: 11.5 g (47 mmol) (IRS, 2SR, 3RS, 4RS) -N- [2,3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-l-yl] acetic acid amide as a red-brown oil (approx 94% based on (lRS, 2SR, 3RS, 4RS) -N- [2,3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-l-yl] acetic acid amide), Η-ΝMR (CDC1 ₃ ).

Example 12

Pre-cleaning: Extraction of (-) - 2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one (formula II) 30 L of water were placed in a 630 L stirrer (enamelled steel) and 8 , 35 kg of hydrochloric acid (technical, 32%) added. Then 3.7 kg of sodium chloride and 150 kg of (-) - 2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one (89%) were introduced into the reactor. The mixture was stirred vigorously at room temperature (experience has shown that emulsions can form if the stirring speed is too high). After 30 minutes the stirrer was switched off and after a further 30 minutes the phases could be separated very well. The purified (-) - 2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one obtained was used immediately after extraction for the preparation of (IR, 4S, 5R, 6S) -2- Acetyl-5,6-dihydroxy-2-azabicyclo [2.2.1] heptan-3-one used. Yield: approx. 133 kg (-) - 2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one (approx. 100%, 1H-NMR (CDC1 ₃ ) corresponds.

Example 13 (IR, 4S, 5R, 65) -2-acetyl-5,6-dihydroxy-2-azabicyclo [2.2.1] heptan-3-one (Formula III)

250 kg of aqueous N-4-methylmorpholine-N-4-oxide solution (50%), 132 L of water and 68 kg of tert-butanol were placed in a 2,500 L stirrer (stainless steel) and 830 L of acetone were then added. 20 kg of 4% aqueous osmium tetraoxide solution were added to this mixture at room temperature. 150 kg of (-) - 2-acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one were then metered in over the course of 1 hour so that the kettle temperature did not exceed 30 to 35 ° C. and stirring was continued for 1 hour , At a residual (-) - 2-acetyl-2-azabicyclo [2.2. l] hept-5-en-3-one of less than 0.2%, 58 kg of aqueous sodium bisulfite solution (40%) were added at 10 to 50 ° C. within 1 hour. At a temperature of 10 to 18 ° C, the reaction solution was then adjusted to pH = 5 with sulfuric acid (20%). The residue was centrifuged off and washed with acetone (2 × 20 L). After combining mother liquor and wash liquor, the mixture was concentrated by distilling off acetone, tert-butanol and water at 200 to 30 mbar and a temperature below 45 ° C. The reaction mixture was cooled to 20 ° C. and adjusted to pH = 2 with sulfuric acid (20%) at 12 to 20 ° C. The mixture was then extracted with ethyl acetate (4 × 670 L) and the combined organic phases were concentrated at 30 to 200 mbar and a temperature of below 45 ° C. After the internal temperature had risen above 45 ° C. at 30 to 50 mbar, the distillation was stopped and 620 L of methanol were added to the residue. At 200 mbar and an internal temperature of 30 ° C, ethyl acetate and methanol up to a total of 400 L were distilled off. The reaction solution was cooled to room temperature and then directly to the next step to prepare [IS, 2R, 6S, 7R] -8-acetyl- used.

Yield approx. 59% (IR, 4S, 5R, 6S) -2-acetyl-5,6-dihydroxy-2-azabicyclo [2.2.1] heptan-3-one,

1H-NMR (CDC1 ₃ ) corresponds.

Example 14

(IS, 2R, 6S, 7R) -8-acetyl-4,4-dimethyl-3,5-dioxa-8-azatricyclo [5.2.1.0 ^{, 6} ] decan-9-one

(Formula IVa = Formula IV with R ² = R ³ = methyl)

21 kg of toluene-4-sulfonic acid monohydrate were placed in a 2500 L stirrer (stainless steel) and at room temperature with 1240 kg (IR, 4S, 5R, 6S) -2-acetyl-5,6-dihydroxy-2-aza- bicyclo [2.2.1] heptan-3-one solution (approx. 19%) and 250 kg of 2,2-dimethoxypropane.

The reaction solution was heated at 50 ° C for 1 hour, then cooled to 35 ° C and with

1200 L of methanol were added. After the addition of methanol, the (IS, 2R, 6S, 7R) -8-acetyl-

4,4-dimethyl-3,5-dioxa-8-azatricyclo [5.2.1 determined, the solution filled into containers and diluted with methanol for the preparation of (1R, 2S, 3R, 4R) -N- [2,3-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan- 1 -yl] acetic acid amide.

Yield: 195 kg (IS, 2R, 6S, 7R) -8-acetyl-4,4-dimethyl-3,5-dioxa-8-azatricyclo [5.2.1.0 ² ' ⁶ ] - decan-9-one (approx. 68% based on (IR, 4S, 5R, 6S) -2-acetyl-5,6-dihydroxy-2-azabicyclo-

[2.2.1] heptan-3-one, Η-ΝMR (CDC1 ₃ ). Example 15

(IR, 2S ^ R, 4R) -N- [2-isopropylidenedioxy-4- (hydroxymethyl) cyclopentan-l-yl] acetic acid amide (formula Va = formula V with R ² = R ³ = methyl), not isolated

1323 kg of an (IS, 2R, 6S, 7R) -8-acetyl-4,4-dimethyl-3,5-dioxa-8-azatricyclo [5.2.1.0 ^2.6 ] decan-9-one solution (approx. 5.3%) in methanol were introduced into a 2500 L stirrer (stainless steel) and cooled to approx. 5 ° C. In the course of about 4 hours, 46 kg of sodium borohydride were added in 12 portions of 3 to 5 kg in such a way that an internal temperature of 10 ° C. was not exceeded in the agitator. After the addition had ended, the reaction mixture was warmed to about 20 ° C., stirred for 1 hour and then mixed with 53 L NaOH (30%). The methanol was repeatedly distilled off in vacuo and the bubble was added accordingly

E water added. The aqueous solution was then mixed with 780 L of acetone. After the aqueous phase had been separated off, the (lR, 2S, 3R, 4R) -N- [2,3-isopropylidendioxy- 4- (hydroxymethyl) cyclopentan-l-yl] acetic acid amide solution was used directly without isolation for the preparation of (lR , 2S, 3R, 4R) -N- [2,3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan- 1 -yl] acetic acid amide.

Example 16

(IR, 2S, 3R, 4R) -iV- [2 -isopropylidendioxy-4- (methoxymethyl) cyclopentan-l-yl] acetic acid amide (formula Via = formula VI with R ¹ = R ² = R ³ = methyl), not isolated 484 kg (1R, 2S, 3R, 4R) -N- [2,3-isopropylidendioxy-4- (hydroxymethyl) cyclopentan-l-yl] acetic acid amide solution in acetone (approx. 15%) were added 70 kg of sodium hydroxide were added and the mixture was stirred at 25 ° C. for 30 minutes. After a phase setting time of 30 minutes, the aqueous phase was removed. After adding a further 30 kg of 30% sodium hydroxide solution, the mixture was heated to 50 ° C. Thereafter, over the course of 75 minutes, 123 kg of dimethyl sulfate (DMS) and 30% sodium hydroxide solution were added in parallel so that a pH of 11 to 13 was maintained at an internal temperature of 50 ° C. After 15 minutes of stirring, the reaction solution was cooled to room temperature. After a phase setting time of 30 minutes, the aqueous phase was removed. The acetone was distilled off in vacuo to a residual amount of 500 L and the (1R, 2S, 3R, 4R) -N- [2,3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan- 1 -yl] acetic acid amide solution to

Cooling to 25 ° C directly to (1R, 2S, 3R, 4R) -2,3-isopropylidenedioxy-4- (methoxymethyl) cyclopentane-1-amine implemented. The yield was not determined and the solution was used directly to prepare

(1 R, 2S, 3R, 4R) -2,3-isopropylidenedioxy-4- (methoxymethyl) cyclopentane-1-amine was used.

1H-NMR (CDC1 ₃ ) corresponds.

Example 17

(lR, 2S, 3R, 4R) -2,3-isopropy! idendioxy-4- (methoxymethyI) cycIopentan-l-amine (formula Ia = formula I with R ¹ = R ² = R ³ = methyl)

In a 630 L stirrer (stainless steel) 460 kg (lR, 2S, 3R, 4R) -N- [2,3-isopropylidene-dioxy-4- (methoxymethyl) cyclopentan-l-yl] acetic acid amide solution in acetone (approx .l3.6%) submitted. The acetone was distilled off at 30 to 300 mbar and a temperature below 45 ° C. until an acetone content of less than 0.1% was reached, and 400 L of ethanol were added to the reaction mixture. 126 kg of sodium hydroxide solution (50% strength) were then added at room temperature and the hydrolysis was carried out at about 100 ° C. and 2 bar over the course of 8 hours. The reaction solution was cooled to room temperature and ethanol was distilled off at 100 mbar and a temperature below 45.degree. 180 L of water were added to the residue and the remaining amount of ethanol was distilled off. After the distillation, there was about 270 L of reaction mixture in the reactor, which was mixed with 140 L of water and then extracted with MTBE (2 × 145 L). The combined organic phases were used directly for the preparation of (1R, 2S, 3R, 4R) -2,3-isopropylidene-dioxy-4- (methoxymethyl) cyclopentane-1-amine hydrogen oxalate. The conversion of (lR, 2S, 3R, 4R) -N- [2,3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-l-yl] acetic acid amide in (lR, 2S, 3R, 4R) -2.3 -Isopropylidenedioxy-4- (methoxymethyl) cyclopentan-l-amine was> 96.5%. Η-ΝMR (CDC1 ₃ ) corresponds.

Example 18

(IR, 2S R _> 4R) -2,3-isopropylidendioxy-4- (methoxymethyl) cyclopentane-l-amine hydrogen oxalate (salt of the compound of formula I with R ¹ = R ² = R ³ = methyl)

The (1R, 2S, 3R, 4R) -2,3-isopropylidenedioxy-4- (methoxymethyl) cyclopentane described in Example 5 was placed in a 630 L agitator (enamelled steel) in an initial charge of 23.3 kg of oxalic acid and 210 L of ethanol -l-amine solution metered in over 30 minutes. After 60% had been added, the solution was inoculated by adding a little (1R, 2S, 3R, 4R) -2,3-isopropylidendioxy-4- (methoxymethyl) cyclopentane-1-amine hydrogen oxalate. The precipitated product was centrifuged off and washed with MTBE / ethanol (60:40) (2 × 120 L).

Yield: 56 kg (1R, 2S, 3R, 4R) -2,3-isopropylidenedioxy-4- (methoxymethyl) cyclopentane-1-amine hydrogen oxalate (approx. 78% based on (1R, 2S, 3R, 4R) -N - [2,3-isopropylidenedioxy-4- (methoxymethyl) cyclopentan-l-yl] acetic acid amide), Η-ΝMR (CDC1 ₃ ).

Claims

Expectations:

1. Process for the preparation of compounds of the formula

and / or mirror image 1 9 wherein R is hydrogen, Cι. ₆ -alkyl, C _3-8 -cycloalkyl or benzyl and in which l) R is methyl and R ^{3 is} ethyl, ii) R ^{2 is} hydrogen and R ^{3 is} C _-6 -alkyl or phenyl, or iii) R ² and R ³ together are one Group of the formula - (CH ₂ ) _n - with n = 4 to 6, and which are present as free amines or as salts of organic dibasic or tripric acids, characterized in that a 2-acetyl-2-azabicyclo [2.2. l] hept-5-en-3-one of the formula

and / or mirror image by cw-hydroxylation of the double bond in a 2-acetyl-5,6-dihydroxy-2-azabicyclo [2.2.1] heptan-3-one of the formula

HO OH and / or mirror image is converted, and this by reaction with a ketone or an aldehyde of the formula R -CO-R, where R ² and R ^{3 have} the meanings mentioned, or by reaction with 2,2-dimethoxypropane or 2,2-dimethyoxybutane, in a ketone or acetal of the formula 0 0 R ² ^ R ³ and / or mirror image 9 "in which R and R have the meanings mentioned, is transferred and this

by reducing the ring opening in a compound of the formula

and / or mirror image 9 ^ in which R and R have the meanings mentioned, is transferred and, if appropriate,

an alcohol or an alcoholate of the formula V by reaction with dimethyl sulfate, benzyl chloride or a halide of the formula R'-X, in which R ^{1 is} the said

Has meaning except hydrogen and X = bromine or iodine, in an ether of the formula

and / or mirror image 9 ^ in which R or R have the meanings mentioned, is transferred,

and wherein a compound of formula V or VI by alkaline hydrolysis in a compound of the formula

and or mirror image in which R ¹ , R ² and R ^{3 have} the meanings mentioned, is converted, and this is optionally reacted by adding a di- or tri-base organic acid to the corresponding salt, in which R ¹ , R ² and R ^{3 are} the said Have meanings.

2. The method according to claim 1, characterized in that the cw-hydroxylation of the double bond is carried out using osmium tetraoxide.

3. The method according to claim 2, characterized in that osmium tetraoxide in an amount of 0.1 to 2.0 mol%, preferably in an amount of 0.2 to 0.9 mol%, based on the compounds of formula II is used and this is regenerated during the reaction.

4. The method according to claim 3, characterized in that the osmium tetraoxide is regenerated by adding a sterically demanding N-oxide or a mixture of a sterically demanding amine with 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 under acid catalysis.

6. The method according to claim 5, characterized in that sulfuric acid and / or p-toluenesulfonic acid is used for acid catalysis.

7. The method 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 method according to at least one of claims 1 to 7, characterized in that the reducing ring opening is carried out with a complex metal hydride, preferably with NaBH ₄ .

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

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

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

12. The method according to claim 11, characterized in that the alkaline hydrolysis at a pressure of 1 to 10 bar, particularly preferably from 1 to 2 bar, and at temperatures from 50 to 150 ° C, particularly preferably from 80 to 100 ° C. becomes.

13. The method according to at least one of claims 1 to 12, characterized in that the organic acid is selected from the group consisting of crystal water-free and / or crystal water-containing oxalic acid, (+) -, (-) - or meso-tartaric acid, (+) - or (-) - Malic acid, tartronic acid, mesoxalic acid and oxaloacetic acid.

14. The method according to claim 13, characterized in that the organic acid used for salt formation is crystal water-free and / or crystal water-containing oxalic acid.

15. Compounds of the formula

HO OH or mirror image

16. Compounds of the formula

or mirror image wherein R ² and R ^{3 have} the meanings given in claim 1.

17. Compounds of the formula

or mirror image wherein R ¹ , R ² and R ^{3 have} the meanings given in claim 1.

18. Salts of dibasic and triphase organic acids of compounds of the formula

or mirror image 1 9 "\ wherein R, R and R have the meanings given in claim 1.