DK155322B - PROCEDURE FOR THE PREPARATION OF 14-HYDROXYMORPHINAN DERIVATIVES AND PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS AND INTERMEDIATE USE FOR THE PROCEDURE - Google Patents

Description

in

DK 155322 B

The present invention relates to a particular process for the synthesis of N-substituted-14-hydroxy-3-substituted-morphinans of the general formula:

'U

2 wherein R represents H or (C 1 -C 6) alkyl and R represents cyclobutyl or cyclopropyl. The process is characterized by the characterizing part of claim 1.

Substance abuse by thrill-seeking youth or people seeking an escape from the realities of everyday life has become more and more common in today's society. One category of drugs with widespread abuse is the narcotic analgesics such as codeine, morphine, meperidine, etc. It is because of the strong ability of these drugs to develop dependence that the drug industry and authorities spend a lot of time and money trying to discovery and development of new non-addictive analgesics and / or drug antagonists.

The present invention has for its object to provide a process for the synthesis of the above-described compounds of the general formula L which will not be dependent on opium alkaloids as starting materials and yet be commercially possible.

United States Patent Nos. 3,775,414 and 3,819,635 already disclose processes for the preparation of compounds of the above kind for the same purpose. However, the method according to the first patent comprises at least 9 steps and the method according to the latter patent comprises at least 12 steps.

The present invention fulfills the above object and further allows the compounds of formula L to be prepared from readily to -35 commonly available 2- (p-alkoxybenzyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline- starting materials al, such as 2- (methoxybenzyl) -1,2,3,4,5,6,7,8-octahydroquinoline, in a complete synthesis comprising 4 - 6 steps.

The compounds of the invention have morphine bases.

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2 nucleus, which is numbered and shown by the following plan formula: 1 6 1 10 Hl7 5 2 I r J »1 * 10 Although there are three asymmetric carbon atoms (stars) in the morphinan molecule, only two diastereoisomeric (racemic) forms are possible. because the iminoethane system associated with positions 9 and 13 is forced geometrically to a cis (1,3-diaxial) fusion. Therefore, these racemates can only differ by the association of rings B and C, in other words by the carbon atom 14 configuration. The only variable will be the cis and trans ratio of the 5 (13) to 8 (14) bonds (Analgetics, Ed.

George de Stevens, Academic Press, New York, p. 137 (1965). When the 5 (13) and 8 (14) bonds are in cis position to each other, the compounds are commonly referred to as "morphinans. The use of a graphical representation of a" morphinan "is intended to include the racemic d1 mixture and the dissolved d- and 1-isomers thereof.

The "morphinan" compounds of the present invention, characterized by the formula L, can each exist as two optical isomers, the left-turn and the right-hand isomer.

The optical isomers can be illustrated graphically as:

morphinans

------ R20

The present invention encompasses the preparation of all the morphinane isomers, including the optical isomers in their dissolved form.

The optical isomers can be separated and isolated by fractionated 35

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3 crystallization of di astereo in summer salts formed with e.g. d- or 1_-tartaric acid or D - (+) - α-bromocampersulfonic acid. The left-turn isomers of the compounds of the invention are the most preferred embodiments.

The term (Cj-Cg) alkyl denotes e.g. methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl and sec-butyl. The term "pharmaceutically acceptable acid addition salt" is defined to include all such inorganic and organic acid salts of the compounds of the invention which are commonly used to produce 10 non-toxic salts of drugs containing amine functions. Illustrative examples would be such salts formed by mixing the compound of formula (L) with hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, phosphoric acid, hydrobromic acid, maleic acid, malic acid, ascorbic acid, citric or tartaric acid, pamoic acid, lauric acid, stearic acid. 15, acid, palmic acid, oleic acid, myristic acid, lauryl sulfate acid, naphtha lens sulfonic acid, li nole or linolenic acid.

The morphine compounds LV (wherein R represents cyclopropyl or cyclobutyl and R represents (C 1 -C 6) alkyl) and LX (wherein R represents cyclopropyl or cyclobutyl) are prepared according to the invention by a complete synthesis comprising 4 to 6 steps. The synthesis is effective and appears commercially useful. Scheme I illustrates, on the one hand, the process of the invention for the preparation of N-cyclobutylmethyl-14-hydroxy-3-methoxy-morphinan (LVa) and N-cyclobutylmethyl-3,14-dihydroxymorphinan (LXa), and the preparation of the starting compounds used.

35 (LV) (LX)

- 4 DK 155322 B

ISLAND

Example> rgyTf ^ ch30 CH3 ° la y Ha

Example 2 y yt o / _ - f ^ rOf '· * Π * j6j? I ^ <pS ch3o [V]

ch3 ° | ^ J

Example 3 IVa

CHoO, 'l I CH3 ° Η0 ** | IN

3 HO "I J II

Va in Example 4 V * a Λ I (Ή <Example 5> / X / ^ T1 ch3 ° '

CH3 ° HO '^ IJ

Vila LVa

Example 12

HO ^^ T I

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5

By opening the 9,10-epoxide group in compounds such as IIa and IVa according to the procedure of Example 3, 9,10-diol compounds are obtained which may exist in conformations as illustrated by the following planar formulas (and the four optical isomers thereof). , wherein R

o represents cyclobutyl or cyclopropyl, and R represents (C 1 -C 6) alkyl. oh 2? ΦΓΤ ^ Ί 0

-L

10 h / HC HCV 'i-V

v ,. XOX

(trans-diol) (cis-diol)

OH

cf> Ct> ττΛ ^ H0 '20 HO' * _ <S '/ ^) _ OR2 V γΟ) - OR2 (cis-diol) (trans-diol) In accordance with the process of the present invention, it is believed that the product, obtained at the opening of the 9,10-epoxide group of Compounds IIla and IVa, as well as being completely in possession of the trans-9β, 10O1-diol ratio of Compound Va (and its corresponding -30 mirror image) with only traces of the smaller desirable trans-diol Via.

The present invention also relates to the novel intermediates of the formula:. Q

r2o V ^ l

HO-'U

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Wherein R represents cyclopropyl or cyclobutyl and R represents (C 1 -C 6) alkyl, preferably methyl.

Preferred embodiments of the present process for the preparation of compounds of formula (L) are those wherein 5 (1) step a) is carried out in tetrahydrofuran, toluene or benzene; (2) reducing the compound of formula (V) in step a) with borane dimethyl sulfide; (3) reducing the compound of formula (V) in step a) with borane which is formed in situ by reaction of sodium borohydride with a compound in the form of boron trifluoride, boron trifluoride tetrahydrofuran complex or trifluorine cool etherate; (4) the borane under step a) is used in a ratio of approx. 1 mole of compound V to 1.33 to 2.0 moles. borane; (5) the borane under step a) is used in a ratio of approx. 1 mole of compound V to 1.6 to 1.9 mole of borane; (6) the borane under step a) is used in a ratio of approx. 1 mole of compound V to 1.75 mole of borane; (7) step a) is carried out by means of heat at a temperature in the range of approx. 50 to 115 ° C; (8) step a) is carried out in toluene under reflux; (9) treating the boron complex of compound VII in step b) with an acid in the form of phosphoric acid, orthophosphoric acid, pyrophosphoric acid or polyphosphoric acid; (10) treating the boron complex of compound VII under step b) with anhydrous phosphoric acid and phosphorus pentoxide; (11) treating the boron complex of Compound VII under step b) with a large excess of anhydrous phosphoric acid and phosphorus pentoxide; (12) step b) is carried out at a temperature in the range of 50 to 100 ° C; (13) step b) is carried out at a temperature in the range of 70 to 75 ° C;

In step (14) step b), a temperature in the range of 70 to 75 ° C is performed

with anhydrous phosphoric acid and phosphorus pentoxide; (15) the boron complex of compound VII after the reduction step a) is hydrolyzed with aqueous acid prior to the cyclization step b).

The most preferred embodiment of the present invention 35 is a process for preparing the compound of formula (L '):

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7 5 \ Γλ \ / i (l ') KJI / Lph 10 2 wherein R represents hydrogen or methyl, and comprising the successive step a) of reducing the compound of formula (Va): jgj / j> <v *> CH, 0 x 1 20 HO '' with borane in a molar ratio of approx. 1.75 mole of borane to approx. 1 mole of compound Va in toluene by heat at a temperature in the range of approx. 50-115 ° C to produce a boron complex of the compound of formula (Vila): 30 <νΛ (VIIa)

CH3 ° HO "" M

b) treating the boron complex of the compound Vila with a large excess of a 6.4: 1 mixture of anhydrous phosphoric acid: phosphorus pentoxide by heat at a temperature in the range of approx. 70-75 ° C, until the ring formation is substantially complete, to give the compound of formula (LVa):

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s. "

CH30 I

and, if desired, c) demethylating the compound LVa with NaSC2Hg, hydrogen bromic acid, boron bromide or pyridine, hydrochloride to give the compound of formula (LXa):

15 yJ

JQH &; HO in 20 and, if desired, d) convert the compound LXa to a non-toxic pharmaceutically acceptable acid addition salt thereof in a manner known per se.

The compounds N-cyclopropylmethyl-14β-hydroxy-3-methoxy-morphinan, N-cyclobutylmethyl-14β-hydroxy-3-methoxymorphinane, N-cyclopropylmethyl -3,140-dihydroxymorphinane and N-cyclobutylmethyl-3,14β-dihydroxymethyl are known and described in U.S. Patent No. 3,819,635.

In the present context, the term "inert organic solvent" means an organic solvent which does not participate in the reaction so that it appears unchanged after the reaction. Such solvents are methylene chloride, chloroform, dichloroethane, tetrachloromethane, benzene, toluene, ether, ethyl acetate, xylene, tetrahydrofuran dioxane, dimethylacetamide and the like.

The present invention will be described in more detail below with examples in which all temperatures are expressed in ° C and VPC means vapor phase chromatography. IR means infrared spectrum and NMR means nuclear magnetic resonance spectrum.

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9

Preparation of Starting Compounds Example 1 2-Cyclobutylcarbonyl-1- (p-methoxybenzyl) -1.2.3.4.5.6.7.8-octahydroiso-5-quinoline (Hal

Triethylamine (22.2 g, 0.22 mol) is slowly added to 1- (p-methoxy-benzyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline, hydrochloricl Ia (29.4 g, 0.1 mole) dissolved in 200 ml of methylene chloride with stirring and ice bath cooling. Next, cyclobutylcarbonyl chloride (13 g, 0.107 mol) in 10 ml of methylene chloride is added dropwise with stirring to the mixture keeping the temperature at 0 to 5 ° C. After stirring the reaction mixture for 1 hour at room temperature, 100 ml of water are added, the mixture is acidified by the addition of 50 ml of 10% sulfuric acid and the methylene chloride is separated.

If desired, the methylene chloride solution containing IIa can be used directly for the next step or concentrated to produce an oil which solidifies on standing. Recrystallization of a sample of the solidified material from acetone gives the crystalline product Ila, m.p. 89-9Γ.

Various organic tertiary amines commonly used as proton acceptors in acylation reactions can be used in place of triethylamine in the above process. Such amines are tri- (lower) alkyl amines, e.g. trimethylamine, triethylamine and the like, pyridine, d in methyl aniline, N-methylpiperidine and the like.

EXAMPLE 2 2-Cyclobutylcarbonyl-9,10-epoxy-1- (p-methoxybenzyl) perhydrosoilinole down to IVa

Process A - Peracetic Acid Oxidation To a solution of 2-cyclobutyl carbonyl-1- (p-methoxybenzyl) -1,2,3,4,5,6,7,8, -octahydroisoquinoline (IIa) (0.1 mol ) In 230 ml of methylene chloride, peracetic acid (40%, 23.8 g, 0.12 mol) is added at such a rate that the temperature is maintained at 30-35 ° C. After stirring the obtained solution at room temperature for 1 hour, 200 ml of water is added and 35 excess peracetic acid is destroyed by the addition of 100 ml of 10% sodium bisulfite solution. The methylene chloride phase is separated and concentrated under reduced pressure to give an oily residue which is constituted by the isomeric epoxides trans IIla and cis IVa in the ratio of 23:78

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10 according to vapor phase chromatographic analysis (VPC). The two epoxides can, if desired, be separated by column chromatography using an alumina or silica column (eluting with diethyl ether).

The epoxide in least amount (IIa), melting point 118 ° C, has "transconfiguration", and the epoxide in greatest amount (IVa), melting point 82-84 °, has "cis configuration" with respect to steric ratios of p the methoxybenzyl group and the oxirane group.

Process B - Pertrifluoroacetic Acid Oxidation To a solution of 2-cyclobutylcarbonyl-1- (p-methoxybenzyl) - 1,2,3,4,5,6,7,8-octahydroisoquinoline (IIa) (0.05 mole) in 125 Sodium carbonate (20 g, 0.19 mol) is added to methylene chloride and the mixture is cooled to 0 °. A solution of pertri fluoroacetic acid is prepared by mixing trifluoroacetic anhydride (16.6 g, 0.077 mole) and 90% hydrogen peroxide (2.94 g, 0.077 mole) in 35 ml of methylene chloride at 0 °.

The peracid solution is added dropwise to the reaction mixture of IIa at a rate such that the reaction temperature is maintained at 0 to 5 °. After completion of the addition, the reaction mixture is stirred for 0.5 hour at 0 to 5 °, and the excess peracid is then destroyed by the addition of 10% sodium bisulfite solution with stirring until the evolution of CO 2 ceases. The methylene chloride phase is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to an oily residue which is constituted by the isomeric epoxides IIa and IVa at a trans: cis ratio of 35:65 according to VPC.

25

Example 3 2-Cyclobutylcarbonyl-9,10-dihydroxy-1- (p-methoxybenzyl) perhydrozoylamino no-lin

The mixture of isomeric epoxides IIa and IVa from the peracetic acid oxidation in Example 2 is dissolved in 300 ml of acetone and cooled to 0 °. To this solution is first added 30 ml of water and then 30 ml of concentrated sulfuric acid at such a rate that the temperature is kept below 25 °.

After stirring the reaction mixture for 1 1/2 hours at 25 °, a water portion of 150 ml and a toluene portion of 300 ml are added. The obtained two-phase mixture is made basic with sodium hydroxide solution and the toluene layer is separated and concentrated to a residual oil. This oil, upon stirring with 300 ml of cyclohexane, gives a suspension of white solid which is collected on a filter. The white solid consists essentially of it

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n desired trans-diol Va contaminated with the isomeric trans-diol Via as shown by VPC. The yield of Va calculated from the starting amine 1a is 75%. The cyclohexane filtrate is again treated with sulfuric acid to give an additional 10% yield of trans-diol. Further purification of the white solid is carried out by crystallization from acetonitrile to give material having a melting point of 145-147 ". Instead of the concentrated sulfuric acid used above, other acids such as nitric acid, hydrochloric acid, hydrogen bromide acid or strong organic acids such as all cooling sulphonic acid, trifluoroacetic acid and the like are used.

Hydrolysis of the pure trans-epoxide in at least amount IIa in accordance with the above process yields only the desired trans-diol Va, while hydrolysis of the cis-epoxide in greatest amount IVa gives the desired trans-diol Va together with some of the isomeric trans. -diol Via in a Va: VIa ratio of 86:14.

15

Preparation of End Products Example 4 2-Cyclobutylmethyl-9,10-dihydroxy-1-fp-methoxybenzyl perhydroisoquinoline 20 (Vila)

To a solution of 2-cyclobutylcarbonyl-9,10-dihydroxy-1- (p-methoxybenzyl) perhydroisoquinoline Va (30 g, 0.08 mol) in 300 ml of tetrahydrofuran is added borane dimethyl sulfide pure solution (14 ml, 0.14 mol ) through a syringe needle under a nitrogen atmosphere. The resulting mixture is heated to reflux for 2 hours and then concentrated under reduced pressure to remove the solvent. The resulting boron complex of the cyclobutyl methylamine Vila can be used directly for the next reaction, or it can be hydrolyzed with aqueous acid, such as hydrochloric acid to produce Vila, mp 120-122 ° C. Reduction of trans-diol Va amido function with the following boron sources gives also Vila.

1) Borane-tetrahydrofuran complex.

2) In situ generated borane in tetrahydrofuran using sodium borohydride and boron fluoride gas or boron trifluoride tetrahydrofuran complex or boron trifluoridal cooling etherate.

Example 5 N-Cyclobutylmethyl-14fl-hydroxy-3-methoxymorphinan Π-Val

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12

Procedure A - Rinas' drilling with boron conrolx.

To the boron complex residue from the borane reduction reaction (0.08 mol) in Example 4 is added 320 g of anhydrous phosphoric acid (prepared from 85% phosphoric acid and phosphorus pentoxide) and 50 g of phosphorus pentoxide. The mixture 5 is stirred at room temperature for 0.5 hour, and then at 70-75 ° for a period of 4 hours. The reaction mixture is diluted with 200 ml of water and then poured into a mixture of 600 ml of concentrated ammonium hydroxide and 1 liter of crushed ice. The mixture is extracted with 400 ml of heptane and the heptane extract is dried over sodium sulfate. Concentration of the dried heptane extract 10 gives 23.1 g of oil (85% yield) of product LVa. This oil is dissolved in acetone and treated with anhydrous hydrogen chloride gas to give crystalline hydrochloride salt of product LVa, mp 248-250 °.

Example 6 Left-handed N-cyclobutylmethyl1-14fl-hydroxy-3-methoxymororhinane fLVaM.

By replacing racemic Ia with right-hand end 1- (p-methoxybenzyl) -1,2,3,4,5,6,7,8-octahydroxyquinoline in the method of Example 1, hydrochloride and sequentially using the methods of Examples 2 -20 are obtained the left-turn product LVa '.

The procedures of Examples 4 and 5 are carried out as follows. To a solution of left-turn 2-cyclobutylcarbonyl-9,10-dihydroxy-2- (p-methoxybenzyl) perhydroisoquinoline (10 g, 0.0267 mol) in 100 ml of toluene, borane dimethyl sulfide pure solution (6 ml, 0.057 mol) is added through syringe needle under nitrogen atmosphere. The resulting solution is refluxed for 3 hours, concentrated under reduced pressure to remove about 40 ml of the solvent, and the boron complex of the left-turn cyclobutyl-methylamine Vila is used directly in the cyclization reaction.

Closure of the boron complex of the left-turn cyclobutyl-30-methylamine Vila is carried out by portionwise addition of the above-mentioned toluene-borane complex mixture to 200 g of anhydrous phosphoric acid and 35 g of phosphorus pentoxide while stirring and maintaining a temperature in the range of 0-25 ° C. After the addition is complete, the mixture is heated and stirred for a period of 5 hours at 70 ° C and then poured into a mixture of 400 ml of concentrated ammonium hydroxide with an amount of ice sufficient to maintain a temperature of about 25 ° C. The mixture is extracted with toluene, the toluene extract is washed with water and then concentrated under reduced pressure to produce

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13 rotating N-cyclobutylmethyl-14/8-hydroxy-3-methoxy-morphinan (LVa ') base.

The oily base is converted to the sulfate salt by treatment with sulfuric acid to give 7.2 g (61% yield) of left-turn N-cyclobutylmethyl-14β-hydroxy-3-methoxy-morphinanesulfate salt, mp 232-5 237 ° C (decomp. .), [a] d-55.4 ° C. (C = 0.56, CH 3 OH).

Example 7 N-Cyclobutylmethyl1-3.14-dihydroxymorphinan (LXa)

A mixture of N-cyclobutylmethyl-14β-hydroxy-3-methoxymorphinan 10 (LVa) (1.0 g, 2.58 mmol) and 10 ml of 48% HBr is refluxed under a nitrogen atmosphere for a period of 5 minutes. After cooling, the reaction mixture is diluted with water and made basic with aqueous ammonium hydroxide. The aqueous basic mixture is extracted with several portions of chloroform and the combined chloroform extracts are dried over anhydrous sodium sulfate.

After evaporation of the solvent, the residual oil (730 mg) is taken up in dry ether and the solution obtained is filtered through diatomaceous earth charcoal. The filtrate is treated with a saturated solution of hydrogen chloride in dry ether and the hydrochloride salt thus obtained is collected and crystallized from methanol-acetone to give 565 mg (56.5%) of N-cyclobutylmethyl-20,14-dihydroxymorphinane, hydrochloride (LXa), mp 272-274 ° (decomp.). The IR and NMR spectra were consistent with this structure.

Analysis calculated for C 21 H 29 NO 2 HCl * 1/2 CH 3 OH (percent): 25 C, 67.97; H, 8.49; N, 3.49.

Found (percent): C, 68.10; H, 8.14; N, 3.80.

Acidification of the filtered dry ether solution referred to above with appropriate acids yields various "pharmaceutically acceptable acid addition salts" of LXa.

The 3-methoxy ether function on N-cyclobutylmethyl-14β-hydroxy-3-methoxymorphinan can also be cleaved by treatment with ether cleavage agents such as NaSCgHg, boron tri bromide or pyridine hydrochloride to give the desired demethylated product LXa.

Claims (11)

A process for the preparation of 14-hydroxymorphinan derivatives of the formula: wherein R is cyclobutyl or cyclopropyl and R is H or (C 1 -C 6) alkyl and pharmaceutically acceptable acid addition salts thereof, characterized in that it comprises, in successive steps a) reducing the compound of formula (V): 2 ° _ / ^ Ncr JA-'J \ (V). R 2 represents E 2 'wherein R represents cyclobutyl or cyclopropyl and R represents (C 1 -C 8 alkyl with borane, boron dimethyl sulfide or borane-tetrahydrofuran complex in an inert organic solvent to give a boron complex of the compound of formula (VII): 82 "r Ok uoh (vid 35 2 / \ K \ KC • RO * \ \ EO '. LJ 2 DK 155322 B wherein R represents cyclobutyl or cyclopropyl and R represents (C VII with acid to give the compound of formula (LV): 10 u 2 wherein R represents cyclobutyl or cyclopropyl and R represents (C 1 -C 4) alkyl; and, if desired, 0 2 15 c) cleaves the R LV by treatment with NaSC2Hg, hydrobromic acid, boron tribromide or pyridine hydrochloride to give the compound of formula (LX): 2 ° R 2 R 2 R 2 CH 2 R 2 & aX 2 0 O wherein R represents cyclobutyl or cyclopropyl, and, if desired, d) prepared compound of formula (LV) or (LX) for a pharmacist isic acceptable acid addition salt thereof. Process according to claim 1, characterized in that the compound 30 of formula (V) under step a) is reduced with borane dimethyl sulfide. Process according to claim 1, characterized in that the compound of formula (V) under step a) is reduced with borane generated in situ by reaction of sodium borohydride and boron fluoride or sodium borohydride and boron trifluoride tetrahydrofuran complex or sodium borohydride and boron trifluoridal cooling etherate. Process according to any one of claims 1-3, characterized in that during step a) the borane is used at a ratio of approx. 1 mole of compound V to 1.33 to 2.0 mole of borane. DK 155322 B A process according to any one of claims 1 to 4, characterized in that step a) is carried out by means of heat at a temperature in the range of from approx. 50 to 115 ° C. Process according to any one of claims 1 to 5, characterized in that the boron complex of compound VII in step b) is treated with an acid in the form of phosphoric acid, orthophosphoric acid, pyrophosphoric acid or polyphosphoric acid. Process according to any one of claims 1-5, characterized in that the boron complex of compound VII in step b) is treated with anhydrous phosphoric acid and phosphorus pentoxide. Process according to any one of claims 1 to 7, characterized in that step b) is carried out at a temperature in the range of 50 to 100 ° C. Process according to any one of claims 1 to 8, characterized in that the boron complex of compound VII after the reduction step a) is hydrolyzed with aqueous acid prior to the cyclization step b). A compound for use as an intermediate in the process of claim 1, characterized in that it has the formula: 20. N-C-R RO, Ί or qJ 25 Λ wherein R represents cyclopropyl or cyclobutyl and R represents (C A compound according to claim 10, characterized in that R is methyl. 30 35