WO1998015557A1

WO1998015557A1 - Method for the manufacture of biotine (+)

Info

Publication number: WO1998015557A1
Application number: PCT/EP1997/005482
Authority: WO
Inventors: Walter Brieden; John Mcgarrity
Original assignee: Lonza Ag
Priority date: 1996-10-09
Filing date: 1997-10-06
Publication date: 1998-04-16
Also published as: AU4944397A

Abstract

Disclosed is a novel method for the manufacture of biotine (+) having formula (I) in which a furoimidazol derivative having general formula (II) is acylated in position N-3, the acylated compound is made to react with an S donor giving a thienoimidazol, the acyl group is removed in position N-3, the side chain is introduced by means of a Grignard reactant, and after elimination of the hydroxy group, hydrogenation of the unsaturated compound obtained and separation of protective groups in position N-1 the end product biotine (+) is obtained. Biotine (+) is an essential vitamin and is used inter alia in the pharmaceutical sector.

Description

Process for the production of (+) - biotin

The invention relates to a new process for the preparation of (+) - biotin of the formula

a vitamin essential for humans, which is commonly known as vitamin H.

(+) - Biotin is used as pharmaceuticals for the treatment of eg dermatosis or as a feed additive with growth-enhancing effects for farm animals

Numerous syntheses for the production of (+) - biotin have been published. the synthesis disclosed in EP-B 0 273 270 and EP-B 0 270 076, which, starting from tetronic acid, reaches the (+) - biotin.

It has been found that a major disadvantage of this synthesis is that in the last stage of this known biotin synthesis, ie in the removal of the protective groups, in the thienoimidazole pentanoic acid of the general groups which is provided with a protective group in both the N 1 and N 3 positions formula

there is a significant loss of yield, which cannot be remedied by normal optimization efforts There was therefore the task of developing a synthesis which eliminated this problem. This problem could be solved with the new process according to claim 1. The starting product of the synthesis according to the invention, the furoimidazole derivative of the general formula

where R represents a protective group can be prepared in a known manner in accordance with the regulations of EP-B 0 270 076, EP-A 0 624 587 or EP-A 0 647 228

The meaning of R as a protective group includes, for example, easily removable protective groups from the series phenyl- (Cι _-6 ) alkyl or naphthyl- (Cι. _Δ ) -alkyl, the aromatic nuclei of these groups with C _{) -6-} alkyl , C _1-6 alkoxy, hydroxy, a halogen atom, amino, (Cι. ₆ ) alkylamino or (Cι _-6 ) -dialkylamino may be substituted expediently R is a phenyl- (C _2. ₆ ) alkyl or naphthyl (. ₂ C ₆₎ alkyl group, optionally containing one chiral center has Preferably, R is (R) - or (S) - 1-phenylethyl, benzyl, or (R) - or (S) -l-naphthylethyl

In the first stage a) of the process according to the invention, the furoimidazole derivative of the general formula II mentioned at the beginning is converted into the thienoimidazole derivative of the general formula

where R has the meaning given

In a first sub-step a _t ), an acyl group is introduced in the N-3 position of the furoimidazole derivative. The acylating reagents customary in the art, such as, for example, the aliphatic or aromatic acid halides such as acetyl chloride, propionyl chloride or benzoyl chloride, the aliphatic or aromatic Carboxylic acid anhydrides such as acetic anhydride, the halogen formic acid esters such as chloroformic acid ethyl ester or ketene. The acetic acid anhydiide, which can act both as a reactant and as a solvent, has proven to be particularly suitable. The reaction in this step is expediently carried out at elevated temperature, preferably under reflux conditions. when working in the presence of a base, for example a tertiary amine or a polar aprotic solvent such as N, N-dimethylformamide or N, N-dimethylacetamide

The furoimidazole derivative obtained after the first sub-step ai), which is acylated in the N-3 position, can be isolated in a customary manner, advantageously further reacted in sub-step a ₂ ) with a salt of a thiocarboxylic acid into the acylated thienoimidazole. Alkali is useful as salts of thiocarboxylic acids - Or alkaline earth thioacetates or alkali or alkaline earth thiobenzoates, preferably the alkali thioacetates K- or nathioacetate used

It may also be advantageous to add a radical scavenger such as hydroquinone. It is advantageous to work in the presence of a polar aprotic solvent such as BN, N-dimethylformamide or N, N-dimethylacetamide. The reaction temperature is advantageously chosen in the range from 50 ° C. to 150 ° C.

The acylated thienoimidazole obtained in this way can be isolated in a customary manner, advantageously after the removal of the salts obtained in a ₂ ) by water treatment, the direct further conversion in sub-step a ₃ ) to the thienoimidazole derivative of the general formula III by removing the sub-step aj ) introduced acyl group

The splitting off of the acyl group is expediently achieved in sub-step a ₃ ) by treatment with a mineral acid such as, for example, hydrochloric acid or sulfuric acid at elevated temperature. It may be advantageous in the presence, for example, of a lower aliphatic alcohol such as methanol or ethanol as the solvent to work After customary work-up, the thienoimidazole derivative of the general formula III can be obtained in a very high purity in a yield of over 80% based on the furoimidazole derivative of the general formula II used

In the second stage b) of the reaction according to the invention, the thienoimidazole derivative of the general formula III is converted into the thienoimidazole pentanoic acid of the general formula

where R has the meaning given

The side chain is first introduced in a substep b ^ with a Grignard reagent of the general formula

XMg (CH ₂ ) ₄ MgX V

wherein X represents a halogen atom, in the presence of carbon dioxide to the hydroxy derivative of thienoimidazole pentanoic acid of the general formula

This reaction is carried out essentially analogously to the specification from EP-B 0 273 270. The Grignard reagent is generally prepared directly from 1,4-dichloro- or 1,4-dibromobutane and magnesium. The reaction expediently proceeds in the presence of a Ethers such as, for example, tetrahydrofuran or diethyl ether at temperatures between -70 ° C. and 40 ° C. The reaction is preferably carried out in such a way that deprotonation at the N-3 position, for example using a simple Grignard compound such as, for example, n-butyl magnesium chloride, with alkyl lithium or an alkali metal hydride in a suitable polar aprotic solvent. The reaction mixture is usually mixed with carbon dioxide at -30 ° C. to 20 ° C.

The resulting hydroxy derivative of thienoimidazole pentanoic acid of the general formula VI is not known from the literature and is consequently also part of the invention. The preferred derivative is that 5- [(3aS, 4S, 6aR) -4-hydroxy-2-oxo-l - [(R) -l-phenylethyl] hexahydrothieno [3,4-d] imidazol-4-yl] pentanoic acid (general formula VI with R = (R) -l-phenylethyl)

The hydroxy derivative of the thienoimidazole pentanoic acid can be isolated from the reaction mixture in a customary manner, usually direct reaction in step b ₂ ), in which the hydroxyl group is eliminated, and the thienoimidazolylidene pentanoic acid of the general formula

wherein R has the meaning given is obtained

The hydroxyl group is expediently eliminated by acid treatment, for example using a mineral acid such as hydrochloric acid or sulfuric acid or a lower aliphatic carboxylic acid such as acetic acid at elevated temperature. The reaction is usually carried out in the presence of an inert solvent such as toluene, tetrahydrofuran, ethyl acetate, dimethylformamide, N, N-N or acetonitrile. The resulting thienoimidazolylidene pentanoic acid of the general formula VII can in turn be isolated from the reaction mixture in a manner customary in the art, generally proceeding directly to sub-step b ₃ ), catalytic hydrogenation with hydrogen, to the thienoimidazole pentanoic acid of the general formula IV mentioned. The hydrogenation is expediently carried out in the presence of a conventional hydrogenation catalyst selected from the series platinum, palladium, rhodium, ruthenium or nickel, optionally applied to an inert support. A palladium catalyst, either in the form of a palladium salt such as palladium acetate or in metallic form, applied to an inert support such as eg coal, used The hydrogenation with hydrogen is advantageously carried out in the presence of a suitable inert solvent such as toluene, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide or acetonitrile at a temperature between 20 ° C and 150 ° C, preferably ice 20 ° C and 80 ° C and pressures from 1 bar to 100 bar, preferably 1 bar to 10 bar

After the hydrogenation has ended, the thienoimidazole pentanoic acid of the general formula IV can be isolated from the reaction mixture in a manner customary in the art, generally by filtration The thienoimidazole pentanoic acid of the general formula IV can be obtained from this second stage b), calculated over all the sub-steps, in a yield of over 70%

In the last stage c) of the process according to the invention, the protective group R of the preliminary stage is removed by acid treatment or in the course of the hydrogenation mentioned under b ₃ ) and the target product (+) - biotin is thus obtained.

Suitable acids are, for example, trifluoroacetic acid, methanesulfonic acid or hydrogen bromide. As a rule, in the presence of an inert solvent such as toluene,

Tetrahydrofuran, ethyl acetate, N, N-dimethylformamide or acetonitrile worked at elevated temperature. The deprotection in the last stage takes place quantitatively without loss of yield

The resulting (+) - biotin can be obtained in very high purity and in total yields of about 60%, based on the furoimidazole derivative of the general formula II used

Examples:

example 1

Process for the preparation of (3aS, 6aR) -3-acetyltetrahydro-l - [(R) -l-phenylethyl] thieno [3,4-d] imidazole-2,4-dione

In an argon atmosphere, 49.0 g (0.199 ol) (3aS, 6aR) -tetrahydro-l - [(R) -l-phenylethyl) furo [3,4-d] imidazole-2,4-dione in 300 ml of N , N-dimethylacetamide and heated to 100 ° C. 30.3 g (0.298 mol) of triethylamine and 24.4 g (0.239 mol) of acetic anhydride were then added dropwise. Then 0.5 g of 4-dirnefhylaminopyridine was added. After stirring at 100 for 26 hours ° C, 34.1 g (0.296 mol) of potassium thioacetate and 0.22 g (2.0 mmol) of hydroquinone were added at 100 ° C and kept at this temperature for a further 20 hours. After cooling to room temperature, 500 ml of water and 200 ml of ethyl acetate were added The precipitate was filtered off, washed with water and dried under high vacuum. The title compound was obtained in a yield of 31.8 g (52%)

1H-NMR (CDC1 ₃ , 400 MHz) 7.40 - 7.26 (m, 5 H),

5.40 (q, J = 7.1 Hz, 1 H), 5.18 (d, 1 H),

4.58 - 4.55 (dd, 1H),

3.42 - 3.36 (dd, 1H),

2.87 (d, 1H),

2.57 (s, 3 H), 1.71 (d, J = 7, l Hz, 3 H)

Example 2

Process for the preparation of (3aS, 6aR) -tetrahydro-l - [(R) -l-phenylethyI] thieno

[3,4-d] imidazole-2,4-dione

1.00 g (3.28 mmol) (3aS, 6aR) -3-acetyltetrahydro-l - ((R) -l-phenylethyl) thieno (3,4-d) - imidazole-2,4-dione were added in 10 ml Methanol and 6 drops of sulfuric acid conc refluxed overnight. After cooling, the mixture was made weakly basic with 2N NaOH and the product precipitated. After filtration and drying, 0.48 g (56%) of the title compound was obtained

Η NMR (CDC1 ₃ , 400 MHz) 7.44 - 7.39 (m, 2 H),

7.36 - 7.31 (m, 2 H),

7.30 - 7.25 (m, 1 H),

5.80 (s, br, 1 H),

5.33 (q, J = 7.4 Hz, 1 H),

4.64 - 4.59 (m, 1H),

4.05 (d, J = 7.4 Hz, 1 H),

3.24 (dd, J = 7.4 Hz, J = 13.4 Hz),

2.75 (d, J = 13.4 Hz, 1 H),

1.64 (d, J = 7.4 Hz, 3 H)

Example 3

Process for the preparation of (3aS, 6aR) -tetrahydro-l - [(R) -l-phenylethyl] thieno [3,4-d] imidazole-2,4-dione

In an argon atmosphere, 1,137 g (4.60 mol) of (3aS, 6aR) tetrahydro-l - ((R) -l-phenylethyl) furo (3,4-d) imidazole-2,4-dione and 5400 ml Acetic anhydride (57.1 mol) initially charged. The reaction mixture was kept at the reflux temperature for 9 hours. The excess acetic anhydride and the acetic acid formed were then distilled off under vacuum 2460 ml of N, N-dimethylacetamide heated to 100 ° C. were then added to the hot reaction mixture. After cooling to room temperature, 632.0 g (5.51 mol) of potassium thioacetate and 5.5 g of hydroquinone were added and the mixture was heated for 2.5 hours After a short time, the potassium acetate precipitated. The reaction mixture, cooled to room temperature, was then mixed with 3400 ml of water and, after further cooling to 10 ° C., was filtered. The filter cake was washed in succession with 2500 ml of cold water and 2200 ml of cold methanol. The resulting solid became then resuspended in 4500 ml of methanol. After adding 524 ml of hydrochloric acid conc, the reaction mixture was kept at the reflux temperature for 5 hours, then cooled to room temperature and neutralized with 2700 g of 20% -KHCO ₃ solution with cooling. The resulting suspension was filtered at 0.degree , the filter residue was washed with cold water and then dried to constant weight. 1014 g ( 83%) of the title product in the form of a brown solid with a GC content of 98.7%, mp 149.5 ° C - 150.6 ° C

Example 4

Process for the preparation of 5 - ((3aS, 4S, 6aR) -4-hydroxy-2-oxo-l - [(R) -l-phenylethyl] hexahydrothieno [3,4-d] imidazol-4-yI) pentanoic acid

2.00 g (7.5 mmol) (3aS, 6aR) -tetrahydro-l - ((R) -l-phenylethyl) thieno (3,4-d) -imidazole-2,4-dione were used in a previously Argon-inertized apparatus placed in 30 ml of tetrahydrofuran and cooled to -80 ° C. 3.10 g (1.21 mmol / g) of Digrignard reagent previously prepared from 1,4-dichlorobutane and magnesium chips were then added and the mixture was stirred at -80 ° for 1 hour C Then a further portion of Digrignard reagent of 9.30 g was added and heated to -20 ° C. After two hours of stirring at this temperature, CO _{2 was introduced} until saturation. The mixture was then warmed to room temperature, the reaction solution was added to 30 ml of water and with hydrochloric acid adjusted to pH 1.5 After addition of 50 ml of hexane, the suspension was filtered at 0 ° C. Drying the filter residue led to 2.18 g (66%) of the title product, mp 205 ° C.-206 ° C. Η NMR (CDC1 ₃ , 400 MHz) 12.60 - 11.00 (s, br, 1 H),

7.47 - 7.25 (m, 5 H), 6.83 (s, 1 H), 5.80 - 5.50 (m, 1 H), 4.97 (q, J = 7.1 Hz) , 1 H),

4.62 - 4.56 (dd, 1H),

3.81 - 3.78 (d, 1 H), 2.88 - 2.80 (dd, 1 H), 2.23 - 2.17 (m, 2 H), 2.13 - 2.08 (d, 1 H),

1.82-1.66 (m, 2H), 1.58-1.42 (m, 2H), 1.54 (d, J = 7.1 Hz, 3H), 1.40-1.30 (m, 2 H)

Example 5

Process for the preparation of (3aS, 6aR) -5- (2-oxo-l - [(R) -l-phenyIethyI] hexahydrothieno [3,4-d] imidazoI-4-ylidene) pentanoic acid

2.00 g (5.49 mmol) 5 - ((3aS, 4S, 6aR) -4-hydroxy-2-oxo-l - ((R) -l-phenylethyl) hexahydrothieno (3,4-d) imidazole- 4-yl) pentanoic acid was placed in 10 ml of N, N-dimethylformamide and 0.2 g of sulfuric acid conc and heated to 60 ° C. After stirring for one hour at 60 ° C., the solvent was removed on a rotary evaporator and the residue was taken up in 50 ml of dichloromethane and the organic phase is washed with water. The organic phase is concentrated after drying over magnesium sulfate. 1.98 g (100%) of the title product are obtained in the form of a viscous oil

Η NMR (CDC, 400 MHz) 7.43 - 7.21 (m, 5 H),

7.07 (s, br, 1 H), 5.59 (t, J = 7.3 Hz, 1 H), 4.98 (q, J = 7, 1 Hz, 1 H), 4.52 - 4.40 (m, 2 H),

2.82-2.77 (dd, 1H), 2.42-2.36 (dd, 1H), 2.23-2.18 (t, 2H), 2.02-1.96 ( m, 2 H), 1.65 - 1.45 (m, 2 H),

1, 57 (d, J = 7, 1 Hz, 3 H)

Example 6 Process for the preparation of 5- (3aS, 4S, 6aR) -hexahydro-2-oxo-l - [(R) -l-phenylethyl] thieno [3,4-d] imidazol-4-yl) pentanoic acid

25.00 g (68.58 mmol) 5 - ((3aS, 4S, 6aR) -4-hydroxy-2-oxo-l - ((R) -l-phenylethyl) hexahydrothieno (3,4-d) imidazole- 4-yl) pentanoic acid, 150 ml of N, N-dimethylformamide, 0.67 g of sulfuric acid conc and 3.64 g of Pd 10% on C were placed in an autoclave. The reaction mixture was then at a temperature of 80 ° C. and Hydrogenated at a hydrogen pressure of 10 bar, followed by hot filtration, washing with hot N, N-dimethylformamide and 500 ml of water added to the filtrate. The resulting white precipitate was filtered after standing at 4 ° C. for 5 hours, giving 16.5 g of Title product corresponding to a yield of 69% mp 212 ° C - 214 ° C

Η NMR (CDC1 ₃ , 400 Mhz) 1 1, 95 (s, br, 1 H),

7.39 - 7.37 (m, 2 H),

7.34 - 7.29 (m, 2 H),

7.25 - 7.21 (m, 1H), 6.69 (s, 1H),

4.96 (q, J = 7, 1 Hz, 1 H),

4.47 - 4.43 (dd, 1H),

4.12 - 4.10 (m, 1H),

3.10 - 3.07 (m, 1 H), 2.50 - 2.47 (m, 1 H),

2.20 (t, J = 7.3 Hz, 2 H),

2.08 (d, J = 12.5 Hz, 1 H),

1.70 - 1.60 (m, 1 H), l, 54 (d, J = 7, l Hz, 3 H), 1.55 - 1.40 (m, 3 H),

1.38 - 1.27 (m, 2 H)

Example 7

Process for the preparation of 5- (3aS, 4S, 6aR) -hexahydro-2-oxo-l - [(R) -l-phenylethyl] thieno [3,4-d] imidazol-4-yl) pentanoic acid

10.00 g (37.6 mmol) (3aS, 6aR) -tetrahydro-l - ((R) -l -phenylethyl) thieno (3,4-d) -imidazole-2,4-dione were in one with argon The previously inertized apparatus was placed in 160 ml of tetrahydrofuran and cooled to -80 ° C. 18.8 ml of n-butylmagnesium chloride (2 mol) were then added dropwise over the course of 1 hour so that the temperature did not exceed -70 ° C. This reaction solution was then after 30 Minutes of stirring to a Digrignard solution prepared from 1 1, 94 g 1, 4-dichlorobutane, 5.7 g magnesium shavings and 0.9 g 1,2-dibromoethane, in 160 ml tetrahydrofuran and 4.8 g tetramethylene diamine at -20 ° C. added dropwise After a brief stirring, dried CO _{2 was} introduced for 2.5 hours until saturation. 100 ml of acetic acid were then added with cooling and the tetrahydrofuran was removed on a rotary evaporator The residue was heated to 80 ° C. over an hour, then mixed with 50 ml of water and then extracted three times with 75 ml of toluene. The combined toluene phases were extracted successively with 100 ml of 33% NaOH solution and 20 ml of IN NaOH. The combined aqueous Phases were adjusted to pH 1.5 at 0 ° C. with HC1 conc and then extracted four times with 100 ml of toluene. The combined toluene phases were finally concentrated and the residue was taken up in 100 ml of a mixture of tetrahydrofuran with water in a ratio of 4. This solution was used

240 mg palladium acetate added In an autoclave, the reaction mixture was hydrogenated at 85 ° C. for 4 hours at a hydrogen pressure of 20 bar. Then 100 ml tetrahydrofuran was added and the mixture was filtered hot

The rotary evaporator was evaporated down, the residue which had precipitated was filtered at 0 ° C. 11.26 g of the title product were obtained, corresponding to a yield of 71%, mp 212 ° C.-214 ° C.

Example 8

Process for the production of (+) - biotin

5.00 g (13.82 mmol) 5- (3aS, 4S, 6aR) -hexahydro-2-oxo-l - ((R) -l-phenylethyl) thieno (3,4-d) imidazol-4-yl ) Pentanoic acid were stirred in 29.8 g (260 mmol) of trifluoroacetic acid and 3.0 g of toluene under argon for 4 hours at 65 ° C. 85 g of toluene were then added. After concentration, 15 ml of acetone were added and the mixture was stirred at 0 ° for 30 minutes C stirred filtration, washing with acetone and drying gave 3.55 g (99%) (+) - Biotιn in the form of a light yellow solid with an HPLC content of 94.5% mp 229 ° C - 230 ° C

Claims

Claims:

1 Process for the preparation of (+) - biotin of the formula

characterized in that a furoimidazole derivative of the general formula

wherein R represents a protective group, a) in the first stage in the thienoimidazole derivative of the general formula

where R has the meaning given, in this first stage ai) the furoimidazole derivative is first acylated with an acylating reagent in the N-3 position a ₂ ) the acylated compound is converted into the acylated thienoimidazole with a salt of a thiocarboxylic acid and a) in the acylated thienoimidazole, the acyl function introduced in the N-3 position is removed again, in the second stage the thienoimidazole derivative of the general formula III is converted into a thienoimidazole pentanoic acid of the general formula

transferred, in this second stage b]) the thienoimidazole derivative with a Grignard reagent of the general formula

XMg (CH ₂ ) ₄ MgX V

wherein X represents a halogen atom, in the presence of carbon dioxide in a hydroxy derivative of thienoimidazole pentanoic acid of the general formula

where R has the meaning given, is converted and then b ₂ ) the hydroxyl group is eliminated and the resulting

Thienoimidazolylidenpentanoic acid of the general formula

b ₃ ) is catalytically hydrogenated with hydrogen and in the last stage c) the protective group R ^{1 is} removed

A method according to claim 1, characterized in that in the first stage a) the intermediates from aj and a _{2 are} not isolated

A method according to claim 1 or 2, characterized in that acetic anhydride is used as the acylating reagent

Method according to one of claims 1 to 3, characterized in that the conversion to the acylated thienoimidazole in step a ₂ ) with an alkali or

Alkaline earth thioacetate in the presence of a polar aprotic solvent at 50 ° C to 150 ° C.

Method according to one of claims 1 to 4, characterized in that the removal of the acyl group in the N-3 position in step a ₃ ) is carried out in the presence of an acid

Method according to one of claims 1 to 5, characterized in that in the second stage b) the intermediates from b] and b _{2 are} not isolated

Method according to one of claims 1 to 6, characterized in that the conversion into the hydroxy derivative of thienoimidazole pentanoic acid of the general formula VI in stage bi) with a Grignard reagent prepared from 1,4-dichloro- or 1,4-dibromobutane in a Temperature between -70 ° C and 40 ° C in the presence of an ether

Method according to one of claims 1 to 7, characterized in that the elimination of the hydroxy group in step b ₂ ) takes place in the presence of an acid

Method according to one of claims 1 to 8, characterized in that the hydrogenation in step b) is carried out in the presence of a palladium catalyst

Method according to one of claims 1 to 9, characterized in that the hydrogenation in stage b ₃ ) is carried out at a temperature between 20 ° C and 150 ° C and a hydrogen pressure of 1 to 100 bar

11. The method according to any one of claims 1 to 10, characterized in that the removal of the protective group R ¹ in the last stage c) is carried out by acid treatment of the precursor.

12. Hydroxy derivatives of thienoimidazole pentanoic acid of the general formula

wherein R represents a protecting group.

13. 5 - ((3aS, 6aR) -4-hydroxy-2-oxo-l - [(R) -l-phenylethyl] hexahydrothieno [3,4-d] imidazol-4-yl) pentanoic acid