DE1229533B - Process for the preparation of pyridine derivatives - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

C07d

German KL: 12 p-1/01

Number: 1229 533

File number: H 52045 IV d / 12 ρ

Filing date: March 13, 1964

Opening day:! December 1966

The invention relates to a method of manufacture of pyridine derivatives of the general formula

(D

where Ri and R _{3 are} hydrogen, hydroxyl or lower alkoxy or aralkoxy groups and R2 and Rj each represent either a hydroxy group, a lower alkoxy or aralkoxy group or R2 and R ₄ together represent an oxygen atom or an optionally substituted methylenedioxy group or Ri and R2 together and R ₃ and R ₄ together each denote an oxygen atom, as well as the conversion of these pyridine derivatives into vitamin Be (pyridoxine) or acid addition salts thereof, which is characterized in that 4-methyl-oxazole is mixed with a dienophilic compound of the general formula

Ri \ / R ₃

"> CH - CH = CH - CH (T (II)

R ₂ '^ R ₄

in which Ri, R2, R ₃ and Rj have the above meaning, heated, a dehydrating agent added and the reaction product optionally converted in a manner known per se into vitamin ββ (pyridoxine) and this with acids into acid addition salts.

It is believed that the reaction described above proceeds according to the following scheme:

Ri

R ₂ -CH R ₃

CH HC-R ₄

\ /
CH

II

HC

H ₃ C - C

CH Process for the production of pyridine derivatives

Applicant:

F. Hoffmann-La Roche & Co. Aktiengesellschaft, Basel (Switzerland)

Representative:

G. Schmitt, lawyer, Lörrach (Bad.), Friedrichstr. 3

Named as inventor: Dr. John Mervyn Osbond, Welwyn Garden City, Hertfordshire (Great Britain)

Claimed priority: Great Britain March 21, 1963 (11,167) - -

I. Ri R ₃ R ₃ HC-R ₄ HC-R ₄
/ CH
/ \ / \ /
H - CO CH
I \ l
₃ C - C CH
\ /
N
Ri S /
C. H ls.2 ν-Π CH H CH
\ / \ I \ / \
I HO-C
! I. j H; I.
) C —C
\ /
N

609 729/391

Ri
R ₂ -CH R ₃

HC-R ₄

In these formulas, Ri, R ₂ , R ₃ and R _{4 have} the above meanings. The formulas framed by dotted lines denote hypothetical, non-isolated intermediate products.

The reaction sequence outlined here is, as far as the intermediate products framed by dotted lines are concerned, not fully secured.

According to one embodiment of the process according to the invention, the 4-methyl-oxazole is combined heated with the dienophilic compound of the formula II, whereupon the dehydrogenating agent is added in a separate process step. the preferred embodiment of the process, however, is the 4-methyl-oxazole together with to heat the dienophilic compound in the presence of the dehydrating agent.

The 4-methyloxazole used as starting material can be prepared as follows:

Ethyl acetoacetate is chlorinated and the resulting α-chloroacetoacetic acid ethyl ester with Formamide cyclized in the presence of formic acid to give 4-methyl-5-ethoxycarbonyl-oxazole. This Product is hydrolyzed and then converted to 4-methyloxazole decarboxylated.

Lower alkoxy groups are to be understood as meaning those with 1 to 7 carbon atoms, in particular the methoxy and ethoxy groups. Lower aralkoxy groups are in particular the benzyloxy and the phenethyloxy group.

Examples of dienophilic compounds of the formula II in which Ri and R _{3 are} hydrogen atoms and R ₂ and R _{4 are} hydroxyl groups or lower alkoxy or aralkoxy groups are butene- (2) -diol and its ethers, such as dimethyl ether or diethyl ether the dibenzyl ether.

Examples of dienophilic compounds of the formula II in which R ₁ and R _{3 are} hydrogen atoms and R ₂ and R ₄ together are a methylenedioxy group or a substituted methylenedioxy group are compounds of the general formula

HC-CH ₂ -OR ₅

5, 4 3 / \

HC-CH ₂ -OR ₆

(III)

wherein the symbols Rs and Re denote hydrogen atoms, lower alkyl, aryl or acyl groups, it being possible for both substituents R ₅ and Re to be linked to one another by a lower alkylene group to form a ring.

Such dienophilic compounds, which represent acetals or ketals, are in particular: 2-methyl-4,7-dihydro-1,3-dioxepin, 2,2-dimethyl-4,7-dihydro-1,3-dioxepin, 2-n Propyl-4,7-dihydro-1,3-dioxepin, 2-isopropyl-4,7-dihydro-1,3-dioxepin and 2,2-pentamethylene-4,7-dihydro-1,3-dioxepin.
Dienophilic compounds of the formula II in which R ₂ and R ₄ together represent an oxygen atom are, for example, 2,5 - dihydrofuran, 2,5 - dihydroxy-2,5-dihydrofuran and 2,5-dialkoxy-2,5-dihydrofurans, such as 2,5-dimethoxy-2,5-dihydrofuran. Dienophilic compounds of the formula II, in which each of the substituent pairs Ri, R ₂ and R ₃ , R _{4 represents} an oxygen atom, are fumaraldehyde and maleic aldehyde.

A preferred embodiment of the process according to the invention is that the reaction components heated under pressure in the presence of a dehydrating agent.

Suitable dehydrating agents are, for. B. nitrobenzene, halogenated and / or alkylated nitrobenzenes, such as B. 2,5-dichloro-nitrobenzene, l, 3-dichloro-4-nitrobenzene, l ^ -Dichlor-S-nitrobenzene, l-chloro-2,4-dinitro-benzene, l-chloro-2-nitro-benzene, l-chloro-4-nitrobenzene, 1-chloro-2-methyl-3-nitro-benzene, 1,2-dimethyl - 3 - nitro - benzene, 1 - methyl - 2 - nitro - benzene, 1 - methyl - 3 - nitro - benzene and 1 - methyl - 4 - nitrobenzene. Other dehydrating agents that can be used are nitroanilines, such as o-nitroaniline, 2,4-dinitroaniline, 2,6-dinitroaniline, also 4-amino-3-nitrotoluene and other nitro-substituted aromatic compounds, such as 1,5-dinitronaphthalene, o-nitro-anisole, o-nitroacetophenone and p-nitro-acetophenone. Also suitable are: halogenated ketones, such as Hexachloroacetone, certain salts, e.g. B. mercury acetate, bromine and quinones, such as chloranil, also also dehydrogenation catalysts, such as palladium-carbon, e.g. B. suspended in pseudocumene. The connections from the first group of dehydrogenating agents listed here, namely nitrobenzene, halogenated and / or alkylated nitrobenzenes are preferred.

It is advisable to use the dienophilic compounds in excess, e.g. B. in a crowd from 5 to 20 moles per mole of 4-methyl-oxazole. The dienophilic compounds act in high concentrations at the same time solubilizing, so that there is no need to add solvents. With only a little A solvent is expediently added to an excess of dienophilic compounds. You can do this an acid such as B. acetic acid or propionic acid, use. However, dehydration can also occur in other solvents, e.g. B. in methanol, dioxane, triethylamine or in Ν, Ν-dimethylformamide carried out will.

If the reaction mixture is heated to high temperatures for an excessive period of time, the reaction product may decompose. However, heating at 150 to 200 ^° C. for 10 to 50 hours does not yet have any noticeable effect on the yield. The dienophilic compound with the 4-methyloxazole is preferably heated ^{to 150 to 200 °} C. in a closed system in the presence of the dehydrating agent for 10 to 20 hours.

The reaction can be carried out in the presence of a stabilizer, e.g. B. in the presence of hydroquinone carried out will. Preferably, however, in an inert gas atmosphere, for example in a nitrogen atmosphere, worked.

As mentioned, the pyridine compounds of the formula I can be converted into vitamin Be in a manner known per se

(Pyridoxine) are transferred. Carboxyl, carbalkoxy or aldehyde groups can help here complex metal hydrides, e.g. B. by the action of lithium aluminum hydride, in hydroxymethyl groups being transformed. Acids form addition salts of the vitamin Be.

example 1

In a laboratory autoclave, 200 g of 4,7-dihydro-1,3-dioxepin (2.0 mol), 8.3 g of 4-methyl-oxazole (0.10 mol), 7.7 g of 2,5-dichloro Pour in l-nitrobenzene (0.04MoI) and a spatula tip of hydroquinone. The reaction mixture was heated for 16 hours in an oil bath at 18O ⁰ C. The pressure rose to 4.5 atmospheres during the reaction. After the reaction had ended, the contents of the autoclave were subjected to distillation at normal pressure and the excess dioxepin was recovered. The distillation residue was taken up in 200 ml of 1η hydrochloric acid and the aqueous solution was extracted twice with 75 ml of ether to remove the non-basic components. The acidic solution obtained was concentrated to dryness in a rotating evaporator and the crystalline residue was recrystallized from methyl alcohol. Pure formaldehyde acetal hydrochloride of pyridoxine was obtained. (F. 201 to 204 ⁰ C).

5.4 g (0.025 mol) of the above compound were mixed with 25 ml of 25% strength methanolic hydrochloric acid and the mixture was ^{heated in a flask with a Vigreux distillation attachment for 3 1} ^ hours just enough that methylate formed distilled over. It was then evaporated sharply and the crude crystalline pyridoxine with a melting point of 203 to 205 ^° C. was recrystallized from methyl alcohol. Pure pyridoxine hydrochloride with a melting point of 209 to 210 ^° C. was obtained.

B e i s ρ i e 1 2

In a laboratory autoclave 352.4 g of 2-phenyl-4,7-dihydro-1,3-dioxepin (2.0 mol), 8.3 g of 4-methyloxazole (0.10 mol), 7.7 g of 2.5 -Dichlor-1-nitrobenzene (0.04 mol) and a spatula tip of hydroquinone filled in. The reaction mixture was heated for 16 hours in an oil bath at 180 ⁰ C, the pressure at 2 atmospheres increased. The contents of the autoclave were then subjected to distillation under a water-jet vacuum to recover excess 2-phenyl-4,7-dihydro-1,3-dioxepins. The distillation residue was taken up in 200 ml of 1η hydrochloric acid and the solution was washed twice with 75 ml of ether. The acidic solution obtained was concentrated to dryness in a rotating evaporator and the crystalline residue of pyridoxine hydrochloride was recrystallized from methyl alcohol. A product with a melting point of 204 to 206 ^° C. was obtained.

Example 3

In a laboratory car Tdav was 14.2 g of 2 n-propyl-4,7-dihydro-1,3-dioxepin (1.0MoI), 4.15 g of 4-methyl-oxazole (0.05 mol), 3.85 g Filled in 2,5-dichloro-1-nitrobenzene (0.02 mol) and a spatula tip of hydroquinone. The mixture was heated 14 hours in an oil bath at 180 ⁰ C, the pressure at 2 atmospheres increased. The contents of the autoclave were then subjected to distillation under a water jet vacuum and excess 2-n-propyl-4,7-dihydro-1,3-dioxepin was recovered. The distillation residue was taken up in 100 ml of 1N hydrochloric acid and the solution was washed twice with 40 ml of ether. After evaporation of the acid solution to dryness, the residue was recrystallized from methyl alcohol to give pyridoxine hydrochloride was obtained, mp 204-205 ⁰ C.

Example 4

In a laboratory autoclave were 142.2 g of 2-isopropyl-4,7-dihydro-1,4-dioxepin (1.0 mol), 4.15 g of 4-methyl-oxazole (0.05 mol), 3.85 g Filled in 2,5-dichloro-1-nitrobenzene (0.02 mol) and a spatula tip of hydroquinone. The autoclave was heated for 24 hours in an oil bath at 180 ⁰ C, with the pressure on

2 atmospheres rise. The contents of the autoclave were then worked up as described in Example 3, pyridoxine hydrochloride having a melting point of 202 to 204 ^° C. being obtained.

Example 5

200 g of 4,7-dihydro-1,3-dioxepine (2.0 mol), 8.3 g of 4-methyl-oxazole (0.10 mol), 4.9 g of nitrobenzene (0.04 mol ) and a spatula tip entered hydroquinone. The autoclave was maintained for 14 hours in an oil bath at a temperature of 180 ⁰ C, with the pressure on

3 atmospheres rise. The work-up and conversion into pyridoxine hydrochloride were carried out as described in Example 1, a product with a melting point of 208 to 209 ^° C. being obtained.

Example 6

140.0 g of 2,5-dihydrofuran (2.0 mol), 8.3 ^ -methyl-oxazole (0.10 mol), 7.7 g of 2,5-dichloro-1-nitrobenzene (0 , 04 mol) and a spatula tip of hydroquinone. The autoclave was heated 14 hours in an oil bath at 180 ⁰ C, whereby the pressure to 15 atmospheres increased. The excess 2,5-dihydrofuran was then distilled off at normal pressure and the residue was taken up in 200 ml of 1η hydrochloric acid. The acidic solution obtained was washed twice with 80 ml of ether and then evaporated to dryness in a rotating evaporator. The crystalline residue was recrystallized from methyl alcohol to give 2-methyl-3-hydroxy-4,5-epoxydimethylpyridin hydrochloride, melting at 235-240 ⁰ C. The conversion of this compound is pyridoxine (described in the literature SA Harris and F ο 1 kers, J. Am. Chem. Soc, 61, p. 1245, 3307, [1939]).

Example 7

There were 8.3 g (0.1 mol) of 4-methyl-oxazole together with 200 g (1.75 mol) of 2-methyl-4,7-dihydro-1,3-dioxepin and 12.3 g (0, 1 mol) nitrobenzene in an autoclave at 165 ^° C. (outside temperature) under nitrogen (5 atmospheric pressure) for 46 hours. The reaction mixture was then distilled, the distillate being collected in an ice-cooled vessel. First, it was distilled at 133 ° C / 730 mm, with 10 ml of distillate being collected. The further distillation was carried out at 100 ° C./50 mm. There were in this way 160 g of 2 - methyl - 4,7 - dihydro - 1,3 - dioxepin with a

Recovered content of 0.5% (0.8 g) of 4-methyl-oxazole.

The remaining semi-crystalline distillation residue was treated with water and a steam distillation subjected until no more nitrobenzene was released. The hot aqueous fraction was decanted and the remaining substance (tar) washed with warm water. The watery, tar-free Solution was treated with charcoal (1 g) and filtered. After evaporation of the filtrate to A pale yellow solid substance remained dry and recrystallized from 150 ml of methyl ethyl ketone yellow needle-shaped crystals (9.3 g) with a melting point of 185 to 186.5 ° C were obtained. Concentration of the mother liquor produced a further amount of substance (1.4 g) with a melting point obtained from 183 to 184 ° C. Pure pyridoxine acetal was obtained by recrystallization from methanol obtained with a melting point of 189.5 to 190 ° C.

A solution of 9.75 g of the pure pyridoxine acetal obtained according to the above information in 20 ml 3η-hydrochloric acid and 30 ml of water were heated to 80 ° C. in an open vessel, with a stream of nitrogen was passed through the solution. After 105 minutes the hydrolysis was complete. the The solution was then filtered and evaporated to dryness. The crystalline residue was with treated with warm ethanol, filtered and dried. There were 9.7 g of pyridoxine hydrochloride from Melting point 205 to 207 ° C obtained.

Claims (5)

Patent claims: 1. Process for the preparation of pyridine derivatives of the general formula Ri (I) 40 where Ri and R3 are hydrogen, hydroxyl or lower alkoxy or aralkoxy groups and R2 and R4 each represent either a hydroxy group, a lower alkoxy or aralkoxy group or R ₂ and R4 together represent an oxygen atom or an optionally substituted methylenedioxy group or Ri and R2 together and R3 and R4 together each denote an oxygen atom, as well as the conversion of these pyridine derivatives into vitamin Be (pyridoxine) and its acid addition salts, characterized in that 4-methyl-oxazole is mixed with a dienophilic compound of the general formula Ri \ / R ₃ ) CH - CH = CH - CHC (II) in which Ri, R2, Rs and R4 have the above meaning have, heated, added a dehydrating agent and the pyridine derivative formed, if necessary in a known way in vitamin Be (pyridoxine) and this is converted into acid addition salts with acids. 2. The method according to claim 1, characterized in that there is nitrobenzene as the dehydrating agent or a halogenated and / or alkylated nitrobenzene is used. 3. The method according to claim 1 or 2, characterized in that the mixture of Reactant heated to about 150 to 200 ° C. 4. The method according to claim 1, 2 or 3, characterized in that one is considered a dienophile Compound 2 - methyl - 4,7 - dihydro - 1,3 - dioxepin, 2,2-dimethyl-4,7-dihydro-1,3-dioxepin, 2-n-propyl - 4,7 - dihydro - 1,3 - dioxepin, 2 - isopropyl-4,7-dihydro-1,3-dioxepin, 2-phenyl-4,7-dihydro-1,3 - dioxepin, 4,7 - dihydro -1,3 - dioxepin or 2,5-dihydrofuran are used. 5. The method according to any one of claims 1 to 4, characterized in that the dienophile Compound in excess, especially in an amount of 5 to 20 moles per mole of 4-methyloxazole, used.