DE1620544A1 - New pantothenic acid derivatives and processes for their preparation - Google Patents

Description

ΡαΓΕΝΪΑΝ WALTE

DR.-ING. BY KREiSLER DR.-ING. SCHÖNWALD DR.-ING. TH. MEYER DR. FUES DIPL-CHEM. ALEK VON KREISLER DIPL-CHEM. CAROLA KELLER DR.-ING. KLDPSCH KDLN ^ DEICHMANNHAUS

Cologne, the Ιέ. December 1969 Kl / En '

P 16 20

Takeda Chemical Industries, Ltd.,

27, Doshomachi 2-chome, Higashi-ku, Osaka (Japan)

Manufacturing

The invention relates to the production of new pantothenic acid derivatives, a process for their production and a process for the production of pantethine derivatives from these pantothenic acid derivatives. The new pantothenic acid derivatives have. the general formula
CHOIR "

t P ι 2 / Y ^X 2

R ₁ OCH, - C - CH - CONHCH ₂ CH ₂ COn j (l)

rvtr -ΓΊΙ

on, Un ₂

wherein R ₁ O- and R ₀ O- for hydroxyl groups, acyloxy groups with

2 to 7 carbon atoms or substituted alkoxy radicals which can be converted into hydroxyl groups by hydrolysis or reduction, although the case is excluded that R ₁ and ″ * ■

/ R ₂ both "stand for oxygen atoms.

The new compounds of the formula (I) are valuable starting materials for the preparation of pantethine derivatives. It was found that pantethine derivatives when using the pantothenic acid derivatives as starting products easily in good yield and at "low cost" without deposition of any intermediate product the reaction can be produced »whereby the time required for the production of the pantethine derivatives is very short.

New document ^ ^? | i

-SAD ORIGINAL

In formula (i), R _{1 is} O and RgO hydroxyl groups, aeyloxy groups having 2 to 7 carbon atoms, for example acetyloxy, propionyloxy, butyloyloxy, benzoyloxy and furoyloxy, or substituted alkoxyl radicals which can be converted into hydroxyl groups by hydrolysis or reduction , e.g. hydroxymethyl, benzyl and pyranyl. .

The compounds of formula (1) are prepared by a process produced, which is characterized in that one compounds the formula

CH, OR ₂
R ₁ OCH ₂ - C -CH - CONHCH ₂ CH ₂ COOCOOr ¹ (i) ¹

wherein R ₁ O- and Rp ° - have the meaning mentioned and R ^{1 represents} alkyl, aryl or aralkyl, is reacted with ethyleneimine. The reaction can be carried out in the presence of a solvent, for example water or in organic solvents. The reaction generally proceeds smoothly at room temperature, but can be "heated or cooled" if necessary.

The compounds of formula (i) 'can be prepared by tertiary amine salts of the corresponding pantothenic acids with lower alkyl esters of chloroarboxylic acid (e.g. methyl ester, Ethyl ester, etc.) in the presence of a solvent at room temperature or with cooling.

Examples of compounds of the formula (I) include:

aS ^ -Diacetyl-pantothenic acid ethylenimido ^ /

2 ^l -Benzoyl-pantotherisäureäthyienimido ^ '- Benzoyl-pantothenäureäthylenirnido 4 ^> -Füroyl-pantothensäureäthylenimido

2 *, 4 ^r -dipropionyl-pantothenic acid ethylenimide ο 2 ^l -benzyl-pantothenic acid ethylenimido

^ •• -Pyranyl-pantpthensäureäthylenimido

The M / ^ rmndiung \ t) thus obtained is used as starting material for

BATH ORIGINAL

from '

the production / pantethine derivatives. For this purpose, the compound (I) can be used as such in purified form or as a reaction mixture. According to the invention Pantethine derivatives of the general formula ν

CH, 0R ₀ .

ι 2 ι 2 ■■■ --- '

(R ₁ OCH ₂ - C - CH-CONCH ₂ CH ₂ CONHCh ₂ CH ₂ - S -) ₂ (H) y - ■ ■■■ \ - ■■■ ^: .- ■: ■ -. · .- ■

wherein R 0- and R ₉ O- have the meaning mentioned in connection with formula (I), prepared by a process which is characterized in that compounds of formula (I) are reacted with hydrogen sulfide or alkali metal salts of thiosulfuric acid and the reaction product of Subject to oxidation.

Alkali salts of thiosulphuric acid which are suitable for the purposes of the invention are, for example, sodium thiosulphate, potassium thiosulphate and ammonium thiosulphate. The reaction can be carried out in the presence of solvents, for example water and organic solvents such as tetrahydrofuran, dimethylformamide, acetone, ethyl alcohol, ethyl acetate and chloroform. These solvents can be used alone or in admixture with one another. In general, the Reaktipn proceeds smoothly at about 0 to 40 ⁰ C. ";,

If hydrogen sulfide is used for the reaction, hydrogen sulfide in gaseous form is preferably added to the solution of the starting material introduced. When using alkali salts of thiosulfuric acid, the reaction proceeds more smoothly when an acidic material is added, such as hydrochloric acid and sulfuric acid * to the reaction system, where pantethein-. derivatives are formed. The patetheine derivatives thus obtained are intermediate stages of the products according to the invention and have when using hydrogen sulfide the formula

CH ^ 0R ₀ -.

R ₁ OCH ₂ - C - CH- CONHCH ₂ CH ₂ CONHCa ₂ CH ₂ SH "

-00 9.818 / 1829 _Bm mm ^ [

and when using alkali salts of thiosulfuric acid the formula

CH, 0R ₀
R ₁ O - CH ₀ -C-CH- CONHCH ₀ Ch ₀ CONHCH ₀ CH ₀ S - SO, Me

1 d J dd d d J

CH

where R, O- and R ₀ O- have the meaning already mentioned and Me is an alkali salt.

The pantethine derivatives are then oxidized subject, whereby the corresponding Pante thinder iva te are formed. The oxidation can be done by an oxidizing agent is added directly to the reaction mixture or to a solution containing the pantetheine derivative will. The solution is made by taking the pantetheine derivative separated from the reaction mixture in the usual way, e.g. by extraction or condensation, and then the derivative in a solvent such as water, ethanol or chloroform, dissolves. The amount of thiosulfate used is equimolar to the starting material or slightly higher.

Suitable oxidizing agents are air, oxygen, hydrogen peroxide, iodine, periodic acid, etc. The oxidation continues for as long carried out until a thiol reaction becomes negative, measured with sodium nitroprusside, or no more iodine consumed will. The oxidation is preferably carried out at temperatures from 0 to 60.degree. After completion of the oxidation can the formed pantethine derivative, if desired * easily separate in the usual way, e.g. by extraction, filtration, condensation or chromatography.

By using the compounds (i) as a starting material Pante thinder iva te of the formula ("II.) can thus be prepared in good yield with a few simple reaction steps. Furthermore, in the method according to the invention, any of the Reactions can be carried out easily without separating the intermediates at each reaction stage. The time it takes to

00 98 18/1829 - BAD original

Completion of all reactions is required .igt - very briefly. As examples of pantethine derivatives of the formula: '(It) be, called:

2 ¹ , ² I- '-Diaeetyl-pante thin \ ·

2 ^l -Benzoyl-pantethine \

4'-benzoyl-pantethine

4'-furoyl pantethine

2 ', 4'-Dipropionyl-pantethine _ ·

2'-benzyl-pantethine

2 ^f j ^ '- dihydroxymethyl pantethine.

4'-pyranyl pantethine. . -

The pantethine derivatives of the formula (II) are available as starting products more advantageous for the synthesis of coenzyme A ' than pantethine itself because the derivatives in which the OH group in the 2'-position by acetyloxy, benzoyloxy, benzyloxy etc. is protected, easily practically only the Λ'-phosphate of pantethine derivatives through phosphorylation

while using pantethine itself a rather poor yield of the desired 4 ^! Phosphate is obtained by the formation of 2'-phosphate and 2; ', 4'-cyclic phosphate as by-products. If, for example, 2 i-benzylpantethine is used as protected pantethine, it is phosphorylated in good yield to 2'-benzylpantethine, above the benzyl residue in the 2'-position by treatment with metallic sodium in aqueous ammonium easily into the OH residue with the formation of pantethine phosphate can be converted. ~:

Example 1 -.

a) Production of Pantoth & nsäüreäthylenimidderivaten . In 5 NC ml of tetrahydrofuran 3.0 g of 2 ^I _J 4'-Diacetylpantothensäure and 1.0 g of triethylamine are dissolved '. To the solution are added dropwise with stirring p., 1 g of ethyl chloride in 5 ml of tetrahydro-

-BAD ORIGINAL 0098 18/1829

furan given while cooling to -20 to -1O ° C, so that the reaction can take place. A solution of 1.1 g of ethyleneimine and 2.5 g of triethylamine is obtained within 10 minutes in 20 ml of tetrahydrofuran dropwise to the reaction mixture added so that the reaction takes place for a further hour. The precipitated triethylamine hydrochloride is filtered off. The tetrahydrofuran is distilled off from the piltrate under reduced pressure. The residue is dissolved in ethyl acetate solved. The solution is made with 1 above sodium hydrogen carbonate solution and then washed with water. After dehydration the ethyl acetate is distilled off, with 5.2 g of 2 ', 4'-Diacetylpantothensäureäthylenimid can be obtained in the form of a farbüceen, syrupy substance.

infrared spectrum: \ liq. _om -l ^ _{35 (} J _ _{coo) j l65} O-l68O (0 CONH, 0 C0N <"? ^H 2), 1240 (CEXOO).

b) Production of patethin derivatives. . The filtrate obtained according to a) is saturated with hydrogen sulfide, idem gaseous hydrogen sulfide is introduced while cooling with ice. The solution is left to stand overnight and then treated in the manner described in Example 1 and concentrated under reduced pressure to give 3 * 4 g of 2 ^l , 4 <jf-diacetylpantethine.

The one with a solvent system of n-butanol / acetic acid / Water (4: 1: 5) developed paper distribution chromatogram gives a single spot with an Rf value of 0.85 Use of potassium cyanide and sodium nitroprusside as Reagents. ~

Infrared spectrum: λ ι *? · ^{Cm "1} 1755 (acetyl) I655, 1530

IUcIJv

(Amido) I23O (acetyl).

Example 2 .

a) Production of pantothenic acid ethylene amide derivatives . To a solution of 3.2 g of 4'-benzoylpantothenic acid in 15 ml

00 98 18/1829 bad original

Tetrahydrofuran are given 1.1 g of triethylamine. 1.1 g of ethyl chlorocarbonate in 5 ml of tetrahydrofuran are added dropwise to the solution with stirring, while the mixture is cooled ^{to -20 to -JO 0 C.}

After> 0 minutes, the precipitate is filtered off and the filtrate is added to 0.7 g of ethyleneimine in 10 ml of tetrahydrofuran with stirring, while the mixture is cooled to -10 to -15 ° C., whereby a reaction takes place. After a reaction time of one day, the solvent is distilled off under reduced pressure. The residue is dissolved in ethyl acetate and the solution is washed with an aqueous solution of sodium hydrogen carbonate and then with water. After dehydration, the ethyl acetate is distilled off, with 2.4 g of 4 ^I -benzoylpantothenic acid ethyleneimide being obtained in the form of a pale yellow, syrupy substance,

Infrared spectrum: Λ J ¹ J * cm " ¹ 1720 (0 CO-O), 16.70 - I690 ·

CH ₂ ^max ;

(0 CONH, V> CON ^ j).

CH ₂

b) Manufacture of panthland derivatives . ·

To a mixture of 2.4 g of 4 ^I -Benzoylpahtothensäureäthyleri> imid in 10 ml of ethyl alcohol and 1.0 g of sodium thiosulfate (Na ₂ S ₂ 0, .5H ₂ O) in 10 ml of water] 5.2 ml of 2N-chlorinated water ■ chemical acid given with stirring. The reaction is allowed to take place for 1 hour. The reaction mixture is distilled under reduced pressure to remove the ethyl alcohol and washed with ethyl acetate. An aqueous phase is separated off from the mixture treated in this way and evaporated to dryness under reduced pressure, 1.8 g of 4 ^f -benzoyl-S-sulfopantethein being obtained. This reaction product is dissolved in 30 ml of water. 15 ml of an aqueous solution of 0.7 g of iodine and 0.5 g of calcium iodide in 15 ml of water are added dropwise to the solution. The oxidation is allowed to take place for about a day until iodine is no longer consumed. The severed one

0098! 8/1829 _{BAD 0RielNAL}

oily phase is extracted with ethyl acetate and washed with water. After dehydration, the treated evaporated oily phase to remove the ethyl acetate, 1.5 g of 4'-benzoylpantethine being obtained.

The one with a solvent system of n-butanol / acetic acid / Water (4: 1: 5) developed paper distribution chromatogram gives a single spot at an Rf value of 0.9 when using potassium cyanide and Ni troprussidnatriurn as a reagent. '.

Infrared spectrum: λ ^ ¹ J cm " ¹ 1720 (benzoyl) 1660, 1540

ΓΠ3Χ

(Amido) 1260, tl ^ (benzoyl).

Example 3

To a mixture of 1.9 g of the 2 ^l , 4 ^l -diacetyl-pantothinsic acid ethyleneimido prepared according to Example 1 in 10 ml of ethyl alcohol and 1.8 g of sodium thiosulfate (Na ₃ S ₂ O., 5H ₂ O) in 10 ml of water 3 * 2 ml of 2N hydrochloric acid are added dropwise with stirring so that a reaction takes place for 1 hour. The reaction mixture is distilled under reduced pressure to remove the ethyl alcohol. Ethyl acetate is added to the residue. The aqueous phase is separated from the solution and evaporated to dryness under reduced pressure, 1.2 g of 2 ^! , 4 ^f -diacetyl-S-sulfopantethein can be obtained. A few drops of concentrated sulfuric acid are added to the product dissolved in 20 ml of water while stirring, whereupon 0.3 ml of a JO ^ igen aqueous hydrogen peroxide solution are stirred in. After stirring for some time, the mixture is concentrated under reduced pressure, an oily phase separating out. The oily phase is extracted with ethyl acetate and the extract is evaporated to dryness. The ethyl acetate is distilled off, with 0.8 g of 2 ^f r4 ^! -Diacetyl-pantethln is obtained, which is identified on the basis of the product obtained according to Example 2 v / ird.

BATH ORIGINAL 0098 18/1829

Example 4 :

a) Production of pantothenic acid ethylene imldderivaten .

1.1 "g of triethylamine are added to a solution of 3 g of ^ '- puroyl-pantothenic acid in 15 ml of tetrahydrofuran, whereupon 1.1 g of ethyl chlorocarbonate in 5" ml of tetrahydrofuran are added dropwise with stirring, whereby to -20 Ms-JO ⁰ G is cooled and one. Reaction takes place. After a reaction time of 1 day, crystals are filtered off. The filtrate is added with stirring to a solution of 0.7 g of ethylene imine in 10 ml of tetrahydrofuran, while cooling to -10 to -15 ° C. A reaction takes place here. After a reaction time of 1 day, the solvent is distilled off under reduced pressure. The residue is dissolved in ethyl acetate and the solution is washed with 1 of the above aqueous sodium hydrogen carbonate solution and then with water. After dehydration, the ethyl acetate is distilled off, 2.0 g of 4 ^f- furoylpantothenic acid ethyleneimine being obtained as a pale yellow syrupy substance.

Infrared spectrum: λ ^ J * era ^-1 '1730 (ύ CO-O), ΐ66θ- 1685

(V CONH,

b) Production of pantethine derivatives .

To a mixture of 2 g ^ '- Furoylpantothensäureäthylenimid in 10 ml of methyl alcohol and 1.8 g of sodium thiosulfate (Na ₂ S ₂ O ₅ .5H ₂ O) in 10 ml of water are added dropwise 3.2 ml of 2N hydrochloric acid with stirring, with one Reaction takes place. After 1 hour, the resulting solution is distilled under reduced pressure to remove the methyl alcohol. Ethyl acetate is added to the residue. The aqueous phase is separated from the solution and evaporated to dryness under reduced pressure, 1.3 g of V-furoyl-S-sulfopantethein being obtained. The product is dissolved in 30 ml of water. 0.6 g of iodine and 0.5 g of potassium iodide are added dropwise to the solution in 15 ml of water until no more discoloration is observed. The solution obtained

009818/1829

BATH

- ίο -

is narrowed. The separated oil phase is extracted with ethyl acetate. After washing with water, the ethyl acetate and the water are distilled off, 1.2 g of 4 ¹ -furoylpantethine being obtained.

The one with a solvent system of n-butanol, acetic acid and water (4: 1: 5) developed paper distribution chromatogram gives a single spot at an Rf value of 0, b5 when using potassium cyanide and sodium nitroprusside as reagents.

J cm ~ ^l

9Χ

(Amido) 1240 (furoyl).

Infrared spectrum: λ ^ ¹ J * 'cm ~ ^l 1750 (Furoyl) 16.57 * 1535

ΓΠ9Χ

Example 5

a) Production of pantothenic acid ethylene imide derivatives .

To a solution of 9.0 g of 2'-benzyl-pantothenic acid and 3.0 g of triethylamine in 20 ml of ethyl acetate is added dropwise a solution of 2.5 g Äthylchlorcarbonat in 15 ml of ethyl acetate at -10 ⁰ C under stirring, and a reaction takes place. After 15 minutes, a solution of 1.2 g of ethyleneimine and 3.7 g of triethylamine in 38 ml of ethyl acetate is added dropwise to the solution so that the reaction takes place for a further hour. The precipitate is filtered off. The filtrate is washed with a solution of sodium hydrogen carbonate and then with water. After drying with sodium hydrogen sulfate, the solvent is distilled off, 9.3 g of ^ '- benzyl-pantothenic acid ethylene imide being obtained.

Infrared spectrum: λ ^ * cm " ¹ 750, 700 (CgH ₅ -CH ₂ ), I67O-

CH ₂
I69O (0 CONH / i CON '!).

■ ^CH 2

b) Production of pantethine derivatives.

The filtrate prepared according to a) is treated with hydrogen sulfide saturated by introducing gaseous hydrogen sulfide. The solution is left to stand overnight,

009818/1829 _ÖAo

. 1620844

- li -

whereupon nitrogen is introduced to remove excess hydrogen sulfide to be removed completely, after whichJO ml of water are added. Then a solution of iodine in Ethyl acetate added to the resulting solution, Ms no ver ■ coloring by the iodine is determined more * The watery Phase is separated from the reaction solution. The residue is with a sodium hydroxide solution and then with Washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off from the solution, giving a colorless syrup * The syrup is dissolved in a small amount of chloroform, and made into solution ether is added, whereby 3.6 g of 2'-benzylpantethine precipitates will.

The with a solvent system of n-butanol, acetic acid and water (Mr; 1: 5) '' developed Papierverteilungschromatögramm gives a single spot at Rf value of 0.05 hei use of potassium cyanide and nitro, n prussidnatrium as Reagentie.

Infrared spectrum: Λ J ¹ J * cm " ¹ 1655, 1528 (Amido) 750,

ΓΠ3Χ ■ "

(Benzyl).

. BAD ORIG'NAL

Q098 1 8/1829

Claims (5)

Claims wherein R ^ O- "and RgO- are hydroxyl groups, acyloxy groups with 2 to 7 carbon atoms or substituted alkoxy groups which can be converted into hydroxyl groups by hydrolysis or reduction, but R ₁ and R _{2 are not} both allowed to be hydrogen atoms. 2) Process for the preparation of pantothenic acid derivatives of general formula CH ₃ OR ₂ ^ CH ₂ R ₁ OCH ₅ -C-CH-CONHCH ₂ Ch ₂ CON J (I) CH ₅ ^CH 2 wherein RjO- and RgO- hydroxyl groups, acyloxy groups with 2 to 7 carbon atoms or substituted alkoxy radicals which can be converted into hydroxyl groups by hydrolysis or reduction, but R ₁ and R ₂ may not both be hydrogen atoms, characterized in that one Compounds of the general formula ^: CH ₅ OR ₂ R ₁ OCH ₂ - C - CH - CONHCH ₂ Ch ₂ COOCOOR '(I) V CH ₅ wherein R ₁ O- and R ₂ O- have the meaning mentioned and R ^! for .Alkyl, aryl or aralkyl, reacts with ethyleneimine " 3) Process for the preparation of fantethine derivatives of the general formula Neue ümeriaaen ^ n.? SiAbe.2NMSatz3d ·· Matcumm * - > · * · * ■ Ό09818 / 18 29 BATH ORIGINAL ₅ g
(R ₁ OCH ₂ - C - CH - CONCh ₂ CH ₂ CONHCH ₂ CH ₂ - S -) ₂ (II) where R _{1 is} O and RgO hydroxyl groups, aeyloxy groups with 2 to 7 carbon atoms or substituted alkoxy groups which can be converted into hydroxyl groups by hydrolysis or reduction, but where R ₁ and R _{2 are} not both hydrogen atoms, characterized in that compounds of the general formula (I), in which R ₁ O and R ₂ O have the same meaning as in formula (II), are reacted with hydrogen sulfide or alkali salts of thiosulfuric acid and the reaction product then subjected to oxidation, 4) Method according to claim J5, characterized in that the oxidation is carried out using air _? Carries out oxygen, iodine or hydrogen peroxide as an oxidizing agent, 5) Process according to Claims 3 and 4, characterized in that a compound of the general formula (I) is used in which R ₁ O- is a * hydroxyl group ^ and RaP- is a benzyloxy group. ^, ^ · ^ _; ^ _; -;>«?«> "-. 'ϊ,?; ^! "ϊ'ϊ'; α ^ -7ΐI ■■: '·: r, \ 00SB 18/1 8 * 9 - _BÄD original