DE2305758C3 - - Google Patents

Description

C _A H, CH =

• X

^ - (CH ₂ ) ,, - Halogen _{() V)}

U)

The inventive method is explained in detail below:

In process (a), a 2-methyl-5- (iO-haloalkyl) -pyridini (II) is first dissolved in, for example, glacial acetic acid, then mixed with hydrogen peroxide, peracetic acid, perbenzoic acid or perphthalic acid and at a temperature, for example from 50 to 100 ° C, allowed to react for about 2 to 10 hours to give an oily 2-methyl-5- (ti) -haloalkyl) -pyridine-N-oxide (111) in good yield. An acid anhydride such as acetic anhydride, propionic anhydride, butyric anhydride, benzoic anhydride or monochloroacetic anhydride is added to the resulting N-oxide (111) in a slight excess of the theoretical amount. The mixture is allowed to react under reflux for about 30 minutes, then freed from the excess acid anhydride and the acid formed as a by-product and the residue under reduced pressure to give an ester of 2-hydroxymethyl-5- (aj-haloalkyl) pyridine (IV) distilled. The ester (IV) can be conveniently hydrolyzed by a known saponification method, that is, by heating with an acid or by reaction with a base at room temperature or with heating to give 2-hydrcixymethyl-5- (co-haloalkyl) pyridine (V) .

The 2-hydroxymethyl-5- (ü) -haloalkyl) pyridine (V) obtained in this way is dissolved in an organic solvent such as t-butanol, acetone or dioxane. An aqueous potassium permanganate solution, dichromic acid or potassium dichromate or sodium dichromate, for example, is added dropwise to the solution with cooling, e.g. B. at about 0 ° to 10 ⁰ C, added and allowed to react at a temperature within this range or at room temperature for 30 minutes to 2 hours. The main reaction product is extracted with an organic solvent such as chloroform, 1,2-dichloroethane, ether or benzene, the extract is dried and the solvent is driven off by distillation. The residue is recrystallized from a suitable solvent, for example hexane or (> o 1,2-dichloroethane, containing the desired 5 (o> haloalkyl) -picolinic acid. An oxidizing agent such as lead tetraacetate, manganese oxide or a chromic anhydride-pyridine complex is used , a 2-formyl-5- (w-haloalkyl) -pyridine is formed as an intermediate product, which can be further oxidized with silver oxide or the like to obtain the desired 5- (iü-haloalkyl) -picolinic acid.

In the process (b) is a 2-methyl-5- (w-haloalkyl) -pyridine (II) with benzaldehyde in the presence of a carboxylic anhydride, such as acetic anhydride or propionic anhydride or a combination of a carboxylic anhydride with a carboxylic acid alkali metal salt, such as potassium acetate or sodium acetai, or reacted in the presence of a dehydrating agent such as polyphosphoric acid at 100 to 200 ⁰ C for 20 to 50 hours. After the reaction has ended, the reaction mixture is freed from the unreacted benzaldehyde by steam distillation and the residue is extracted with ether. The extract is concentrated and further distilled under reduced pressure to give a purified 2-styryl-5- (co-haloalkyl) -pyridine (VI), which is obtained in the same manner as in process (a) to obtain the desired 5- (co-haloulkyl) picolinic acid can be oxidized.

In process (c), selenium dioxide is added in portions to a 2-methyl-5- (iy-haloalky)) pyridine (II) in a solvent such as dioxane or xylene, or without using a solvent. After the addition has ended, the mixture is ^{heated to 100 to 200 °} C. for 3 to 10 hours until the reaction is complete. In order to remove insolubles, the reaction mixture is filtered as it is if a solvent was used for the reaction, or after being diluted with a solvent such as dioxane or ethyl acetate if no solvent was used. The filtrate is concentrated under reduced pressure to precipitate the desired 5- (u) -haloalkyl) -picolinic acid in the form of crystals, which are collected by filtration and recrystallized from a suitable solvent such as η-hexane to obtain a purified product.

The 5- (oj-haloalkyl) -picolinic acids according to Invention represent compounds with an excellent hypotensive effect.

The effectiveness of the compounds according to the invention is described below with reference to the Experimental report illustrated.

Test report
Hypotensive effects on spontaneously hypertensive rats

5- (üJ-haloalkyl) -picolinic acids according to the present invention and fusaric acid as a control were orally administered spontaneously to hypertensive rats (provided by the Council for the spontaneously hypertensive rat) cannulated with a conical cannula and the blood pressure was checked at fixed time intervals measured. The average of the minimum blood pressures divided by the baseline blood pressures in several rats, expressed as a percentage, was taken as a measure of the hypotensive effect. Furthermore, the time required from the start of administration until the blood pressure returned to its initial value (duration of action) was measured. The results obtained are summarized in Table 1. The LD ₅₀ values of the compounds according to the invention were given in Table 1 for the normal mouse. The measurements were carried out according to the method of I. Napatsii, T. Nagat su. K. M i ζ uta η i. H. LJ me ζ awa, M. M atsu ζ a ki and T. Taniguchi. (Nature, 230, 381, 1971).

Table 1

Hypertensive effect of S-iw-halogenated-picolinic acid on hypertensive rats, duration of effect (administered dose 25 mg / kg) and LD ₅₀ in normal mice.

example Substituents Extent of Effect number of No. in position S of hypotcnsiveii duration ² ) lall 5- (i'i-Mulogcnalkyl) - Effect') picülinsa'urc (%) (Lesson) 1 - (CH ₂ J ₃ Cl 73.0 48 6th 2 - (CHACl 72.0 72 5 3 - (CH ₂ J ₅ Cl 82.5 72 5 4th - (CH ₂ JbCl 93.0 72 4th 5 - (CH ₂ J ₃ Br 70.0 72 4th 6th - (CH ₂ ^ Br 83.0 72 4th 7th - (CH ₂ J ₄ F 68.0 72 6th 8th - (CH ₂ J ₅ F 73.5 24 6th Fusaric acid 9 - (CH ₂ J ₃ CH ₃ 82.5 72 4th (Control)

(mg / kg)

500 t 50 470 1 85 530 i 95 650 ± 50 500 ± 50 600 ± 50 350 ± 50 400 t 50

360 i 30

,. ,. ,. . ,,,. , Average minimum blood pressure., ",," ,.

) Extent of the nypoiensive effect = ~, ", -r 'null /«).

Baseline blood pressure

² ) Time required from the start of administration until the blood pressure returns to its initial value.

The results given in the test report illustrate the excellent hypotensive effect of the S-icü-haloalkylJ-picolinic acids.

The invention is explained in detail below with reference to the examples.

example 1
S-P'-chloro-n-propyO-picolinic acid

40

2.73 g of 2-methyl-5- (3'-chloro-n-propyl) pyridine in 10 ml of acetic acid are ^{heated with 1.6 ml of 30% strength hydrogen peroxide at 70 to 80 °} C. for 3 hours. A further 1.2 ml of 30% strength hydrogen peroxide are added to the reaction mixture and this is heated to 70 to 80 ° C. for a further 9 hours. After the end of the reaction, the reaction mixture is concentrated to one third of the original volume under reduced pressure, diluted with water to restore the original volume, concentrated again to one third of the original volume and extracted 5 times with 10 ml of ether each time. The ether layer was treated with anhydrous potassium carbonate to remove the acetic acid and then the ether was distilled to give quantitative yield of 2-methyl-5-p'-chloro-n-propylJ-pyridine-N-oxide in the form of a pale yellowish oil (a strong absorption band as a result of the N-oxide group appears at ν 1270 cm- 'in the IR spectrum). The N-oxide is dissolved in 1 ml of acetic anhydride and added dropwise to 4 g of acetic anhydride, which is refluxed with heating and stirring. After the addition is complete, the mixture is refluxed for a further 20 minutes with stirring and the Acetic anhydride is driven forward under reduced pressure, crude 2-acetoxymethyl-5- (I'-chloro-n-propyl) pyridine is produced as a brown-black oil (strong absorption bands of the silicate group appear at r 1735 cm- 'and ν 1220 cm - 'in the IR spectrum) 20 ml of concentrated hydrochloric acid are added to the oily residue and this is heated under reflux for 3 hours 50 ml of ether extracted The ethereal layer is dried over anhydrous potassium carbonate and freed from the ether by distillation, with 2.26 g of a dark oily residue can be obtained. 5 ml of water and then gradually a solution of 2.8 g of potassium permanganate in 90 ml of water are added dropwise to this unpurified 5- (3'-chloro-n-propyl) -2-hydroxymethylpyridine, while stirring vigorously and cooling with ice will. After completion of the dropwise addition, the stirring is continued for one hour at 0 "C. To the mixture is added 1 ml of methanol to decompose the excess Kaliumpermangannts, and it is stirred at 5O ⁰ C for 20 minutes.

The precipitated manganese dioxide is collected by filtration and washed thoroughly with 100 ml of boiling Water washed up. The filtrate and the washing fractions are combined with dilute hydrochloric acid brought a pH of 5, concentrated under reduced pressure to 20 ml and four times with 40 ml of ether extracted. The ethereal layer is released from the ether to give 5- (3'-chloro-n-propyl) -picolinic acid crystals freed from the mixed solvent n-Hcxan to ligroin = 2: l to give 0.82 g of colorless Crystals with a melting point of 127 to 128 "C are recrystallized.

Elcmcntaranalysc (CmI IhiNO ^ CI):

Calculated C 54.15, 115.05, N 7.02%;
found: C 54.00, H 5.01. N 7.27%.

In the manner described above, the compounds summarized in Table 2 were synthesized.

Table 2

\ uspmiL! sm; ilcn; il 1 nilpioiUikt

J-Mclh \ 1-5-1 ·.-ΙηιΙομαι- 5 - (.-- ll; iloi! I: n; ilkyll-

ilkyll-pyriilin picolinic acid

O
■ N

K 11, I ₁ Ur

I K

K II.-Kl

κ ii ..) ,. ⁽ ι

IK) (K

Hone

HO (K

HO (K

IK) (K

IK) (K

HO (K

O
N (CIIjI ₄ CI C) "
N (C 11, I ₄ Hr O ' N (CIIj) ₄ I- " O ^;
N (CII-KCI O '
N

Out
prey Schnii
punk ι .-Iz-
I Cl I. ■ oniiel Anal) se
ucluiulc
C. I "1.1
Ii | bi calculate
Il 2 (i 122 123 ( “Η ,,, ΝΟ, Ην December 44
(44.29) 4.11
(4.131 3S 104 105 ( , "II ,, N (U I 5 (i.44 5.71

(CHjKl- '

110 III C _n II ₁₁ NO.! (O. (. (><O ^l )

Ki2.54l (M) N)

4S III) 104 (, .. 11 ,,, NOjCI 5'1. ^ S.SO

(5. ¹ Ml

lOd 107 ( "," Π, j NO, Mr , 4 ^), 4. (i7 5, (i 5
(5.4) 1 100 U) I ( , JIu NO, I. Ä d.ll
K). 13) 7.34
(7.10) 11) 114 ( π 11 ₁₄ NO., (I. 5S.2I
I5S.O3) (1.23
l (i.02l K). 15)

Ko ¹ M

Il eis ρ ie I 2
5- (4'-t) lil «rp-buiyl) -picolinsilurc

To I2, ^r > g 2-methylyl-. ^r ) - (4'-clilor-nl-) iilyl) -pyricline, which is dissolved in 3 ml of acetic acid, 18 ml of 30% hydrogen peroxide solution are added dropwise and the mixture is heated to 70 to 80 ° C for 1 hour.

After the reaction has ended, the excess hydrogen peroxide is decomposed with Nuinumbisuifit and a reaction mixture is extracted with ether. The ethereal layer is washed with an aqueous solution of sodium carbonate, then with water, dried over anhydrous sodium sulfate and the ether is driven off by distillation, oily 2-methyl-5- (4'-chloro-n-butyl) -pyridm-N- oxide will reverberate. The resulting N-oxicl is added to 50 ml of acetic acid anhydride and refluxed for one hour. After the reaction has ended, the acidic anhydride is removed from the Rciiklionsgcmiseh by distillation under reduced pressure under the influence of 2-acctoxymethyl-S-i'l'-ehloMi-butyO-pyridine. This rabbit is dissolved in 50 ml of concentrated sylic acid, while Suinden is heated to a gentle reflux. Made weakly alkaline with aqueous ammonia and coated with ether. The lliherischc Schichl is distributed via potassium nitrate get rock. | O net and the ether deslillaliv. Oily 2-llydmxymeth.vl- ^r > - ('r-clilor-n-butyl) -pyridine is obtained.

To 2 ^r ) ml of benzene, which reveals 2Jd μ Bciietraacclat, under reflux and stirring dropwise 1.0 hg of the 2llydro \ ymeihyl ^r )

,) s ('l'-i.'hloi-n-bulyl) pyridiiis added. After completion of the addition, the mixture with stirring NN iihrend ^Ί Γ) minutes and reflux is heated aiiichlicßcnd siehciigclasscu and the precipitated Blciacetat by liliiatiuii nbgeux'iiui. The liltral wiril mn water

so washed, freed from the HessigslHirc with potassium carbonate, and then the benzene is deslillutiv at reduced pressure under a concentration of 0.2 g before 2 · Ι · Όι · ηι, νΙ · 5 · (4 ^ι ^ ^< ΙιΙοι ·· η · ΙηιΐγΙ) ρ ^ ΐ'''κΙϊη.

This aldehyde, dissolved in ethyl alcohol (b ml), win

ss drop by drop with stirring at Ruumtempcraltii a mixture of silver oxide, which was produced in the usual way from 1.02 g of silver nitrate, and O.b | Sodium hydroxide dissolved in 12 ml of water was added.

After completing the Iropfenwciscn /iisal/.es win

The stirring was continued for 40 minutes and the precipitated silver was separated off by nitration. The aqueous layer is extracted with ether to clear up the unreacted material, to a level of ^r 1, 2 with dilute hydrochloric acid, 1 and 2

ds ether extracted. After expelling the ether reu colorless Kristalle.die resullit from l.igroin-lle \ an (l; 2) ink l'f stop of wcnlen i'-chloro-iibuiyO-picolinsilurc umkrisiall Sierl Yield: O, ^r '■ (!'. iK g (12 ⁿ / ii).

«!! IB33 / I

Example J

5- (5'-chloro-n-pentyl) -pic () linsiiiire

! • "in a mixture of 1, ^c ) 7 g of 2-methyl-5- (5'-chloropen (yl) pyridine, 3.18 g of benzaldehyde and ¹ , Ib g of acetic anhydride are heated to 160 ° C. for 24 hours After cooling, the reaction mixture is acidified by adding dilute hydrochloric acid, and steam is introduced into the acidified mixture to remove the unreacted benzaldehyde by distillation. The residue is made alkaline and extracted with ether. The ethereal layer is washed with water, dried over potassium carbonate and im Vacuum distilled to obtain 1.1 g of an oily substance which boils at 160 to 165 ° C. (0.5 mm Hg). The molecular weight was determined by the mass spectrum to be 285 and the oily substance was confirmed to be a 2-styryl derivative , 1 g of Styrylderivats are dissolved in 20 ml of acetone, and the solution 2.15 g Kaliumpermanganai portionwise at a temperature of 5 to 10 "C was added. After completion of the addition, the mixture is at 10 to 15 ⁰ C while St J unden touched. The precipitated manganese dioxide is separated off by filtration and washed with acetone. The filtrate and the washing solutions are combined and treated in the same way as in Example 1, with crude 5- (5'-chloro-n-pentyl) picolinic acid. Yield: 440 mg (50%). After recrystallization from l.igroin a purified product erhallen, (.Las melts at 1ij to 114 ^l C.

Example 4
V (5'-Chlui-n-pent \ I) picolinic acid

In oil) ml of pyridine 4 ;: 2-Meih \ I ''> - ⁽¹ V-chloro η peni \ l) pyridin and S, Si: suspended selenium dioxide and while i hours gerühri under reflux The precipitated metallic selenium is carried. Filtration is separated off and washed with water. Steam is introduced into the ureaclion to remove the pyridine

is decolorized with activated charcoal and evaporated to dryness. The residue is recrystallized from l.igroin while maintaining ■) - (5'-chloro-n-pentyl) picolinic acid with a melting point of II) to 114.degree. Yield: 1.85 g (4 I ¹ Vo)

The 2-Meih> 1-5- ((i) -halogenalk1) -pyridines to be used according to the invention as starting material were obtained as follows:

Example 5
2-methyl-5- (J'-chloro-n-prop \ l) pyridine

Fin mixture of 4.08g 2-methyl-5- (i'-hydiOxyn-propyl) -pyridine. 5.15 g of p-Toltiolsull'onylchlorid and 15ml anhydrous pyridine is stirred at 40 C for 10 hours. The reaction mixture is poured into 50 ml of fish water and extracted four times with JO ml of ether. The ethereal layers are combined, washed three times with Ϊ0 ml of water, dried over water-free potassium carbonate, and the ether is expelled desüllaliv. The residue is distilled in vacuo while keeping _{1 1} g of 2-methyl-5- (1-chloro-n-propyl) pyridine. Boiling point 84 C / 0.6 mm Hg.

NMR:

r 1.67
r 2.64
r 2.%
r 6.51
r 7.27
r 7.50
τ 7, <- l Ϊ

MS:

I. I 1.1 (JIIs) (2 11 m)

d, 0.4 ppm)
dd, 0.4 ppm.
d, 1.5 ppm)
ppm)
ppm)

.S ppm)

M 16 ^l )

Main fragmentation peaks 77 106

(which indicates the existence of a chlorine atom)

Melting point of the picrate: I} 7 ~ I! 8 ¹ C.

! ■■ .leineniaranal \, e of the picrate (C ₁ , 11 iiNiC); (I):
Calculated N-15.18, Il i, 7 ^l ). C 14.05 ¹ Vo;
found: N 44, ^l > 2, 11 J.6 ^l >. C 14, J i%.

In the above-described manner, the table i ii zusaniinengelaßlen compounds were synthcli Sierl.

table )

\ UN] MMrSlU.Ul ¹ I l.ll

2-MiMliyl'S-liydritxy ulkylpyriilin

y
alkyl pyridine

k, 'ill | trash \ l:

Λιι.ιΙ-, μ: ι '., Γ Ί

lieuii '(Stluiii'l / pnnkll iiol'iimli'ii (hi-ui
lminll |! l (%) ·) <· H

K II, 1,1) 11

I. »
N

ΚΊΙ., Ι, Ι

t, "ιι, .Ν, ο ι .is.?:

11 · - IM Π I -IK ₁ -I ¹ Jl

(1 * 1. Ml

H 11, I ₁ (St.

,, ι H ΙΙ ,, Μ

KII (II. IM K 7

C ₁ JI ₁ -N ₁ I), (I .1 (,,. Io.!. Is IVM

(IM HS C) (. | (I, S (. | (4.IM (1. '. VZl

. (11..I ₁ (III

<ι ,, ΙΙ | .Ν, (Ι.Μι partly U 111 Ci

Ί ΜινΙιιίιΙι 'ιΚ ". I lu I, ils l'iki.il

Example 6
2-methyl-5- (3'-chloro-n-propyl) pyridiri

To a mixed solution containing 4.08 g of 2-methyl-5- (3'-hydroxy-n-propyl) pyridine and contains 2.35 g of anhydrous pyridine, 3.38 g of thionyl chloride are added dropwise at a temperature not to exceed 40 ° C. while cooling with ice Temperature added. The solution turns dark brown. After the addition is completed, the Solution stirred at room temperature for 3 hours and the reaction mixture in 30 ml Eiswasscr poured. After adding 2 ml of concentrated aqueous ammonia, the mixture is washed three times with 20 ml of ether extracted. The ether layer is washed with 20 ml of water over anhydrous potassium carbonate dried and freed from the ether by distillation. The residue is obtained in vacuo distilled from 2.73 g of 2 methy! -5- (i'-ch! or-n-propyl) -pyridine. It was found that the product is the same substance. 2-methyl-5- (3'-chloro-n-propyl) -pvridine was, obtained in Example 5.

Example 7
2-methyl-5- (5'-chloro-n-pentyl) pyridine

150 mg of iron (III) nitrate are added to 600 ml of liquid ammonia, followed by gradually adding 12.7 g of metallic sodium, cut into small pieces, while stirring. When the addition is complete, gray sodium amile precipitates out in about 30 minutes. 58.6 g of 2-methyl-5-vinyl pyridine are added in small portions to the mixture. After the addition, the stirring is continued for 3 hours. 158 g of 1-bromo-) chloropropane are added dropwise to the reaction mixture. After the addition has ended, the stirring is continued for Ί hours, and then the liquid is reduced under reduced pressure. 500 ml of water are added to the residue and this is extracted four times with 200 ml of ether. The ethereal layer is extracted with dilute hydrochloric acid. The hydrochloric acid layer is washed with 200 ml of ether, made ammonia with aqueous ammonia with simultaneous cooling with ice, and extracted three times with 200 ml of ether. The ethereal layer is dried over anhydrous potassium carbonate and the alluvium is vein'eben by distillation. The oily residue is dissolved in 300 ml of methyl alcohol and hydrogenated in an autoclave in the presence of Rancy nickel under a hydrogen pressure of 50 kg / cm ² at 30 to 50 ° C. for 2 hours. After the Rancy nickel has been separated off by filtration, the methyl alcohol is removed from the reaction mixture by distillation. The residue is obtained in vacuo with 63 g (65% yield) of 2-methyl-5- (5'-eh! Or-n-pentyl) pyridine as a colorless oil, which at 97 to 98 ° C / 0.15 mm Hg boils, preserved, ίο melting point of the picrate: 107 to 108 ⁰ C.

Elementary Analysis of Picrate (CwH 1 N ₄ O ₇ Cl): Calculated: C 47.84, 114.49, N 13.13%; Found: C 47.99, H 4.46, N 13.18%.

Example 8 2-methyl-5- (6'-chloro-n-hexyl) pyridine

1.15 g of metallic sodium in wire form are added to 10 ml of anhydrous tetrahydrofuran and then 5.85 g of 2-methyl-5-vinylpyridine dissolved in 10 ml of anhydrous tetrahydrofuran was added dropwise. After the addition has ended, stirring is continued under reflux for 5 hours. Then be the : 13 g of 4-chlorobutyl-p-toluenesulfonate were added to the mixture. The mixture is stirred under reflux for 2 hours, transferred to 50 ml of ice water and extracted with ether. The essential layer is made in the same manner as in Example 5 to obtain Treated 2-methyl-5- (6'-chloro-n-hexyl) -pyridine in a yield of 57%. Boiling point: IOI "C7O, O9 mm Hg.

Example 9 2-methyl-5- (5'-fluoro-n-peniyl) pyridine

A mixture of 6.65 g of 2-methyl 5 (5'-ehlor-n-penlyl) -pyridine, 20 g of diethylene glycol and 3.0 g of potassium fluoride are stirred while the mixture is at 1.5 "C for 25 hours let react. After successful cooling through

.) o Leave to stand, the reaction mixture becomes 30 ml Water was added and extracted four times with 20 ml of ether The ethereal layer is washed with 50 ml water, over anhydrous potassium carbonate dries and freed from the ether by distillation. Dci

• Is residue is under reduced pressure inside LrIuI von 2, IHg (M'Vii Ausheule) laiblovcm J-NKmIuI 5 (5'fluoro n pentyl) pyrulin, which ^{distilled at 68 ι '() ..' mm 11) 1} , boiling

Claims (2)

HOOC CH ₂ ) ,, - halogen (D H ₃ C CH ₂ ) ,, - halogen (Π)