DE2408813A1 - N-CARBAMOYLOXYPYRIDINIUM SALT AND METHOD OF PREPARING THE SAME - Google Patents

Description

The invention relates to N-carbamoyloxypyridinium salts and a process for their preparation.

It is known that heteroaromatic bases such as pyridine, Isoquinoline and quinoline with alkylating agents to the corresponding N-alkylpyridinium, -isoquinolinium or -quinolinium salts can be implemented.

It is also known that in the reaction of acyl halides with pyridine, extremely reactive N-acylpyridinium halides which are considerably stronger acylating agents than the acid chlorides themselves. The acylquinolinium salts behave atypically insofar as they easily add suitable nucleophiles to the 2-position be converted to relatively stable addition compounds, of which the so-called Reissert compounds and that in the 2-ethoxyl-ethoxycarbonyl-l ^ -dihydroquinoline which has become known as a peptide reagent in recent years the most famous representatives are.

Carbamoylpyridinium salts are also known, of which the stable diphenylcarbamoylpyridinium chloride is the best known compound.

Compounds of this structure type show in aqueous solution carboxy-activating properties that enable them to convert carboxylic acids in aqueous solution into anhydrides or with suitable Convert amines into amides.

Pyridine N-oxides can be converted into N-alkoxypyridinium salts just as easily as pyridine with alkylating agents

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However, the production of N-acyloxypyridinium salts has so far remained limited to special cases. The reaction of pyridine N-oxides with acid chlorides, anhydrides or sulfochlorides does not usually stop at the level of the N-acyloxypyridinium salts , but leads to substituted pyridines with the incorporation of a nucleophile and the rejection of the N-oxide oxygen E. Ochiai "Aromatic Amine Oxides", Elsevier 1967 and A. Katritzky "Chemistry of Heterocyclic N-Oxides" from the series "Organic Chemistry - a Series of Monographs", Academic Press 1971, and to an article by K. Thomas and D. Jerchel in the journal Angewandte Chemie 70, 719-146 (1958). From this and from the publications cited at these points it emerges that N-acyloxypyridinium salts are very difficult to grasp and are extremely easily attacked by nucleophiles.

It has now been found that N-carbamoyloxypyridinium salts of the general formula '

in which:

R-,, R ₂ = identical or different

an alkyl group with 1-4 carbon atoms, in particular methyl, ethyl or isopropyl, optionally substituted, for example by an alkoxy or aryl group, an aryl, preferably an unsubstituted or substituted phenyl group, cycloalkyl, for example cyclohexyl or cyclopentyl,. Alkylaminocarbonyl-dialkylaminocarbonyl, e.g. methyl. or dimethylaminocarbonyl or acyl, for example acetyl or an alkoxycarbonyl group, for example methoxy- or ethoxycarbonyl, but with the restriction that only one of the radicals R-j_ or R _{2 is} alkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonyl or acyl;

R ^ and R ₂ = together the atoms required to complete a heterocyclic ring or ring system, in particular a pyrrolidine, piperidine, morpholine, perhydroazepine, tetrahydrocmnoline or dihydroindole ring or an imidazolidone ring

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R-, and Rp = together the necessary to complete a piperazine

ring, which with its second nitrogen atom represents the <

bond to a similar second molecular residue corresponding to the general formula Atoms;

R ₃ , R ^, R ₅ = H, alkyl such as methyl or ethyl, aryl such as phenyl, aralkyl such as phenyl-C -, - C, -alkyl, halogen, e.g. chlorine, cyano, alkoxy with 1-4 carbon atoms , Acylamino, alkoxycarbonylamino or alkylureido and

X = an anion of low nucleophilicity or basicity, in particular Cl ", BF ^" or ClO ^

obtained when Ν, Ν-disubstituted carbamide chlorides of the general formula

^R l

^ N - C - Cl R _? · - "Il ^ 0

wherein

R-, and Rp have the meaning given above,

with pyridine-N-oxides of the general formula

in which R _05, R ^, and R ₁ - the abovementioned meaning, at temperatures between 0 ° and 40 ⁰ C, preferably between 0 ° and 20 ⁰ C, is reacted.

The reaction can generally be carried out in almost all aprotic solvents, sometimes even in alcoholic or water-containing systems, for example in ^acetone: methylene - ^x chloride, Essigester, dioxane, tetrahydrofuran, dimethylformamide or ethanol, isopropanol, Methylglykül, or ethanol / Water.

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The class of compounds of the N-carbamoyloxy-pyridinium salts is new and available in a surprisingly diverse range of structures.

The simple N, N-dialkylcarbaramide chlorides, Carbamide chlorides derived from saturated heterocyclic amines, from aliphatic-aromatic secondary ones Amine-derived carbamide chlorides, aromatic carbamide chlorides, but also allophanoic acid chlorides with pyridine-N-oxides implemented.

The pyridine N-oxides can be substituted by alkyl, aryl, acylamino, alkoxyl or alkoxycarbonylamino groups or by halogen be substituted one or more times, but they should not carry any strongly electron-withdrawing substituents. For example, 4-nitropyridine-N-oxide cannot be reacted with carbamide chlorides.

Depending on the nature of the substituents of the carbamide chloride or N-oxide used, N-carbamoyloxypyridinium salts ^{c of} different stability and sensitivity to hydrolysis are obtained. The compounds derived from 2-alkylpyridine-N-oxides and Ν, Ν-dimethylcarbamide chloride are particularly stable.

The pyridine N-oxides used as starting materials

are known and their preparation can be found in "Aromatic Amine Oxides ", Elsevier 1967, taken from summarized literature

will.

While most pyridine -N-oxides are advantageously produced from the corresponding pyridines by peracid oxidation are some special representatives, e.g. the 2- and 4-alkoxypyridine N-oxides and the 4-chloropyridine-N-oxide more easily via the corresponding nitropyridine-N-oxides by nucleophiles Exchange, e.g. with the corresponding alcoholates, accessible.

Special pyridine N-oxides can also be prepared by reacting pyrylium salts with hydroxylamine, e.g. 2,4,6-Trimethylpyridine-N-oxide from 2,4,6-trimethylpyrylium perchlorate and hydroxylamine (A. Balaban and C. Nenitzescu, Annalen d. Ch. 625, p. 74).

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Ν, Ν-disubstituted carbamic acid chlorides are phosgenated of the corresponding secondary amines, · for the preparation of the allophanic acid chlorides are those of H. Ulrich, J.N. Tilley in J.Org.Chem. 29, 2401 (1964) and the methods described in DT-OS 2 008 116 are available.

The new carbamoyloxypyridinium salts are best prepared in aprotic media, e.g. in solvents such as acetone, methyl ethyl ketone, ethyl acetate, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chloroform, perchlorethylene, Chlorobenzene, toluene, 1,2-dimethoxyethane, 2,2-bismethoxyethyl ether, Ν, Ν-dimethylformamide, tetrahydrofuran, di'oxane or in mixtures thereof. In some cases it is even possible to use alcoholic or even aqueous alcoholic solutions.

The reaction temperature is not critical within the range -from 0-40 ⁰ C, but a reaction temperature has been proven best of 10-20 °. In individual cases, the reaction temperature can be increased ^{to 50 °} C. without disadvantages for the yield or purity of the reaction products. The order in which the reactants are added is also not critical, but the reaction of allophanoic acid chlorides with pyridine N-oxides generally gives purer products if the pyridine N-oxide is added to the initially charged allophanoic acid chloride.

The stoichiometric ratios of the reactants are also generally not critical. On the other hand, it has been found that the yields are almost never improved by using one of the two reactants in excess. In alLfpmeinen gives the Carbamoyloxypyridiniumchloride in yields between - ^L 60 and 95% of theory.

The exchange of the ionic chlorine formed during the conversion of carbamide chlorides for other "hard" anions usually does not cause any difficulties. An exchange for perchlorate or fluoborate is particularly advantageous, since carbamoyloxypyridinium perchlorate and fluorobarate have a pronounced tendency to crystallize. In some cases, the anion exchange "can even occur during the production of the

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set of Na ClO ^ or NaBF ^ in alcoholic solution to the reaction mixture can be achieved. This way of working is particularly recommended then if the N-Carbamoyloxypyridiniumchloride especially are sensitive to light or contain groups that can be easily split off by chloride, e.g. alkoxy groups. One more way consists in doing without the isolation or purification of the chlorides and the crude product with an aqueous one or alcoholic solution of sodium tetrafluoborate or sodium perchlorate.

The N-carbamoyloxypyridinium salts of the invention are at Exclusion of moisture stable even over a long period of time, but the shelf life can be reduced by storage at low temperature to be improved. Some of these compounds, in particular the derivatives of carbamide chlorides, whose radicals R- and Rp are straight-chain Alkyl groups with 2 or more carbon atoms tend to decompose on exposure to light. In neutral aqueous In solutions, the compounds derived from carbamide chlorides and those derived from allophanoic acid chlorides are only slowly broken down Compounds, on the other hand, disintegrate quickly, usually within 1-10 hours.

The following table contains examples of compounds of the general formula that are obtained by the process according to the invention can be produced.

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i> Tabel

co to co σ>

Subst. No.

CH-

CH,

R-

■ 4

CH,

^ -OC ₂ H ₅

CIO,

ClO,

Mp dec.

163-67

168-70

86

90

100-102 '

95-100 *

production method

A.
A.

yield

89 % 85 %

89 % 80 %

CD Ό0 CO

O
H

ro

tn I. ο co to I. co co O co <n O

Sub st

No.

10

11

12th

N-

CH, -

CH CH

^C 2 ^H 5-

C ₂ H ₅ .

-N-

J
5

NH-C-OC ₉ H ₁ -

-W +

ClO,

ClO

Fp. Dec.

100-102 '

150 '

95-100 °

production method

yield

%

%

%

QO OO -i

4-> rf O Φ

IA

co

co

OO

approx

"Sft

"SR CO

co

in co

in H

O O

cr>

O CvJ

; m

¹ H.

O O O i O O O O CM in H I. I. I. co O O in H H H

HO

H Ü

- 1 + H.g

g p

te

OJ

• s

tr · »

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Q J- '

Subs t

No.

20th

21

22nd

N-

O,

/ CH ₂

23

24.

26th

—CH ₂ - CH,

<Θ

Cl

ClO

.Θ

Fp. Dec. | production method

144-46 °

> 90 ^c

100-102 °

102-104 ⁽

r *

yield

80

82

90 %

81

87

90

80 %

«Η H ο H co OD CO σ> ο CD

Subst. Mr.

27

28

29

30th

32

33

CIJ

-I

NHCOCIL

Cl

ClO

BF,

C3S

ClO;

Fp. Dec.

112-14 ¹

93-95 '

65-70 °

144-48 °

80-82

production method

yield

60 Ji

57

• 72 %

90

83 %

50

60

Subst. No.

Q CO UO OJ CD

34

36

37

38

O-

CH, I CH ^ -CH

³ >

CH ₃ -CH

CH

Co-OC ₂ H ₅

CONH ₂

CH

χΘ

Fp. Dec.

162-63

egg

200

158

152 * 154

production method

yield

60 %

50 %

75%

80 %

82 %

O CO CO

Subst, no.

41

42

43

44

N-

/ CHo-CH, CHo

I ₂ ^ n ₂

CH ²

, CH ₂ -CH ₂

N-

CH ₂ -CH ₂

Λ ~ ^CH 2

CH,

CH

X ¹

ClO

(r

ClO

.Θ

Fp. Dec.

85-86 °

80 '

104-106 °

76-78 ^c

140-144

production method

yield

90

80 %

75

84

76

85 %

O CO OO

Subs t. Wr.

45

47 48 49

50

r:

CH.

Cl-

ci-

cas

zcß

Fp. Dec

160-162 °

98-100 ^c

218-220

125-128 °

109-112

production method

■ A

yield

95 %

90 %

85 %

80 %

75 %

ro j> ο

O) CT)

co cn ο

Noun
No.. - 55 R ^ ^N " ^ll 3 χθ Fp. Dec. • yield A-G 56 λ-ΐΛ R5 Manufacturing
procedure H 51 CH ₃ -NH-C-N 87-89 ° 62 % rv>
Previous year
Previous year
β 52 η <t ■ egg © 105 °. A. 80 % 53 η -ψ ^ ... Cl © 88-89 ° • A 70 % . H
VJl
I. 54 ³ "^ NC -N ^X ci9 168-170 ° A. 75 % A. cm / Il * \
3 0 C10 169-173 ° 65 % ^{2 5} ^ NC / Il 173-180 °
* A. 80 % Il A.

Q H

em ι O CO CO 8th CjO co *****
O CO cn

Noun

Ur.

57

58

59

60

N-

HN

H 0

^CH 3 ° T 0

CH,

χθ

Cl

Fp. Dec.

production method

173-183 221-223 180-185

yield

60 %

70

70

90

■ J> O CO OO

The N ^ carbamoyloxypyridinium salts of the invention are valuable acylating agents with weakened reactivity, which are relatively unselectively attacked by nucleophiles. They are particularly reactive. opposite imino ₅ TFII © i- or OH groups and in aprotic solution also to carboxyl, _P n to the reagies with them under carboxyl activation ^ _c

This reactivity enables the M
for crosslinking of vegetable or animal protein * ₀ sondere in particular gelatin or similar binders of natural or synthetic origin _s, the carboxyl and amino groups may furthermore contain ^ for the modification of the peptide, _o

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example 1

1 (Dimethyla Elno cari3onyloxy) T3yriainiim-Qhlgri d (compound 1)

To 13 g (G _? 2 KoI) Fyriäin-Ko :: id in 100 al acetone is added dropwise at G-15 ° 22 -j DimsthylcarDamidchlorla ^ ö _? 204 mol} «liacli Γ, 3 Ydzic sucks off the colorless crystals which have precipitated out» washes with acetone \ wA trookixst in the VstoiuSc

melsp'oiikt? 163-16? "(Zer-s,)

It 5iA3 Hs 13 _? 82 CIs 17 * 5 E: 5 ₅ β2 Κι 13 ^ 5 CIi 17.0

äU3 oe'jrce ΰΪ2η Ci "ί" > .ϊ if /, J Ana Ivse: ride η

Example 2

1 (Morpholine- R-carbonyloxy) "PTriainium ^ chloride (Compound 15")

To 19 g of pyridine N-oxide (0.2 McI) in 100 ml of methylene chloride one drips with stirring to 20 ° 3G g of morpholine carbamide chloride in 50 ml of methylene chloride. After 60 minutes, 100 ml of acetone are added added, filtered off with suction, washed with acetone and dried under the exclusion of light in vacuo. For analysis, it is crystallized from ethanol Acetone and dried in vacuo.

Yield crude: 45 g (92 %) Melting point: 104-106 ° (decomp.)

If one the same compound without the addition of acetone forth, ~ ^ ~ 'sowird a decomposition melting point of 132 ° found.

Analysis calculated for Cs 45.7 H: 5.7 N: 10.7 Cl: 13.5 C ₁₀ H ₁₃ N ₂ O ₃ CLO, 5 H ₂ O

Found C: 45.8 H: 5.7 N: 10.8 Cl: 13.7

Example 3

1 (diet hylaain ooar bonyloxy) ~ 3-methylpyridinium perchlorate

"""""l:'. (connection 11)

! ι

2 ^ / 1-asung Ύοη 22 g (0 J2 mol) 2-methylpyridine-N-oxide in 100 ml.

Ζ% & 2? one drips rirtar stirring eel 0-10 ⁰ C 2? g (0.2 mol) of diethyl AQ-1233 "S £ 1836 / 09ga

carbamide chloride in 50 ml of ether. Stirring is continued for 2 hours at 5 °, cooled to 0 °, decanted off the excess ether from the oil and gives 36 g of sodium perchlorate in ethanol to _f After standing overnight, is filtered off from the precipitated NaCl, concentrated under vacuum at T - 30 ° and lets stand to crystallize.

Yield 40 g (65 % of theory), melting point: 130-132 (decomp.)

Example 4

! (Morpholine carbonyloxyQpyridinium fluoborate (compound 16)

To the solution of 14 g of sodium fluorate in 25 ml of water is added

the solution of 24.5 g (.0.1 mol) of compound 15. After 60 ^ivJ minutes, it is suctioned off. Yield: 25 g, melting point: 138-140 ° (decomp.).

Example 5

l- (Morpholine carbonyloxy ) pyridinium perchlorate (compound TTJ

20 g of sodium perchlorate in as little water as possible are added to the solution of 24.5 g (0.1 mol) of compound 15 in 60 ml of water. The mixture is left to stand for 30 minutes and filtered off with suction.
Yield: 27 g Melting point: 150-152 ° C (decomp.)

Example 6

1- (Morpholine-N-carbonvloxv) -3-ethoxycarbonylaminopyridinium-

perchlorate (compound 34)

30 g (0.2 mol) of morpholine carbamide chloride are added dropwise at RT to 36.4 g (0.2 mol) of 3-ethoxycarbonylaminopyridine N-oxide in 150 ml of isopropanol. After 30 minutes, 30 g of sodium perchlorate in 150 ml of ethanol are added and the mixture is left to stand overnight. The crystals which have precipitated out are filtered off with suction.
Yield: 50 g Melting point: 162-163 ° C (decomp.)

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Example 7

1 (imidazolidone-N-carbonyloxy) pyridinium chloride (compound 58)

HIf N-C-

I I

ο - FeP

To dissolve 29.7 g of imidazolidone-N-carbonyl chloride (0.2 mol)
(prepared according to H.Ulrich et al., J.Org.Chem. 29,2403) in
150 ml of methylene chloride are added dropwise at 0-10 °, 19 g of pyridine-N-oxide (0.2 mol) in 50 ml of methylene chloride. After 30 minutes, suction off. washes with acetone and dries in vacuo

Yield 43 g (88%) decomp. Melting point 221-223 °
Analysis ber. A. C ₉ H ₁₀ N ₃ O ₃ Cl C: 44.4% H: 4.41% N: 17.7% Cl: 14.6% found. C: 44.1% H: 4.1% N: 18.0% Cl: 14.3%

Example 8

1 (N _t N'-dimethylureido-N-carbonyloxy) -2-methyl-pyridinium chloride

(Compound 51)

CH, NH-C-N-

■> Q \ Pftds. Cl

ö CO- N ^ / - ¹

For the solution of 30.1 g (0.2 mol) of NjN'-dimethylallotfianyl chloride, prepared by phosgenation of Ν, Ν'-dimethylurea according to H.Ulrich et al, J.Org.Chem. 29.2402, 22 g (0.202 mol) of 2-methylpyridine-N-oxide are added dropwise to 1-50 ml of methylene chloride at 0-10 °
in 50 ml of methylene chloride. The precipitated colorless crystals are filtered off with suction, washed with a little acetone and dried in vacuo.

Yield: 41.5 g (80%) Melting point: 105 ° (decomp.) A-G 1233 ♦ - 20 -

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Example 9

1 (N-methoxycarbonyl-N-phenyl-carbonyloxy) pyridinium chloride

(Compound 60)

CH ^ -P-N-C-O-Mm Cl ^

b ^ = ⁷

To dissolve 9.5 g (0.1 mol) of pyridine N-oxide in 200 ml of methylene chloride 21.3 g of N-methoxycarbonyl-N-phenylcarbamide chloride are added dropwise at 0 ° in 200 ml of methylene chloride. The separated crystals are filtered off with suction and dried i.V.

Yield: 27.3 g (90 %) Melting point: 113-134 ° (dec.)

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Claims (4)

Claims. γJ ₀ R ₁ and R ₂ = identically or differently alkyl, cycloalkyl, aryl or R ₁ stands for alkyl, cycloalkyl or aryl and R ₂ stands for alkylaminocarbonyl, dialkylaminocarbonyl, Acyl or alkoxycarbonyl, or R- and R ₂ = together the members required to complete a saturated or unsaturated N-heterocycle. or the remaining members of a piperazine ring, which with its second nitrogen atom creates the connection to a similar second molecular residue corresponding to the general formula, R ,, R ^ and Rc = hydrogen, alkyl, aralkyl, aryl, halogen, cyano, Alkoxy, acylamino, alkoxycarbonylamino or alkylureido and X = an anion. . 2. Process for the preparation of N-carbamoyloxypyridinium salts the general formula where mean: .R ₁ and R ₂ = identically or differently alkyl, cycloalkyl, aryl or R ₁ stands for alkyl, cycloalkyl or aryl and R ₂ stands for alkylaminocarbonyl, dialkylaminocarbonyl, Acyl or alkoxycarbonyl, or A-G 1235 ....... 22 - ■ 509836/0950 R-j and R2 = together to complete a saturated or unsaturated N-heterocycle required ■ members, or the remaining members of a piperazine ring, the one with its second nitrogen atom the connection to a similar second, the general one Produces the corresponding molecular residue, R ,, Rr and R ₅ = hydrogen, alkyl, aralkyl, aryl, halogen, cyano, alkoxy, acylamino, alkoxycarbonylamino or alkylureido and X = Chlorine, characterized in that one carbaminochloride of the general formula ¹ ^ NC-Cl ^R 2 O wherein R-, and Rp have the meaning given above, with Pyridine-N-oxides of the general formula ^V 3 ^R 5 in which R ^, Ra and R ^ have the meaning given above for Temperatures between 0 and 40 C converts. ' 3. Process for the preparation of N-carbamoyloxy-pyridinium tetrafluccborates or perchlorates of the general formula according to claim 2, wherein X ^^ stands for BF ^ w or ClO ^^, thereby characterized in that the carbamidochlorides with the pyridine-N-oxides in the presence of sodium fluoroborate or sodium perchlorate implements » 4. Process for the preparation of N-carbamoyloxypyridinium tetrafluoroborates or perchlorates of the general formula according to claim 2, A-G 1233 - 23 - 50 9-8 36/0960 wherein X represents BF / ^ 'or ClO, ---, characterized in, one d®ß the Carbamoyloxyp3 ^r ridiniumchloride the general formula according to claim 2 flucrborat with aqueous solutions of sodium tetraborate · or reacting Natriuniperchlorat. B O 9 8 3 S / υ 9 5 O