CS250686B2 - Method of quaternary aminothioles production - Google Patents

Description

In our related Czechoslovak patent specification No. 250,658 a new process for the preparation of carbapenem derivatives of the general formula I is described.

R ‘

R ^&

SAR ^1if

COOR® 11) in which

R ⁸ represents a hydrogen atom and R ¹ represents a radical selected from the group consisting of hydrogen and optionally substituted C 1 -C 10 alkyl, alkenyl and alkynyl groups, C 3 -C 6 cycloalkyl and cycloalkylalkyl groups and 1 to 6 atoms carbon in the alkyl, phenyl, aralkyl, aralkenyl and aralkynyl moiety wherein the aryl moiety is a phenyl moiety and the aliphatic moiety contains 1 to 6 carbon atoms, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl groups wherein the heteroatom or heteroatoms are selected from the group consisting of one to four oxygen, nitrogen and sulfur atoms and wherein the alkyl moiety attached to the heterocyclic moiety contains 1 to 6 carbon atoms, wherein said substituent or substituents of the above-mentioned moieties are selected from the group consisting of alkyl groups of 1 to 6 carbon atoms, optionally substituted; amino, halogen, hydroxyl or carboxyl, halogen atoms, radicals of the formula -OR ³ ,

O -OCNR ⁴ R ^5, about ^11, 4 -cnr ³ R ^4, -NR ³ R ^4,

NR ⁵ -SO 2 NR ³ R ⁴ R ³ -nhicnr about ^4, about

R ³ CNR ⁴ -, -CO ² R ³ , -, o

—OCR ³ , —SR ³ ,

O

the heteroatom or heteroatoms are selected from the group consisting of one to four oxygen, nitrogen and sulfur atoms and the alkyl moiety attached to the heterocyclic radical contains 1 to 6 carbon atoms, or R ³ and R ⁴ together with the nitrogen atom to which at least one of these radicals is bonded to form a five or six membered nitrogen-containing heterocyclic ring, and R ⁹ is as defined above for R ³ , except hydrogen or

R ¹ and R ⁸ together form an alkylidene group having 2 to 10 carbon atoms, optionally substituted by a hydroxyl group,

A represents a cyclopentylene group, a cyclohexylene group or an alkylene group having 2 to 6 carbon atoms, optionally substituted by one or two alkyl groups having 1 to 4 carbon atoms,

R ² represents hydrogen, an anionic charge or a negative conventional readily removable carboxyl protecting group provided that when R ² is hydrogen or a protecting group, there is also present a charge balancing anion, and

R ¹⁴ represents an aromatic or non-aromatic heterocyclic radical containing a quaternized nitrogen attached to the radical A via a ring nitrogen atom to form a quaternary ammonium group,

O-SR ⁹ , and pharmaceutically acceptable salts thereof, characterized in that the intermediate of formula IV

O -> CN, -N 3, -OSO3R ^3, -OSO 2 R ^3, -NR ³ SO 2 R ^4, -NR ³ C = NR ^4, -NR ⁴ CO 2 R ³ and -NO 2, in which

R ³ and R ⁴ are each independently hydrogen, alkyl, alkenyl or alkynyl of 1 to 10 carbon atoms, cycloalkyl, cycloalkylalkyl or alkylcycloalkyl of 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl a phenyl, aralkyl, aralkenyl or aralkynyl group wherein the aryl moiety is a phenyl moiety and the aliphatic moiety contains 1 to 6 carbon atoms, a heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl moiety in which:

(IV) wherein

R ¹ and R ⁸ have the abovementioned meaning,

R ² 'represents a conventional, easily cleavable carboxyl protecting group and L represents a conventional cleavable group, reacted with a thiol of formula VII

^HS-A-R14 X ^- (VII) in which

A and R ¹⁴ are as defined above and X ^- represents a balancing anion, in an inert solvent in the presence of a base, to form a carbapenem derivative of the general formula Γ a residue of the general formula

in which

R ^1, R ^8, R ^2, A, R ¹⁴ and X 'have the above meanings, then optionally deprotected carboxy for R ^2' to give the corresponding unprotected compound of formula I or a pharmaceutically acceptable salt thereof.

Carbapenem derivatives of formula I are effective antibacterial agents or among the products useful for the preparation of such agents.

One of the starting materials for this process is the thiol of the above formula (VII), the process of which is the subject of the present invention.

Accordingly, the present invention provides a process for the preparation of quaternary amine thiols of formula VII

HS — A — R ¹⁴ X “(VII) in which

A represents a cyclopentylene group, a cyclohexylene group or a radical of formula R10 _R12

I I —c --- c—

RH ³ wherein R

R ', R H, R ¹² and R ¹³ independently of one another are hydrogen or alkyl having 1 to 4 carbon atoms,

X - represents the balancing anion and

R ¹⁴ represents a radical of formula

wherein R 17 _{and R} e is _{n z} and _v .i ie _with one another are hydrogen, alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, alkoxy of 1 up to 4 carbon atoms or amino, wherein

R ¹⁰ and R ²⁰ are each independently C 1 -C 4 alkyl or C 1 -C 4 alkylthio or a radical of formula

-N 7, 2¾ where

R ²³ is C 1 -C 4 alkyl and

Z is sulfur, oxygen, S-O, or a group

R ^21- _R 22 wherein R ²¹ _{and R} 22 are each independently hydrogen or C 1 -C 4 alkyl;

characterized by the sulfide of formula VIII S ^ ~ (Vlil) in which

A is as defined above, reacted with a strong acid and an amine corresponding to the radical R ¹⁴ as defined above.

In accordance with a preferred embodiment, compounds of formula (VII) are prepared wherein:

A is -CH 2 CH 2 -, -CHCH 2 -,

CH3

or —CH2CH—.

CH3

In the case of certain compounds of formula (VII) bearing a cycloalkylene or branched alkylene group in the meaning of the symbol A, one or more asymmetric carbon atoms leading to the formation of diastereoisomers may be present.

The invention includes mixtures of these diastereoisomers as well as individual pure diastereoisomers.

One preferred R ¹⁴ substituent group is represented by the formula

Of this subgroup of compounds, those in which A is -CHCH 2 - are preferred,

CH3 —CH2CH2—,

or —CH2CH—.

CH3

According to another preferred embodiment, the invention provides a process for the manufacture of those compounds in which

-N

N

x.

which represents the above-defined, optionally substituted heteroaryl radical containing at least one ring nitrogen atom and attached to the carbon atom of radical A, via a ring nitrogen atom, to form a quaternary ammonium group.

Preferred compounds of the above group are those wherein A is -CH 2 CH 2 -, -CHCH 2 -,

CH3

or —CH2CH—.

CH3

In accordance with another preferred embodiment, the invention provides a process for the preparation of compounds wherein the radical of the formula is a pyridinium radical.

Of this subgroup of substances, those compounds in which A is -CHCH 2 - are preferred,

CH3 —CH2CH2—,

or —CH2CH—.

CH3

In accordance with a most preferred embodiment, the present invention provides a process for the preparation of compounds of formula (VII) wherein the group —A — R ¹⁴ represents a residue of (1) (2) ch ₃

~ / 7 __ (1)

(12) + setter -CHXH, N - ^ = Y ⁶ -CH ₃ (13) • CH, CHnN

NH, or (5) (6) (14 ) (7) _of ch ch _from n. __ / -one

CH.CHUÍ / ”

Z. A. \ ^ Z

KCJ

7.

R, R or S, S diastereoisomers on two asymmetric carbons of the cyclohexyl group.

(8)

SCH · (9)

-CH2CH2M

OCH, + FA

Another preferred group of quaternized R ¹⁴ substituents is represented by the formula

in which

R ²³ has the above meaning and residue (10)

Italy (11)

The R or S diastereoisomers represents a piperazine, morpholine, thiomorpholine or thiomorpholine-S-oxide moiety which may be substituted as described above.

In accordance with a preferred embodiment, the invention provides a process for preparing those compounds in which the residue is present

represents the remainder of the formula

CH, ' ^w V_y ^S '

Preferred substances from this preferred subgroup are those wherein A is -CHCH 2 -,

CH3

CH>

CH, \ / - μ ⁺ 'nh, \ r ~~ \ h

CH.

\ r ~ \ / ^CH j »NS -> 0 or - w N + - / + \ - / - Τ 'CH i .5

Of this subgroup, those compounds in which A is -CHOH2- are preferred,

CH3 —CH2CH—

AND

CH 3 or - (CH 2) 2 -, and most preferably those wherein A is -CH 2 CH 2 -.

Most preferred are those in which the grouping —CB2CH2—

CH 3 or - (CH 2) 2 -, and most preferred are those in which A is -CH 2 CH 2 -.

According to an even more preferred embodiment, the invention provides a process for making those compounds in which the residue is present

- N '1) z V represents a group ch ₅

-N \ _Z s-> o

CH,

CHy, _/ CHj

CH ₃

CHS \

means the rest

CR ', 3 CH, \ / / ... X

-N ⁺ Oi X (both cis- and β-diastereoisomers) Cl ^/ A · CH _a

- · M Λ, Μ'ρ nrhb JJ ^<y VZ x cy

J

The reaction of the invention may be carried out in the presence or absence of an inert organic solvent, which is preferably a non-polar organic solvent such as methylene chloride, benzene, xylene, toluene and the like. When the amine and sulfide reactants are liquid or. if the solid amine is soluble in the liquid sulfide reactant, it is preferred to carry out the reaction without using another solvent.

The precise selection of the strong acid used for the reaction is not critical and may be, for example, a strong inorganic or organic acid such as hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid and the like.

The quaternary thiolamine product of formula (VII) may be produced at a temperature in the range of about -20 ° C to 100 ° C, at X ⁵ or

The preferred reaction temperatures range from about 50 ° C to about 70 ° C.

The sulfide reactant, aromatic amine and acid are preferably used such that the sulfide and acid are present in roughly equimolar amounts, while the amine is used in excess, for example in a ratio of 2 to 3 moles of amine for each mole of sulfide or acid.

The resulting quaternary thiolamine will contain a balancing anion whose character will be determined by the acid used. However, it is possible to replace this balancing anion in a conventional manner with another.

The invention is illustrated by the following non-limiting examples.

Example 1 (2-mercaptoethyl) pyridinium methanesulfonate ¹ H-NMR (perdeuterodimethylsulfoxide, δ values):

2.32 (3H, singlet, CH 3 SO 3),

2.61, 2.70, 2.73, 2.82 (1H, part B of system A2B, SH],

3.07 (2Ή, multiplet / s D2O 3.08 (2H, triplet, J = 6.5 Hz) /, CH2S),

4.76 (2H, triplet, J = 6.5 Hz, CH2 N + J, 8.19 (2H, multiplet, Hm of the pyridinium residue)),

8.6 (1H, multiplet, Ho of the pyridinium residue),

9.08 (2H, double doublet, J = 6.8 Hz, J = 1.4 Hz, Ho of the pyridinium residue).

UV (water): A _max

206 (ε 5,230),

258 (ε 3,760) nm.

Method A

4- MsOH

55C hours

HS

1- (2-mercaptoethyl) pyridinium chloride permulite S-1. χ- / i'1sO ci (Ms = methanesulfonyl)

To a suspension of pyridinium methanesulfonate in pyridine, prepared under cooling by dropwise addition of 1.95 ml (0.03 mol) of methanesulfonic acid to 8.0 ml (0.099 mol) of pyridine, was added 1.96 ml (0.033 mol) of ethylene sulfide. The resulting mixture was stirred at 55 ° C for 16 hours and then concentrated under reduced pressure to a thick syrup which was mixed with a few milliliters of water. The resulting solution is applied to a μ-Bondapak C-18 (40 x 16 cm) column and the column is eluted with water. Lyophilization of the appropriate fractions gave 6.5 g (91%) of a colorless syrup-like product.

IR (film): in _max

300 - 2600 (wide belt, SH),

635 (pyridinium residue),

490, 1200 (sulfonate residue),

068, 1060, 1045, 791, 780 ^cm-first

An aqueous solution of 9.4 g (0.04 mol) of crude 1- (2-mercaptoethyl) pyridinium methanesulfonate was applied to a column (2.5 x 41 cm) of Permutit S1 (Cl ^- ) ion exchanger. The column is eluted with water at a rate of 0.5 ml per minute, the appropriate fractions are combined and lyophilized. 7.0 g (100%) of a yellowish syrup product are obtained, which product is used as is in the following stage. ¹ H-NMR (denterium oxide, δ values):

3.22 (2H, multiplet, CH 2 S),

4.88 (multiplet, CH2 N +),

8.18 (2H, multiplet, Hm of the pyridinium residue),

8.7 (1H, multiplet, Hp of the pyridinium residue),

9.0 ppm (2H, multiplet, Ho of the pyridinium residue).

Method B

C <

Κ 5.6 ml (70 mmol) of ice-cooled pyridine are added 4.05 g (35 mmol) of pyridine hydrochloride and 2.1 ml (35 mmol) of ethylene sulfide. The mixture was heated to 65 ° C and stirred for 75 minutes while switching to a two-phase system. The lighter phase was removed, the oily residue was washed five times with 10 ml of ether each time and dried under high vacuum. The title compound is obtained (yield 90-100%), which is used without further purification in the next step. Example 2

1- (2-mercaptoethyl) -3,5-dimethylpyridinium methanesulfonate

ch ₂

To a suspension of 3,5-lutidinium methanesulfonate in 3,5-lutidine prepared by adding 0.65 ml (0.410 mol) of methanesulfonic acid to 2.51 ml (0.022 mol) of cold 3,5-lutidine is added 0.655 ml (0.011) mol) ethylene sulfide. The resulting mixture was stirred at 55 ° C for 24 h under nitrogen, then cooled to 23 ° C and diluted with 5 mL of water and 5 mL of ether. The organic layer was separated and the aqueous solution was washed six times with 4 ml of ether each time. The ether residues were removed by evaporation in vacuo and the aqueous solution was applied to a 2.5 x 6.0 cm] μ-Bondapak C-18 column which was eluted with water to give 2.4 g (91 percent) by lyophilization of the appropriate fractions. colorless syrup product IR (film):

Vmax

520 (SH)

628 (pyridinium residue),

600, 1 495, 1 325, 1 305, 1 283, 1 200 (sulphonate),

040, 938, 765, 680 cm ¹ .

¹ H-NMR (perdeuterodimethylsulfoxide, δ in ppm):

2.31 (3H, singlet, CH 3 SO 3 "),

2.47 (6H, singlet, CH3 on pyridinium residue),

2.57, 2.66, 2.69, 2.78 (1H, part B of system A2B, SH),

3.06 (2H, multiplet / deuterium oxide added (2H, triplet, J = 6.5 Hz) /, CH2S),

4.65 (2H, triplet, J = 6.5Hz, CH2 N +), 8.34 (1H, singlet, Hp of the pyridinium residue),

8.79 (2H, singlet, Ho of the pyridinium residue).

UV (water): λ _max 271 (ε 4860) nm.

Analysis:

calculated:

H, 6.66; N, 5.14.

23.54% S;

found:

H, 6.49; N, 5.17.

24.18% S.

Example 3

3-hydroxymethyl-1- (2-mercaptoethyl) pyridinium trifluoromethanesulfonate

To 2.91 ml (0.030 mol) of 3-pyridinmethanol was added dropwise first 1.327 ml (0.015 mol) of trifluoromethanesulfonic acid and then 0.89 ml (0.015 mol) of ethylene sulfide. The resulting homogeneous mixture was heated to 50-70 ° C under nitrogen in an oil bath for 20 hours, then taken up in 15 ml of water and extracted five times with 5 ml of dichloromethane each time. The aqueous phase is concentrated in vacuo and the residue is applied to a reverse phase column (C 18). Elute the column with water and evaporate the appropriate fractions!

/ ~ C \. N- (CR ₃ SO 3 C to give a pale yellow oil which was rechromatographed give a nearly colorless oil. After drying in vacuo over phosphorus pentoxide gave 4.50 g (94 percent) of product as viscous oil.

IR (film): in _max

450 (s, OH)

560 (w, SH) cm ^-1 , ¹ H-NMR (d 6, P-value 8):

9.10 - 8.05 (multiplet, 4H, aromatic protons),

5.01 (triplet, J = 5.5Hz, 2H, N-CH2); 4.93 (singlet, 2H, —CH2OH),

4.43 (broad singlet, 1H, —OH),

3.43 - 3.18 (multiplet, 2H, S - Cl), 2.34-2.10 (multiplet, 1H, SH).

Example 4

4-Hydroxymethyl-1- (2-mercaptoethylpyridinium trifluoromethanesulfonate)

- cf.so;

ó o

To a solution of 1.634 g (0.015 mol) of 4-pyridinmethanol in 10 ml of dichloromethane under nitrogen at 0 ° C was added dropwise 1.327 ml (0.015 mol) of trifluoromethanesulfonic acid, rapidly precipitating a pale brown oily material. An additional 1.635 g (0.015 mol) of 4-pyridine-methanol was added to the mixture, and the solvent was evaporated under reduced pressure. To the oily residue was added 0.891 ml (0.015 mol) of ethylene sulfide and the resulting mixture was heated in an oil bath at about 60 ° C for 3 hours. The reaction mixture is taken up in 15 ml of water and the aqueous solution is washed five times with 5 ml of dichloromethane each time. After removal of the organic solvent residues by evaporation in vacuo, the remaining aqueous solution is applied to a reverse phase (Cie) column which is eluted with water. Evaporation of the appropriate fractions gave an oily material which was further dried in vacuo over phosphorus pentoxide to give 4.64 g (97%) of the product as a colorless oil.

IC (film): in _max

455 (s, OH).

565 (w, SH) cm ^1st

.//** '

M $ O

To a suspension of 2-methylpyridinium methanesulfonate in 2-methylpyridine prepared by adding 0.65 mL (0.010 mol) of methanesulfonic acid to 2.17 mL (0.022 mol) of cold 2-methylpyridine was added 0.655 mL (0.011 mol) of ethylene sulfide. The reaction mixture was stirred under nitrogen at 55 ° C for 21 hours, then cooled to 23 ° C and diluted with 5 mL of water. The aqueous solution was washed six times with 4 ml of ether each time, evaporated in vacuo to remove the last traces of organic solvents and loaded onto a column (2.5 x 10 cm), u-Bondapak C-18. The column is eluted with water, the appropriate fractions are combined and lyophilized. This afforded 2.13 g (85%) of the title compound.

IR (film): in _max

520 (SH)

623 (pyridinium residue),

574, 1512, 1485, 1412, 1195 (sulfonate), 1038 ^cm-first

¹ H-NMR (perdeuteroacetone, δ values in ppm):

¹ H-NMR (perdeuterodimethylsulfoxide + + deuterium oxide, values <$ in ppm):

9.07, 8.18, (AB-quartet, J = 6.8 Hz, 4H, aromatic protons),

5.03 (singlet, 2H, GH 2 OH),

4.96 (triplet, J = 6.5 Hz, 2H, N-CH2), 4.09 (broad singlet, 1H, —OH),

3.5 - 3.1 (multiplet, 2H, S - CH2),

2.25 (broad singlet, 1H, -SH).

Example 5

1- (2-mercaptoethyl) -2-methylpyridinium methanesulfonate

59 ° C + MsOH_____ hours

2.37 (3H, singlet, CH 3 SO 3 -),

2.83 (3H, singlet, CH3 on pyridinium residue),

3.09 (2H, J = 6.9Hz, CH 2 S),

4.71 (2H, triplet, J = 6.9 Hz, CH2 N +), 7.93 (2H, multiplet, Hm of the pyridinium residue),

8.44 (1H, multiplet, Hp of the pyridinium residue),

8.89 (1H, multiplet, Ho of the pyridinium residue).

UV (water): λ _max 266 (ε 3,550) nm.

250688

Example 6

AND.

1- (2-mercaptoethyl) -4-methylpyridinium methanesulfonate ° C

M with Ql ·! * hours

To a suspension of 4-picolinium methanesulfonate in 4-picoline, prepared by adding 0.65 mL of methanesulfonic acid (0.010 mol) to 2.14 mL (0.022 mol) of 4-picoline, was added with cooling 0.655 mL (0.011 mol) of ethylene sulfide. The reaction mixture was stirred at 5 ° C for 24 hours under nitrogen, then cooled to 23 ° C and diluted with 5 mL of water and 10 mL of ether. The organic layer is washed five times with 5 ml of ether each time and after removal of the last traces of ether under reduced pressure, it is applied to a column (2.5 x 10 cm) of μ-Bondapak C-18. The column is eluted with a mixture of 15% acetonitrile and 85% water and the appropriate fractions are lyophilized. 2.66 g (100%) of a colorless syrup-like product are obtained.

IC (film). V _m ax

500 (SH)

640 (pyridinium residue),

572, 1 520, 1478, 1 200 (sulphonate),

040, 833 and 768 cm ^1st

¹ H-NMR (perdeuterodimethylsulfoxide, δ in ppm):

2.31 (3H, singlet, CH 3 SO 3 -),

2.62 (singlet, CH3 on pyridinium residue),

2,2-2,9 (4H, SH, CH3 on pyridinium residue),

3.04 (2Ή, multiplet, CH2S),

4.68 (2H, triplet, J = 6.4Hz, CH 2 N +),

8.01 (2H, doublet, J = 6.6 Hz, Hm, pyridinium residue),

8.89 (2H, doublet, J = 6.6 Hz, Ho of pyridinium residue).

UV (water): Amax

256 (ε 4100),

221 (ε 7,544) nm.

B.

1- (2-mercaptoethyl) -4-methylpyridinium p-toluenesulfonate

in.' / \ nO / ~

-of

,. / Ή - / / π- · —-—

To a suspension of 1.72 g (0.01 mol) of p-toluenesulfonic acid in 6.5 ml of benzene was added 1.17 ml (0.012 mol) of 4-picoline, and the resulting mixture was stirred at 23 ° C under nitrogen for 30 minutes. 0.65 ml (0.011 mol) of ethylene sulphide was added thereto, and the mixture was stirred at 75 ° C for 24 hours, after which an additional 0.65 ml (0.011 mol) of ethylene sulphide was added and stirring was continued at 75 ° C for 24 hours. The reaction mixture was cooled to 23 [deg.] C. and diluted with 5 ml of water and 8 ml of ether, the aqueous layer was separated and washed three times with 8 ml of ether each time, and the last traces of organic solvents were removed by evaporation in vacuo. μ-Bondapak C-18 eluting with water gave 2.94 g (90%) of the title compound as a colorless syrup.

IR (film): in _lliax

510 (SH),

640 (pyridinium residue),

595, 1 582, 1 475, 1 200 (sulphonate),

1031, 1010, 818 ^cm-first

¹ H-NMR (perdeuterodimethylsulfoxide, δ in ppm):

2.29 (3H, singlet, CH3 on pyridinium residue),

2.61 (singlet, CH 3 Ph),

2.4-2.8 (4H, SH, CH 2 Ph),

3.03 (2H, multiplet / addition of deuterium oxide yields a triplet (J = 6.4 Hz at 3.04), CH 2 S),

4.68 (2H, triplet, J = 6.4Hz, CH 2 N +),

7.11, 7.49 (4H, two doublets, J = 7.9 Hz, phenyl),

8.00 (2H, doublet, J = 6.5 Hz, pyridinium Hm),

8.89 (2H, doublet, J = 0.5 Hz, Ho of pyridinium residue).

UV (water): λ max

256 (ε 4,315),

222 (ε 17,045) nm.

Example 7

AND.

4-methylthiopyridine

5 Β 8 8 7

The preparation of this compound has been described by King and Ware in J. Chem. Soc., 873 (1939). The procedure described in the above-cited work is described below.

SMd (Me = Methyl, Et = Ethyl)

B.

Dissolve 5.5.5 g (50.0 mmol) of 4-mercaptopyridine (Aldrich) in 50 ml of boiling absolute ethanol and remove the insoluble material by filtration through a pad of diatomaceous earth. The filtrate was heated to redissolve the solids, and after cooling to about 50 ° C, 3.17 mL (51.0 mmol) of methyl iodide (Aldrich) was added in one portion. The resulting mixture was allowed to crystallize. Filtration of the solid afforded 6.77 g (26.7 mmol) of the title compound as the hydroiodide. The yield was 53.5%.

¹ H-NMR (deuterium oxide, δ in ppm):

2.70 (3H, singlet, --SCH 3) a

7.65-7.77-8.35-8.48 (4H, type A2B2, aromatic protons).

IR (nujol): ν max

615, 1585 (aromatics) and

780 cm ¹ .

UV (water): A _max

227 (ε 2.02 χ 10 ⁴ ) a

298 nm (ε 1.64 χ 10 ⁴ ).

6.33 g (25.0 mmol) of the above hydroiodide are dissolved in 40 ml of water, the insoluble material is filtered off and washed with 10 ml of water. 5 g of sodium hydroxide in pellets are added to the filtrate at 0 to 5 ° C, the aqueous layer is saturated with sodium chloride and extracted three times with 25 ml of diethyl ether each time. The combined organic extracts were washed twice with brine, dried (MgSO 4) and evaporated. 2.92 g (23.4 mmol) (total yield 50%) of the title compound are obtained.

⁴ H-NMR (deuterium oxide, δ in ppm):

2.48 (3H, singlet, -CH 3) and

7.03 - 7.13 - 8.38 - 8.48 ppm (4H, typ

A2B2, aromatic protons).

IR (film): Vmax

580 and 800 cm ^-1 .

4-methylthio-N- (2-mercaptoethyl) pyridinium methanesulfonate

CH3SO3H

KO / ⁵ ~ 50-60 ° C

\..-IN

Xo>

To 0.65 mL (10.5 * mmol) of freshly distilled methanesulfonic acid was slowly added 2.75 g (22.0 mmol) of 4-methylthiopyridine while cooling in ice. To the resulting solid mixture was added 0.66 mL (11.0 mmol) of freshly distilled ethylene sulfide (Aldrich) and the resulting mixture was heated at 50-60 ° C for 21 h. As the reaction proceeds, the solids pass into solution. After cooling, the reaction mixture was dissolved in 5 ml of water and the solution was washed five times with 4 ml of diethyl ether each time. The cloudy aqueous layer was filtered through diatomaceous earth and the filtrate was purified by reverse phase silica gel column chromatography (10 g Cie micro Boudapack) using water as eluent. Fractions of 10 ml are collected. Fractions 2 and 3 were combined and purified again by reverse phase column chromatography. From fraction 2, 1.258 g (4.48 mmol; yield 42.6 ^(a / o)) of the title compound was obtained as a viscous oil.

^{] 1} H-NMR (perdeuterodimethylsulfoxide, CFT-20, δ in ppm):

2.32 (3H, singlet, CH 3 SO 3 -),

2.72 (3H, singlet, -SCH 3),

2.68 (1H, multiplet, SH);

2.9-3.2 (3H, multiplet, 'CI-I2S'),

4.59 (2H, triplet, J = 6.4 Hz, —Cl2N ')

7.97 (2H, doublet, j = 7.2 Hz, aromatic protons) a

8.72 (2H, doublet, J = 7.2 Hz, aromatic protons).

IR (v-substance): v _max

630, 1200 (wide band, —SO3)

785 and 770 cm ¹ .

Example 8

1- (2-mercaptoethyl) -3-methoxypyridinium methanesulfonate

Z A A MsOH

M / z0 '(O / ⁺ / \' \ fe IZ

-N

MccO Ms () c _; u / v xv * · / '·. / On

To 698 mg (6.4 mmol) of 3-methoxypyvidine pre-cooled to 5 ° C was added dropwise 0.216 mL (3.05 mmol) of methanesulfonic acid and 0.19 mL (3.2 mmol) of ethylene sulfide. The mixture was heated for 18 hours at 60 ^Q C, then cooled to 20 ^Q C, diluted with 10 ml water and washed three times with 10 mL of ether. The aqueous phase was evaporated under high vacuum for 15 minutes and then applied to a reverse phase column (C 18). The title compound is eluted with water. The appropriate fractions were combined and evaporated under high vacuum. 61.6 mg (yield 76.3%) of the desired thiol is obtained.

IR (dichloromethane): v _max 2550 (w, SH) a

620, 1600, 1585 tin ^-1 (m, aromatics).

¹ H-NMR (perdeuterodimethylsulfoxide, δ in ppm):

8.90 - 7.90 (4H, multiplet, C-H aromatic residue),

4.72 (2H, triplet, J = 6.6Hz, CH 2 N +),

4.01 (3H, singlet, OCH 3),

3.5 - 3.0 (multiplet, covering CH2S),

2.66 (1H, doublet, J = 9.5 Hz, J = 7.5 Hz, SH);

2.31 (3H, singlet, CH 3 SO 3 ^- ).

Example 9

3-methylthio-1- (2-mercaptoethyl) pyridinium chloride

Sf-U \ CJ et al

To a solution of 3.00 g (0.016 mol) of 3-methylthiopyridine in 10 ml of ether was added 15 ml of 1N hydrochloric acid and the mixture was shaken well. The aqueous phase was separated, washed with 10 ml of ether and evaporated. The remaining hydrochloride was dried under vacuum over phosphorus pentoxide. To the white solid hydrochloride was added 1.88 g (0.015 mol) of 3-methylthiopyridine and 0.89 ml (0.015 mol) of ethylene sulfide, and the mixture was heated in an oil bath at 55-65 ° C under nitrogen for 15 hours. A slightly cloudy oil is formed which is taken up in 125 ml of water and the solution is washed with dichloromethane. The aqueous solution is concentrated to a volume of about 25 ml and homogeneous by addition of a few drops of acetonitrile. The resulting aqueous solution was applied to a reverse phase (Cia) column which was eluted with water. Evaporation of the appropriate fractions gave 2.66 g (80%) of the desired product as a pale yellow viscous oil.

IR (film): in _max

410 cm ^-1 (broad band, SH).

¹ H-NMR (perdeuterodimethylsulfoxide + deuterium oxide, values <S in ppm):

8.88 - 7.88 (multiplet, 4H, aromatic protons),

4.70 (triplet, J = 6.5 Hz, 2H, N-CH 2),

3.08 (unbalanced triplet, J = 6.5 Hz, 2H,

S — CH2),

2.64 (singlet, 3H, S-CH 3).

The starting 3-methylthiopyridine was prepared as described by J. A. Zoltewiez and C. Nisi in J. Org. Chem. 34, 765 (1969).

Example 10 1- (2-mercaptoethyl-2,6-dimethylpyridmium methanesulfonate)

A mixture of 19.2 ml (0.165 mol) of 2,6-dimethylpyridine and 3.27 ml (0.050 mol) of methanesulfonic acid was stirred for 15 minutes, then 4.17 ml (0.070 mol) of ethylene sulphide was added and the resulting mixture was stirred in nitrogen. The mixture was stirred at 100 ° C for 42 hours. After cooling to 25 ° C, the reaction mixture is diluted with 45 ml of ether and 30 ml of water, the two layers are separated and the organic layer is extracted twice with 5 ml of water each. The aqueous phases are combined, filtered through a pad of diatomaceous earth, washed twice with 15 ml of ether each time, stripped of the last traces of organic solvents in vacuo, and loaded onto a column (3.0 x 12 cm), Bondapak C-18. The column is eluted with a mixture of 3% acetonitrile and 97% water. Lyophilization of the appropriate fractions yielded 2.5 g of the syrupy impure title compound which, after purification by μm-Bondapak C-18 high pressure liquid chromatography, afforded 0.90 g (7%) of the title compound.

IC (film); V.nax 2,520 (SH),

640 and 1625 (pyridinium residue),

585, 1490, 1200 cm ^-1 (sulfonate residue).

¹ H-NMR (perdeuterodimethylsulfoxide + deuterium oxide, δ in ppm):

2.36 (3H, singlet, CH 3 SO 3 -),

4.62 (2H, multiplet, CH 2 N +),

7.74 (2H, multiplet, Hm, pyridinium residue),

8.24 (1H, multiplet, pyridinium lipid).

UV (water): λ _max 272 (ε ₄₀₈₀ ) nm.

Example 11

2-methylthio-3-methyl-1- (2-mercaptoethyljimidazolium trifluoromethanesulfonate)

——— -7 ' λ O / _β , · - ·· - cs.if! y.íC ·> <«,, / i ...? with 0 'Λ -rTF. SO ^ř - · / / \ - i \ Ma ........-..... in HSCH, C -1, - j W -. č- \ f CrlSCC To 4.0 g (0.03 mmol) 2-Methylthio-1-methyl-

thylimidazole [prepared by the method of A. Wohl and W. Marckwald, Chem. Ber. 22, 1353 (1889) was added dropwise 1.38 ml (0.015 mol) trifluoromethanesulfonic acid under nitrogen at 0 ^° C, then 0.9 ml (0.015 mol) ethylene sulfide was added and the mixture was heated to nitrogen for 24 hours under nitrogen. The reaction mixture was triturated three times with ether, the residue was taken up in acetone, the solution was filtered and the filtrate was evaporated to give 4.2 g (82%) of the product as a semi-crystalline solid which was used for the next reaction without purification. .

IC (film): in _lliax 2,550 (w, shoulder) cm ^-1 .

@ ¹ H-NMR (CDCl3, .delta. In ppm): 7.97 (singlet, 2H,

4.66 (triplet, J = 7 Hz, 2H, methylene), 4.17 (singlet, 3H, N-Me,

3.20 (doublet of triplets, J = 7 Hz, J ‘9 Hz, 2H, methylene),

2.72 (singlet, 3H, S-Me),

2.20 (triplet, J = 9Hz, 1H, —SH).

Example 12

3-Amino-1- (2-mercaptoethyl) pyridinium chloride

HjíV

H d ⁺ n. H and ^N = NH, r hsch = h / ^x

Cl

1.50 g (0.016 mol) of 3-aminopyridine are taken up in 15 ml of 1N methanolic hydrochloric acid and the resulting solution is evaporated. To the remaining oily hydrochloride was added

1.32 g (0.015 mol) of 3-aminopyridine and 0.89 ml (0.015 mol) of ethylene sulfide were added and the mixture was heated in an oil bath at 60 DEG-65 DEG C. for 2 hours under nitrogen. (0.015 mol) was continued for 65 hours at 55-65 [deg.] C., then the reaction mixture was washed with dichloromethane and taken up in 25 ml of water, and the aqueous solution was applied to a reverse phase column (C18) and eluted with water. evaporation of the appropriate fractions gave 1.26 g (44%) of the desired product as a colorless viscous oil.

IR (film): y _max

180 (NH 2) cm ^-1 .

¹ H-NMR (perdeuterodimethylsulfoxide, δ in ppm):

8.19 - 7.59 (multiplet, 4H, aromatic protons),

4.59 (triplet, J = 6.2Hz, 2H, N-CH2),

3.5 (broad singlet, 2H, —NH2),

3.20 - 2.77 (multiplet, 3H).

dl-1- (2-mercapto-2-methylethyl) pyridinium methanesulfonate d 13 d-dl (1- (2-mercapto-1-methylethyl) pyridinium methanesulfonate)

SH

MíO

WITH

MnOH

HS w v'J> \ .z /

MzCT

To 7.83 g (0.097 mol) of cold pyridine was slowly added 1.95 ml (0.030 mol) of methylsulfonic acid, the resulting mixture was stirred at 40 ° C for 15 minutes, then 2.59 ml (0.033 mol) of dl were added. The mixture was stirred at 60 ° C under nitrogen for 90 hours. The pyridine was evaporated in vacuo, the residue was mixed with water and purified by chromatography (HPLC, Bondapak C-18 preparative column). The appropriate fractions were combined and lyophilized to give 1.14 g (15%) of dl-1- (2-mercapto-2-methylethyl) pyridinium methanesulfonate as a colorless syrup.

IR (film): in _max 2,520 (SH),

640 (pyridinium residue),

1180 (s, CH 3 SO 3 -),

040 (CH 3 SO 3 -) cm ^-1 .

¹ H-NMR (perdeuterodimethylsulfoxide, δ in ppm):

1.35 (doublet, J = 6.8 Hz, 3H, CH 3 CHS), 2.30 (singlet, 3H, CH 3 SO 3 -),

2.90 (doublet, J = 8.5 Hz, 1H, SH),

3.2 - 3.7 (multiplet, CHSH),

4.52 (double doublet, J _gcm = 12.9 Hz, J = 8.4 Hz, CHCH 2 N +),

8.0 - 8.4 (multiplet, 2H, Hm, pyridinium residue),

8.5 - 8.8 (multiplet, 1H, pyridinium Hp residue),

9.04 (double doublet, J = 1.4 Hz, J = 6.7

Hz, 2H, Ho of the pyridinium residue).

UV (water): A _max

208 (ε 5,267),

259 (ε 3,338) nm.

Analysis:

for C 9 H 15 NO 3 S 2. 2H2O calculated:

% C, 37.88;% H, 6.71;% N / 4.91;

22.47% S;

found:

% C, 37.49;% H, 6.85;% N, 4.86.

22,09% S.

As a second product, 0.82 g (11%) of dl-1- (2-mercapto-1-methylethyl) pyridinium methanesulfonate was obtained as a colorless syrupy material.

IR (film): in _max

500 (SH)

628 (pyridinium residue),

1180 (sulphonate),

035 (sulfonate) cm ^-1 .

¹ H-NMR (perdeuterodimethylsulfoxide, δ in ppm):

1.69 (doublet, J = 6.8 Hz, 3H, CHaCHN +) 2.31 (singlet, 3H, CH 3 SO 3 -),

3, Q - 3.3 (multiplet, 2H, CH 2 S),

4.2 - 5.2 (multiplet, 1H, CHN +)

8.0 - 8.4 (multiplet, 2H, Hm of the pyridine residue),

8.5 - 8.8 (multiplet, 1H, Hp of the pyridinium residue),

9.0 - 9.2 (multiplet, 2Ή, Ho pyridinium residue).

UV (water): A _max

209 (ε 4,897),

258 (ε 3,838) nm.

Analysis:

Calcd for C9H15NO3S2.1.5H2O:

C, 39.11; H, 6.56; N, 5.07;

found:

% C, 39.13;% H, 5.92;% N, 5.20.

Example 14 dl-1- (2-mercapto-1-cyclohexyl) pyridinium methanesulfonate

0.65 ml (0.01 mol) of methanesulfonic acid was added dropwise to 2.42 ml (0.03 mol) of pyridine while cooling. After stirring under nitrogen for 10 minutes, 1.377 g (0.0102 mol) of dl-cycloliexane sulfide (85% purity) was added and the mixture was stirred at 72 ° C for 25 hours. Excess pyridine was evaporated in vacuo and its last traces removed by distillation with water. The distillation residue is mixed with water and chromatographed on a 5x13 cm column of μ-Bondapak C-18 using 0-2% aqueous acetonitrile as eluent. After lyophilization of the appropriate fractions, 1.57 g (53%) of the product were obtained as a colorless syrup.

IR (film): in _max

500 (SH)

625 (pyridinium residue),

1190 (SO 3 -) cm ¹ .

’NMR NMR (perdeuterodimethylsulfoxide, δ in ppm):

1.2 - 2.5 (multiplet, 8H, protons of the cyclo hexyl residue),

2.32 (singlet, 3H, CH3SO3-),

2.82 (doublet, J 9.8 Hz, SH),

3.0 - 3.5 (multiplet, 1H, CSHj)

4.2 - 4.9 (multiplet, 1H, CI-IN +)

8.0 - 8.3 (multiplet, 2H, Hm, pyridinium residue),

8.4 - 8.8 (multiplet, 1H, pyridinium Hp residue),

8.9 - 9.3 (multiplet, 2H, Ho of the pyridinium residue).

UV (water: A _max

214 (ε 5,365),

258 (ε 3500).

06 86

Analysis: calculated:

% C, 46.88;% H, 6.88;% N, 4.56;

for C12H19NO3S2. H2O found ·

H, 6.46; N, 4.65.

Example 15

N-methyl-N- (2-mercaptoethyl) thiomorpholinium methanesulfonate Mc

Μα · ’Ν

Ms > OH

HS

Λ O.

N S -k \ - /

M sG ~

To ice-cooled 5.00 g (42.7 mmol) of N-methylthioijiorfoline [see JM Lehn and J. Wagner, Tetrahedron, 26, 4227 (1970)] was added 1.47 mL (20.5 mmol). methanesulfonic acid and 1.30 mL (21.4 mmol) of ethylene sulfide. The mixture is heated at 65 ° C for 24 hours, then diluted with 25 ml of water, the aqueous solution is washed three times with 25 ml of diethyl ether each time, freed from traces of organic solvent in vacuo and applied to a reverse phase silica gel column from which name washes out with water. The appropriate fractions were combined and evaporated. It is obtained

4.80 g (86% yield) of the desired thiol as an oil.

IR (film): in _max

550 cm ^-1 (w, SH).

¹ H-NMR (perdeuterodimethylsulfoxide, δ in ppm):

3.25 - 2.95 (6H, multiplet, CH2 N +),

3.32 (311, singlet, CH 3 N +),

3.20 - 2.65 (7H, multiplet, CH 2 S, SH);

2.32 (3H, singlet, CH3SO3).

Example 16

1-methyl-1- [2-mercaptoethyl) morpholinium trifluoromethanes ulfonate

KσK 3.29 ml (0.030 mol) of N-methylmorpholine at 10 ° C was added dropwise first to 1.327 ml (0.015 mol) of trifluoromethanesulfonic acid and then 0.89 ml (0.015 mol) of ethylene sulfide. The resulting yellow-brown solution under nitrogen for 18 hours at an oil bath at 50-60 ^Q C, volatiles were removed in vacuo and the oily residue is taken up in 10 ml water. The aqueous solution was washed three times with 5 ml of diethyl ether each time, the remaining organic solvent was removed in vacuo and the aqueous solution was applied to a Cle reverse phase column. The column is eluted with water, then with 5% aqueous acetonitrile and finally with 10% aqueous acetonitrile. Evaporation of the appropriate fractions gave a white solid which, after drying, ^r - λ ___ /

CN5O4 in vacuo over phosphorus pentoxide gave 1.92 g (41% yield) of the desired product.

IR (KBr): v _Niax 2360 (- SH) cm ^1st

¹ H-NMR (perdeuteroacetone, δ values in PPm):

4.25 - 3.6 (multiplet, 8H),

3.49 (singlet, 3H, N - CH 3),

3.35 - 2.7 (multiplet, 5H).

Example 17

Λ.

1- (2-acetylthioethyl) -1,4-dimethylpiperazinium bromide

O

II

CHjCS

O

II

CH ^C S

Sr acetone

-dr

A solution of 2.20 g (0.012 mol) of 2-bromoethylthioacetate [see B. Hansen, Acta Chem. Scand. 11, 537-540 (1957)] and 1.95 ml (0.014 mol) of 1,4-diinethylpiperazine in 4 ml of acetone are stirred at 50 ° C for 65 hours. After cooling to 25 ° C, the liquid phase is separated from the resin by decantation. The residue was triturated twice with diethyl ether. 3.2 g (90%) of a hygroscopic yellowish powder product are obtained.

IC (nujol): at _max

685 (C-0 thioester group] cm ^1.1 H NMR (deuterium oxide, δ values in ppm):

2.37, 2.39 (two singlets, 6H),

CH3CO,

II o

3.18 (singlet, 3H).

B.

1,4-dimethyl-1- (2-mercaptoethyl) piperazinium bromide hydrochloride θ N + N - i Br

CH ^ CS ^

HCt Heat

A solution of 1.1 g (3.7 mmol) of 1- (2-acetylthioethyl) -1,4-dimethylpiperazinium bromide in ml of 6N hydrochloric acid was heated at 80 ^° C under nitrogen for 1 hour and then concentrated under reduced pressure. 0.41 g (38%) of a white powder product is obtained.

Ή-NMR (perdeuterodimethylsulfoxide, δ in ppm):

2.90 (singlet,

CH>

3.26 (singlet,

Analysis:

for C 8 H 20 N 2 SBrCl. H2O calculated:

H, 7.16; N, 9.05.

10.35% S;

found:

% H, 7.46;% N, 9.19;% S: 10.19.

^X g _r ~ _{h / Cl}

Example 18

AND.

1- (2-acetylthioethyl) -1,4,4-trimethylpiperazinium bromide iodide

O

II

CH ^ CS

Br / -OH, 55--60

O

CH ^ CS, Ν N + \ __ y \

Br | l

To a suspension of 1- (2-acetylthioethyl) -1,4-dimethylpiperazinium bromide (1.48 g, 5.0 mmol) in isopropanol (10 mL) was added methyl iodide (0.373 mL, 6.0 mmol) and the mixture was heated for 30 h. 55 to 60 ° C. The solvents were evaporated under reduced pressure, the residue was triturated with hexane and the solid material was filtered off. 1.85 g of this solid is obtained, which is dissolved in 8 ml of hot water and diluted with acetone (70 to 80 ml) until turbid. Two successive crystallizations gave 1.5 g (68%) of the title compound, melting at 220-225 ° C with decomposition.

IR (KBr-technology j: v _max

692 cm ^-1 (C = O).

¹ H-NMR (deuterium oxide, <5 ppm):

2.40 (singlet, 3H, CH3COO),

3.37 (singlet, N-CH 3),

3.39 (singlet, N-CH 3),

3.99 (singlet).

UV (water: λ _max 226 (. 13,144) nm).

Analysis:

Calcd for C11H24N2OSBrI:

% C, 30.08;% H, 5.51;% N, 6.38;

B.

1- (2-mercaptoethyl-1,4,4-trimethylpiperazinium bischloride)

. N + \ _ / \

6N HCl

HS \ / ΓΛ Z A / + \ -7 \

Br _s i "Permutit

S-1 ci, 2Ci -

A mixture of 1.84 g (4.19 mmol) of 1- (2-acetylthioethyl) -1,4,4-trimethylpiperazinium bromide iodide and 15 ml of 6N hydrochloric acid was heated to 57 ° C under nitrogen for 2.5 hours. The solution is concentrated to dryness under reduced pressure, the solid residue is suspended in 10 ml of water and an ion exchanger is added to the vigorously stirred suspension. Permutit Sl (Cl ^- ) until solution is formed. This solution was applied to a column (1.2 x 60 cm) of Permutit S1 (I ^- ) ion exchanger and the column was eluted with water at a rate of 1.5 ml / min. The appropriate fractions were combined and lyophilized to give 0.93 g (85%) of a white powder, m.p. 190-191 ° C.

IR (nujolj: in _max

460 (SH) cm ^-1 .

found:

% C, 30.48;% H, 5.53;% N, 6.86.

¹ H-NMR (deuterium oxide, δ in ppm):

3.4 (singlet, N - CH 3),

3.45 (singlet, N - CH 3),

4.07 (singlet).

Analysis:

Calcd for C9H22N2SCl2.0.75H2O:

C, 39.34; H, 8.62; N, 10.20; S, 11.67;

found:

H, 8.39; N, 10.55; S, 11.15.

Claims (5)

A process for the preparation of quaternary amine thiols of the general formula VII HS-A-R ¹⁴ X (VII) OF THE INVENTION or a residue of the general formula wherein wherein A represents a cyclopentylene group, a cyclohexylene group, or a radical of formula _{R &} lt _; 12 &gt; I | R11 _R13 where R ^10, R ^11, R ¹³ and R ^{1 Z} independently are hydrogen or alkyl having 1 to 4 carbon atoms, X ^- means balancing anion and R ¹⁴ represents a radical of formula R ^Z3 represents an alkyl group having 1 to 4 carbon atoms and Z is sulfur, oxygen, S-O or a group R ^Z1 r22 where R ^Z1 and R ^zz independently are hydrogen or alkyl having 1 to 4 carbon atoms, characterized in that the sulfide of formula VIII 'wherein ,,, and R ( ¹⁷⁾ and R ( ¹⁸⁾ independently of one another are hydrogen, (C1-C4) -alkyl, (C1-C4) -alkyl, (C1-C4) -alkylthio, (C1-C4) -alkoxy or amino, of the general formula wherein R ¹⁹ and R ^{Z (J} independently of one another are C 1 -C 4 alkyl or C 1 -C 4 alkylthio in which: A is as defined above, reacted with a strong acid and an amine corresponding to the radical R ¹⁴ as defined above. 2. The process of claim 1, wherein the reaction is carried out at a temperature in the range of -20 ° C to 100 ° C. 3. A process according to claim 1, wherein the strong acid is hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid or trifluoromethanesulfonic acid. 4. The process of claim 1 wherein the reaction is carried out in the presence of a non-polar organic solvent, preferably methylene chloride, benzene, xylene, or toluene. 5. A process according to claim 1, 2, 3 or 4 wherein the amine and sulfide reactants are liquid or the amine reactant is a solid and the sulfide reactant is liquid and the solid amine is soluble in the liquid sulfide, the reaction is carried out without additional solvent. Severography, n. P., Plant 7, Most