DE1695383A1 - delta? -thiazolines and process for their preparation - Google Patents

Description

PATENT ADVOCATE DR. HANS-GÜNTHER EGGERT, DIPLOMA CHEMIST

5 KOLN-LINDBNTHAl. mBR-KINTGEN ^ STRASSB 2. _Λ _

Cologne, February 2nd, 1968 Sl / ho -29-

LABORATOIRE ROGER BELLON

159 avenue du Roule, 92 Neuilly S / Seine (France

-Thiazolines and process for their preparation

It is known to use thiazolines of a thioamide -C * ^ to produce the the heteroatoms have sulfur and 2 nitrogen positions; with the exception of thioaoetamide

However, the aliphatic thioamides are very difficult to prepare and largely unknown, consider what to apply this procedure restricts.

It has now been found a method that the production of ^ -thiazolines available on the market, or easily accessible starting materials.

The invention relates to substituted thiazolines the general formula

R _n - O ^ CH ₀

l I

103313/21

• in the R, a branched or unbranched lower Denotes an alkyl radical, an aryl radical, substituted aryl radical or a lower aralkyl radical and Rp represents a hydrogen atom or a lower alkyl radical.

Preferably R 1 denotes a lower alkyl radical, a phenyl radical, one with one or more halogen or lower alkoxy radicals substituted phenyl radical, a lower phenylalkyl radical, naphthyl radical or lower Naphthylalkyl radical. Lower alkyl radicals are straight-chain or branched radicals with a maximum of 6 Understood carbon atoms.

The inventive method for the production of

2
substituted ^ -Thiazolinen of the formula I is characterized by the fact that one O-alkylthioester of the formula

R ₁ -C

OR

HN

in which R _{1 has} the meaning mentioned and R stands for a lower alkyl radical, with ethylene imines of the formula

CH ₉

CH-R ₂

in the Rg has the meaning mentioned, or their Reacts reaction products with H «S.

The inventive reaction of an O-alkylthioester with an ethyleneimine proceeds according to the following reaction scheme j

R ₁ -C CH ₀

· Ρ. + R O H

^{N 4 R}

(II) (IH) (D

where R, R ₁ and R _{0 have} the stated meaning ".

2 Then the formed ^ -thiazoline is isolated,

The reaction can be carried out at room temperature; however, it is preferred at a moderately elevated temperature worked to speed up the response. .

It is possible to work without a solvent, but the presence of the reaction makes it more polar and preferential promoted non-proton-active solvents with high dielectric constant, such as dirnethyiformamide, hexamethyl-phasphortriamid and similar solvents.

The use of an excess of the ethyleneimine or its is likewise favorable for the course of the reaction Implementation product,

The result of the method according to the invention is surprising and cannot be foreseen. As can be seen from British Patent 52 3 ¹ T, the corresponding thioamide is obtained in almost quantitative yield by reacting an O-alkylthioester with a secondary amine, such as diethylamine, piperidine or pyrrolidine. This reaction can be represented, for example, as follows: ■

R, - ä ^ J + HN - ^ R ₁ - C ^ ^ + G _o H _R 0H

^x ^ 0C _o H _c \ ^L ^^ * °

In contrast to this expected result, according to the invention, under the same conditions the conversion of a ethyleneim or ^ its reaction product, with an 0-alkylthioester does not have the corresponding

1 0 9 8 1 β / 2 1 0 β

Receive thioamides, but ring closure occurs,

that of substituted ^, thiazolines with good yields leads. The following reaction equation can be used to express the overall course:

• β

+ NH "

The thioamide may be formed as an intermediate; however, the reaction does not stop at this stage: the intermediate product is stored immediately with opening of the aziridine ring according to the possible reaction mechanism shown schematically to:

CH-R,

However, the invention is not intended to be limited to the hypothesis

will.

2
The substituted ^ -thiazoline bases are not very stable in a slightly acidic, aqueous medium and especially in the heat. If, therefore, a solution of 2-eenzylthiazoline is evaporated in a small excess of hydrochloric acid diluted to 1/5 in vacuo without exceeding 60 ° C., 2-phenylacetamidoethyl mercaptan is obtained, which is mainly in the form of rays

109016/2196

Protective agent can be used;

HO ^x

CH ₀ -SH

NH-CH ₂

The hydrochloride can, however, in an alcoholic medium can be obtained if an excess of acid is avoided.

The substituted ^ -thiazolines are related to others isosteric hetero rings, therapeutic use Find; their methyl iodide, and ethyl iodide, which are light Missing obtained from the bases can condense to form cyanines will.

Further, used as a radioprotectant they represent the most appropriate starting materials ^"s for the preparation of 2-aminoalkyl represents.

According to another embodiment of the invention, an O-alkylthioester is reacted with the reaction product of an ethylene imine with H ₃ S, ie a β-aminoethyl mercaptan. In particular, 0-ethyl thioesters are reacted with according to the following reaction equation:

109010/2106

HS.

¹ CH ₀

R-C

NH -

C ti

' sh | ? ^H 2

CH ₂

^ R-C N-

CiL

+ SH

+ C ₂ H ₅ OH

This reaction takes place by simply refluxing the reactants; the end of the reaction is indicated by the cessation of H ₂ S evolution. Cysteamine is a technical product = ,. which is obtained by reacting with ethyleneimine.

H ₂ S

The following examples are intended to illustrate the invention.

example 1

2.25 g of O-ethylthioacetate (0.02 mol) are placed in a reaction vessel equipped with a stirrer, and 0.903 g of ethyleneimine (0.022 mol) are then added dropwise in such a way that the temperature does not exceed JOC. The reaction vessel is kept closed and stirred for 5 hours. A small amount of a viscous residue that has settled on the bottom of the reaction vessel is then removed by decanting. The supernatant liquid is subjected to fractional distillation. After passing over a group consisting of ethanol head fraction containing the 2-methylthiazoline distilled at 33 to 34 ° C under 15 mm Hg or at 14-3 to 145 ⁰ C under 760 mm Hg. It is obtained as a pure substance with a yield of 64.5 % . The salt with picric acid has a melting point of 169 to 170 ° C, the methyl iodide a melting point of 233 ° C (with decomposition). The characteristic data of the base and its salts are given in Table I.

Example 2

The procedure described in Example 1 was repeated, wherein 2.64 g (0.02 mole) of O-ethylthiopropionate and 0.903 g (0.022 mol) Kthylenimine used as starting materials

became. In this implementation, 2-ethyl-

O
thiazoline ,. that distilled over at 51 ° C. below 13 mm Hg, obtained with a yield of $ 69. The addition salts with picric acid and methyl iodide had melting points of 138 to 139 ° C and 101 ° C. The characteristic data of the base and its salts are given in Table 1.

Example 3

5 g of O-ethylthiocaproate were placed in a reaction vessel and then 1.34 S of ethyleneimine were added, the mixture being kept at a temperature below 30.degree. The reaction vessel was left at room temperature for 6 days. 0.225 g of a residue deposited on the bottom of the reaction vessel was separated off by decanting, and the above liquid was subjected to fractional distillation. After a head fraction consisting of ethanol had passed over, 2-n-pentylthiazoline was distilled over at 115 ° C. under 27 mm Hg with a yield of 58.5 % in the form of a colorless oil. The base formed with picric an addition salt, the melting temperature was 128 ⁰ C. The properties of the base and its salts are listed in Table I. ■

Example 4

In a reaction vessel were added 5> 4 g east-Äthylphenylthioacetat introduced and then 1.29 S Ä'thylenimin added, the temperature of the mixture was kept below 30 ⁰ C. After reacting for 12 days at room temperature, 0.235 g of an insoluble residue was removed by decantation and the above liquid was distilled. After passing over a top fraction consisting of ethanol was 2-benzylthiazoline, which at I53 ⁰ C below l8 mm Hg

109816/2196

or at 1Ö7 ° C below 30 mm Hg, in the form of a yellow, slowly crystallizing oil obtained. The yield was £ 6.

The addition salts of 2-benzylthiazoline with picric acid or with. Methyl iodide had melting points of 145 ⁰ C and 176 ⁰ C. The properties of the base and its salts are listed in Table I.

Example 5

15 g of O-ethyl thiobenzoate are placed in a round bottom flask. 4.30 g of ethyleneimine are then introduced with stirring, the temperature of the mixture being regulated so that it does not exceed 32.degree. After 6 days, a small amount of an insoluble residue is separated off by decanting and the above liquid is subjected to fractional distillation. This gives 2-phenylthiazoline, which changes to a yellow oil at 149 ° C. below 18 mm Hg. The yield is Qo%. The addition salts with picric acid and methyl iodide have melting points of 175 ° C and 160 ° C, respectively. The properties of the base and its salts are given in Table I.

Example 6 ,

2.64 g (0.02 mol) of O-methylthio-valerate are placed in a round bottom flask (boiling point 146 to 148 ° C.) and 0.905 g (0.022 mol) of ethyleneimine are then added dropwise with stirring, the temperature of the mixture being below 30 ⁰ C is held. After a five-day reaction at room temperature, the residue is separated off by decanting and the above liquid is distilled off. In this way, on the one hand, methanol and, on the other hand, 2-isobutylthiazoline, which distills over at 75 ° C. under 14 mm of mercury. The yield obtained is $ 64. 2-Isobutylthiazoline forms salt-like addition compounds with picric acid and methyl iodide, the melting points of which are 113 to 114 ° C and 113 ° C, respectively. The properties of the base and its salts are given in Table I below

109816/2 196

listed.

This table also shows the properties of 2-ß-naphtylthiazoline and, 2- (α-methylnaphtyl) -thlazoline and their salts indicated, which 'after that in the preceding Examples described procedures were prepared.

10981672196

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Example 7

To 4.16 g (0.04 mol) of O-Äthylthioacetat is added dropwise 2.28 g (O _s o4 mol) of 2-Methyläthylenimin, wherein it controls the temperature so that, should not be exceeded 50 ° C. After reacting the mixture for 8 days at room temperature, a small amount of a solid residue is removed by decantation and then the above liquid is distilled. After a top fraction consisting of ethanol, 2,4-dimethyl- "thiazoline is obtained, which passes over at 46 to 47 ° C. below 18 mm Hg. The yield is 70 $.

Under the same conditions were 2-phenyl-4-methylthiazoline and 2-benzyl-4-methylthiazoline.

The characteristic data of the produced in this example Products and their salts with picric acid are summarized in Table II below.

1098 16/2 198

S 2,4-disubstituted TABLE II

Jj ^ ² - Thiazolines

Example ... BASE

analysis

R ₁ R ₀ Kp ⁰ C yield ru. CHN

»■. γ CH, CH ^ E ₁₈ 46-47 70 1.4965. C ₅ H ₉ NS calc. 52.16 7.88 12.17 σ> colorless oil ■ found. 52.27 8.05 12.31

C ₆ H ₅ CE ₅ . E ₁₂ 136-38 75 1.5968 ^c io ^H ll ^{NS ber} * ⁶ T '? ^{8 β> 2β 7 '91}

golden yellow oil 67.57 6.38 8.06

C ₆ H ₅ CH ₂ CH, E ₁₂ 14 l-42 66 1.5636 C ₁₁ H ₁₅ NS calcd. 69.09 6.85 7.33 cd

slightly yellowish 68.90 6.92 7.60 year oil

150 ° il ^H 12 ^N 4 ° 7 ^{S over} "3 ⁸ > 3 ⁸ 3.51 16.28

ο (alcohol) gef. 38.45 3.56 16.30

S IJO ⁰ C ₁₆ H ₁ ^ N ₄ O ₇ S calcd . 47.29 3Al 13.79

w (acetone) gef; 47.31 3.50 13.72

ίο '145 ° C ₁₇ H ₁₆ N ^ O ₇ S calc. 48.57 3.84 13.33

ω (alcohol) .. found. 48.54 3.99 13.33

P. I. K R. A. T E. C. A. η a 1 y s e H N Mp ⁰ C

Those from the reaction between those described in Example 7 Q-alkylthioesters and substituted aziridines Products are 2,4-disubstituted thiazolines. This structure

is determined by its nuclear magnetic resonance spectra (NMR)

ρ
confirmed and shown by aromatization of these ^ d -thiazolines with the help of chloranil or JO volume percent hydrogen peroxide to the corresponding 2,4-disubstituted thiazoles.

The NMR spectrum of disubstituted thiazoline, in which R, stands for a phenyl radical, shows a doublet at 1.4 «f, which corresponds to the methyl group in a CH-CE, group; the neighboring proton appears at 4.68c / in the form of a curve, which is to be analyzed as part M of a system ABMX, whose two protons A and B have resonance maxima in the form of two quadruplets, which are at 2.91 and 5.41β, respectively. It the following parameters are obtained;

^J AB ⁼ 11 hertz 7.75 It ^J BM ⁼ 8th »I. ^J MX ⁼ 6.5 U

The NMR spectrum of disubstituted thiazolines, in which R, is a benzyl radical, shows a doublet (2 protons) J; ^ y'Hertz at ~ 5, Tl d , which can be traced back to a benzylic methylene group in the 2-position, while the NMR spectrum of disubstituted thiazolines, in which R, stands for a methyl radical, shows a doublet (2 protons) J ¹ ^ 1.50 Hertz at 2.17 o, which is caused by the methyl radical in the 2-position. In addition, one observes in these spectra an increasing splitting of the signal originating from the proton M, which shows the existence of a homoallyl coupling between this proton and that of the substituent of the carbon atom in the 2-position.

1098 16/2196

Weinberger and Greenhalgh (Canad. J. Chem. (1963) 41,1038) have shown that such a coupling occurs only with protons that are in the 4-position on the carbon atom. This determines the position of the CH, group.

Example 8

3 »15 g (0.0125 mol) of 0-ethyl p-isoamyloxythiobenzoate become in a round bottom flask together with 1 ml (0.02 mol) of ethylene

imin u: heats.

imine and 5 ml hexametapol for one hour at 100 ⁰ C

m. The hexametapole is removed under a vacuum of 0.1 mm by heating in a water bath. The residue, which crystallizes more or less completely after inoculation, is taken up in water and extracted with ether. After drying over Na ₂ SOh, ₁ g of a residue is obtained which, by distillation, gives 2.35 g of 2- (p-isoamyloxyphenyl) thiazole. Kp _{n Q1} : 150 to 152 ° C (boiling point below 0.01 mm Hg), yield: 75 to J6% '.

Example 9 ■

A solution of 11.30 g (0.05 mol) of 0-ethyl-3,4-dimethoxythiobenzoate (Pp 63 ⁰ C ethanol) and 4.3 g (0.10 mol) of ethyleneimine in 20 ml of hexametapol are 1 hour heated to 100 ° for a long time. The hexametapole is then evaporated under a vacuum of 0.1 mm Hg by heating in a water bath. The residue is taken up in water and extracted with ether. After drying and removing the solvent, the residue is distilled. DA in are 7.25 g of 2- (3,4-Dimethoxyphenyl) -thiazoline, _Kp: l48 hold- membered to 150 ° C in a yield of 65%.

Example 10

14.90 g (0.05 mol) of O-ethyl 3,4,5-triethoxythiobenzoate

(Pp 57 ° C, ethanol) together with 4.3 g (0.1 mol)

109816/2196

A'thylenimin heated in 20 ml hexametapol one hour at 100 ⁰ C. The solvent is driven off under a vacuum of 0.1 mm Hg in a water bath and the residue is taken up in water. After extraction with ether, drying and removal of the solvent a residue is obtained of 15, 1 g ^^, which, after distillation, 9.58 g of pure, crystalline 2 ~ (J 5,4 _J-5 Triäthoxyphenyl) -thiazoline results. Bp _{0 Q} nt 157 ° C. Yield ": 65 $. The hydrochloride produced from this base is sparingly water-soluble.

Example 11

6 g (0.03 mol) of O-ethyl p-chlorothiobenzoate are added with 2.58 g (0.06 mol) ethyleneimine and 10 ml of dimethylformamide mixed.

The mixture is held at 100 ° C for one hour. At-

Finally, the dimethylformamide is placed in a water bath

evaporated under a vacuum of 18 mm Hg and the residue distilled.

This gives 4 g of 2- (p-chlorophenyl) thiazoline. Kp _{0 Q} / -:

120 ° 0. Yield

Example 12 .

11 ^ 0 g (0.05 mol) of 0-A'thyl-J 5,4-dimethöxythiGbenzoat are heated together with 4 g (0.07 mole) of 2-Methyläthylenimin in 20 ml dimethylformamide for 2 hours at 100 ⁰ C. After the solvent has been removed in vacuo at 100 ° C., the residue is distilled. This gives 2- (3,4-dimethoxyphenyl) thiazoline in the form of an oil which slowly crystallizes. Bp _{0 1 mm} : 156 ⁰ C. Yield 54 %. The characteristic data of the thiazolines prepared in Examples 8 to 12 and their salts with acids are summarized in Table III below.

109816/2196

Vf

CH ₂
CH-R ₂

TABE L LE III

example

R ₁

R ₂

Kp ⁰ C

»· Ρ ° 0

Yield of free base

11

12th

ω cn

H = 150-152
0.01 H = 120
ο, οβ H = 148-150
0.1 CH, = 156
0.1 H -157,
0.04

49 ° (raw)
45 ° (raw)
91 ° (ethanol)

crystallized

slow

Pp: 55 (raw)

62 ° (raw)

54 ° (petroleum ether)
75 ° (petroleum ether \)

75-76 68

65 54

65

70 74

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νονό

03

ITVH

from the

ΟΛΟΛ co CVt tni> vovo mm

HH HH

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K \ K \ HH

t ^
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ΚΛΟΥ Κ \ Η

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Ϊ3

OCU t-O

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φ φ

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P ₄ U OO 109816/2196

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Example 13

This example is intended to show the influence of the temperature, the duration of the reaction, the solvents and the quantities of reactants used on the course of the reaction between O-alkylthioesters and Kthylenimin, or show its derivatives. For this purpose, to avoid the influence of the solvent and the Molar ratios of the reactants to show the reaction was O-ethyl-p-isoamyloxythiobenzoate with fithylenimine in the presence of a solvent and without a solvent under the conditions given in Table IV below implemented. The results are shown in this table.

(A)

TABLE IV

^0C 2 ^H 5

+ HN

• (B)

iso -

+ C ₀ H _n -OH

109816/2196

«4

A.
(Mole) B.
(Mole) Solution
middle - benzene temperature 8th duration yield back
happier
Thioester a) - Without solvents - benzene 1 Thiazoline 1 1.2 With solvent THP ^X 22nd Days 25th 1 1.6 1.6 H. M. T. P. 100. 10 hour 0 b) 1.6 D. M. P. 60 63 1 1.6 D. M. P. Reflux 10 Min. 1 1.6 It 60 Min. 15th 22nd 1 1.6 H 60 Min. 28 100 Λ 1 100 60 Min. 0 0 1 100 Min. 68-70 0 1 100 Min. 70-72 0 75

^X THF = tetrahydrofuran

The influence of the reaction time was continued by the implementation of 0-ethylthioacetate with itthylenimin among those given in Table V. Conditions illustrated:

TAB EL LE V

(C)

+ HN (D)

Γη

+ C ₂ H ₅ OH

Reaction conditions:

Without solvent, at room temperature, reactants: 1 mol

(C) + 1.10 moles (D)

Implementation time

6 hours

2 days

4 days

6 days

yield

28.2 28.30 10 9816/2196

23.5

54.5

According to Tables IV and V, the reaction takes place from room temperature instead of; however, a moderately increased temperature accelerates them considerably.

Moreover, the presence of polar ^ tind makes it more preferable non-proton-active solvent with high dielectric constant favors (hexamethylphosphoric triamide H.M. P.T., dimethylformamide D.M.F.). In addition, the use of an excess of the ethyleneimine favorable for the reaction process.

Example 14

This example is intended to illustrate the reaction of an O-ethyl thioester with cysteamine. One mole of O-ethyl p-ethoxythiobenzoate is 1.07. Mol cysteamine heated to reflux until HgS evolution ceased (about 12 hours). After the alcohol has evaporated under vacuum, the residue is in the form of a solid mass and is recrystallized from petroleum ether. Yield 95 % » mp 75 ° C. ·

Table VI summarizes the results of these four experiments which show the general applicability of this reaction%

OC ₂ H ₅

109816/2196

as

TABLE VI

R, Thioester Gysteamine Solvent Heating Kp C

yield

1 mole 1.02 moles without 1 ^h

1 ^hour , 30 min, bp ₃₄ : 46-48

1 mol 1.02 mol without bp ₁₄ : 140 °

1 mole 1.02 moles without 12 ^h

1 mole 1.02 moles without 12 ^h F 54 °

(Petrol

ether)

F Tf

(Petrol

ether)

95%

10 9 816/2196

Claims (1)

PATENT CLAIMS indgr R, a branched or unbranched lower one ~ Is alkyl, aryl, substituted aryl or lower aralkyl and Rp is a hydrogen atom or a lower alkyl radical, and their salts with non-toxic acids. 2. Substituiertet -Thiazoline according to claim 1, characterized characterized ,, that the radical R, a phenyl or halogen or lower alkoxy radicals one or more times substituted phenyl radical. 3 · Substituted thiazolines according to claim 1 or 2, characterized by * that the remainder with a Chlorine or lower alkoxy radicals with two to five carbon atoms or with several lower alkoxy radicals is phenyl substituted with 1 to 5 carbon atoms. 4. Substituted A thiazolines according to claim 1, characterized characterized in that the radical R- is a phenyl-substituted alkyl radical, preferably a benzyl radical. 2
5. Substituted thiazolines according to claim 1, characterized in that the radical R is a naphthyl- or naphthyl-substituted lower alkyl radical. 109816/2196 169538 6. Process for the preparation of substituted A-thiazolines according to one of claims 1 to 5. » characterized, that you have an O-alkylthioester of the formula R C ^ II R ₁ - C II. ^ * OR ■ "■. in which R _{1 has} the meaning mentioned and, R ^ jTUr is a lower alkyl radical, with an aziridine. formula "HN . CH, XEI ■ or its reaction product with H _? S converts., Where has the meaning mentioned. 7. The method according to claim 6, characterized in that the reaction in the presence of an excess of Aziridine or its reaction product with HpS. '-. ■■ - ■■ ..- .. ■■■ 8. The method according to claim 6 or 7, characterized in that that the reaction can be carried out in the presence of a polar, non-proton-active solvent with a high dielectric constant, preferably dimethylformamide or Performs hexamethylphosphoric triamide. 9. The method according to any one of claims 6 to 8, characterized characterized in that the reaction is carried out at a temperature between room temperature and the reflux temperature .performs the reaction mixture. 10 9 8 16/2196 10. 2-isobutylthiazoline. 11. 2-n-Pentylthiazoline. 12. 2- (p-chlorophenyl) thlazoline. 13. 2- (p-Ethoxyphenyl) thiazoline. Xk. 2- (p-Isoamyloxyphenyl) thiazoline. 15 x 2- (j5 * ^ -dimethoxyphenyl) -thiazole n. 16. 2-C5.4 _J 5-triet (oxyphenyl) thlazoline. I ?. 2-benzyl-4-methyl-thlazoline. 18. 2-757 ^I i " ^:: Dini & fchaxyphenyl) -4-methylthiazoline. 10 9 8 16/2196