DE3411242A1 - ALKYL CHLORINE SULFATE INTERMEDIATE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF - Google Patents

Description

PROF. DR. DR. J. REITSTÖTT-ER - "DR. * WERNER KINZEBACH DR. ING. WOLFRAM BUNTE (, 9Ββ-ΐΒ7β)

REITSTÖTTER. KINZEBACH fl, PARTNER POST BOX 78Ο, D-8ÖO0 MUNICH 43

411242

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APPROVED REPRESENTATIVES AT THE EUROPEAN PATENT OFFICE EUROPEAN PATENT ATTORNEYS

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Munich, May 2, 1984 M / 25 028

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LEO PHARMACEUTICAL PRODUCTS LTD. A / S

(L0VENS KEMISKE FABRIK PRODUKTIONSAKTIESELSKAB) Industriparken 55, DK-2750 Ballerup, Denmark

Alkyl chlorosulfate intermediates and Process for their manufacture

POSTAL ADDRESS; D-8OOO MUNICH 43. POST BOX 78Ο

M / 25 028 /

'S-

The invention relates to alkyl chlorosulfate intermediates which can be used for the preparation of α-haloalkyl esters or alkylene diesters of carboxylic acids. The invention also relates to methods of making these new intermediate compounds. These processes can also be used to prepare compounds of similar structure. 10

The invention relates to intermediate compounds of the general formula I

0 R ₁ Cl-SOCX (I)

Il I

0 R ₂ wherein

X is a halogen atom, e.g. a chlorine or bromine atom, or another good leaving group, for example

0
η

wise Cl-S-O-, means and

η
0

R ₁ and R _{2 represent} a hydrogen atom or a lower alkyl group.

The "term lower alkyl" preferably denotes a straight or branched alkyl group having 1 to β, in particular 1 to 6 and particularly preferably 1 to A carbon atoms.

The compound of the formula I in which R ₁ and R _{2 are} a hydrogen atom and X is a chlorine atom is known from Ber.60, 2288 (1927).

The compounds of general formula I are very effective reagents for introducing the

028 «-

- C - X group, for example in the production of a-halo-R ₂

alkyl esters of the general formula II

"1
RCOCX (II)

! I I

0 R ₂

wherein R ₁ and R _{2 have} the meanings given above, X is a halogen atom and R is an organic radical. A salt of a carboxylic acid R-COOH is reacted with a compound of the general formula I (X = halogen), the compounds of the general

15 "my formula II receives in better yields and in higher purity than with the usual process which reacts a dihaloalkane with a carboxylic acid salt.

Depending on the reactivity of the leaving group X compared to the reactivity of the chlorosulfonyloxy group as a leaving group, compounds of the general formula Ha

0 R ₁
RCOCX ¹ (Ha)

R ₂

produce, in which R, R ₁ and R _{2 have} the meanings given above and X ^f for X or for 0
RCO-, ie if X is a lower or the same

0
before has reactivity like Cl-SO-.

If

The compounds of the general formula I are chlorosulfonic acid esters. Because a-halogen-substituted alcohols

M / 25 028 -5 "

do not exist, it is not possible to obtain these compounds by the usual method by reaction of To prepare sulfuryl chloride with such an alcohol.

According to the invention, the compounds of the general Formula I can be prepared by reacting chlorosulfonic acid with a compound of the general formula III

Y-C-X (III)

* 2
converts, in which R ^, R ₂ and X have the meanings given above and Y is a better leaving group than the X group. If the group Y has the same reactivity as the group X, the reaction leads to bis (chlorosulfate) alkanes. The reaction is carried out with or without a solvent, depending on the reactants in question. Is carried out at a temperature between -20 ° and 100 ⁰ C.

In a second process according to the invention, the compounds of the general formula I in which X is Halogen, in particular a chlorine atom, is obtained by photochemical halogenation of alkyl sulfates general formula V

0 R ₁

Cl-S-O-CH (V)

η ι
0 R ₂

in which R * and R _{2 have} the meanings given above, are prepared by dissolving the compounds of the general formula V, if desired, in an inert organic solvent, such as carbon tetrachloride, in which the desired halogen is dissolved

_{M / 25028}

introduces with simultaneous irradiation of the solution. After the reaction has ended, the product is isolated, e.g. by distillation.

_{If the radicals R 1} and R _{2 are} in the general formula I

0
for hydrogen and X for Cl-SO-, then you can do this

ti

IQ 0

The compound bis (chlorosulphate) methane is produced by one reacts chloromethylchlorosulfate and sulfur trioxide. The compound is obtained from the reaction mixture, by distilling at low pressure.

The invention is explained in more detail below with the aid of the examples.

example 1
Chloromethyl chlorosulfate

Mix chlorosulfonic acid (200 ml, 3 ^ 9 g, 3 mol) and Bromochloromethane (100 ml, 194 g, 1.5 mol) and heated 3 h at reflux. A large amount of bromine forms · The mixture is cooled, poured onto ice, 100 ml are added Methylene chloride is added, the organic phase is washed with 100 ml of water, dried over magnesium sulfate and removed the solvent together with the bromine in a vacuum. The residue (93.7 g) is distilled in vacuo and receives chloromethylchlorosulfate at 45-50 ° C / i2 to 13.3 mbar (9-10 mmHg).

M / 25 028 γ

Λ-

Example 2 Chloromethyl Chlorosulfate 5

A solution of chlorosulfonic acid (58.3 g, 33.3 ml, 0.5 mol) is added dropwise from a dropping funnel during over a 1/2 hour period to an ice cold solution of chloroiodomethane (44.1 g, 18.3 ml, 0.25 mol) in 100 ml of methylene chloride. The mixture is stirred for a further hour while cooling, the mixture is poured into ice and washed organic phase with water, decolorized with sodium thiosulphate and dried over magnesium sulphate. Almost The colorless organic phase is concentrated in vacuo (22.4 g) and distilled in vacuo, chloromethylchlorosulfate being obtained at 42-45 ° C / i2 mbar (9 mmHg).

Example 3 Chloromethyl chlorosulfate

A flask containing 10 ml of methyl chlorosulfate is placed in a water bath at room temperature and chlorine is bubbled through through the liquid, which is irradiated with UV light using a high pressure lamp. After 3 h you can see in the NMR spectrum that a 70% conversion to chloromethylchlorosulf at has taken place. The mixture is cooled in ice and 4.6 ml of methanol are added to remove any unreacted Destroy methyl chlorosulfate. The distillation in vacuo gives pure chloromethylchlorosulfate,

30 Kp. 55 ° C / 26.6 mbar (20 mmHg).

Example 4

a-Chlo rethylchlo rsulfate
A reaction flask containing 15 ml of ethyl chlorosulfate

-AO-

ben are placed in a water bath at room temperature and irradiated with UV light from a high pressure lamp while chlorine is bubbled through the liquid. The reaction is followed by NMR spectroscopy and the chlorination is stopped, when all the starting material has been used up. It is flushed with nitrogen and the product is distilled (a mixture of chlorinated products) in vacuo over a Vigreux column. The fraction with a boiling point from 49-51 ° C / i3.3 mbar (10 mmHg) contains oc-chloroethylchlorosulfate.

The IR spectrum (CH ₂ Cl ₂ ) shows strong bands at 1415, 1192, 900 and 600 cm ^-1 . The NMR spectrum (CDCl ₃ ) shows peaks at ei = 1.97 (d, J = 5.9 He, 3H) and 6.47 (q, J = 5.9 Hz, 1H) ppm.

Example 5
α-chloroethylchlorosulfate

10 ml of chlorosulfonic acid are slowly added to an ice-cold, stirred solution of 9.3 ml of 1-chloro-1-iodoethane in 50 ml of methylene chloride. After stirring for a further hour while cooling with ice, the dark red one is poured Mixture on ice, the aqueous phase extracted with methylene chloride and washed the combined, organic Phases with aqueous sodium bicarbonate and aqueous sodium thlosulfate. The almost colorless, organic phase it is dried and concentrated in a vacuum. Distillation in vacuo gives a-chloroethylchlorosulfate, which is with the product obtained according to Example 4 is identical.

• M-

Example 6 Bromomethyl Chlorosulfate
5

Chlorosulfonic acid (52.4 g, 30 ml, 0.45 mol) is added in four equal portions at half hour intervals an ice-cold, stirred solution of bromoiodomethane (22.1 g, 7.55 ml, 0.1 mol) in 100 ml carbon tetrachloride.

After stirring for a further half an hour, the mixture is poured onto ice and filtered. The organic phase is washed with water, decolorized with sodium thiosulphate and dried over magnesium sulphate. Distillation in vacuo gives bromomethylchlorosulfate at 62-66 ° C / 16.0 mbar (12 mmHg).
¹ H-NMR: 6.00 (CDCl ₃ )
Analysis: for CH ₂ BrClO ₃ S

calculated: C 5.73% H 0.96% S 15.31%

found: 5.88 0.96 15.63. 20th

Example 7 Bis (chlorosulfate) methane

Chloromethyl chlorosulfate (65.2 g, 40 ml, 395 mmol) and sulfur trioxide (38.3 g, 478 mmol) are mixed at room temperature, after 20 days the mixture is poured into ice and 100 ml of methylene chloride are added. The organic phase is washed with water (100 ml), dried over magnesium sulfate and the solvent is removed in vacuo. The residue is distilled under vacuum [13.3 to 14.5 mbar (10-11 mmHg)] to give chloromethyl chlorosulfate (starting material) at 41-45 ⁰ C and bis (chlorsulfai ^ methane at 102-105 ⁰ C / 10.6-13.3 mbar (8-10 mmHg) obtained. ¹ H-NMR: 6.15 (CCl ₄ )
35

M / 25 028 X

Analysis: for ₂₂₂

Calculated: C 4.90 # H 0.82% S 26.17 Ji Cl 28.9450 found: 5.12 0.86 25.79 28.79.

Example 8

Bis (chlorosulfate) methane

74.6 ml of chlorosulfonic acid are slowly added to a stirred, ice-cold solution of 15 ml of methylene iodide in 100 ml of methylene chloride. After stirring for a further 30 min, the reaction mixture is poured onto ice. The organic phase is separated off, washed with aqueous sodium bicarbonate and sodium thiosulfate and dried over magnesium sulfate. The solvent is removed by distillation at atmospheric pressure and the residue is distilled in vacuo. Bis (chlorosulphate) methane distilled at 108-110 ⁰ C / 13.3 mbar (10 mmHg).

Example 9 Bis-d »1-dioxopenicillanate) methane

Mix 150 ml of water, 200 ml of methylene chloride, 1.0 g of tetrabutylammonium hydrogen sulfate, 13.4 g (160 mmol) of sodium bicarbonate and 11.65 g (50 mmol) of 1,1-dioxopenicillanic acid and cooled to ⁰ C. 2 During a 5 g (21 mmol) of bis (chlorosulfate) methane in 30 ml of methylene chloride are added over a period of half an hour. The mixture is allowed to ^{react for 1 hour at 2 °} C. and for 1 hour at room temperature. The reaction mixture is separated and the aqueous phase is extracted with 100 ml of methylene chloride. The combined methylene chloride phases are dried over MgSO. and filtered. Isopropanol is added and methylene chloride is removed in vacuo, bis- (1,1-di-

■ Kb-

oxopenicillanate) methane crystallizes. After filtration and drying, a pure product is obtained whose NMR is identical to that of an authentic sample, see U.S. Patent 4,309,347.

Example 10 g-chloroethyl 1,1-dioxopenicillanate

The temperature of a mixture of 8.85 g of sodium 1,1-dioxopenicillanate, 35 ml of water, 35 ml of methylene chloride, 11.7 g of sodium bicarbonate and 1.2 g of tetrabutylammonium hydrogen sulfate adjusted to 20 to 22 ° C, added over a period of 15 min to the stirred Mix 7.17 g of α-chlorothylchlorosulfate and stir for a further 30 minutes, then add 5 g of sodium iodide and then Add sodium thiosulfate to decolorize the mixture. The organic phase is separated off, dried and concentrated in vacuo. Ethyl acetate is added and removes remaining methylene chloride in vacuo. The product (a mixture of two diastereoisomers) crystallizes from ethyl acetate.

In the NMR spectrum (CDCl,) you can see both diastereoisomers, which are referred to below as A and B: The spectrum of A shows peaks at 6 = 1.45 (s, 3H), 1.65 (s, 3H), 1 .87 (d, J = 5.5 Hz, 3H), 3.49 (d, J = 4 Hz, 2H), 4.40 (s, 1H), 4.67 (t, J = 4 Hz, 1H ) and 6.59 (q, J = 5.5 Hz, 1H) ppm The spectrum of B shows peaks at 6 = 1.48 (s, 3H),

1.65 (s, 3H), 1.87 (d, J = 5.5 Hz, 3H), 3.49 (d, J = 4 Hz, 2H), 4.42 (s, 1H), 4, 67 (t, J = 4 Hz, 1H) and 6.63 (q, J = 5 _f 5 Hz, 1H) ppm. 35

H / 25 028 Wed 3411242

• AU.

Example . Bromomethyl 1,1-dioxopenicillanate

This compound is, as in the production of oc-chloroethyl-1,1-dioxopenicillanate described, prepared by converting α-chloroethylchlorosulfate with bromomethylchlorosulfate replaced. 10

The NMR spectrum (CDC1,) shows peaks at S = 1.50 (s, 3H), 1.63 (s, 3H), 3.50 (d, J = 4 Hz, 2H), 4.45 (s , 1H), 4.67 (t, J = 4 Hz, 1H), 5.76 (d, J = 5 Hz, 1H) - and 6.08 (d, J = 5 Hz, 1H) ppm. 15th

Claims (5)

Claims \ JX Intermediate alkyl chlorosulfate compounds of general formula I. 0 R ₁ Cl-SOCX (I) π ι
0 R ₂ wherein X is a halogen atom, e.g. a chloro- or bromatoin, or another good exit group, for example 0
η
wise Cl-SO-, means and ti
0 R ^ and Rg denote a hydrogen atom or a lower alkyl group, with the proviso that, if X denotes a chlorine atom, at least one of the radicals R ₁ or Rp denotes a lower alkyl group. 20th 2. Intermediate compounds according to claim 1, namely bis (chlorosulfate) methane,
α-chloroethylchlorosulfate and
Bromomethyl chlorosulfate. 3. Process for the preparation of a compound of the general formula I. 0 R ₁ Cl-S-O-C-X (I) η t
0 R ₂ wherein X is a halogen atom, e.g. a chlorine or bromine atom, or another good leaving group, e.g. -35 M / 25 028 2 3 A 1 1 2 A t! wise Cl-SO-, means and
O R ₁ and R _{2 represent} a hydrogen atom or a lower alkyl group, characterized in that chlorosulfonic acid with a compound of the general formula III 10 R ₁
YCX (III) wherein R-., R ₂ and X have the meanings given above and Y means a better leaving group than group X, at a temperature between -20 ° and 100 ⁰ C depending on the reactants in a solvent or without a solvent. 4. A process for the preparation of a compound of the general formula I according to claim 3, wherein X is a halogen atom, in particular a chlorine atom, means, characterized in that an alkyl chlorosulfate of the general Formula V 0 R <| Cl-SO-CH (V) η t
0 R ₂ wherein R ^ and R _{2 have} the meanings given above, photochemically halogenated, the alkyl chlorosulfate, if desired, in a suitable, inert organic solvent, such as carbon tetrachloride, in which the desired halogen is dissolved with simultaneous irradiation M / 25 1st of the solution, and then, after the reaction has ended, the product is isolated, e.g. by distillation. 5 5. A process for the preparation of a compound of the general formula I according to claim 3, wherein R> j and R ₂ Il Mean hydrogen and X stands for Cl-S-O-, thereby characterized in that chloromethylchlorosulfate is reacted with sulfur trioxide and the reaction product is removed the reaction mixture isolated by distillation at low pressure.