IE903607A1 - Process for the preparation of a secondary or tertiary dialkyl dicarbonate - Google Patents

Abstract

New process for the preparation of dialkyl dicarbonates. This process is characterised in that an alkali metal alkyl or aralkyl pyrocarbonate and a diacid dihalide are brought into contact in the presence of a complexing agent. Application to peptide chemistry.

Description

-1IE 903607 -IR PROCESS FOR THE PREPARATION OF A SECONDARY OR TERTIARY DIALKYL DICARBONATE The present invention relates to a new process for the preparation of a secondary or tertiary dialkyl dicarbonate. It relates more particularly to the preparation of di-tert-butyl dicarbonate from phosgene, diphos5 gene or triphosgene.

It has long been known to prepare di-tert-butyl dicarbonate, often called BOC2O, from tert-butyl pyrocarbonate and phosgene, as described, for example, by J.H. Howe in the Journal of Organic Chemistry 27, 1901 (1962).

It is also known, according to the paper published by Pozdov, Smirnova, Podgornova, Zentsova and le Kalei in Zhurnal Organicheskoi Khimii, Vol. 15, No. 1, pages 106-109 in 1979 and translated in the Journal of Organic Chemistry USSR 1979, page 95, to prepare di-tertbutyl dicarbonate by condensing tert-butyl carbonate with an acid chloride in a mixture of toluene and dimethylformamide. When we reproduce these tests, the di-tertbutyl dicarbonate yields obtained are insufficient.

The present invention has made it possible, inter alia, to prepare di-tert-butyl dicarbonate directly from a diacid dichloride or equivalent substance in good yields .

It consists in condensing a secondary or tertiary alkyl pyrocarbonate with a diacid dihalide or equivalent substance in the presence of at least one complexing agent. - 2 The reaction can be written diagrammatically as follows : ri’ 0 F1' il ? f1' · C -O-S-OH t (C0)n X2 —-) ftj- C -0-C-0 -C-O-f -Rj'- ««2+ (n-J)CO+2MX 1/ »3 W with X representing a leaving group, advantageously chosen from among the acyloxy groups and the halide groups, preferably chloride and bromide; with Rj', R2* and R3 being aryl or, preferably, alkyl (in accordance with the definition in the DUVAL chemical dictionary) or hydrogen, with the proviso that rJ, R2' and R3‘ cannot simultaneously be hydrogen, and R1', R2 and R3 advantage10 ously being such that only one of them, and preferably none, is hydrogen; with n representing an integer chosen from among one and two; with M representing an alkali metal of low atomic radius, advantageously lithium and sodium; with the proviso that if the said diacid dihalide is phosgene, diphosgene or triphosgene and the complexing agent is a tertiary monoamine, or an amine chosen from among l,4-diazabicyclo(2,2,2)octane, 1,8-diazabicyclo(5,4,0)undec-7-ene, hexamethylenetetramine, N-methylpiperidine or N-ethylpiperidine, the alkali metal is lithium and preferably sodium. The sum of the carbon atoms of r/, R2 and R3' is advantageously at most equal to 25 and preferably at most equal to 12.

Advantageously, X is so chosen that R2 (Rj1) (R3) C—0—COOH has a pKa greater than that of HX and preferably with a value at least equal to 2. - 3 The preferred HX has a pKa at most equal to 2 and is most frequently a hydrogen halide, advantageously hydrogen bromide or above all hydrogen chloride.

The tert-butyl pyrocarbonate is obtained in a 5 manner known per se, for example by carbonation of a tert-butylate.

Among the tert-butyl pyrocarbonates it is preferred to employ the alkali metal salts and most particularly the sodium salt (M = Na).

The sequestering agents which can be used are advantageously chosen on the one hand from among the amines and on the other hand from among the ethers whose molecules comprise at least one other ether group, i.e., di- or poly-ethers Thus, the sequestering agents which can be used are advantageously chosen so that they contain either at least one amine group or one ether group and at least one amine and/or ether group so as to form a complexing agent which is advantageously at least bidentate, preferably tridentate, the ether and/or amine groups being separated by at least 1, advantageously 2, atoms and by at most 4, advantageously at most 3, atoms, the separating atoms in general being carbon atoms.

If the atoms which are deemed to ensure the coordination are linked to one another by 2 branches, thus forming a ring, it is preferable that at least one branch should comprise at least 3 chain members and the other at least 2 chain members.

The amine groups which can be used must not be capable of reacting with phosgene, oxalyl halides or the - 4 like, and are preferably tertiary amine groups.

The complexing molecules advantageously have from 3 to 75 carbon atoms, preferably from 6 to 39.

The bulk and the mobility of the complexing 5 molecules must be such that the bidentate, tridentate or polydentate structures shall be complex-forming. Such is not the case with l,4-diaza(2,2,2)bicyclooctane; this explains the poor result obtained (Example B).

In general terms, this restriction can be quanti10 fied by stating that the bicyclic systems which have at most 8 chain members, especially where the bridgeheads are the atoms which ensure the coordination, of the type of diazabicyclooctane, diazabicycloheptane and lower homologues and, to a lesser extent diazabicyclononane, are to be avoided. More generally, it is advantageous to avoid any bicyclic system in which the bridgeheads are atoms intended to ensure the coordination, and in which 2 of the branches, not counting the bridgeheads, have at most 2 chain members, preferably at most 3 chain members, if the third branch has a length of less than 7 chain members .

The at least bidentate character, with preferably at least one amine group, is necessary for phosgene and its derivatives, but not for oxalyl halides and equiva25 lent substances.

There may be mentioned as being of particular interest at least 3 classes of complexing agents including oxygenated tertiary amines, oxygenated or sulphurcontaining, cyclic or macrocyclic polyethers, and cryptands.

The first class consists of sequestering agents of general formula: N -[- CHRi — CHR2 — 0 — (CHR3 — CHR4 — 0)n — R5] 3 (I) in which n is an integer higher than or equal to 0 and lower than or equal to approximately 10 (0 < n 10), Rx, R2, R3 and R4, which are identical or different, denote a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms and Rs denotes an alkyl or cycloalkyl radical containing from 1 to 12 carbon atoms, a phenyl radical or a radical of formula -C^H^-CgHj, or CmH2m+1-C6H4-, m being between 1 and approximately 12.

The second class of complexing agents consists of cyclic, preferably macrocyclic, polyethers containing from 6 to 30 atoms in the ring and preferably from 15 to 30 atoms in the ring and consisting of 2 to 10, preferably 4 to 10, -0-X units in which X is either -CHR5-CHR7or -CHR6-CHR8-CRgR7, Rs, R7, R8 and Rg, which are identical or different, being a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms, it being possible for one of the Xs to be -CHR6-CHR8-CRgR7- when the -O-Xunits include the -O-CHRg-CHR7 group.

The third class of complexing agents consists of the compounds of general formula: R10-Y[A - D] p A - Y - R10 Ila R10-Y Λ D D P *-Rl0 lib - 6 X χ R10-Y D λ x\ r A q A Y-R10 in which: - Y denotes 0, N or P; - A denotes an alkylene group containing from 1 to carbon atoms, - D denotes 0, S or N-Rn where Ri! denotes an alkyl radical containing from 1 to 6 carbon atoms, - R10 may denote an alkyl radical containing from 1 to 6 carbon atoms, and p, q and r, which are identical or different, are integers between 1 and .

According to a preferred embodiment of the process of the invention at least one sequestering agent is employed, of formula (I), in which Rlr R2, R3 and R4 denote a hydrogen atom or a methyl radical, R5 and n having the above meaning.

Among these latter compounds, it is still more particularly preferred to use sequestering agents in the case of which n is higher than or equal to 0 and lower - Ί than or equal to 6 and in the case of which R5 denotes an alkyl radical containing from 1 to 4 carbon atoms.

There may be mentioned: - tris(3-oxabutyl)amine of formula: N-(CH2-CH2-O-CH3) 3 - tris(3-oxaheptyl)amine of formula: N- (CH2-CH2-O-C,H9) 3 - tris (3,6-dioxaheptyl) amine of formula: N- (CH2-CH2-O-CH2-CH2-O-CH3) 3 - tris(3,6,9-trioxadecyl)amine of formula: N- (CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH3) 3 - tris(3,6-dioxaoctyl)amine of formula: N- (CH2-CH2-O-CH2-CH2-O-C2H5) 3 - tris(3,6,9-trioxaundecyl)amine of formula: N- (CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-C2H5) 3 - tris (3,6-dioxanonyl) amine of formula: N- (CH2-CH2-O-CH2-CH2-O-C3H7) 3 - tris(3,6,9-trioxadodecyl)amine of formula: N- (CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-C3H7) 3 - tris(3,6-dioxadecyl)amine of formula: N- (CH2-CH2-O-CH2-CH2-O-C4H9) 3 - tris(3,6,9-trioxatridecyl)amine of formula: N- (CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-C4Hg) 3 - tris(3,6,9,l2-tetraoxatridecyl)amine of formula: N- (CH2-CH2-0- (CH2-CH2-0) 3-CH3) 3 - tris(3,6-dioxa-4-methylheptyl)amine of formula: N- (CH2-CH2-O-CHCH3-CH2-O-CH3) 3 and - tris(3,6-dioxa-2,4-dimethylheptyl)amine of formula: N- (CH2-CHCH3-O-CHCH3-CH2-O-CH3) 3 . - 8 Among the compounds of formula (I) it is preferred to employ tris(dioxaheptyl)amine (or TDAJ .

The preparation of these sequestering agents is described in French Patent Application 79/05,438, pub5 lished under No. 2,450,120.

The cyclic ethers which can be employed in the process according to the invention include compounds such as dioxane or macrocyclic ethers known by the general name of crown ethers, which are described in French Patent 69/43,879, published under number 2,026,481.

Examples of crown ethers capable of being employed according to the invention and which may be mentioned are: Some of the compounds of the third class of 15 complexing agents are described in French Patent 70/21,079, published under number 2,052,947. Examples of compounds of this class which are suitable for carrying out the process of the mentioned are: CH3 - 0 - CH2 - CH2 9 invention and which may - CH2 - CH2 - OCH3 be - 10 According to a first preferred process for implementing the invention, sodium tert-butylate is brought into contact with carbon dioxide, and phosgene or diphosgene or triphosgene is then added.

The complexing agent may be introduced at any time, before the carbonation or before the introduction of phosgene or diphosgene or triphosgene.

According to a second preferred process, the phosgene, diphosgene or triphosgene is introduced first of all and the tert-butyl pyrocarbonate is then added, it being possible for the complexing agent to be added at any time.

The reaction can be carried out in any solvent, whatever the nucleophilicity of the medium. Among the solvents there may be mentioned: - aromatic hydrocarbon derivatives such as: benzene xylenes toluene, - oxygenated solvents such as dioxane and dimethyl ethers of ethylene glycol or of polyethylene glycols and mixtures thereof, which solvents can act as complexing agent(s).

According to a preferred embodiment of the inven25 tion use is made of between 0.3 and 1 mole of a diacid dihalide or equivalent substance per mole of tertbutylate employed.

The reaction temperature is advantageously between -10°C and 60°C. - 11 The present invention will be illustrated more completely with the aid of the following examples, which must not be considered as limiting the invention.

Examples 1 and 2 and comparative test A Typical operating method. Influence of the quantity of TDAX Into a 250-ml reactor are charged: 12.8 g of sodium tert-butylate (0.075 mole) 150 ml of dry toluene.

C02 is introduced at room temperature and results in heat being evolved. The introduction is carried out over thirty minutes. The introduction of CO2 is then stopped and the reaction mixture is cooled to 15°C, at which temperature the TDA3 is added in a first step, followed by phosgene over 2 h 30 min. The reaction mixture is very thick. It is then allowed to return to 35°C and is stirred for 2 hours 30 min, and then optionally for another 1 hour at 55°C.

After cooling, 100 ml of iced water are added. The organic phase, washed with 3 x 100 ml of water and dried over 15 g of sodium sulphate, is evaporated down at room temperature. The product obtained, orange in colour, is analysed by gas chromatography.

TEST Period of phosgene intro- duction Period at 35°C Period at 55°C Phosgene quantity (moles) TDAX (ml) RY % Comparative A 2 h 30 2 h 30 1 h 0.102 0 31 Example 1 2 h 30 2 h 30 1 h 0.078 3 58 Example 2 2 h 30 2 h 30 0 0.097 3 41 RY means the yield on the material introduced, that is to say: quantity of product obtained (moles) - % quantity of tert-butylate introduced (moles) Example 3 Influence of the temperature The operation is performed as in Example 1 by charging in 0.075 mole of sodium tert-butylate 0.112 mole of phosgene 150 ml of toluene 3 ml of TDAX (0.0015 mole).

The carbonation is carried out at 10eC and the reaction temperature is then taken to 55°C and, at this - 13 temperature, phosgene is introduced for 2 h 30 min; the reaction is then continued at this temperature for 3 hours .

An RY of di-tert-butyl dicarbonate of 66 % is obtained.

Example 4 Use of triphosgene The operation is performed as in Example 1 by charging: 0.13 mole of sodium tert-butylate (tBuONa) 0.0167 mole of triphosgene (that is 0.0501 moles of phosgene) ml of toluene 0.015 mole of ΤϋΑχ.

The carbonation is carried out at 10°C and, after the introduction of triphosgene, the reaction is continued at 20°C for 5 h 30 min.

An RY of BOC2O of 51 % is obtained (in this example the RY is calculated in relation to the triphosqene introduced expressed as phosgene).

Example 5 Use of diphosgene The operation is performed as in Example 1 by charging: 0.13 mole of sodium tert-butylate (tBuONa) 0.025 mole of diphosgene (that is 0.0500 mole of phosgene) ml of toluene 0.015 mole of TDAX.

IE 903607 - 14 The carbonation is continued at 20 *C for 5 h 30 min.

An RY of BOC2O of 50 % is obtained (in this example the RY is calculated in relation to the diphos5 gene introduced, expressed as phosgene).

Example 6 12.8 g of tBuONa (0.13 mole) and about 100 ml of toluene are introduced into a 250 ml reactor and C02 is bubbled in for 30 minutes at 5°C, so as to form tertiary butyl pyrocarbonate. After having stopped the introduction of the C02, 5 g of TDAX are added. 6.6 g of oxalyl chloride (0.051 mole) are run in at 5 °C over 15 minutes. The temperature is allowed to return to normal and the mixture is then stirred for 4 hours 30 minutes. After treatment, 7.6 g of a solution are obtained, which is found, by gas phase chromatography, to contain 79% of BOC2O which represents a yield of 54% relative to the oxalyl chloride introduced.

Example 7 Synthesis of B0C20 from oxalyl chloride in the presence of diisopropylethylamine ml of toluene, 12.8 g of tBuONa (130 mM) and 3 ml of diisopropylethylamine are introduced into a 250 ml reactor. To this suspension is added C02, at room temperature, for about 30 minutes, until the flow rate of C02 at the outlet is identical to the flow rate at the inlet.

After having cooled the mixture to 5’C, 6.4 g of oxalyl chloride (42.8 mM) dissolved in 30 ml of toluene are added over 20 minutes, after which the mixture is allowed to return to room temperature, at which it is stirred for 5 hours.

After treatment, 5.05 g of a liquid are obtained, which is found by NMR to contain 30% of BOC2O, which represents a yield of 10% relative to the oxalyl chloride employed.

Comparative Example B Phosgenation in toluene in the presence of 1,4-diaza10 bicyclo(2,2,2Joctane 7.5 g of tBuONa (75 mM) , 1.7 g of 1,4-diazabicyclo(2,2,2)octane (15 mM) and 75 ml of toluene are introduced into a 250 ml reactor. CO2 is introduced into this suspension at room temperature for about 30 minutes until the flow rate of C02 at the outlet is identical to the flow rate at the inlet.

At room temperature, 11.9 g of phosgene (120 mM) are introduced for 2 hours, after which the apparatus is purged with nitrogen while heating the reaction mixture to 55° for 2 hours.

After cooling and treatment, 9.5 g of a white liquid are obtained, which is found to contain 4.6% of BOC2O, which corresponds to a yield of 1% relative to the sodium t.butylate.

Comparative Example C 12.8 g of tBuONa (0.13 mole) and about 100 mi of toluene are introduced into a 250 ml reactor, and C02 is bubbled in for 30 minutes at 5°C, so as to form tertiary butyl pyrocarbonate. 6.6 g of oxalyl chloride (0.051 mole) are - 16 run in at 5°C over 15 minutes. The temperature is allowed to return to normal and the mixture is then stirred for 4 hours 30 minutes. After treatment, 13.9 g of a solution are obtained, which is found by gas phase chromatography to contain 2.6% of BOC2O, representing a yield of 3.2% relative to the oxalyl chloride employed.

Claims (11)

1. Process for the preparation of a dialkyl dicarbonate, characterized in that an alkali metal salt of an alkyl or aralkyl pyrocarbonate monoester and a diacid dihalide are brought into contact in the presence of a complexing agent, with the proviso that, if the said diacid dihalide is phosgene, diphosgene or triphosgene and the complexing agent is a tertiary monoamine, or an amine such as 1,4-diazabicyclo(2,2,2) octane, 1,8-diazabicyclo(5,4,0)-undec-7-ene, hexamethylenetetramine, Nmethylpiperidine or N-ethylpiperidine, the alkali metal is lithium and preferably sodium.

2. Process according to Claim 1, characterized in that the alkyl pyrocarbonate monoester is a sodium salt.

3. Process according to Claim 1, characterized in that the reaction is carried out in an aromatic solvent, preferably in toluene.

4. Process according to Claim 1, characterized in that the complexing agent is chosen from oxygenated tertiary amines especially having an ether group, oxygenated or sulphur-containing, cyclic or macrocyclic polyethers , and cryptands.

5. Process according to Claim 4, characterized in that the oxygenated tertiary amines correspond to the formula: N-[-CHR x - CHR 2 - 0 - (CHR 3 - CHR 4 - O-) n - R 5 ] 3 in which n is an integer higher than or equal to 0 and lower than or equal to approximately 10 (0 < n < 10), R x , R 2 , R 3 and R 4 , which are identical or different, denote a - 18 hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms and R 5 denotes an alkyl or cycloalkyl radical containing from 1 to 12 carbon atoms, a Dhenyl radical or a radical of formula -C H -C.H or c H,-, m being between 1 and approximately 12.

6. Process according to Claim 4, characterized in that the complexing agents correspond to the following formulae II: r R10 - Y-4-A A Y - Rio in which - Y denotes 0, N or P, - A denotes an alkylene group containing from 1 to 3 carbon atoms, - D denotes 0, S or N-R u where R u denotes an alkyl radical containing from 1 to 6 carbon atoms, - R 10 may denote an alkyl radical containing from 1 to 6 carbon atoms, and p, q and r, which are identical or different, are integers between 1 and 5.

7. Process according to Claim 5, characterized in that the oxygenated amine is trisdioxaheptylamine.

8. Process according to Claims 4 and 6, characterized in that the polyether is diethylene glycol dimethyl ether.

9. Process according to Claim 4, characterized in that the polyether is dioxane.

10. Process according to Claim 1 for the preparation of a dialkyl dicarbonate, substantially as hereinbefore described and exemplified.

11. A dialkyl dicarbonate whenever prepared by a process claimed in a preceding claim. Dated this the 9th day of October, 1990. F. BY: