IE67955B1 - 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

The present invention relates to a new process for the preparation of di-tert-butyl dicarbonate, it relates more particularly to the preparation of di-tertbutyl .dicarbonate from phosgene, diphosgene or triphosgene.

It has long been known to prepare di-tert-butyl dicarbonate, often called (BOC)2O, from mixed alkali metal tert-butyl carbonate and phosgene, as described, for example, by J.H. Howe in the Journal of Organic Chemistry 27, 1901 (1962) or in his US Patent No 3,078,294.

It is also known, according to the paper published by Pozdev, Smirnova, Podgornova, Zentsova and le Kalei in Zhurnal Unganicheskoi *, 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-tert20 butyl dicarbonate yields obtained are insufficient.

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

It consists in condensing the mixed alkali metal tert-butyl carbonate with the diacid dihalide or an equivalent in the presence of at least one complexing agent.

The reaction can be written diagrammatically as follows: 2 RgCiR, )(Rg)-O-CO-OM + (CO)nX2->[R2C(R1 XR^-O-CO-feO + CO2+ (n-1 )CO+ 2MX with X denoting a leaving group chosen from among the halide groups, preferably chloride and bromide; with Rx, R2 and R3 being aryl or, preferably, alkyl (in accordance with the definition in the DUVAL chemical dictionary) or hydrogen, with the proviso that Rx, R2 and R3 cannot simultaneously be hydrogen, and Rx, R2R3 advantageously being such that only one of then, and preferably none, is hydrogen; with n denoting an integer chosen from among one and two; with (CO)nX2 denoting an oxalyl dihalide, a carbonyl dihalide or one of their sources (such as polyphosgenes) and M denoting an alkali metal of low atomic radius, advantageously lithium and sodium. The sum of the carbons of Rx, R2 and R3 is advantageously at most equal to 25 and preferably to 12.

When the said diacid dihalide is phosgene, 10 diphosgene or triphosgene, the enmpiAgeing agents must have high complexing properties. Thus the amines described in the European patent application filed in the name of Mitsubishi Ph Ami <-ai Industries limited and published under No 0,256,559, namely tertiary monoamines, or chosen from l,4-diazabicyclo(2,2,2)octane, 1,8-diazabicyclo(5,4,0)undec-7-ene, hexamethyl tetramine, N-methylpiperidine, N-ethylpiperidine, N-methylmorpholine, morpholine, N,N'-dialkylpiperazine, pyridine, quinoline and isoquinoline have an insufficient complexing power because not corresponding to the mobility restrictions described below.

Thus, according to the invention, a process for the preparation of secondary or tertiary dialkyl dicarbonate (or pyrocarbonate) has been developed, wherein a mixed alkali metal secondary or tertiary alkyl carbonate is placed in contact with a diacid dihalide chosen from carbonyl halides and their di- or trimers and oxalyl halides, wherein the said contact is conducted in the presence of a complexing agent chosen from those which have at least one amine functional group or which have an ether functional group comprising at least one other ether functional group and from cryptands, with the condition that when the said diacid HiHal ida is phosgene, diphosgene and/or triphosgene, the complexing agent is neither dioxane nor a tertiary monoamine nor an amine chosen from l,4-diazabicydo(2,2,2)octane, 1,8-diazabicyclo(5,4,o)undec-7-ene, hexamethyltetramine, N-methylpiperadine, N-ethylpiperadine, N-methylmorpholine, morpholine, N,N'-dialkylpiperazine, pyridine, quinoline and isoquinoline.

Advantageously, Z is so chosen that Rj (¾) (R3)C-O-COOH has a pKa greater than that o£ HZ and preferably with a value at least equal to 2.

The preferred HZ has a pKa at most equal to 2 and is most frequently derived from a hydrogen halide, advantageously hydrobromic or above all hydrochloric, in which M represents an alkali metal.

The mixed alkali metal tert-butyl carbonate is 10 obtained in a manner known per se, for example by carbonation of a tert-butylate.

Among the mixed alkali metal tert-butyl carbonates 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.

Thus, the sequestering agents which can be used are advantageously chosen so that they contain either at least one amine functional group or one ether functional group and at least one amine and/or ether functional 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, generally of carbon.

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.

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

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

The bulk and the mobility must be such that the bidentate, tridentate or polydentate structures shall be complex-forming. Such is not the case with 1,4diaza(2,2,2)bicyclooctane; this explains the poor result obtained (Example B).

In general terms, this restriction can be quanti5 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, o£ the type of diazabicydooctane-, heptane and lower and, to a lesser extent nonane, 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, are at most 2 chain members, preferably at most 3 chain members, in length when the third branch has a length of less than 7, expressed in chain members.

The at least bidentate character, with preferably at least one amine functional group, is necessary for phosgene and derivatives, but not for oxalyl halides and 0 equivalents.

There may be mentioned as being of particular interest at least 3 classes of comping· agents including oxygen-containing tertiary amines, oxygen-containing or sulphur-containing, linear, cyclic or macrocydic polyethers, and cryptands.

The first class consists of sequestering agents of general formula: N - [- CHRX — CHR2 — 0 — (CHR3 — CHR4 — 0)n — Rs] 3 (I) in which n is an integer higher than or equal to 0 and lower than or equal to 10 (0 s n s 10), Rx, Rj, 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 or m being between 1 and 12.

The second class of complexing agents consists of cyclic, preferably macrocydic, polyethers containing from 6 to 30 atoms in the ring and preferably from 15 to atoms in the ring and consisting of 2 to 10, preferably 4 to 10, -0-X- units in which X is either -CHRg-CHRy- or -CHRg-CHRg-CRgR?-, Rg, R?, 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 -CHRg-CHRg-CRgR?when the -0-X- units include the -O-CHR6-CHR7 group.

The third class of complexing agents consists of the compounds of general formula: io R10-Y[A - D] p A - Y - R10 Ha - Y denotes O (divalent), N or P (trivalent) in formulae Ila and lib and N or P in the last formula.

- A denotes an alkylene group containing from 1 to 3 carbon atoms.

- D denotes 0, S or N-Rll where Rll denotes an alkyl radical containing from 1 to 6 carbon atoms.

- R10 denotes an alkyl radical containing 1 to 6 carbon atoms. - when in the above formulae the valency of the atoms Y is not satisfied, alkyl radicals R10 then satisfy the said valancies. p, q and r, which are identical or different, are integers included between 1 and 5.

According to a preferred embodiment· of the process of the invention at least one sequestering agent is employed, of formula (I), in which Rx, R2, R3 and R4 denote a hydrogen atom or a methyl radical, Rs 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 than or equal to 6 and in the case of which Rs 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-C4H9) 3 - tris(3,6-dioxaheptyl)amine of formula: N- (CH2-GH2-O-CH2-CH2-O-CH3) 3 - tris(3,6,9-trioxadecyl)amine of formula: N- (CHj-CHj-O-CHj-CHj-O-CHj-CHj-O-C^) 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-(CHj-CHj-O-CHj-CHj-O-CgBp 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-C4Hg) 3 - tris(3,6,9-trioxatridecyl)amine of formula: N- (CHj — Ch2 — 0—CHj — CHj—0—CHj—CHj—O—C4H9) 3 - tris(3,6,9,12-tetraoxatridecyl)amine of formula: N- (CHj-CHj-O- (CHj-CHj-O) 3-CH3)3 - tris (3,6-dioxa-4-dimethylheptyl) amine of formula: N- (CHj—CHj—0—CHCH3—CHj —O—CH3) 3 and - tris (3,6-dioxa-2,4-dime thy lheptyl) amine of formula: N- (CH2-CHCH3-O-CHCH3-CHJ-O-CH3) 3.

Among the compounds of formula (I) it is - 7 preferred to employ tris (dioxaheptyl) amine (or TDA^).

The preparation o£ these sequestering agents is described in French Patent Application 79/05,438, published 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 macroeydic 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 o£ being employed according to the invention and which may be mentioned are: Some o£ the compounds o£ the third class of 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 invention and which may be mentioned are: CH3 - O - C&z - CHj -O- 0¾ - CHj - OCH3 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 cosg>lexing 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, - oxygen-containing 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 invention use is made of a molar quantity of diacid dihalide or equivalents of between 0.3 and 1 times the quantity of tert-butylate employed.

The reaction temperature is advantageously between -10eC and 60*C.

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 TO24 Into a 250-ml reactor are charged: 12.8 g of sodium tert-butylate (0.075 moles) 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 TDAX is added in a first step, followed by phosgene over 2 H 30. The reaction mixture is very thick. It is then allowed to return to 35°C and is stirred for 2 hours 30, 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 GC.

( TEST Period of phosgene intro- duction Period at 35eC Period at 55"C Phosgene quantity (moles) TDA1 (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 o£ tert-butylate introduced (moles) gyawiple 3 Influence of the temperature The operation is performed as in Example 1 by charging in 0.075 moles of sodium tert-butylate 0.112 moles of phosgene 150 ml of toluene 3 ml of TDA 1 (0.0015 moles).

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

An RY of di-tert-butyl dicarbonate of 66 % is obtained. Rrairmle 4 Use of triphosgene The operation is performed as in Example 1 by 0 charging: 0.13 moles of sodium tert-butylate (TBuONa) 0.0167 moles of triphosgene (that is 0.0501 moles of phosgene) ml of toluene 0.015 moles of TDA 1.

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.

An RY of BOC2O of 51 % is obtained (in this example the RY is calculated in relation to the triphos10 gene introduced expressed as phosgene).

Example 5 Use of diphosgene The operation is performed as in Example 1 by charging: 0.13 moles of sodium tert-butylate (TBuONa) 0.025 moles of diphosgene (that is 0.0500 moles of phosgene) ml of toluene 0.015 moles of TDA1.

The carbonation is continued at 20°C for 5 h 30.

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

Ewaniple 6 12.8 g of tBuONa (0.13 moles) and toluene are introduced into a 250 ml reactor and, at 5°C, CO2 is bubbled in for 30 minutes, so as to form tert-butyl carbonate; after having stopped the introduction of the C02, 5 g of TDA1 are added. 6.6 g of oxalyl chloride (0.051 moles) 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 h 30. After treatment, 7.6 g of a solution are obtained, which is found, by GC, to contain 79 % of BOC2O, which represents a yield of 54 % relative to the oxalyl chloride introduced. - 12 gramnle 7 Synthesis of BOC^O from oxalyl chloride in the presence of diisopropylethylamine ml of toluene, 12.8 g of t-BuONa (130 mM) and 5 3 ml of diisopropylethylamine are charged into a 250 ml reactor. To this suspension is added CO2, at room temperature, for about 30 min, until the flow rate of CO2 at the outlet is identical to the flow rate at the inlet.

After cooling to 5°C, 6.4 g of oxalyl chloride 10 (42.8 mM) dissolved in 30 ml of toluene are added over min, after which the mixture is allowed to return to room temperature, at which it is stirred for 5 h.

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 Eyamnle B Phosgenation in toluene in the presence of 1,4-diazabicyclo(2,2,2)octane 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 charged into a 250 ml reactor. C02 is introduced into this suspension at room temperature for about 30 min 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 a nitrogen purge is applied while heating the reaction mixture to 55° for 2 h.

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 grample C 12.8 g of tBuONa (0.13 moles) and toluene (100 ml) are changed into a 250 ml reactor, and, at 5°C, CO2 is bubbled in for 30 minutes, so as to form tert-butyl carbonate. 6.6 g of oxalyl chloride (0.051 moles) are run in at 5°C over 15 minutes. The temperature is allowed to - 13 return to normal snA the mixture is then stirred for 4 h 30. After treatment, 13.9 g of a solution are obtained, which is found by GC to contain 2.6 % of BOC2O, representing a yield of 3.2 % relative to the oxalyl chloride employed.

Claims (12)

1. Process for the preparation of secondary or tertiary dialkyl dicarbonate (or pyrocarbonate), wherein a mixed alkali metal alkyl carbonate is placed in contact 5 with a diacid dihalide chosen from carbonyl halides and their di- or trimers and oxalyl halides, characterized in that the said contact is conducted in the presence of a complexing agent chosen from those which have at 10 least one amine functional group or which have an ether functional group comprising at least one other ether functional group and from cryptants, with the condition that when the said diacid dihalide is phosgene, diphosgene and/or triphosgene, 15 the complexing agent is neither dioxane nor a tertiary monoamine nor an am-ίηο chosen from l,4-diazabicydo(2,2,2)octane, 1,8-diazabicyclo(5,4,0) undec-7-ene, hexamethyl tetramine, N-methylpiperidine, N-ethylpiperidine, N-methylmorpholine, 20 morpholine, N,N* -dialkylpiperazine, pyridine, quinoline and isoquinoline.

2. Process according to Claim 1, characterized in that the said diacid dihalide is oxalyl chloride.

3. Process according to either of Claims 1 and 2, 25 characterized in that the said complexing agent is chosen from linear, cyclic or macrocyclic oxygen-containing or sulphur-containing polyethere.

4. Process according to one of Claims 1 to 3, characterized in that the oxygenm containing tertiary 30 amines correspond to the formula: N- E—ChR 2 ——O— (CHR 3 -CBR 4 -O-) n -R 3 ] 3 in which n is an integer greater than or equal to 0 and smaller than or equal to 10 (0 s n s 10), R x , Rj, R 3 and R 4 , which are identical or different, denote a hydrogen 35 atom or an alkyl radical containing from 1 to 4 carbon atoms and R s denotes an alkyl or cycloalkyl radical containing from 1 to 12 carbon atoms, a phenyl radical or a radical of formula -^Η^-Φ, or m being between 1 and 12.

5. Process according to one of Claims 1 to 3, characterized in that the complexing agents correspond to the following formulae II: RlO-Y[A - 0] p A - Y - Rjq Ha in which 5 - Y denotes 0 (divalent), N or P (trivalent) in formulae Ila and lib and N or P in the last formula, - A denotes an alkylene group containing from 1 to 3 carbon atoms, 10 - D denotes O, S or N-R lx , R X1 denotes an alkyl radical containing from 1 to

6. Carbon atoms, - R 10 denotes an alkyl radical containing 1 to € carbon atoms, - p, q and r, which are identical or different, are 15 integers included between 1 and 5, - when in the above formulae the valency of the atoms Y is not satisfied, alkyl radicals R 10 then satisfy the said valencies. Process according to Claim 4, characterized in that the oxygen-containing amine is tris(3,6-dioxaheptyl ) amine .

7. Process according to Claims 1 to 3, ghar^gtA-pigad in that the polyether is diethylene glycol methyl 5 diether.

8. Process according to one of Claims 1 to 7, characterized in that the reaction is carried out in an aromatic solvent, preferably in toluene.

9. Process according to one of Claims 1 to 8, 10 characterized in that the said mixed alkali metal alkyl carbonate is a lithium or sodium salt.

10. Process according to Claim 2, characterized in that the polyether is dioxane.

11. Process according to Claim 1 for the preparation 15 of a secondary or tertiary dialkyl dicarbonate, substantially as hereinbefore described and exemplified.

12. A secondary or tertiary dialkyl dicarbonate whenever prepared by a process claimed in a preceding claim.