13C-LABELLED CHLORINATED PARAFFINS AND THEIR PREPARATION
20250188006 ยท 2025-06-12
Inventors
- Jon Eigill JOHANSEN (Tiller, NO)
- Alexey GOROVOY (Trondheim, NO)
- Jiri TUMA (Kladno, CZ)
- Solveig VALDERHAUG (Trondheim, NO)
- Jonatan NYGREN (Trondheim, NO)
- Huiling LIU (Trondheim, NO)
Cpc classification
C07C1/34
CHEMISTRY; METALLURGY
C07B2200/05
CHEMISTRY; METALLURGY
International classification
Abstract
The present invention is directed to .sup.13C-labelled chlorinated paraffins, preferably having neither geminal nor terminal chlorine atoms in their structure, processes for their preparation as well as their uses.
Claims
1. A process for preparing .sup.13C-labelled chlorinated paraffins, preferably having neither geminal nor terminal chlorine atoms in their structure, comprising or consisting of the steps of: V) providing an alkene, having: one or more alpha, beta-ethylenically unsaturated double bonds in its main chain, one or more carbon atoms in its main chain being replaced by .sup.13C-atom(s), and optionally one chlorine atom or an odd number of chlorine atoms in its main chain, with the proviso that neither geminal nor terminal chlorines are present and none are present on an atom that is part of an alpha,beta-ethylenically unsaturated double bond, or a mixture of such alkenes, and VI) reacting the alkene or mixture of alkenes with a trichloride, a tribromide or triiodide, preferably a trichloride, more preferably tetraalkylammonium trichloride, even more preferably tetraethylammonium trichloride.
2. The process according to claim 1, characterized in that it additionally includes the steps of Ia) providing an alkanol having at least one, more than one, or all of the carbon atoms of its main chain replaced by .sup.13C-atom(s), IIa) converting the alkanol to a corresponding bromide, IIIa) converting the bromide to a Wittig salt, IVa1) coupling the Wittig salt with an aldehyde to form an alkene having at least one alpha,beta-ethylenically unsaturated double bond in its main chain, wherein the aldehyde optionally has one, more than one, or all of the carbon atoms of its main chain replaced with .sup.13C-atom(s), or IVa2) coupling the Wittig salt with a dialdehyde to form an alkene having at least two alpha,beta-ethylenically unsaturated double bonds in its main chain, wherein the dialdehyde optionally has one, more than one, or all of the carbon atoms of its main chain replaced with .sup.13C-atom(s), or Ib) providing an alkanol or alkenol, particularly alkenol, having at least one, more than one, or all of the carbon atoms of its main chain replaced by .sup.13C-atom(s), IIb converting the alkanol or alkenol, particularly alkenol, to a corresponding halide, particularly a bromide, IIIb) converting the halide to a Grignard reagent, IVb1) coupling the Grignard with a tosylate species, particularly made from alcohol, via a carbon-carbon cross coupling reaction catalysed with copper, nickel or palladium complexes, particularly Li.sub.2CuCl.sub.4, to form an alkene having at least one alpha,beta-ethylenically unsaturated double bond in its main chain, wherein the alcohol species optionally has one, more than one, or all of the carbon atoms of its main chain replaced with .sup.13C-atom(s), or IVb2) coupling the Grignard with a divalent tosylate species made from diol, via a carbon-carbon cross coupling reaction to form an alkene having at least two alpha,beta-ethylenically unsaturated double bonds in its main chain, wherein the diol species optionally has one, more than one, or all of the carbon atoms of its main chain replaced with .sup.13C-atom(s).
3. The process according to claim 1, wherein the alkene is a linear alkene or the alkenes are linear alkenes, respectively.
4. The process_according to claim 3, wherein, in particular in order to prepare .sup.13C-labelled paraffins having an even number of chlorine atoms, it follows: ##STR00043## ##STR00044## ##STR00045## ##STR00046## wherein: R*=.sup.13C.sub.a-n-alkyl, *=.sup.13C; Ph=phenyl; Et=ethyl; R.sup.1=.sup.13C.sub.b-alkylene-residue, optionally including one or an odd number of chlorine atoms with the proviso that no chlorine is on the terminal end of the residue, and wherein the number of double bonds in the alkylene residue is a minimum of one and up to the theoretically possible number of accumulated double bonds; R.sup.2=.sup.13C.sub.b-chloro-alkyl-residue, particularly of the formula .sup.13C.sub.b-C.sub.nH.sub.2n+1yCl.sub.y; R.sup.3=.sup.13C.sub.d-alkylene-residue, optionally including one or an odd number of chlorine atoms with the proviso that no chlorine is on the terminal end of the residue, and wherein the number of double bonds in the alkylene residue is a minimum of one and up to the theoretically possible number of accumulated double bonds; R.sup.4=.sup.13C.sub.d-chloro-alkyl-residue, particularly of the formula .sup.13C.sub.d-C.sub.nH.sub.2nyCl.sub.y; R.sup.5=.sup.13C.sub.e-alkylene-residue, optionally including one or an odd number of chlorine atoms with the proviso that no chlorine is on the terminal end of the residue, and wherein the number of double bonds in the alkylene residue is a minimum of one and up to the theoretically possible number of accumulated double bonds; R.sup.6=.sup.13C.sub.e-chloro-alkyl-residue, particularly of the formula .sup.13C.sub.e-C.sub.nH.sub.2n+1yCl.sub.y; R.sup.7=.sup.13C.sub.f-alkylene-residue, optionally including one or an odd number of chlorine atoms, and wherein the number of double bonds in the alkylene residue is a minimum of one and up to the theoretically possible number of accumulated double bonds; R.sup.8=.sup.13C.sub.f-chloro-C.sub.n-alkyl-residue, particularly of formula .sup.13C.sub.f-C.sub.nH.sub.2nyCl.sub.y; R.sup.9=.sup.13C.sub.g-alkyl or alkylene-residue which can contain 1 double bond; R.sup.10=.sup.13C.sub.g-(chloro)-alkyl-residue, and is the same as R.sup.9 if R.sup.9=.sup.13C.sub.g-alkyl-residue; a, b, c, d, e, f, g=independently from one another an integer of from 1 to the entire number of carbon atoms in the respective alkyl or alkylene residue, preferably each from 1 to 4, and representing the number of .sup.13C carbons in the respective residue; n is an integer from 0 to 28, preferably from 1 to 28, representing the number of carbon atoms in each of the residues and its value is each time independent from its value in the other residues; y is an integer from 0 to 28, preferably from 1 to n-1, representing the number of chlorine atoms in the respective residue.
5. The process according claim 1, wherein the alkenes are prepared from unsaturated fatty acids via the following steps: A) providing an unsaturated fatty acid or a mixture of unsaturated fatty acids, Ca) converting the unsaturated fatty acid or unsaturated fatty acids to a corresponding alkenol or mixture of alkenols, and Cb1) reducing the alkenol or mixture of alkenols to the corresponding alkene or mixture of alkenes, or Cc1) replacing the alcohol group or groups with a leaving group or groups, preferably tosylate, Cc2) coupling an alkyl to the former alcohol carbon, thereby eliminating the leaving group and forming an unsaturated bond; or Da) converting the unsaturated fatty acid or unsaturated fatty acids to a corresponding alkenal or mixture of alkenals, and Db1) coupling the alkenal or mixture of alkenals with Wittig salt to the corresponding alkene or mixture of alkenes.
6. A process for preparing a compound of .sup.13C-labelled or unlabelled chlorinated paraffins, preferably having neither geminal nor terminal chlorine atoms in their structure, by converting an unsaturated fatty acid or a mixture of unsaturated fatty acids to a .sup.13C-labelled or unlabelled chlorinated paraffin or a mixture of .sup.13C-labelled or unlabelled chlorinated paraffins, comprising the steps of: A) providing a .sup.13C-labelled or unlabelled unsaturated fatty acid or a mixture of .sup.13C-labelled or unlabelled unsaturated fatty acids, Ba) chlorinating the unsaturated fatty acid or unsaturated fatty acids and Bb) decarboxylating of the resulting chlorinated acid or acids, or Ca) converting the unsaturated fatty acid or unsaturated fatty acids to a corresponding alkenol or mixture of alkenols, and Cb1) reducing the alkenol or mixture of alkenols to the corresponding alkene or mixture of alkenes, and Cb2) chlorinating the resulting alkene or mixture of alkenes; or Cc1) replacing the alcohol group or groups with a leaving group or groups, preferably tosylate, Cc2) coupling an alkyl to the former alcohol carbon, thereby eliminating the leaving group and forming an unsaturated bond, and Cc3) chlorinating the resulting alkene or mixture of alkenes; or Cd) chlorinating the alkenol or mixture of alkenols; or Da) converting the unsaturated fatty acid or unsaturated fatty acids to a corresponding alkenal or mixture of alkenals, and Db1) coupling the alkenal or mixture of alkenals with Wittig salt to form the corresponding alkene or mixture of alkenes, Db1a) optionally using Wittig salts with at least one .sup.13C-labelled carbon atom in the coupling group, and Db2) chlorinating the resulting alkene or mixture of alkenes.
7. A compound of .sup.13C-labelled chlorinated paraffins having neither geminal nor terminal chlorine atoms in their structure, the compound further comprising: at least two chlorine atoms in their main chain, and at least one, particularly from two to eight, carbon atoms of the main chain replaced by .sup.13C-atoms, preferably represented by the general formula
.sup.13C.sub.m-C.sub.pH.sub.2p+2xCl.sub.x, with m being an integer of from 1 to p, particularly 2 to 8; p being an integer of from 2 to 38, preferably from 8 to 38, particularly 8 to 30; x=2 to p-2, preferably 4 to p-2, more preferably, in the case of SCCP 4 to 6, particularly 4 or 6, in the case of MCCP 6 to 8, particularly 6 or 8, in the case of LCCP 8 to 10, particularly 8 or 10.
8. The compound of .sup.13C-labelled chlorinated paraffins having neither geminal nor terminal chlorine atoms in their structure, according to claim 7, represented by either the general formula A ##STR00047## or general formula B ##STR00048## or general formula D ##STR00049## or general formula E ##STR00050## wherein: R*=.sup.13C.sub.a-n-alkyl, *=.sup.13C; R.sup.2=.sup.13C.sub.b-chloro-alkyl-residue, particularly of the formula .sup.13C.sub.b-C.sub.nH.sub.2n+1yCl.sub.y; R.sup.4=.sup.13C.sub.d-chloro-alkyl-residue, particularly of the formula .sup.13C.sub.d-C.sub.nH.sub.2n-yCl.sub.y; R.sup.6=.sup.13C.sub.e-chloro-alkyl-residue, particularly of the formula .sup.13C.sub.e-C.sub.nH.sub.2n+1yCl.sub.y; R.sup.8=.sup.13C.sub.f-chloro-C.sub.n-alkyl-residue, particularly of formula .sup.13C.sub.f-C.sub.nH.sub.2nyCl.sub.y; R.sup.10=.sup.13C.sub.g-(chloro)-alkyl-residue, and is the same as R.sup.9 if R.sup.9=.sup.13C.sub.g-alkyl-residue.
9. A compound of .sup.13C-labeled chlorinated paraffins having neither geminal nor terminal chlorine atoms in their structure, according to claim 7, wherein the compound further comprises: a general formula A ##STR00051## wherein *=.sup.13C, R*=.sup.13C.sub.a-n-alkyl and R.sup.2=.sup.13C.sub.b-chloro-alkyl-residue, particularly of the formula .sup.13C.sub.b-C.sub.nH.sub.2n+1yCl.sub.y; or selected from the group consisting of i) 6,7,8-.sup.13C.sub.3-2,3,5,6-tetrachlorooctane or 2,3,5,6-tetrachlorooctane-6,7,8-.sup.13C.sub.3 of formula ##STR00052## ii) 1,2,9,10-.sup.13C.sub.4-2,3,8,9-tetrachlorodecane ##STR00053## iii) 9,10,11-.sup.13C.sub.3-2,3,5,6,8,9-hexachloroundecane or 2,3,5,6,8,9-hexachloroundecane-9,10,11-.sup.13C.sub.3 of formula ##STR00054## iv) 11,12,13-.sup.13C.sub.3-3,4,6,7,10,11-hexachlorotridecane or 3,4,6,7,10,11-hexachlorotridecane-11,12,13-.sup.13C.sub.3 of formula ##STR00055## v) 1,2,9,10-.sup.13C.sub.4-2,3,5,6,8,9-hexachlorodecane-1,2,9,10-.sup.13C.sub.4 or 2,3,5,6,8,9-hexachlorodecane-1,2,9,10-.sup.13C.sub.4 of formula ##STR00056## vi) 6,7,8-.sup.13C.sub.3-2,3,5,6,8,9,11,12-octachlorotridecane or 2,3,5,6,8,9,11,12-octachlorotridecane-6,7,8-.sup.13C.sub.3 of formula ##STR00057## vii) 10,11,12-.sup.13C.sub.3-2,3,5,6,9,10-hexachlorododecane ##STR00058## or viii) 10,11,12-.sup.13C.sub.3-2,3,5,6,8,9-hexachlorododecane ##STR00059## ix) 1,2,3-.sup.13C.sub.3-3,4,7,8,11,12-hexachlorotetradecane ##STR00060## x) 13,14,15-.sup.13C.sub.3-3,4,7,8,12,13-hexachloropentadecane ##STR00061## xi) 1,2,3-.sup.13C.sub.3-3,4,8,9,13,14-hexachlorohexadecane ##STR00062## xii) 1,2,3-.sup.13C.sub.3-3,4,12,13,15,16, 18, 19-octachloro-n-heneicosane. ##STR00063## wherein *=.sup.13C; Ph=phenyl; Et=ethyl.
10. A mixture of chlorinated paraffins comprising .sup.13C-labelled chlorinated paraffins having neither geminal nor terminal chlorine atoms in their structure according to claim 7.
11. A method of using .sup.13C-labelled chlorinated paraffins having neither geminal nor terminal chlorine atoms in their structure according to claim 7 as internal standards for analytical processes, in particular for the quantitative analysis of very short-chain chlorinated paraffins (vSCCPs, <C.sub.10), short-chain chlorinated paraffins (SCCPs, C10-C13); medium-chain chlorinated paraffins (MCCPs, C14-C17) and long-chain chlorinated paraffins (LCCPs, C18-C30).
12. A method of use of .sup.13C-labelled chlorinated paraffins having neither geminal nor terminal chlorine atoms in their structure according to claim 7 as reference materials for metabolism and toxicity analysis of chlorinated paraffins.
13. A compound of chlorinated paraffins selected from the group consisting of 9,10,11-.sup.13C.sub.3-1,2,4,5,8,9-hexachloroundecane, 10,11,12-.sup.13C.sub.3-1,2,5,6,9,10-hexachlorododecane, 11,12,13-.sup.13C.sub.3-1,2,6,7,10,11-hexachlorotridecane, 12,13,14-.sup.13C.sub.3-1,2,7,8,11,12-hexachlorotetradecane, 13,14,15-.sup.13C.sub.3-1,2,7,8,12,13-hexachloropentadecane, 14,15,16-.sup.13C.sub.3-1,2,8,9,13,14-hexachlorohexadecane, 1,2,9,10-.sup.13C.sub.4-2,3,8,9-tetrachlorodecane, 8,9,10-.sup.13C.sub.3-1,2,4,5,7,8-hexachlorodecane, and mixtures thereof, particularly 1,2,9,10-.sup.13C.sub.4-2,3,8,9-tetrachlorodecane or 8,9,10-.sup.13C.sub.3-1,2,4,5,7,8-hexachlorodecane.
14. Internal standards for analytical processes, in particular for the quantitative analysis of vSCCPs, SCCPs, MCCPs, LCCPs, comprising or consisting of one or more of the .sup.13C-labelled chlorinated paraffins having neither geminal nor terminal chlorine atoms in their structure according to claim 7, one or more chlorinated paraffins selected from the group consisting of 9,10,11-.sup.13C.sub.3-1,2,4,5,8,9-hexachloroundecane, 10,11,12-.sup.13C.sub.3-1,2,5,6,9,10-hexachlorododecane, 11,12,13-.sup.13C.sub.3-1,2,6,7,10,11-hexachlorotridecane, 12,13,14-.sup.13C.sub.3-1,2,7,8,11,12-hexachlorotetradecane, 13,14,15-.sup.13C.sub.3-1,2,7,8,12,13-hexachloropentadecane, 14,15,16-.sup.13C.sub.3-1,2,8,9,13,14-hexachlorohexadecane, 1,2,9,10-.sup.13C.sub.4-2,3,8,9-tetrachlorodecane, 8,9,10-.sup.13C.sub.3-1,2,4,5,7,8-hexachlorodecane, particularly 1,2,9,10-.sup.13C.sub.4-2,3,8,9-tetrachlorodecane or 8,9,10-.sup.13C.sub.3-1,2,4,5,7,8-hexachlorodecane, or a mixture or more of the chlorinated paraffins selected from the group consisting of 9,10,11-.sup.13C.sub.3-1,2,4,5,8,9-hexachloroundecane, 10,11,12-.sup.13C.sub.3-1,2,5,6,9,10-hexachlorododecane, 11,12,13-.sup.13C.sub.3-1,2,6,7,10,11-hexachlorotridecane, 12,13,14-.sup.13C.sub.3-1,2,7,8,11,12-hexachlorotetradecane, 13,14,15-.sup.13C.sub.3-1,2,7,8,12,13-hexachloropentadecane, 14,15,16-.sup.13C.sub.3-1,2,8,9,13,14-hexachlorohexadecane, 1,2,9,10-.sup.13C.sub.4-2,3,8,9-tetrachlorodecane, 8,9,10-.sup.13C.sub.3-1,2,4,5,7,8-hexachlorodecane, particularly 1,2,9,10-.sup.13C.sub.4-2,3,8,9-tetrachlorodecane or 8,9,10-.sup.13C.sub.3-1,2,4,5,7,8-hexachlorodecane and one or more of the .sup.13C-labelled chlorinated paraffins having neither geminal nor terminal chlorine atoms in their structure according to claim 7.
15. Internal standards for analytical processes according to claim 14, characterized in that the chlorinated paraffins comprise or consist of single chain CP mixtures of .sup.13C.sub.m-C.sub.pH.sub.2p+2xCl.sub.x, with m being an integer of from 1 to p, particularly 2 to 8; p being an integer8, particularly 8 to 30; x=2 to p-1, preferably 2 to 10 or x=2 to p-2, preferably 4 to p-2; and wherein the .sup.13C-labelled single-chain mixtures have chlorine contents of 45-75 weight %, calculated from the analysis on NMR and chlorine titration.
Description
DETAILED DESCRIPTION
[0014] It should be understood that this invention is not limited to the embodiments disclosed in this summary, or the description that follows, but is intended to cover modifications that are within the spirit and scope of the invention, as de-fined by the claims.
[0015] In the present application, including the claims, other than in the operating examples or where otherwise indicated, all numbers expressing quantities or characteristics are to be understood as being modified in all instances by the term about. Accordingly, unless indicated to the contrary, any numerical parameters set forth in the following description may vary depending on the desired properties one seeks to obtain in the compositions and methods according to the present disclosure. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter described in the present description should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
[0016] Also, it should be understood that any numerical range recited herein is in-tended to include all sub-ranges subsumed therein. For example, a range of 1 to 10 is intended to include all sub-ranges between (and including) the recited minimum value of 1 and the recited maximum value of 10, that is, having a minimum value equal to or greater than 1 and a maximum value of equal to or less than 10. The terms one, a, or an as used herein are intended to include at least one or one or more, unless otherwise indicated.
[0017] In the present invention, unless otherwise specified, the reactions are conducted at room temperature, which is understood as being 20 C.
[0018] In the present invention, unless otherwise specified, the reactions are conducted at ambient pressure, which is understood as being 101,325 kPa.
[0019] In the present invention the term fatty acid is used as in the IUPAC Gold Book as: Aliphatic monocarboxylic acids derived from or contained in esterified form in an animal or vegetable fat, oil or wax. Natural fatty acids commonly have a chain of 4 to 28 carbons (usually unbranched and even-numbered), which may be saturated or unsaturated..
[0020] The present invention in a first embodiment is directed to a process for preparing .sup.13C-labelled chlorinated paraffins.
[0021] While with this process in principle any .sup.13C-labelled chlorinated paraffins can be prepared, in the present invention it is preferred for preparing .sup.13C-labelled chlorinated paraffins having neither geminal nor terminal chlorine atoms in their structure.
[0022] This process of the present invention comprises or consists of the steps of:
[0023] V) providing an alkene [0024] having one or more alpha,beta-ethylenically unsaturated double bonds in its main chain, [0025] one or more carbon atoms in its main chain being replaced by .sup.13C-atom(s), [0026] and optionally one chlorine atom or an odd number of chlorine atoms in its main chain, with the proviso that neither geminal nor terminal chlorines are present and none are present on an atom that is part of an alpha,beta-ethylenically unsaturated double bond, or a mixture of such alkenes,
[0027] VI) reacting the alkene or mixture of alkenes with a trichloride, a tribromide or triiodide, preferably a trichloride, more preferably tetraalkylammonium trichloride, even more preferably tetraethylammonium trichloride.
[0028] In some preferred embodiments this process also includes further steps, namely the steps of: [0029] Ia) providing an alkanol having at least one, more than one, or all of the carbon atoms of its main chain replaced by .sup.13C-atom(s), [0030] IIa) converting the alkanol to a corresponding bromide, [0031] IIIa) converting the bromide to a Wittig salt, [0032] IVa1) coupling the Wittig salt with an aldehyde to form an alkene having at least one alpha,beta-ethylenically unsaturated double bond in its main chain, wherein the aldehyde optionally has one, more than one, or all of the carbon atoms of its main chain replaced with .sup.13C-atom(s), or [0033] IVa2) coupling the Wittig salt with a dialdehyde to form an alkene having at least two alpha,beta-ethylenically unsaturated double bonds in its main chain, wherein the dialdehyde optionally has one, more than one, or all of the carbon atoms of its main chain replaced with .sup.13C-atom(s), or [0034] Ib) providing an alkanol or alkenol, particularly alkenol, having at least one, more than one, or all of the carbon atoms of its main chain replaced by .sup.13C-atom(s), [0035] IIb) converting the alkanol or alkenol, particularly alkenol, to a corresponding halide, particularly a bromide, [0036] IIIb) converting the halide to a Grignard reagent, [0037] IVb1) coupling the Grignard with a tosylate species, particularly made from alcohol, via a carbon-carbon cross coupling reaction catalysed with copper, nickel or palladium complexes, particularly Li.sub.2CuCl.sub.4, to form an alkene having at least one alpha,beta-ethylenically unsaturated double bond in its main chain, wherein the alcohol species optionally has one, more than one, or all of the carbon atoms of its main chain replaced with .sup.13C-atom(s), or [0038] IVb2) coupling the Grignard with a divalent tosylate species made from diol, via a carbon-carbon cross coupling reaction to form an alkene having at least two alpha,beta-ethylenically unsaturated double bonds in its main chain, wherein the diol species optionally has one, more than one, or all of the carbon atoms of its main chain replaced with .sup.13C-atom(s).
[0039] In some other preferred embodiments of the process according to the present invention, the employed alkene is a linear alkene or the alkenes are linear alkenes, respectively.
[0040] In one preferred variation of the present invention, in particular in order to prepare .sup.13C-labelled chlorinated paraffins having an even number of chlorine atoms, the process of the present follows schemes 1a) or 1b), respectively (schemes 1a) and 1b) only differing from each other in that in scheme 1b) the aldehyde (4) also has a .sup.13C-labelled carbon atom):
##STR00001##
[0041] In another preferred variation of the present invention, in particular in order to prepare .sup.13C-labelled chlorinated paraffins having an even number of chlorine atoms, the process of the present follows schemes 2a) or 2b), respectively (schemes 2a) and 2b) only differing from each other in that in scheme 2b) the aldehyde (6) also has a .sup.13C-labelled carbon atom):
##STR00002##
[0042] In yet another preferred variation of the present invention, in particular in order to prepare .sup.13C-labelled chlorinated paraffins having an even number of chlorine atoms, the process of the present follows scheme 3:
##STR00003##
[0043] In still another preferred variation of the present invention, in particular in order to prepare .sup.13C-labelled chlorinated paraffins having an even number of chlorine atoms, the process of the present follows scheme 4:
##STR00004##
[0044] In all these variations the variables and residues are as follows:
[0045] R*=.sup.13C.sub.a-n-alkyl (straight chain alkyl), preferably of 0 to 4 carbon atoms, wherein a is the number of .sup.13C in the alkyl chain and is from 1 up to the carbon number in the alkyl chain, preferably from 1 to 4; [0046] =.sup.13C;
[0047] Ph=phenyl; Et=ethyl;
[0048] R.sup.1=.sup.13C.sub.b-alkylene-residue, preferably of 2-28 carbon atoms, wherein b is the number of .sup.13C carbons in the alkylene residue and is from 1 up to the carbon number in the alkene chain, preferably from 1 to 4, optionally including one or an odd number of chlorine atoms with the proviso that no chlorine is on the terminal end of the residue, and wherein the number of double bonds in the alkylene residue is a minimum of one and up to the theoretically possible number of accumulated double bonds, particularly 1 to 9, and the double bonds are preferably not accumulated or conjugated;
[0049] R.sup.2=.sup.13C.sub.b-chloro-alkyl-residue, preferably of 2-28 carbon atoms, wherein b is the number of .sup.13C carbons in alkyl residue, particularly of the formula .sup.13C.sub.b-C.sub.nH.sub.2n+1yCl.sub.y, n is from 2 to 28 and y is the number of chlorine atoms and is from 2 to 28, but preferably 2 to 27;
[0050] R.sup.3=.sup.13C.sub.d-alkylene-residue, preferably of 0 to 26 or of 1-26, carbon atoms, wherein d is the number of .sup.13C carbons in alkylene residue and is from 1 up to the carbon number in the alkylene chain, preferably from 1 to 4, optionally including one or an odd number of chlorine atoms with the proviso that no chlorine is on the terminal end of the residue, and wherein the number of double bonds in the alkylene residue is a minimum of one and up to the theoretically possible number of accumulated double bonds, and the double bonds are preferably not accumulated or conjugated;
[0051] R.sup.4=.sup.13C.sub.d-chloro-alkyl-residue, preferably of 0 to 26 or of 1-26, carbon atoms, wherein d is the number of .sup.13C carbons in alkyl residue, particularly of the formula .sup.13C.sub.d-C.sub.nH.sub.2nyCl.sub.y, n is from 0 to 26 and y is the number of chlorine atoms and is from 0 to 26, but preferably 1 to 25;
[0052] R.sup.5=.sup.13C.sub.e-alkylene-residue, preferably of 0 to 26 or of 1-26, carbon atoms, wherein e is the number of .sup.13C in the alkyl or alkene chain and is from I up to the carbon number in the alkyl or alkene chain, preferably from 1 to 4, optionally including one or an odd number of chlorine atoms with the proviso that no chlorine is on the terminal end of the residue, and wherein the number of double bonds in the alkylene residue is a minimum of one and up to the theoretically possible number of accumulated double bonds, and the double bonds are preferably not accumulated or conjugated;
[0053] R.sup.6=.sup.13C.sub.e-chloro-alkyl-residue, preferably of 0 to 26 or of 1-26, of carbon atoms, wherein e is the number of .sup.13C carbons in alkyl residue, particularly of the formula .sup.13C.sub.e-C.sub.nH.sub.2n+1yCl.sub.y, n is from 1 to 26 and y is the number of chlorine atoms and is from 2 to 26, but preferably 2 to 25;
[0054] R.sup.7=.sup.13C.sub.f-alkylene-residue, preferably of 0-22 carbon atoms, f is the number of .sup.13C in the alkene chain and is from 1 up to the carbon number in the alkene chain, preferably from 1 to 4, optionally including one or an odd number of chlorine atoms, and wherein the number of double bonds in the alkylene residue is a minimum of one and up to the theoretically possible number of accumulated double bonds, and the double bonds are preferably not accumulated or conjugated;
[0055] R.sup.8=.sup.13C.sub.f-chloro-C.sub.n-alkyl-residue, preferably of 0 to 22 carbon atoms, particularly of formula .sup.13C.sub.f-C.sub.nH.sub.2nyCl.sub.y, n is 0 to 22 and y is the number of chlorine atoms and is from 0 to 22, but preferably 0 to 21;
[0056] R.sup.9=.sup.13C.sub.g-alkyl or alkene-residue, preferably of 0-4 carbon atoms if alkyl and of 3 or 4 carbon atoms if alkylene, wherein g is the number of .sup.13C in the alkyl or alkene chain and is from 1 up to the carbon number in the alkyl or alkene chain, preferably from 1 to 4, and can contain 1 double bond;
[0057] R.sup.10=.sup.13C.sub.g-(chloro)-alkyl, preferably of 0 to 4 carbon atoms, with 0, 1 or 2 chlorine atoms and is the same as R.sup.9 if R.sup.9=.sup.13C.sub.g-alkyl-residue; in some preferred embodiments, R.sup.9=R.sup.10-.sup.13C.sub.g-alkyl residue;
[0058] a, b, c, d, e, f, g are, independently from one another, an integer of from 1 up to the number of carbon atoms in the respective alkyl or alkylene residue; in some preferred embodiments they each are from 1 to 4.
[0059] It should be noted here, that in the present invention *=.sup.13C represents the carbon that is at the indicated position in the formula including the necessary hydrogen atoms (i.e. 0 to 3 hydrogen atoms) needed to satisfy the valencies of the carbon atom being at the indicated position (as is commonly done in chemical formulae).
[0060] It should also be noted that in the denotation of the present invention .sup.13C.sub.index means the indexed number of carbon atoms in the following given formula is replaced with .sup.13C carbon atoms, it does not mean that the indexed number of carbons is added. For example, .sup.13C.sub.3-C.sub.6H.sub.12 would mean that three of the six carbon atoms are replaced with .sup.13C isotopes. The exact position of the .sup.13C-isotpoes in the carbon chain may be indicated by numerals preceding the .sup.13C.sub.index-term, for example 2,3,5-.sup.13C.sub.3-C.sub.6H.sub.12 would mean that three of the six carbon atoms are replaced with .sup.13C isotopes and that these are at chain positions 2, 3 and 5. It should also be understood, that the term .sup.13C.sub.index does not necessarily have to be in front of the remaining formula, in some instances it is better in the middle of the formula or at the end, in order to more clearly illustrate the structure and/or to increase intelligibility.
[0061] Compounds (1) are .sup.13C-labelled alcohols, which are commercially available.
[0062] In preferred embodiments, R.sup.1 has the same chain length as R.sup.2.
[0063] In preferred embodiments, R.sup.3 has the same chain length as R.sup.4.
[0064] In preferred embodiments, R.sup.5 has the same chain length as R.sup.6.
[0065] In preferred embodiments, R.sup.7 has the same chain length as R.sup.8.
[0066] In preferred embodiments, R.sup.9 has the same chain length as R.sup.10.
[0067] It should also be noted that the process according to scheme 4 is employed with the proviso that it is only used to prepare .sup.13C-labelled chlorinated paraffins in which the entire chain length is from 10 to 40 carbon atoms.
[0068] The unsaturated aldehydes (4) and (6), unsaturated alcohols (9) and (12), with or without chlorines in the carbon chain, can be prepared by methods known in the art. For example, alcohols can be oxidised according to the Swern reaction and then reacted with a Wittig salt to provide aldehydes having longer chains than the starting alcohol. However, there is no particular limitation on how the aldehydes (4) and (6) or the alcohols (9) and (12) may be prepared.
[0069] In some preferred embodiments of the present invention the aldehydes (4), (6) or alcohols (9) and (12) are prepared from unsaturated fatty acids. For example, this can be done by A) first providing an unsaturated fatty acid or a mixture of unsaturated fatty acids and then either Ca) converting the unsaturated fatty acid or unsaturated fatty acids to a corresponding alkenol or mixture of alkenols or Da) converting the unsaturated fatty acid or unsaturated fatty acids to a corresponding alkenal or mixture of alkenals. These embodiments are especially useful for the synthesis of medium and long chain CP (MCCP and LCCP).
[0070] In some preferred embodiments of the present invention the alkenes in step V) of the process of the present invention are prepared from unsaturated fatty acids, via the following steps: [0071] A) providing an unsaturated fatty acid or a mixture of unsaturated fatty acids, [0072] Ca) converting the unsaturated fatty acid or unsaturated fatty acids to a corresponding alkenol or mixture of alkenols, and [0073] Cb1) reducing the alkenol or mixture of alkenols to the corresponding alkene or mixture of alkenes, or [0074] Cc1) replacing the alcohol group or groups with a leaving group or groups, preferably tosylate, [0075] Cc2) coupling an alkyl to the former alcohol carbon, thereby eliminating the leaving group and forming an alkene or mixture of alkenes; or [0076] Da) converting the unsaturated fatty acid or unsaturated fatty acids to a corresponding alkenal or mixture of alkenals, and [0077] Db1) coupling the alkenal or mixture of alkenals with Wittig salts to form the corresponding alkene or mixture of alkenes.
[0078] Another further embodiment of the present invention is a process for preparing .sup.13C-labelled or unlabelled chlorinated paraffins, preferably having neither geminal nor terminal chlorine atoms in their structure, by converting a .sup.13C-labelled or unlabelled unsaturated fatty acid or a mixture of .sup.13C-labelled or unlabelled unsaturated fatty acids to a .sup.13C-labelled or unlabelled chlorinated paraffins or a mixture of .sup.13C-labelled or unlabelled chlorinated paraffins.
[0079] In a preferred embodiment of the present invention, this process comprises the steps of [0080] A) providing a .sup.13C-labelled or unlabelled unsaturated fatty acid or a mixture of .sup.13C-labelled or unlabelled unsaturated fatty acids, [0081] Ba) chlorinating the unsaturated fatty acid or unsaturated fatty acids and [0082] Bb) decarboxylating of the resulting chlorinated acid or acids, or [0083] Ca) converting the unsaturated fatty acid or unsaturated fatty acids to a corresponding alkenol or mixture of alkenols, and [0084] Cb1) reducing the alkenol or mixture of alkenols to the corresponding alkene or mixture of alkenes, and [0085] Cb2) chlorinating the resulting alkene or mixture of alkenes; or [0086] Cc1) replacing the alcohol group or groups with a leaving group or groups, preferably tosylate, [0087] Cc2) coupling an alkyl to the former alcohol carbon, thereby eliminating the leaving group and forming an alkene or mixture of alkenes, and [0088] Cc3) chlorinating the resulting alkene or mixture of alkenes; or [0089] Cd) chlorinating the alkenol or mixture of alkenols; or [0090] Da) converting the unsaturated fatty acid or unsaturated fatty acids to a corresponding alkenal or mixture of alkenals, and [0091] Db1) coupling the alkenal or mixture of alkenals with Wittig salts to form the corresponding alkene or mixture of alkenes, [0092] Db1a) optionally using Wittig salts with at least one .sup.13C-labelled carbon atom in the coupling group, and [0093] Db2) chlorinating the resulting alkene or mixture of alkenes.
[0094] These processes can be illustrated as in the following schemes 5 and 6, wherein, as an example for illustration purposes only. alpha-linolenic acid is used (the process is of course not limited to linolenic acid):
##STR00005## ##STR00006##
[0095] In preferred embodiments the fatty acids to be employed in this process are selected from C11-C24 unsaturated fatty acids, preferably C11 to C24 polyunsaturated fatty acids, more preferably even more preferably selected from, but not limited to, the following examples as well as mixtures thereof or, possibly, mixtures with other fatty acids: 9Z,12Z-Octadecadienoic acid (Linoleic acid, C18:2);
[0096] 9Z,12Z,15Z-octadecatrienoic acid (alpha-linolenic acid, C18:3);
[0097] 6Z,9Z,12Z-octadecatrienoic acid (gamma-linolenic acid, C18:3);
[0098] 6Z,9Z,12Z,15Z-Octadecatetrawnoic acid (Stearidonic acid, C18:4);
[0099] 10Z,13Z-Nonadecadienoic acid (C19:2);
[0100] 5Z,8Z,11Z-Icosatrienoic acid (Mead acid, C20:3);
[0101] 8Z,11Z,14Z-Eicosatrienoic acid (Homogamma linolenic acid, C20:3);
[0102] 11Z,14Z,17Z-Eicosatrienoic acid (C20:3);
[0103] 5Z,8Z,11Z,14Z-Eicosatetraenoic acid (Arachidonic acid, C20:4);
[0104] 5Z,8Z,11Z,14Z,17Z-Eicosapentaenoic acid (EPA, C20:5).
[0105] Still even more preferably in some embodiments the fatty acids are selected from the group consisting of 9Z,12Z-Octadecadienoic acid (Linoleic acid, C18:2), 9Z,12Z,15Z-octadecatrienoic acid (alpha-linolenic acid, C18:3), 6Z,9Z,12Z-octadecatrienoic acid (gamma-linolenic acid, C18:3), 6Z,9Z,12Z,15Z-Octadecatetrawnoic acid (Stearidonic acid, C18:4), 10Z,13Z-Nonadecadienoic acid (C19:2), 5Z,8Z,11Z-Icosatrienoic acid (Mead acid, C20:3), 8Z,11Z,14Z-Eicosatrienoic acid (Homogamma linolenic acid, C20:3), 11Z,14Z,17Z-Eicosatrienoic acid (C20:3), 5Z,8Z,11Z,14Z-Eicosatetraenoic acid (Arachidonic acid, C20:4), 5Z,8Z,11Z,14Z,17Z-Eicosapentaenoic acid (EPA, C20:5) and mixtures thereof.
[0106] In another embodiment, the present invention is directed to .sup.13C-labelled chlorinated paraffins having neither geminal nor terminal chlorine atoms in their structure, having [0107] at least two chlorine atoms in their main chain, and [0108] at least one, particularly from two to eight, carbon atoms of the main chain replaced by .sup.13C-atoms.
[0109] Preferably these .sup.13C-labelled chlorinated paraffins are represented by the general formula .sup.13C.sub.m-C.sub.pH.sub.2p+2xCl.sub.x, wherein the variables have the following meaning:
[0110] m is an integer of from 1 to p, particularly 2 to 8;
[0111] p is an integer of from 2 to 38, preferably from 8 to 38, particularly 8 to 30;
[0112] x is from 2 to p-2, preferably 4 to p-2, preferably, in the case of SCCP 4 to 6, particularly 4 or 6, in the case of MCCP 6 to 8, particularly 6 or 8, in the case of LCCP 8 to 10, particularly 8 or 10, one especially preferred embodiment is 4 or 6.
[0113] Optionally, and in some embodiments of the present invention preferably, these .sup.13C-labelled chlorinated paraffins are prepared according to a process according to the present invention as outlined above.
[0114] In yet another embodiment, the present invention is directed to .sup.13C-labelled chlorinated paraffins having neither geminal nor terminal chlorine atoms in their structure, optionally and in some embodiments preferred, as described above, which can be (are) represented by [0115] either general formula A
##STR00007## [0116] or general formula B
##STR00008## [0117] or general formula D
##STR00009## [0118] or general formula E
##STR00010## [0119] wherein the variables and residues have the meaning defined above.
[0120] In still another embodiment, the present invention is directed to .sup.13C-labelled chlorinated paraffins having neither geminal nor terminal chlorine atoms in their structure, optionally and in some embodiments preferred, as described above, which can be (are) represented by
##STR00011## [0121] , wherein *=.sup.13C and R* are as defined above, [0122] or are selected from the group consisting of [0123] i) 6,7,8-.sup.13C.sub.3-2,3,5,6-tetrachlorooctane or 2,3,5,6-tetrachlorooctane-6,7,8-.sup.13C.sub.3 of formula
##STR00012## [0124] ii) 1,2,9,10-.sup.13C.sub.4-2,3,8,9-tetrachlorodecane
##STR00013## [0125] iii) 9,10,11-.sup.13C.sub.3-2,3,5,6,8,9-hexachloroundecane or 2,3,5,6,8,9-hexachloroundecane-9,10,11-.sup.13C.sub.3 of formula
##STR00014## [0126] iv) 11,12,13-.sup.13C.sub.3-3,4,6,7,10,11-hexachlorotridecane or 3,4,6,7,10,11-hexachlorotridecane-11,12,13-.sup.13C.sub.3 of formula
##STR00015## [0127] v) 1,2,9,10-.sup.13C.sub.4-2,3,5,6,8,9-hexachlorodecane-1,2,9,10-.sup.13C.sub.4 or 2,3,5,6,8,9-hexachlorodecane-1,2,9,10-.sup.13C.sub.4 of formula
##STR00016## [0128] vi) 6,7,8-.sup.13C.sub.3-2,3,5,6,8,9,11,12-octachlorotridecane or 2,3,5,6,8,9,11,12-octachlorotridecane-6,7,8-.sup.13C.sub.3 of formula
##STR00017## [0129] vii) 10,11,12-.sup.13C.sub.3-2,3,5,6,9,10-hexachlorododecane
##STR00018##
or [0130] viii) 10,11,12-.sup.13C.sub.3-2,3,5,6,8,9-hexachlorododecane
##STR00019## [0131] ix) 1,2,3-.sup.13C.sub.3-3,4,7,8,11,12-hexachlorotetradecane
##STR00020## [0132] x) 13,14,15-.sup.13C.sub.3-3,4,7,8,12,13-hexachloropentadecane
##STR00021## [0133] xi) 1,2,3-.sup.13C.sub.3-3,4,8,9,13,14-hexachlorohexadecane
##STR00022## [0134] xii) 1,2,3-.sup.13C.sub.3-3,4,12,13,15,16,18,19-octachloro-n-heneicosane,
##STR00023## [0135] and mixtures thereof, [0136] wherein * is as defined above.
[0137] In one embodiment of the present invention are those of i), iii), iv) and v) preferred.
[0138] In still a further embodiment, the present invention is directed to mixtures of chlorinated paraffins comprising .sup.13C-labelled chlorinated paraffins having neither geminal nor terminal chlorine atoms in their structure according to the present invention and as described above or prepared according to the process of the present invention as described above.
[0139] In yet another further embodiment, the present invention is directed to the use of .sup.13C-labelled chlorinated paraffins having neither geminal nor terminal chlorine atoms in their structure according to the present invention and as described above or prepared according to the process of the present invention as described above as internal standards for analytical processes, in particular for the quantitative analysis of very short-chain chlorinated paraffins (vSCCPs, <C10), short-chain chlorinated paraffins (SCCPs, C10-C13); medium-chain chlorinated paraffins (MCCPs, C14-C17) and long-chain chlorinated paraffins (LCCPs, C18-C30).
[0140] Still another embodiment of the present invention is the use of .sup.13C-labelled chlorinated paraffins having neither geminal nor terminal chlorine atoms in their structure according to the present invention and as described above or prepared according to the process of the present invention as described above as reference materials for metabolism and toxicity analysis of chlorinated paraffins.
[0141] One further embodiment of the present invention is directed to chlorinated paraffins selected from the group consisting of 9,10,11-.sup.13C.sub.3-1,2,4,5,8,9-hexachloroundecane, 10,11,12-.sup.13C.sub.3-1,2,5,6,9,10-hexachlorododecane, 11,12,13-.sup.13C.sub.3-1,2,6,7,10,11-hexachlorotridecane, 12,13,14-.sup.13C.sub.3-1,2,7,8,11,12-hexachlorotetradecane, 13,14,15-.sup.13C.sub.3-1,2,7,8,12,13-hexachloropentadecane, 14,15,16-.sup.13C.sub.3-1,2,8,9,13,14-hexachlorohexadecane, 1,2,9,10-.sup.13C.sub.4-2,3,8,9-tetrachlorodecane, 8,9,10-.sup.13C.sub.3-1,2,4,5,7,8-hexachlorodecane, 1,2,3-.sup.13C.sub.3-3,4,12,13,15,16,18,19-octachloro-n-hencicosane and mixtures thereof, particularly 1,2,9,10-.sup.13C.sub.4-2,3,8,9-tetrachlorodecane or 8,9,10-.sup.13C.sub.3-1,2,4,5,7,8-hexachlorodecane.
[0142] Not the least, the present invention in other embodiments is directed to internal standards for analytical processes, in particular for the quantitative analysis of vSCCPs, SCCPs, MCCPs, LCCPs, comprising or consisting of [0143] one or more of the .sup.13C-labelled chlorinated paraffins having neither geminal nor terminal chlorine atoms in their structure according to the present invention and as described above or prepared according to the process of the present invention as described above, [0144] one or more of the chlorinated paraffins selected from the group consisting of 9,10,11-.sup.13C.sub.3-1,2,4,5,8,9-hexachloroundecane, 10,11,12-.sup.13C.sub.3-1,2,5,6,9,10-hexachlorododecane, 11,12,13-.sup.13C.sub.3-1,2,6,7,10,11-hexachlorotridecane, 12,13, 14-.sup.13C.sub.3-1,2,7,8,11,12-hexachlorotetradecane, 13,14,15-.sup.13C.sub.3-1,2,7,8,12,13-hexachloropentadecane, 14,15,16-.sup.13C.sub.3-1,2,8,9,13,14-hexachlorohexadecane, 1,2,9,10-.sup.13C.sub.4-2,3,8,9-tetrachlorodecane, 8,9,10-.sup.13C.sub.3-1,2,4,5,7,8-hexachlorodecane, 1,2,3-.sup.13C.sub.3-3,4,12,13,15,16,18,19-octachloro-n-heneicosane and mixtures thereof, particularly 1,2,9,10-.sup.13C.sub.4-2,3,8,9-tetrachlorodecane or 8,9,10-.sup.13C.sub.3-1,2,4,5,7,8-hexachlorodecane, [0145] or a mixture of one or more of the chlorinated paraffins selected from the group consisting of 9,10,11-.sup.13C.sub.3-1,2,4,5,8,9-hexachloroundecane, 10,11,12-.sup.13C.sub.3-1,2,5,6,9,10-hexachlorododecane, 11,12,13-.sup.13C.sub.3-1,2,6,7,10,11-hexachlorotridecane, 12,13,14-.sup.13C.sub.3-1,2,7,8,11,12-hexachlorotetradecane, 13,14,15-.sup.13C.sub.3-1,2,7,8,12,13-hexachloropentadecane, 14,15,16-.sup.13C.sub.3-1,2,8,9,13,14-hexachlorohexadecane, 1,2,9,10-.sup.13C.sub.4-2,3,8,9-tetrachlorodecane, .sup.13C.sub.3-1,2,4,5,7,8-hexachlorodecane, 1,2,3-.sup.13C.sub.3-3,4,12,13,15,16,18,19-octachloro-n-heneicosane and mixtures thereof, particularly 1,2,9,10-.sup.13C.sub.4-2,3,8,9-tetrachlorodecane or 8,9,10-.sup.13C.sub.3-1,2,4,5,7,8-hexachlorodecane, and [0146] one or more other of the .sup.13C-labelled chlorinated paraffins having neither geminal nor terminal chlorine atoms in their structure according to the present invention and as described above or prepared according to the process of the present invention as described above.
[0147] In preferred variations of this embodiment, these internal standards for analytical processes comprise or consist of single chain CP mixtures of .sup.13C.sub.m-C.sub.pH.sub.2p+2xCl.sub.x, with m being an integer of from 1 to p, particularly 2 to 8; p being an integer8, particularly 8 to 30; x=2 to p-1, preferably 2 to 10 or 2 to 7 if p=8, or x=2 to p-2, preferably 4 to p-2; and wherein the .sup.13C-labelled single-chain mixtures have chlorine contents of 45-75 weight %, calculated from the analysis on NMR and chlorine titration.
[0148] It is to be understood that deuterium atoms and .sup.13C atoms occur naturally. Accordingly, any reference to replacing (or the like formulations) in the context of the present invention when relating to the atoms of the glycerol moiety or the alkanol moiety are to be understood as intentional replacements and do not take into account possible naturally occurring deuterium or .sup.13C-atoms.
[0149] The present invention offers a number of advantages over the prior art, a few of which are: [0150] The process of the present invention for preparing .sup.13C labelled chlorinated paraffins, particularly ones that have neither geminal nor terminal chlorine atoms is able to provide these CP with high reliability, good yield and high purity. [0151] The novel .sup.13C labelled chlorinated paraffins, particularly ones that have neither geminal nor terminal chlorine atoms, are of high purity and have very well-defined chlorine content, which also makes quantification of CPs accurate, if they are used as standards, particularly internal standards. [0152] The novel .sup.13C labelled chlorinated paraffins, particularly ones that have neither geminal nor terminal chlorine atoms, are very well suitable as reference materials, because they have a chlorine pattern which is similar to the CP analytes found in the technical mixtures or in the environment. [0153] The reliable preparation of the novel .sup.13C labelled chlorinated paraffins, particularly ones that have neither geminal nor terminal chlorine atoms, ensures that they can be used as Certified Reference Materials (CRMS) for CPs analysis.
[0154] The invention is now described in more detail with reference to the following non-limiting examples. The following exemplary, non-limiting examples are provided to further describe the embodiments presented herein. Those having ordinary skill in the art will appreciate that variation of these examples are possible within the scope of the invention.
EXAMPLES
General Synthesis Procedures
Synthesis of .SUP.13.C-labelled 1-bromoalkane and 1-bromoalkene (2 and 16). General Procedure A
[0155] .sup.13C-labelled-n-alcohol (1 or 15) was converted to the bromides (2 or 16) by conventional methods, either by reaction with HBr-H.sub.2SO.sub.4 or with PBr.sub.3; or in some cases the alcohol was transferred to tosylate first which was then reacted with LiBr to form the bromides.
[0156] A typical procedure of the reaction with PBr3 which was followed is follows: [0157] .sup.13C-labelled-n-alcohol (1) (3 mmol) and pyridine (75 mg) were mixed in pentane (5 ml) and cooled to 40 C. A solution of phosphorus tribromide (32 mg, 1.2 mmol) in pentane (2 ml) was added dropwise to the stirred solution. The mixture was stirred at the cooled temperature for 1 h, and the products were distilled off. The obtained solution of the product was diluted with pentane (10 ml), washed with 5% HCl, 10% HNO.sub.3, water, 5% KHCO.sub.3. The organic phase was dried over MgSO.sub.4, filtered, concentrated. The residue was distilled to give the pure bromides (2), yield 75-80%.
Synthesis of the Wittig Salt (3). General Procedure B
[0158] The bromide (2) (10.0 mmol) and PPh.sub.3 (10.0 mmol) were mixed in dry acetonitrile (25 ml), the mixture was heated to reflux for 72 to 48 hours. The solvent was evaporated and the crude product was purified by column chromatography (silica; eluent EtOAc:MeOH from 90:10, 80:20 to 75:25). Obtained product was dried in vacuo, yield 84%, of white solid 3.
Synthesis of .SUP.13.C-labelled Alkenes (5 and 7). General Procedure C
[0159] Wittig salt (3) (15.6 mmol) wax mixed in dry THF (50 ml) under argon and cooled to 78 C., n-butyllithium (2.5 M, 6.85 ml) was added dropwise. The reaction mixture was then warmed to 40 C. to 10 C. and kept at this temperature for 1.5 hours, before it was cooled to 78 C. again and the aldehyde (4) (15.9 mmol) was added slowly. The reaction mixture was warmed to room temperature and stirred for 16 hours, saturated NH.sub.4Cl solution (50 ml) was added to quench the reaction. The two phases were separated, water phase was extracted with diethyl ether and the combined organic phases were dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica; eluent petroleum ether) and afforded the .sup.13C-labelled alkene (5), yield 85-90%.
[0160] The .sup.13C-labelled alkenes (7) were synthesized in the same way by using 2 equivalents of the Wittig salt (3) and 1 equivalent of the dialdehydes (6).
Synthesis of .SUP.13.C-labelled Alkenes (11 and 14). General Procedure D
a) The Grignard Reagent 8
[0161] Magnesium (1.75 g, 72.0 mmol), dry diethyl ether (6 ml) and a crystal of iodide was added a few drops of the bromide (2) in dry diethyl ether until the reaction started (under argon). The solution of the bromide (2) (total 53.41 mmol) in diethyl ether (18 ml) was added dropwise at such rate as to maintain gentle reflux. After the addition was complete, the mixture was refluxed for 1 hour. The mixture was cooled and more diethyl ether (2.5 ml) added. The mixture (about 2 M) was used directly in the synthesis of 11 or 14.
b) The Tosylates 10 and 13
[0162] p-toluenesulfonyl chloride (7.72 g; 40.5 mmol) in dry DCM (50 ml) was added via dropping funnel to a solution of the alcohol (9; 36.8 mmol) and triethylamine (11.3 ml; 80.9 mmol) in dry dichloromethane (200 ml) at 0 C. in argon atmosphere. The reaction mixture was stirred at 0 C. for 15 minutes, then at room temperature overnight (18 hours). The reaction was quenched with water (250 ml). Two phases were separated and the water phase was extracted with DCM (3100 ml). The combined organic phases were washed with water, 10% NaHCO.sub.3 and water (all 200 ml) and dried over MgSO.sub.4. Crude product was purified by column chromatography (silica; eluent petroleum ether: DCM from 60:40, 50:50 to 25:75) to give the tosylate 10, yield 80-85%
[0163] The ditosylate 13 was made in the same manner from the diol compound 12 (1 equivalent), triethylamine (8 equivalents) and p-toluenesulfonyl chloride (2,2 equivalents) in DCM. The crude product was purified by column chromatography (silica; eluent petroleum ether: DCM from 60:40, 50:50 to 25:75) to give the tosylate 13 as white solid. Recrystallisation in methanol or dichloromethane was also used, this gave a white crystalline product with yields from 34-55%.
c) Cross coupling reaction, the alkenes 11 and 14
[0164] The solution of 8 in diethyl ether (about 2 M) under argon was cooled to 75 C. and a solution of 10 (50 mmol) in THF (50 ml) and dilithium tetrachlorocuprate (10 mmol) (0.1M solution in THF, 100 ml) was added. The temperature increased slowly to around about 30 C. and was kept for 15 minutes. The mixture was cooled one more time to 70 C. and more of the dilithium tetrachlorocuprate solution was added (0.2 ml, 0.02 mmol), the temperature was then increased slowly and the mixture was stirred at room temperature overnight. Silica (50 g) was added to the mixture and the solvents were evaporated. The dry residue was poured on top on a column filled with silica and eluated with heptane. This gave the pure alkene 11, yield 50-60%.
[0165] The .sup.13C-labelled alkene (14) was synthesized in the same way by using 2 equivalents of the Grignard reagent (8) and 1 equivalent of the di-tosylate (13).
Synthesis of Tetraethylammonium Trichloride Et.SUB.4.N(Cl).SUB.3
[0166] A solution of tetraethylammonium chloride (Et.sub.4NCl) in DCM was saturated with Cl.sub.2, the solvent was then removed in vacuo to afford a yellow solid which was stored under argon for later use in the chlorination reaction.
Chlorination and Synthesis of .SUP.13.C-labelled CP (A, B, D and E). General Procedure X
[0167] A solution of Et.sub.4NCl.sub.3 (1.5-2.0 equivalents for each CC bond) in DCM was slowly added via syringe into the solution of the substrate in DCM (5, 0.3 M) at 78 C. in argon atmosphere until the reaction mixture turned yellow. The mixture was stirred for 20 minutes at 78 C., more trichloride solution was added if the yellow colour disappeared.
[0168] After the reaction was quenched with pent-1-ene, the mixture was allowed to warm to room temperature and the Et.sub.4NCl solid formed in the reaction dissolved. The solvent is removed in vacuo and the residue was treated with diethyl ether, which results in the precipitation of EtaNCI again, the solid was filtered off, washed with Et.sub.2O and filtrate evaporated to dryness. The crude product was further purified by column chromatography. All .sup.13C-labelled products were characterized by NMR and GC-MS.
SYNTHESIS EXAMPLES
[0169] The following .sup.13C-labelled CP are listed as examples for further understanding of the present invention, but the content of this invention is not limited to these.
[0170] .sup.13C.sub.3-labelled CP synthesized from .sup.13C.sub.3-1-propanol and straight-chain unsaturated aldehydes (minimum one double bond in the carbon chain) (Scheme 1) was taken as examples. The synthesis of 9,10,11-.sup.13C.sub.3-2,3,5,6,8,9-Hexachlorododecane is described in detail as below:
Example: Synthesis of 9,10,11-.SUP.13.C.SUB.3.-2,3,5,6,8,9-Hexachlorododecane
##STR00024##
.SUP.13.C.SUB.3.-1-bromopropane
[0171] .sup.13C.sub.3-1-propanol (0.97 g, 15.4 mmol) and pyridine (375 mg, 4.75 mmol) were mixed in pentane (25 ml) and cooled to 40 C. A solution of phosphorus tribromide (1.68 g, 6.2 mmol) in pentane (10 ml) was added dropwise to the stirred solution. The mixture was stirred at the cooled temperature for 1 hour, and the products were distilled off. The obtained solution of the product was diluted with pentane (50 ml), washed with 5% HCl, 10% HNO.sub.3, water, 5% KHCO.sub.3. The organic phase was dried over MgSO.sub.4, filtered, concentrated. The residue was distilled to give 1.52 g (12.1 mmol) .sup.13C.sub.3-1-bromopropane, light yellow oil, yield 78.6%.
Triphenyl-.SUP.13.C.SUB.3.-propyl Phosphonium Bromide, the Wittig Salt
[0172] .sup.13C.sub.3-1-bromopropane (1.26 g, 10.0 mmol) and PPh.sub.3 (2.63 g, 10.0 mmol) were mixed in dry acetonitrile (25 ml), the mixture was heated to reflux for 72 hours. The solvent was evaporated and the crude product was purified by column chromatography (silica; eluent EtOAc:MeOH from 90:10, 80:20 to 75:25). Obtained product was dried in vacuo, yield 84%, 3.26 g (8.4 mmol) white solid powder.
Synthesis of 9,10,11-.SUP.13.C.SUB.3.-undeca-2,5,8-triene
[0173] The Wittig salt (3.0 g, 7.8 mmol) wax mixed in dry THF (25 ml) under argon and cooled to 78 C., n-butyllithium (2.5 M, 3.4 ml) was added dropwise. The reaction mixture was then warmed to 40 C. to 10 C. and kept at this temperature for 1.5 hours, before it was cooled to 78 C. again and the aldehyde octa-3,6-dienal (1.0 g, 8.0 mmol) was added slowly. The reaction mixture was warmed to room temperature and stirred for 16 hours, saturated NH.sub.4Cl solution (25 ml) was added to quench the reaction. The two phases were separated, water phase was extracted with diethyl ether and the combined organic phases were dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica; eluent petroleum ether) and afforded the .sup.13C-labelled alkene 9,10,11-.sup.13C.sub.3-undeca,2,5,8-triene, 1.02g (6.7 mmol), yield 86%.
Synthesis of Tetraethylammonium Trichloride Et.SUB.4.N(Cl).SUB.3
[0174] A solution of tetraethylammonium chloride (Et.sub.4NCl) in DCM was saturated with Cl.sub.2, the solvent was then removed in vacuo to afford a yellow solid which was stored under argon for later use in the chlorination reaction.
9,10,11-.SUP.13.C.SUB.3.-2,3,5,6,8,9-Hexachlorododecane
[0175] A solution of Et.sub.4NCl (9.26 g, 39.1 mmol, 6.0 equivalents) in DCM (50 ml) is slowly added via syringe into the solution of 9,10,11-.sup.13C.sub.3-undeca,2,5,8-triene 1.0 g, 6.5 mmol in DCM (130 ml) at 78 C. in argon atmosphere until the reaction mixture turned yellow. The mixture was stirred for 25 minutes at 78 C., then quenched with excess of pent-1-ene. Solvent was evaporated and the crude product purified by column chromatography (eluent petroleum ether: diethyl ether=90:10) and by recrystallization from n-hexane to give 1.23 g (3.25 mmol) of the target compound 9,10,11-.sup.13C.sub.3-2,3,5,6,8,9-Hexachlorododecane, yield 50.0%, purity >99.0% analysed by GC and NMR.
Other Examples of .SUP.13.C.SUB.3.-labelled CP
[0176] Starting from .sup.13C.sub.3-propanol and an unsaturated aldehyde having 1-2 double bonds, .sup.13C.sub.3-CP having 4 or 6 chlorines (Cl.sub.4 or Cl.sub.6) can be synthesized in the same way as 9,10,11-.sup.13C.sub.3-2,3,5,6,9,10-hexachlorododecane; The general structure of .sup.13C.sub.3-Cl.sub.6-CP is as shown in the following formula.
##STR00025##
[0177] with m1, n0, R=n-alkyl, R can also be proton (H).
[0178] The following table 1 shows .sup.13C.sub.3-CP and .sup.13C.sub.4-CP without terminal and geminal chlorines, table 2 shows .sup.13C.sub.3-CP with one terminal chlorine that were all prepared with the process according to the present invention.
TABLE-US-00001 TABLE 1 Examples of .sup.13C.sub.3 and .sup.13C.sub.4Cl.sub.4 or Cl.sub.6-CP according to and prepared with the process according to the present invention Structure Name
TABLE-US-00002 TABLE 2 .sup.13C.sub.3-CPs with terminal chlorine prepared with the process according to the present invention Structure Name