CHEMICAL PROCESS

Abstract

The present invention provides, inter alia, a process for preparing a compound of formula (I) wherein the substituents are as defined in claim 1.

Claims

1. A process for the preparation of a compound of formula (I), ##STR00039## wherein X is halogen; said process comprising: reacting a compound of formula (II), ##STR00040## with a halogenating reagent in a suitable reaction medium comprising an organic carbonate, to give a compound of formula (I).

2. A process according to claim 1, wherein X is chlorine or bromine.

3. A process according to claim 1, wherein X is bromine.

4. A process according to claim 1, wherein the halogenating reagent is selected from the group consisting of bromine, chlorine, iodine, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, pyridinium bromide tribromide, copper(II) bromide, sulfuryl chloride and trichloroisocyanuric acid.

5. A process according to claim 3, wherein the halogenating reagent is selected from the group consisting of bromine, N-bromosuccinimide, pyridinium bromide tribromide and copper(II) bromide.

6. A process according to claim 3, wherein the halogenating reagent is bromine.

7. A process according to claim 1, wherein the compound of formula (II) is prepared by reaction of a compound of formula (III), ##STR00041## with an oxidising reagent in a suitable reaction medium comprising an organic carbonate.

8. A process according to claim 7 wherein the oxidising reagent is sodium hypochlorite.

9. A process according to claim 8, wherein the reaction medium further comprises sulfuric acid.

10. A process according to claim 1, wherein the organic carbonate is selected from the group consisting of dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, butylene carbonate and glycerol carbonate.

11. A process according to claim 1, wherein the organic carbonate is selected from the group consisting of dimethyl carbonate and diethyl carbonate.

12. A process according to claim 1, wherein the intermediate compounds of formula (II) and/or (III) are not isolated.

13. A process according to claim 7, wherein the compound of formula (III) is prepared by: (i) reacting a compound of formula (IV), ##STR00042## with formic acid to give a compound of formula (V), ##STR00043## and (ii) hydrolysing the compound of formula (V) to a compound of formula (III).

14. A process according to claim 13, wherein the hydrolysis step is performed with sodium hydroxide.

15. A process according to claim 1, wherein the process further comprises converting a compound of formula (I) to a compound of formula (VI), ##STR00044## wherein G is selected from the group consisting of hydrogen, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.3alkoxyC.sub.1-C.sub.3alkyl-, C(O)Rr, C(O)X.sup.aR.sup.1 and S(O).sub.2R.sup.1; X.sup.a is oxygen or sulfur; and R.sup.1 is selected from the group consisting of C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, phenyl and 4-fluorophenyl.

Description

EXAMPLES

[0105] The following examples further illustrate, but do not limit the invention. Those skilled in the art will promptly recognise appropriate variations from the procedures both as to the reactants and as to the reaction conditions and techniques.

[0106] The following abbreviations are used: s=singlet; br s=broad singlet; d=doublet; dd=double doublet; dt=double triplet; t=triplet, tt=triple triplet, q=quartet, quin=quintuplet, sept=septet; m=multiplet; GC=gas chromatography, RT=retention time, T.sub.i=internal temperature, MH.sup.+=molecular mass of the molecular cation, M=molar, Q.sup.1HNMR=quantitative .sup.1H Nuclear Magnetic Resonance, RT=room temperature, UFLC=Ultra-fast liquid chromatography.

[0107] .sup.1H NMR spectra are recorded at 400 MHz unless indicated otherwise and chemical shifts are recorded in ppm.

[0108] Some chemical yields have been calculated precisely using quantitative 1H NMR and 1,3,5-trimethoxybenzene or caffeine as an internal standard.

[0109] Conversion was followed by gas chromatography with analysis being conducted on Agilent GC Model 6850 using Agilent 19091U-211 type column with DB-1701 description. Equipment detector FID operated with hydrogen at 300 C. Method hold 2 min at 40 C., 20 C./min until 300 C., hold 2 min at 300 C., total time 19 min.

Example 1Preparation of norbornan-2-yl Formate from Norbornene

##STR00033##

[0110] To a 1.5 L double mantled reactor equipped with an overhead stirrer, reflux condenser and heated addition funnel, was added technical formic acid (88 wt %) (577 g, 11.0 mol, 3.5 equiv) and T.sub.int was set to 90 C. Once the temperature has been reached, molten norbornene (300 g, 3.1 mol, 1.0 equiv) was added dropwise over the course of 2 h. Upon addition the reaction was allowed to stir at this temperature for additional 2 h and the excess formic acid was distilled off under reduced pressure, to yield (386 g, 95% purity) product as a colorless-pale yellow oil, accounting for 83% isolated yield. Product contained 3% of norbornan-2-ol that is target product in subsequent step.

[0111] Distillate contained 10 wt % of product that together with the recovered formic acid can be reused in a subsequent batch. Furthermore, the use of distillation column can diminish the amount of product in the distillate.

[0112] Product purity was determined using quantitative .sup.1H NMR using 1,3,5-trimethoxybenzene as an internal standard.

[0113] .sup.1H, NMR (400 MHz, CDCl.sub.3) ppm: 7.98 (s, 1H), 4.71 (m, 1H), 2.33 (m, 2H), 1.80-1.70 (m, 1H), 1.60-1.40 (m, 4H), 1.20-0.95 (m, 3H).

Example 2Preparation of norbornan-2-ol from norbornan-2-yl formate

##STR00034##

[0114] To a 1 L double mantled reactor equipped with an overhead stirrer, reflux condenser, internal pH probe and addition funnel was added crude norbornan-2-yl formate (110 g, 0.8 mol, 1.0 equiv). To this mixture was added 10% aq NaOH (324 g, 0.88 mol, 1.1 equiv) at T.sub.int=25 C. over the course of 2 h. Cooling is required to maintain this temperature however can be omitted as reaction proceeds at higher temperature equally well. More water can be added if reaction mass becomes difficult to stir. After full addition the reaction mixture is additionally stirred at 25 C. for 1 h. Then 10% aq HCl (15.0 g, 0.04 mol, 0.05 equiv) is added dropwise to set the pH=8. Once pH is reached, dimethylcarbonate 264 g is added in 1 portion. Phases are separated and organic layer is washed with 150 g water.

[0115] Product is obtained as a 20 wt % solution in DMC (359 g, 86% isolated yield).

[0116] Small sample is concentrated under reduced pressure for analytical purposesProduct purity was determined to be 92% using quantitative .sup.1H NMR with 1,3,5-trimethoxybenzene as an internal standard. .sup.1H, NMR (400 MHz, CDCl.sub.3) ppm: 3.75 (m, 1H), 2.25 (m, 1H), 2.12 (m, 1H), 1.66 (m, 2H), 1.56 (m, 1H), 1.50-1.35 (m, 2H), 1.29 (m, 1H), 1.12 (m, 1H), 1.95-0.95 (m, 2H).

[0117] Note: reaction can be carried out by dosing norbornan-2-yl formate to 10% aq NaOH.

Example 3Preparation of norbornan-2-one from norbornan-2-ol

##STR00035##

[0118] To a 1.5 L double mantled reactor equipped with an overhead stirrer, reflux condenser and addition funnel was added 23 wt % (in DMC) solution of norbornol (350 g, 0.73 mol, 1.0 equiv) followed by 10% aq sulfuric acid (139 g, 0.14 mol, 0.2 equiv). To this mixture is added 10 wt % aq NaOCl (553 g, 0.77 mol, 1.05 equiv) at T.sub.int=25 C. over the course of 2 h. Cooling is required to maintain the reaction temperature. Upon completion reaction is additionally stirred at 25 C. for 1 h. Then phases are separated and organic layer is directly used in the following step.

[0119] Product content was determined to be 26 wt % (solution in DMC) using quantitative .sup.1H NMR with 1,3,5-trimethoxybenzene as an internal standard. This product was directly subjected to the following bromination.

[0120] Typical product purity for the product of this procedure was determined to be in the range of from 90% to 95% using quantitative .sup.1H NMR with 1,3,5-trimethoxybenzene as an internal standard.

[0121] .sup.1H, NMR (400 MHz, CDCl.sub.3) ppm: 2.65 (m, 1H), 2.59 (m, 1H), 2.05 (m, 1H), 1.85-1.70 (m, 4H), 1.58-1.38 (m, 3H).

[0122] If required a higher concentration aq NaOCl solution can be used to improve the process volume yield.

Example 4Preparation of 3-bromonorbornan-2-one from norbornan-2-one

##STR00036##

[0123] To a 0.5 L double mantled reactor equipped with an overhead stirrer, reflux condenser, off-gas scrubber and addition funnel was added 26 wt % (in DMC) solution of norbornan-2-one (150 g, 0.35 mol, 1.00 equiv) and T.sub.int is set to 75 C. Then neat bromine (57 g, 0.35 mol, 1.00 equiv) is added dropwise over the course of 2 h. Gas evolution is observable with every drop of bromine added. Conversion is measured by GC. To assure full conversion of the unreacted starting material additional bromine (1.6 g, 0.01 mol, 0.03 equiv) was added. Upon complete addition of bromine the reaction is additionally stirred for 1 h at 75 C. before it is cooled to 25 C. and argon is bubbled through to eliminate residual HBr. Solution is washed 120 g 10% aq NaHSO.sub.3, phases are separated and organic solvent is removed under reduced pressure to afford product as a brown liquid (68 g, 89% isolated yield). Product purity was determined to be 88% using quantitative .sup.1H NMR with 1,3,5-trimethoxybenzene as an internal standard.

[0124] The crude product is then additionally purified by overhead distillation at T.sub.int=80 C. and 2mbar pressure to afford target material as a colourless oil.

[0125] .sup.1H, NMR (400 MHz, CDCl.sub.3) ppm: 3.83 (d, J=3.2 Hz, 1H), 2.79 (m, 1H), 2.72 (m, 1H), 2.29 (m, 1H), 1.98 (m, 1H), 1.80 (m, 1H), 1.65-1.40 (m, 3H).

[0126] .sup.1H NMR coupling constant analysis and estimations of dihedral angles indicates that product is obtained as predominantly exo-isomer (compared to the endo-isomer, a compound of formula (Ib-1)) with bromine atom adapting equatorial position, a compound of formula (Ia-1) below,

##STR00037##

[0127] General reaction conditions for the solvent comparison described in Table 1 below are based on the process described in Example 4.

[0128] All experiments were carried out on a scale of from 2.5 to 10.0 g of norbornane-2-one.

[0129] A solution of norbornan-2-one (1.00 equiv) in solvent (as listed in table below) is heated to Ti=75-80 C. at which point bromine (1.05-1.10 equiv) is added over a course of 1-2 h. The reaction is allowed to stir for an additional hour and then is sampled for GC analysis.

TABLE-US-00001 TABLE 1 Solvent effect on selectivity of bromination Side SM Prod Prod Selectivity Reactivity S/R Solvent (%) (%) (%) (%) (%) factor Acetic Acid 0 78.4 21.6 78 100 3.6 Methylcyclohexane 14.6 79.4 6.0 93 84 3.9 Heptane* 88 12 Cyclohexane 11.3 81.7 7.0 92 88 4.5 Dimethylcarbonate 0.2 93.8 5.9 94 100 15.2 Diethylcarbonate 1.8 93.2 5.0 95 98 13.8 *Bromine consumed by the reaction solvent.

[0130] Analysis was done by Gas Chromatography and in all cases only 3 signals analyzedstarting material, norbornan-2-one (SM), 3-bromonorbornan-2-one (Prod) and over brominated side product, 3,3-dibromonorbornan-2-one, a compound of formula (VII) (side prod).

##STR00038##

[0131] While not included in Table 1, the reactions in alkane solvents (methycyclohexane, heptane and cyclohexane) exhibit more impurities including bromination of the reaction solvent.

[0132] In Table 1 Reactivity is expressed as % Prod/(% Prod+% Starting material)*100

[0133] In Table 1 Selectivity is expressed as % Prod/(% Prod+% Side products)*100

[0134] In Table 1 Selectivity is linked with Reactivity in a comparative S/R (Selectivity/Reactivity) parameter that is expressed as % Prod/(% Starting material+% Side product)

[0135] The above results demonstrate that the organic carbonate solvents used in the process of the invention achieve high selectivity (reduced side products) and conversion to the desired product.