PREPARATION AND PURIFICATION OF CIS-2-ALKENOIC ACIDS
20250346551 ยท 2025-11-13
Assignee
Inventors
- Jakob Oren (Nesher, IL)
- Nasif YASSIN (Tamra, IL)
- Nicka CHINKOV (Kibbutz Mishmar Haemek, IL)
- Ronit YAHALOMI SEGUI (Kiryat Bialik, IL)
- Ari AYALON (Haifa, IL)
Cpc classification
C07C51/00
CHEMISTRY; METALLURGY
C07C51/00
CHEMISTRY; METALLURGY
C07C51/64
CHEMISTRY; METALLURGY
C07C51/43
CHEMISTRY; METALLURGY
C07C57/02
CHEMISTRY; METALLURGY
C07C51/347
CHEMISTRY; METALLURGY
C07C57/02
CHEMISTRY; METALLURGY
C07C51/43
CHEMISTRY; METALLURGY
C07C45/63
CHEMISTRY; METALLURGY
International classification
C07C51/347
CHEMISTRY; METALLURGY
C07C51/64
CHEMISTRY; METALLURGY
C07C45/63
CHEMISTRY; METALLURGY
Abstract
A method of purification of crude cis-2-alkenoic acid by thermal separation, comprising wiped-film evaporation or vacuum distillation of the crude cis-2-alkenoic acid, under a temperature-reduced pressure profile whereby isomerization of cis-2-alkenoic acid into trans-2-alkenoic acid is minimized.
Claims
1. A method of purification of crude cis-2-alkenoic acid by thermal separation, comprising wiped-film evaporation or vacuum distillation of the crude cis-2-alkenoic acid, under a temperature-reduced pressure profile whereby isomerization of cis-2-alkenoic acid into trans-2-alkenoic acid is minimized.
2. The method according to claim 1, comprising wiped-film evaporation of crude cis-2-alkenoic acid of the formula RCHCHCOOH wherein R is a straight alkyl chain CH.sub.3(CH.sub.2).sub.n, with 3n10.
3. The method according to claim 2, wherein the cis-2-alkenoic acid is cis-2-decenoic acid and wherein the wiped-film evaporation is carried out at a temperature of not less than 150 C. and reduced pressure of <5 mbar.
4. The method according to claim 3, wherein the temperature is in the range from 150 to 180 C. and the reduced pressure is 1-5 mbar, whereby isomerization of the cis isomer to the trans isomer is suppressed such that the level of the trans isomer is less than 1.0% by HPLC area.
5. The method according to claim 1, wherein the wiped-film evaporation comprises a step of collecting a condensate and returning it to the feed stream of the wiped-film evaporator.
6. The method according to claim 1, wherein the crude cis-2-alkenoic acid is prepared by a process comprising the steps of: brominating 2-alkanone to give 1,3-dibromo-2-alkanone; and rearranging the 1,3-dibromo-2-alkanone to the cis-2-alkenoic acid.
7. The method according to claim 1, wherein the crude cis-2-alkenoic acid is prepared by a process comprising the steps of: rearranging 1,3-dibromo-2-alkanone in an alkaline environment in the presence of a catalytically effective amount of an alkali metal salt of cis-2-alkenoic acid and isolating from the reaction mixture cis-2-alkenoic acid, either in the form of the free acid or in the form of the alkali metal salt.
8. The method according to claim 7, wherein the crude cis-2-alkenoic acid is prepared by a process comprising the steps of: gradually adding the 1,3-dibromo-2-alkanone to a reaction vessel which was previously charged with an alkaline aqueous solution of Na.sub.2CO.sub.3, K.sub.2CO.sub.3, or a mixture thereof and a catalytically effective amount of an alkali metal salt of cis-2-alkenoic acid, at elevated temperature.
9. The method according to claim 7, wherein the process of preparing the crude cis-2-alkenoic acid comprises separating the reaction mixture into aqueous and organic phases, and working-up the aqueous phase, to recover therefrom cis-2-alkenoic acid, either in the form of the free acid or in the form of the alkali metal salt.
10. The method according to claim 9, wherein the process of preparing the crude cis-2-alkenoic acid comprises working-up the aqueous phase by washing with an organic solvent, followed by phase separation, to obtain a purified aqueous phase.
11. The method according to claim 7, wherein the process of preparing the crude cis-2-alkenoic acid comprises optional dilution of the reaction mixture with water and washing with an organic solvent, followed by phase separation, to obtain a purified aqueous phase.
12. The method according to claim 10, wherein the process of preparing the crude cis-2-alkenoic acid further comprises acidifying the purified aqueous phase to obtain a biphasic medium, comprised of a heavy, salt-containing aqueous phase, and a light organic phase consisting essentially of the cis-2-alkenoic acid in the form of the free acid.
13. The method according to claim 6, wherein the process of preparing the crude cis-2-alkenoic acid comprises rearranging 1,3-dibromo-2-alkanone selected from the group consisting of: ##STR00010##
14. The method according to claim 13, wherein the 1,3-dibromo-2-alkanone, used in the rearrangement reaction, is a crude 1,3-dibromo-2-alkanone obtained by the steps of: brominating the corresponding 2-alkanone selected from the group consisting of 2-heptanone, 2-octanone, 2-nonanone, 2-decanone and 2-undecanone in concentrated hydrobromic acid by the addition of elemental bromine, whereby 1,3-dibromo-2-alkanone is formed in the reaction mixture alongside 3,3-dibromo-2-alkanone; maintaining the reaction mixture over a hold time adjusted to maximize the interconversion of 3,3-dibromo-2-alkanone to 1,3-dibromo-2-alkanone; and collecting the crude 1,3-dibromo-2-alkanone by phase separation.
15. The method according to claim 6, wherein the process of preparing the crude cis-2-alkenoic acid comprises rearranging 1,3-dibromo-2-alkanone in the presence of catalytically effective amount of the alkali metal salt of cis-2-alkenoic acid of up to 10 mol % based on 1,3-dibromo-2-alkanone.
16. The method according to claim 8, wherein the process of preparing the crude cis-2-alkenoic acid comprises removing a minor portion of the aqueous phase before or after the aqueous phase is worked-up, and using said portion of the aqueous phase to supply the catalytically effective amount of alkali metal salt of cis-2-alkenoic acid in a rearrangement reaction of the corresponding 1,3-dibromo-2-alkanone.
17. The method according to claim 7, wherein the process of preparing the crude cis-2-alkenoic acid comprises supplying the catalytically effective amount of the alkali metal salt of cis-2-alkenoic acid to the rearrangement reaction in the form of aqueous solution recovered from an earlier rearrangement reaction.
18. The method according to claim 1, wherein the cis-2-alkenoic acid is cis-2-decenoic acid.
Description
IN THE DRAWINGS
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EXAMPLES
Methods
GC: Gas-Chromatograph HP 7890A
[0065] Method (CDA): Initial temp. 50 C., held 2 min, then raised to 280 C. at 10 C./min and held for 5 min, then raised to 300 C. at 10 C./min and held for 2 min. [0066] Injector: 250 C. [0067] Detector: 300 C. [0068] Split ratio: 1:40 [0069] Concentration of the product sample: 20 mg/ml DCM [0070] Injection amounts: 1 l sample [0071] Column: Agilent J&W Columns, HP-5, 30 m0.32 mm0.25 [0072] Part no. 19091J-413, Ser. No. USF302346H
.SUP.1.H-NMR Spectroscopy
[0073] Spectra were taken on an Avance III, 500 MHz instrument.
HPLC: Agilent 1220 LC System
[0074] Chromatographic conditions for CDA: [0075] Wavelength: =214 nm [0076] Column: Akzo Nobel, Kromasil, 250 mm*4.6 mm ID*5 m+Pre-Column C18 [0077] Mobile phase: [A]H.sub.2O+0.1% H.sub.3PO.sub.4 (conc. 85%): [0078] [B] Acetonitrile (AcN) [0079] Gradient profile:
TABLE-US-00003 Time (min) H2O (%) AcN (%) 0 42 58 28 42 58 30 5 95 45 5 95 46 42 58 [0080] Post time: 9 min [0081] Flow: 1.0 ml/min [0082] Injection volume: 5.0 l [0083] Column temperature: 25 C. [0084] Sample temperature: 20 C. [0085] Retention time of CDA: 14.6 min
Example 1
Preparation of Cis-2-Decenoic Acid
Step 1:
[0086] Into a mixture of 2-decanone (200 g, 1.28 mol) and aq. 48% HBr (300 g), stirred and cooled to 10 C., was added bromine (410 g, 2.56 mol), dropwise over 2 h. The reaction started immediately with the start of the addition of the bromine and no accumulation of bromine was observed.
[0087] The reaction was exothermic and accompanied by the emission of HBr gas, just before the end of the addition of the bromine, which was absorbed in a scrubber.
[0088] Most of the reaction took place during the addition of the bromine and cooking at room temperature (20 C.) for 6 hours. After standing overnight (15 h) at room temperature, without stirring, the composition of the reaction mixture stabilized. Partial conversion of the 3,3-dibromo-2-decanone (3,3-DBD) to the desired product, 1,3-dibromo-2-decanone (1,3-DBD), took place. To the reaction mixture was added water (160 g) at RT, with stirring for 30 min, and the phases were separated.
[0089] An aqueous phase (627 g) was obtained containing 50% HBr (d=1.51 g/ml) and crude DBD (404 g, d=1.43 g/ml). The concentration of 1,3-DBD in the crude product was 69.6% (GC, area %).
Step 2:
[0090] An aqueous solution of K.sub.2CO.sub.3, in a concentration of 25% w/w, was prepared in a 1 L stirred reactor by the batchwise addition of K.sub.2CO.sub.3 (200 g) to water (600 g). The reaction was exothermic. To this solution was added a part of the aqueous phase (which contained CDA-K) of the reaction mixture (50 g) remaining from a previous run (named AP-RM; see comparative Example 3). The clear solution obtained was heated to 40 C. and crude DBD of step 1 (200 g) was added to it dropwise over 60 min. The progress of the reaction was monitored by GC and by the change in the pH. The reaction was completed by cooking at 50 C. for 3.0 h, with mechanical stirring.
[0091] It should be pointed out that without the addition of AP-RM, the reaction only starts spontaneously two hours after the addition of the crude DBD.
[0092] The end of the reaction was determined by the pH (drop in the pH from 13.3 to 9.3) and by GC analysis of the reaction mixture (disappearance of 1,3-DBD to <1%, area %). After completion of the reaction, cooling to RT and stopping the stirring, an organic phase appeared above the aqueous phase which contained unreacted 3-bromo-2-decanone (3-BD) and 3,3-DBD, and by-products formed by a condensation reaction of crude DBD. The phases were separated. The organic phase (39 g) was organic waste. 50 g of the aq. phase was taken for use in the next run.
[0093] In order to reduce the amount of impurities to a minimum, the remainder of the aqueous phase (950 g) was washed three times with dichloromethane (DCM, 3250 g).
[0094] After the washing stage, an aqueous phase was obtained containing cis-2-decenoic acid potassium salt (CDA-K), organic by-products, KBr and KHCO.sub.3. In order to obtain the crude cis-2-decenoic acid (CDA), the aqueous phase was acidified by the dropwise addition of aq. 32% HCl (193 g) over 1 h. During the acidification (final pH=1.1), CO.sub.2 (calculated at 63 g) was emitted.
[0095] After stopping the stirring, an aqueous phase (955 g) was obtained containing salts: KCl and KBr (heavy phase, d=1.19 g/ml) and wet crude CDA (light phase, 71 g, d=1.07 g/ml).
[0096] Evaporation of the DCM and lights from the wet CDA under vacuum (at T.sub.B=50 C.) gave crude CDA (50.5 g), which was analysed by GC and .sup.1H-NMR (see
[0097] The purity of the crude CDA obtained was 88.2% (by GC area %). The main impurity in the crude product was 2-bromomethylidene nonanoic acid (BMNA): 8.8% (by GC, area %).
Example 2
Preparation of Cis-2-Decenoic Acid
Step 1:
[0098] Into a mixture of 2-decanone (400 g, 2.564 mol) and aq. 48% HBr (600 g), stirred and cooled to 10 C., was added bromine (800 g, 5 mol), dropwise over 5 h. The reaction started immediately with the start of the addition of the bromine and no accumulation of bromine was observed. The reaction was exothermic and accompanied by the emission of HBr gas, just before the end of the addition of the bromine, which was absorbed in a scrubber.
[0099] Most of the reaction took place during the addition of the bromine, and after standing overnight at room temperature, without stirring, the composition of the reaction mixture stabilized. Partial conversion of the 3,3-dibromo-2-decanone (3,3-DBD) to the desired product, 1,3-dibromo-2-decanone (1,3-DBD), took place. To the reaction mixture was added water (300 g) at RT, with stirring for 30 min, and the phases were separated.
[0100] An aqueous phase (1207 g) was obtained containing 49.5% HBr (d=1.51 g/ml) and crude DBD (789 g, d=1.42 g/ml). The concentration of 1,3-DBD in the crude product was 70.4% (GC, area %).
Step 2:
[0101] An aqueous solution of K.sub.2CO.sub.3, in a concentration of 25% w/w, was prepared in a 2 L stirred reactor by the batchwise addition of K.sub.2CO.sub.3 (400 g) to water (1200 g). The reaction was exothermic. To this solution was added a part of the aqueous phase of the reaction mixture of CDA-K (50 g) remaining from a previous run. The clear solution obtained was heated to 40 C. and crude DBD (Step 1, 400 g) was added to it dropwise over 70 min. The progress of the reaction was monitored by GC and by the change in the pH. The reaction was completed by cooking at 40 C. for 1.0 h, then at 50 C. for 2.0 h, with mechanical stirring.
[0102] The end of the reaction was determined by the pH (drop in the pH from 12.7 to 9.6) and by GC analysis of the reaction mixture (disappearance of 1,3-DBD to <1%, area %). After completion of the reaction, cooling to RT and stopping the stirring, an organic phase appeared above the aqueous phase which contained unreacted 3-BD and 3,3-DBD, and by-products formed by a condensation reaction of crude DBD. The phases were separated. 50 g of the aq. phase was taken for use in the next run.
[0103] In order to reduce the amount of impurities to a minimum, the aqueous phase (1943 g) was washed three times with dichloromethane (DCM, 3500 g).
[0104] After the washing stage, an aqueous phase was obtained containing cis-2-decenoic acid potassium salt (CDA-K), organic by-products, KBr and KHCO.sub.3. In order to obtain the crude cis-2-decanoic acid (CDA), the aqueous phase was acidified by the dropwise addition of aq. 32% HCl (401 g) over 1 h. During the acidification (final pH=1.9), CO.sub.2 (calculated at 127 g) was emitted.
[0105] After stopping the stirring, an aqueous phase (2017 g) was obtained containing salts: KCl and KBr (heavy phase, d=1.19 g/ml) and wet crude CDA (light phase, 128 g, d=1.03 g/ml).
[0106] Evaporation of the DCM and lights from the wet CDA under vacuum (T.sub.B=50 C.) gave crude CDA (102 g), which was analyzed by GC, HPLC and .sup.1H-NMR (.sup.1H-NMR spectra in
[0107] Based on the results, the purity of the crude CDA obtained was 89.7% (by GC area %) and 90.0% (by HPLC, area %). The calculated yield of crude CDA was 67% based on 1,3-DBD.
Example 3 (Comparative)
Preparation of Cis-2-Decenoic Acid
[0108] Step 1 was carried out as in Example 1. The rearrangement reaction of Step 2, however, was carried out without the addition of the alkali metal salt of cis-2-alkenoic acid.
Step 2:
[0109] An aqueous solution of K.sub.2CO.sub.3, in a concentration of 25% w/w, was prepared in a 1 L stirred reactor by the batchwise addition of K.sub.2CO.sub.3 (200 g) to water (600 g). The reaction was exothermic. The clear solution obtained was heated to 40 C. and crude DBD (200 g; obtained as previously described) was added to it dropwise over 60 min. The progress of the reaction was monitored by GC and by the change in the pH.
[0110] The mixture of aq. K.sub.2CO.sub.3 and crude DBD was stirred for 3 h at a temperature of 50 C. Based on the pH (unchanged at 13) and on GC, it was seen that no reaction had taken place.
[0111] Then suddenly, the temperature in the reactor started to rise spontaneously and reached 76 C. within ten minutes. The end of the reaction was determined by the pH (drop in the pH from 13.3 to 9.5) and by GC analysis of the reaction mixture (disappearance of 1,3-DBD to <1%, area %). The phases were separated, and 50 g of the aqueous phase was taken for use in the next run (i.e., the procedure of Example 1).
Example 4
Preparation of Cis-2-Undecenoic Acid
Step 1:
[0112] Into a mixture of 2-undecanone (218 g, 1.28 mol) and aq. 48% HBr (300 g), stirred and cooled to 10 C., was added bromine (410 g, 2.56 mol), dropwise over 3 h. The reaction started immediately with the start of the addition of the bromine and no accumulation of bromine was observed. The reaction was exothermic and accompanied by the emission of HBr gas, just before the end of the addition of the bromine, which was absorbed in a scrubber.
[0113] Most of the reaction took place during the addition of the bromine and cooking at room temperature (20 C.) for 3.5 hours. After standing overnight (16.5 h) at room temperature, without stirring, the composition of the reaction mixture stabilized. Partial conversion of the 3,3-dibromo-2-undecanone (3,3-DBUD) to the desired product, 1,3-dibromo-2-undecanone (1,3-DBUD), took place. To the reaction mixture was added water (160 g) at RT, with stirring for 30 min, and the phases were separated.
[0114] An aqueous phase (627 g) was obtained containing 50% HBr (d=1.50 g/ml) and crude DBUD (415 g, d=1.39 g/ml). The concentration of 1,3-DBUD in the crude product was 69.1% (GC, area %).
Step 2:
[0115] An aqueous solution of K.sub.2CO.sub.3, in a concentration of 25% w/w, was prepared in a 1 L stirred reactor by the batchwise addition of K.sub.2CO.sub.3 (200 g) to water (600 g). The reaction was exothermic. The clear solution obtained was heated to 40 C. and crude DBUD of Step 1 (200 g) was added to it dropwise over 20 min. The progress of the reaction was monitored by GC and by the change in the pH.
[0116] The mixture of aq. K.sub.2CO.sub.3 and crude DBUD was stirred for 1 h at a temperature of 50 C., for 1.5 h at a temperature of 60 C., and for an additional 1.5 h at a temperature of 70 C. Based on the pH (unchanged at 13) and on GC, it was seen that no reaction had taken place.
[0117] Next, to the reaction mixture was added a part of the aqueous phase of the reaction mixture of CDA-K (10 g) dropwise over 15 min. At the end of the addition, the temperature in the reactor started to rise and reached 82 C. within 10 min. This mixture was then stirred for an additional 2 h at 70 C.
[0118] The end of the reaction was determined by the pH (drop in the pH from 13 to 10) and by GC analysis of the reaction mixture (disappearance of 1,3-DBUD to <1%, area %).
[0119] In order to reduce the amount of impurities to a minimum, the reaction mixture (960 g) was washed three times with dichloromethane (DCM, 3250 g) at RT. It should be mentioned that the first phase separation was slow.
[0120] After the washing stage, an aqueous phase was obtained containing cis-2-undecenoic acid potassium salt (CUDA-K), organic by-products, KBr and KHCO.sub.3. In order to obtain the crude cis-2-undecenoic acid (CUDA), the aqueous phase was acidified by the dropwise addition of aq. 32% HCl (132 g) over 1 h. During the acidification, CO.sub.2 was emitted.
[0121] After stopping the stirring, an aqueous phase (762 g) was obtained containing salts: KCl and KBr (heavy phase, d=1.15 g/ml) and wet crude CUDA (light phase, 53 g, d=1.07 g/ml) which was analysed by GC and .sup.1H-NMR (see
[0122] Evaporation of the DCM and lights from the wet CUDA under vacuum (at T.sub.B=50 C.) gave crude CUDA (35 g).
[0123] It is seen that in this Example, a small amount of alkali metal salt of a homologue acid (CDA-K) was used to advance the preparation of CUDA. The aqueous phase obtained containing cis-2-undecenoic acid potassium salt (CUDA-K), with an insignificant amount of CDA-K, can be used to supply, for the next run, a catalytically effective amount of CUDA-K to be added to the alkaline K.sub.2CO.sub.3 solution before the slow addition of the crude DBUD starts, to ensure an efficient, manageable reaction.
Example 5 (Comparative)
Preparation of Cis-2-Nonenoic Acid
Step 1:
[0124] Into a mixture of 2-nonanone (from Sigma-Aldrich; 182 g, 1.28 mol) and aq. 48% HBr (300 g), stirred and cooled to 10 C., was added bromine (410 g, 2.56 mol), dropwise over 3 h. The reaction started immediately with the start of the addition of the bromine and no accumulation of bromine was observed. The reaction was exothermic and accompanied by the emission of HBr gas, just before the end of the addition of the bromine, which was absorbed in a scrubber.
[0125] Most of the reaction took place during the addition of the bromine and cooking at room temperature (20 C.) for 2.0 hours. After leaving overnight (17 h) at room temperature, with stirring, the composition of the reaction mixture stabilized. Partial conversion of the 3,3-dibromo-2-nonanone (3,3-DBN) to the desired product, 1,3-dibromo-2-nonanone (1,3-DBN), took place. To the reaction mixture was added water (160 g) at RT, with stirring for 30 min, and the phases were separated.
[0126] An aqueous phase (624 g) was obtained containing 50% HBr (d=1.50 g/ml) and crude DBN (382 g, d=1.47 g/ml). The concentration of 1,3-DBN in the crude product was 70.6% (GC, area %).
Step 2:
[0127] An aqueous solution of K.sub.2CO.sub.3, in a concentration of 25% w/w, was prepared in a 1 L stirred reactor by the batchwise addition of K.sub.2CO.sub.3 (200 g) to water (600 g). The reaction was exothermic. The clear solution obtained was heated to 46 C. and crude DBN from Step 1 (191 g) was added to it dropwise over 45 min. The progress of the reaction was monitored by the change in the pH and the T.sub.R.
[0128] Based on the pH (unchanged at 13) and on GC, it was seen that no reaction had taken place during the addition of the crude DBN. Immediately after the addition of the crude DBN, the pH started to go down and the T.sub.R started to go up.
[0129] The end of the reaction was determined by the pH (drop in the pH from 13.3 to 9.1) and by GC analysis of the reaction mixture (disappearance of 1,3-DBN to <1%, area %). The phases were separated. The organic phase (42.6 g) was organic waste.
[0130] In order to reduce the amount of impurities to a minimum, the aqueous phase (948 g) was washed three times with dichloromethane (DCM, 3250 g).
[0131] After the washing stage, an aqueous phase was obtained containing cis-2-nonenoic acid potassium salt (CNA-K), organic by-products, KBr and KHCO.sub.3. In order to obtain the crude cis-2-nonenoic acid (CNA), the aqueous phase was acidified by the dropwise addition of aq. 32% HCl (227 g) over 1 h. During the acidification, CO.sub.2 was emitted.
[0132] After stopping the stirring, an aqueous phase (978 g) was obtained containing salts: KCl and KBr (heavy phase, d=1.19 g/ml) and wet crude CNA (light phase, 51 g, d=1.02 g/ml) which was analysed by GC and .sup.1H-NMR (see
[0133] Evaporation of the DCM and lights from the wet CNA under vacuum (at T.sub.B=50 C.) gave crude CNA (46.6 g).
Example 6 (Comparative)
Preparation of Cis-2-Octenoic Acid
Step 1:
[0134] Into a mixture of 2-octanone (from Sigma-Aldrich; 164 g, 1.28 mol) and aq. 48% HBr (300 g), stirred and cooled to 10 C., was added bromine (410 g, 2.56 mol), dropwise over 3 h. The reaction started immediately with the start of the addition of the bromine and no accumulation of bromine was observed. The reaction was exothermic and accompanied by the emission of HBr gas, just before the end of the addition of the bromine, which was absorbed in a scrubber.
[0135] Most of the reaction took place during the addition of the bromine and cooking at room temperature (20 C.) for 2.5 hours. After leaving overnight (15 h) at room temperature, with stirring, the composition of the reaction mixture stabilized. Partial conversion of the 3,3-dibromo-2-octanone (3,3-DBO) to the desired product, 1,3-dibromo-2-octanone (1,3-DBO), took place. To the reaction mixture was added water (160 g) at RT, with stirring for 30 min, and the phases were separated.
[0136] An aqueous phase (636 g) was obtained containing 50% HBr (d=1.51 g/ml) and crude DBO (358 g, d=1.54 g/ml). The concentration of 1,3-DBO in the crude product was 71.0% (GC, area %).
Step 2:
[0137] An aqueous solution of K.sub.2CO.sub.3, in a concentration of 25% w/w, was prepared in a 1 L stirred reactor by the batchwise addition of K.sub.2CO.sub.3 (200 g) to water (600 g). The reaction was exothermic. The clear solution obtained was heated to 49 C. and crude DBO from Step 1 (182 g) was added to it dropwise over 1 h. The progress of the reaction was monitored by the change in the pH and the T.sub.R.
[0138] Based on the pH (unchanged at 13) and on GC, it was seen that no reaction had taken place during the addition of the crude DBO. Immediately after the addition of the crude DBO, the pH started to go down and the T.sub.R started to go up.
[0139] The end of the reaction was determined by the pH (drop in the pH from 13.7 to 9.3) and by GC analysis of the reaction mixture (disappearance of 1,3-DBO to <1%, area %).
[0140] Before starting the washings, water (75 g) was added to the reaction mixture (982 g). In order to reduce the amount of impurities to a minimum, the reaction mixture was washed four times with dichloromethane (DCM, 4250 g).
[0141] After the washing stage, an aqueous phase was obtained containing cis-2-octenoic acid potassium salt (COA-K), organic by-products, KBr and KHCO.sub.3. In order to obtain the crude cis-2-octenoic acid (COA), the aqueous phase was acidified by the dropwise addition of aq. 32% HCl (178 g) over 1 h. During the acidification, CO.sub.2 was emitted.
[0142] After stopping the stirring, an aqueous phase (938 g) was obtained containing salts: KCl and KBr (heavy phase, d=1.18 g/ml) and wet crude COA (light phase, 44 g, d=1.00 g/ml) which was analysed by GC and .sup.1H-NMR (see
[0143] Evaporation of the DCM and lights from the wet COA under vacuum (at T.sub.B=50 C.) gave crude COA (41.3 g).
Example 7 (Comparative)
Preparation of Cis-2-Heptenoic Acid
Step 1:
[0144] Into a mixture of 2-heptanone (from Sigma-Aldrich; 146 g, 1.28 mol) and aq. 48% HBr (300 g), stirred and cooled to 10 C., was added bromine (410 g, 2.56 mol), dropwise over 3 h. The reaction started immediately with the start of the addition of the bromine and no accumulation of bromine was observed. The reaction was exothermic and accompanied by the emission of HBr gas, just before the end of the addition of the bromine, which was absorbed in a scrubber.
[0145] Most of the reaction took place during the addition of the bromine and cooking at room temperature (20 C.) for 4.5 hours. After standing overnight (17 h) at room temperature, with stirring, the composition of the reaction mixture stabilized. Partial conversion of the 3,3-dibromo-2-heptanone (3,3-DBH) to the desired product, 1,3-dibromo-2-heptanone (1,3-DBH), took place. To the reaction mixture was added water (160 g) at RT, with stirring for 30 min, and the phases were separated.
[0146] An aqueous phase (631 g) was obtained containing 50% HBr (d=1.52 g/ml) and crude DBH (351 g, d=1.60 g/ml). The concentration of 1,3-DBH in the crude product was 72.6% (GC, area %).
Step 2:
[0147] An aqueous solution of K.sub.2CO.sub.3, in a concentration of 25% w/w, was prepared in a 1 L stirred reactor by the batchwise addition of K.sub.2CO.sub.3 (200 g) to water (600 g). The reaction was exothermic. The clear solution obtained was heated to 49 C. and crude DBH from Step 1 (173 g) was added to it dropwise over 1 h. The progress of the reaction was monitored by the change in the pH and the T.sub.R.
[0148] Based on the pH (unchanged at 13), it was seen that no reaction had taken place during the addition of the crude DBH. Immediately after the addition of the crude DBH, the pH started to go down and the T.sub.R started to go up.
[0149] The end of the reaction was determined by the pH (drop in the pH from 13.5 to 9.3) and by GC analysis of the reaction mixture (disappearance of 1,3-DBH to <1%, area %). After completion of the reaction, cooling to RT and stopping the stirring, an organic phase appeared above the aqueous phase which contained unreacted 3-BH and 3,3-DBH, and by-products formed by a condensation reaction of crude DBH. The phases were separated. The organic phase (24 g) is organic waste.
[0150] Before starting the washings, water (50 g) was added to the reaction mixture (948 g). In order to reduce the amount of impurities to a minimum, the diluted reaction mixture (998 g) was washed three times with dichloromethane (DCM, 3250 g).
[0151] After the washing stage, an aqueous phase was obtained containing cis-2-heptenoic acid potassium salt (CHA-K), organic by-products, KBr and KHCO.sub.3. In order to obtain the crude cis-2-heptenoic acid (CHA), the aqueous phase was acidified by the dropwise addition of aq. 32% HCl (193 g) over 1 h. During the acidification, CO.sub.2 was emitted.
[0152] After stopping the stirring, an aqueous phase (1014 g) was obtained containing salts: KCl and KBr (heavy phase, d=1.18 g/ml) and wet crude CHA (light phase, 45 g, d=1.00 g/ml) which was analysed by GC and .sup.1H-NMR (see
[0153] Evaporation of the DCM and lights from the wet CHA under vacuum (at T.sub.B=50 C.) gave crude CHA (44 g).
Examples 8A-8B (Comparative)
Purification of Crude Cis-2-Decenoic Acid by Silica Gel Column Chromatography
8A
[0154] 1.54 g of crude CDA was placed on top of a 24 cm 22 mm diameter glass column packed with 75 mL silica-gel 60 (Merck 0.04-0.063 mm). The initial eluent was hexane and a head of 240 mL eluent was discarded. Then the eluent changed to 5% ethyl acetate-95% hexane. An extra 140 mL eluent was discarded then a 60 mL fraction was collected. The solvents were removed under reduced pressure affording 0.36 g of pure CDA (99% by HPLC % area).
8B
[0155] 2.35 g of crude CDA was placed on top of a 35 cm 022_mm diameter glass column packed with 100 mL silica-gel 60 (Merck 0.04-0.063 mm). The initial eluent was hexane and a head of 300 mL eluent was discarded. Then the eluent was changed to 5% ethyl acetate-95% hexane. An extra 210 mL eluent was discarded then a 65 mL fraction was collected.
[0156] This fraction was combined with the fraction of 8A and solvents were removed under reduced pressure affording 0.95 g of pure CDA (99% by HPLC % area) which was analyzed by GC and .sup.1H-NMR (see
Example 9
Purification of Crude Cis-2-Decenoic Acid by Distillation (Laboratory Scale)
[0157] Crude CDA (CDA content 70% by HPLC assay) was distilled under reduced pressure. The distillation apparatus consisted of a 100 mL three-neck flask connected to a short Vigreux column through a Y connector. A water-cooled condenser and four-flasks rotating receiver were attached to the vacuum pump (2 mbar). Crude CDA (79.7 g) was placed in the distillation flask, vacuum and heating were applied. Distillation started at a 77-83 C. vapor temperature at the distillation head; pure CDA was obtained at a vapor temperature of 95-105 C. (bottom temp 130-140 C.). 43 g of CDA was collected, with CDA content of 96.7% (assay by HPLC). The distilled CDA was 97.6% pure by GC (% area), accompanied by 0.6% trans-decenoic acid and ca. 0.5% bromomethylidene nonanoic acid. The distillation yield was 75%.
Example 10
Purification of Crude Cis-2-Decenoic Acid by Wiped-Film Evaporation (Mini Pilot-Scale)
[0158] A mini pilot scale study was performed to determine the evaporation conditions that achieve purification of crude CDA to reach a high CDA assay (90%) alongside good yields (>90%).
[0159] For CDA purification a glass WFE 0.12 m.sup.2 was used, a 1 L bottom flask for residue and a 200 ml flask for distillate collection. The heating was performed by thermal oil circulated by a LAUDA system to the WFE jacket. The vapors were passed through the condenser, and cooled by chilled 7 C. ethylene glycol-water. Crude CDA was dosed to the WFE by a peristaltic pump (over Teflon tube). In order to monitor the feed and distillation rate during the performed runs, lab measuring cylinders were used for the crude inlet and distillate outlet. A vacuum was reached by an oil vacuum pump, accompanied by an acetone-dry ice trap to prevent DCM from reaching the pump.
[0160] A series of runs were performed, varying the conditions (temperature, diminished pressure, feed flow rate, rotation speed, D/F ratio) and testing their influence on the assay and impurities profile. Operation conditions and results of tests are tabulated in Table C.
TABLE-US-00004 TABLE C Feed flow Distillate Rotation CDA CDA impurities T Vacuum rate flow rate rate D/F Assay Purity Trans BMNA Yield Run C mbar ml/min ml/min rpm % % % % % % Runs A1-A3 (invention) and A4 (comparative) Crude CDA feed for runs A1-A4 71 88.19 0.63 7.43 Distillates obtained from A1-A4 A1 150 3.8 20 11 175 55 94 96.3 0.4 1.3 84 A2 150 4.1 14 9.9 175 71 98 95.9 0.9 1.7 88 A3 180 4.2 35.3 23.6 175 67 95 95.1 0.6 2.8 89 A4 145 5.6 7 4 175 57 95 96.8 0.8 1.1 42 Runs B1-B3 (invention) and B4 (comparative) Crude CDA feed for runs B1-B4 68.8 88.7 0.6 8.0 B1 150 3.9 15 11.1 175 74 94.1 95.8 0.8 1.7 88 B2 150 3.5 15.2 12.7 250 83 91.9 95.6 0.9 2.0 91 B3 150 3.8 16.8 12.4 250 73 92.1 95.5 0.8 1.9 90 B4 150 5.7 14.1 8.2 175 58 93.4 97.3 0.5 1.2 47
[0161] The results tabulated in Table C show that a product of high CDA assay (90%) with a good production yield in the range of 80-90% can be achieved by wiped film evaporation of the crude product at a temperature above 150 C., e.g., from 150 C. to 180 C. While good assay results were observed in several runs when a deep vacuum was not created (A4, B4), these runs were shown to result in low productivity/low yield. Therefore, it is beneficial to hold an evaporation run at a low pressure (<4.5 mbar). To get a desirable ratio D/F near 71%, feed flow is maintained in the range of 14-15 ml/min at 150 C. and 35 ml/min at 180 C.
Example 11
Purification of Crude Cis-2-Decenoic Acid by Wiped-Film Evaporation (Pilot Scale)
[0162] The WFE system for crude purification included a 0.4 m.sup.2 WFE from Canzler and 100 L bottom tank, both made of stainless steel 316. The WFE was heated with thermal oil from an electrical heater (Lauda, 48 kW); the bottom tank was not heated. The CDA crude was fed in by a peristaltic pump from a 200 L drum and placed on balances WI-1 to the top of the WFE system. The residue was collected in the bottom tank and was drained at the end of each run. The vapors were condensed in a 0.75 m.sup.2 stainless steel condenser cooled by water from a cooling tower. The distillate was collected in a 100 L glass distillate receiver and was withdrawn with a diaphragm pump P-3 at the end of each run. The condenser and the distillate receiver were connected to a deep-vacuum dry pump, CXS250 from Edwards.
[0163] Several exploratory runs were made to define best evaporation conditions for the crude CDA (63.6 kg, assay 67% w/w, HPLC).
[0164] Good results (recovery of pure CDA with Assay 90% (by HPLC)) were obtained by carrying out a two pass distillation mode at 175-180 C., 1 mbar, feed rate 27 kg/hr for the 1.sup.st pass, (189 C., 1 mbar pressure at top) yielding 40 kg CDA (77% assay w/w) and 55 kg/hr for the 2.sup.nd pass, (180 C., 1 mbar pressure at top) to yield 23.8 kg in-spec. CDA (98% assay). The bottoms of the 2.sup.nd pass (11 kg) were also distilled at 175-180 C. and a feeding rate of 60 kg/hr, yielding 7 kg in-spec CDA (93%). The total yield of the WFE purification was 72% in-spec (>95% assay) CDA from the crude CDA product.
Example 12
Thermal Isomerization of CDA
[0165] A study was conducted to determine the thermal isomerization of CDA. The CDA was charged into a flask, equipped with a magnetic stirrer, a thermocouple, and a condenser.