WO/2000/024923 | THE ENZYME-MEDIATED SYNTHESIS OF PEPTIDOMIMETICS |
JP2009120585 | THICKENER |
WO/2010/067871 | Nε-ACYL-L-LYSINE-SPECIFIC AMINOACYLASE |
CORDOVA ARMANDO (SE)
DEIANA LUCA (SE)
IBRAHEM ISMAIL (SE)
WO2016171538A1 | 2016-10-27 | |||
WO2016096905A1 | 2016-06-23 | |||
WO2015144902A1 | 2015-10-01 |
US6022718A | 2000-02-08 | |||
DE60215729T2 | 2007-08-30 | |||
US20170081277A1 | 2017-03-23 | |||
US6022718A | 2000-02-08 |
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Claims 1. A process for enzymatic synthesis of amides of formula III from amines of formula I and compounds of formula II, wherein R1 is selected from the group comprising C1-12alkyl-, C1-12alkenyl-, C1-12alkynyl-, C1- 12alkoxy-, C1-12alkyl-O-C1-12alkyl-, C1-12alkyl-OC(O)-C1-12alkyl-, C1-12alkyl-NH-C1-12alkyl-, C1- 12alkyl-NHC(O)-C1-12alkyl-, C3-12cycloalkyl-, C3-12cycloalkenyl-, C5-12aryl-, C3-12cycloalkyl-C1- 6alkyl-, C3-12cycloalkenyl-C1-6alkyl- and C5-12aryl-C1-6alkyl-, which R1 may optionally be substituted with one or more substituent selected from the group comprising hydrogen, hydroxy, oxy, halogen, carboxy, amine, amide, C1-6hydroxyalkyl-, C1- 6haloyalkyl-, C1-6amineoxyalkyl-, C1-6amideyalkyl-, C1-6carboxyalkyl-, C1-6sulfuralkyl-, C1- 6sulfidealkyl- and C1-6alkoxy-, and wherein one or more carbon in a cycloalkyl, cycloalkenyl or aryl may be substituted with one or more heteroatoms selected from O, N or S, wherein R2 is selected from the group comprising hydrogen, C1-30alkyl-, C1-30alkenyl-, C1- 30alkynyl-, C1-30alkoxy-, C1-30alkyl-O-C1-12alkyl-, C1-30alkyl-OC(O)-C1-12alkyl-, C1-30alkyl-NH-C1- 12alkyl-, C1-30alkyl-NHC(O)-C1-12alkyl-, C3-12cycloalkyl-, C3-12cycloalkenyl- and C5-12aryl-, C3- 12cycloalkyl-C1-6alkyl-, C3-12cycloalkenyl-C1-6alkyl- and C5-12aryl-C1-6alkyl-, which R2 may optionally be substituted with one or more substituent selected from the group comprising hydrogen, hydroxy, oxy, halogen, carboxy, amide, C1-6hydroxyalkyl-, C1-6haloyalkyl- , C1-6carboxyalkyl-, C1-6sulfuralkyl-, C1-6sulfidealkyl- and C1-6alkoxy-, and wherein one or more carbon in a cycloalkyl, cycloalkenyl or aryl may be substituted with one or more heteroatoms selected from O, N or S, wherein R3 is selected from the group comprising hydrogen, C1-6alkyl-, C1-6alkenyl-, C1-6alkynyl- , C1-6alkoxy-, C1-6alkyl-O-C1-6alkyl-, C1-6alkyl-OC(O)-C1-6alkyl-, C1-6alkyl-NH-C1-6alkyl-, C1-6alkyl- NHC(O)-C1-6alkyl-, C3-12cycloalkyl-, C3-12cycloalkenyl- and C5-12aryl-, C3-12cycloalkyl-C1-6alkyl-, C3- 12cycloalkenyl-C1-6alkyl- and C5-12aryl-C1-6alkyl-, which R3 may optionally be substituted with one or more substituent selected from the group comprising hydrogen, hydroxy, oxy, halogen, carboxy, amine, amide, C1-6hydroxyalkyl-, C1- 6haloyalkyl-, C1-6amineoxyalkyl-, C1-6amideyalkyl-, C1-6carboxyalkyl-, C1-6sulfuralkyl-, C1- 6sulfidealkyl- and C1-6alkoxy-, wherein one or more carbon in a cycloalkyl, cycloalkenyl or aryl may be substituted with one or more heteroatoms selected from O, N or S, and wherein R is a bond or C1-6alkyl-, characterized in that the lipase is immobilized on a rotary bed reactor or on a spin-fixed-bed reactor and a Dean- Stark apparatus is used for dehydration. 2. The process according to claim 1, wherein R1 is selected from the group comprising C1-6alkyl-, C1-6alkenyl-, C1-6alkoxy-, C1-6alkyl- O-C1-6alkyl-, C3-6cycloalkyl-, C3-6cycloalkenyl-, C6-7aryl-, C3-6cycloalkyl-C1-3alkyl-, C3- 6cycloalkenyl-C1-3alkyl- and C5-7aryl-C1-3alkyl-, which R1 may optionally be substituted with one or more substituent selected from the group comprising hydrogen, hydroxy, oxy, halogen, carboxy, C1-3hydroxyalkyl-, C1-3haloyalkyl-, and C1-3alkoxy-, and wherein R2 is selected from the group comprising hydrogen, C5-15alkyl-, C5-15alkenyl-, C5- 15alkoxy-, C5-15alkyl-O-C1-6alkyl-, and C5-15alkyl-OC(O)-C1-6alkyl-, which R2 may optionally be substituted with one or more substituent selected from the group comprising hydrogen, hydroxy, oxy, halogen and carboxy, wherein R3 is selected from the group comprising hydrogen, C1-3alkyl-, C1-3alkoxy- and C1- 3alkyl-O-C1-3alkyl-, and wherein R is a bond or C1-3alkyl-. 3. The process according to claim 1, wherein R1 is C5-7aryl-C1-3alkyl-, which R1 may optionally be substituted with one or more substituent selected from the group comprising hydrogen, hydroxy and C1-3alkoxy-, wherein R2 is selected from the group comprising C5-16alkyl- and C5-15alkenyl-, and wherein R3 is hydrogen, methyl or ethyl, and wherein R is a bond. 4. The process according to claim 1, wherein compounds of formula III are compounds of formula IV wherein n is 1 or 2, wherein R2 is selected from the group comprising hydrogen, C3-30alkyl-, C3-30alkenyl-, C3- 30alkynyl-, C3-12cycloalkyl-, C3-12cycloalkenyl- and C5-12aryl-, which R2 may optionally be substituted with one or more substituent selected from the group comprising hydrogen, hydroxy, oxy, halogen, carboxy, amide, C1-6hydroxyalkyl-, C1-6haloyalkyl- , C1-6amideyalkyl-, C1-6carboxyalkyl-, C1-6sulfuralkyl-, C1-6sulfidealkyl- and C1-6alkoxy- and C5- 12aryl-, and wherein one or more carbon in a cycloalkyl, cycloalkenyl or aryl may be substituted with one or more heteroatoms selected from O, N or S, wherein R4 or R5 is selected from the group comprising hydrogen, C1-6alkyl-, C2-6alkenyl-, C2- 6alkynyl-, C3-10cycloalkyl-, C3-10cycloalkenyl- and C5-12aryl-, which R4 or R5 may optionally be substituted with one or more substituent selected from the group comprising hydroxy, oxy, halogen, carboxy, amine, amide, C1-6hydroxyalkyl-, C1- 6haloyalkyl-, C1-6amineoxyalkyl-, C1-6amideyalkyl-, C1-6carboxyalkyl-, C1-6sulfuralkyl-, C1- 6sulfidealkyl- and C1-6alkoxy-, and wherein one or more carbon in a cycloalkyl, cycloalkenyl or aryl may be substituted with one or more heteroatoms selected from O, N or S, wherein R6 is selected from the group comprising hydrogen, hydroxy, oxy, halogen, carboxy, amine, amide, C1-10alkyl-, C2-10alkenyl-, C2-10alkynyl-, C3-12cycloalkyl-, C3-12cycloalkenyl- and C5- 12aryl-, which R6 may optionally be substituted with one or more substituent selected from the group comprising hydrogen, hydroxy, oxy, halogen, carboxy, amine, amide, C1-6hydroxyalkyl-, C1- 6haloyalkyl-, C1-6amineoxyalkyl-, C1-6amideyalkyl-, C1-6carboxyalkyl-, C1-6sulfuralkyl-, C1- 6sulfidealkyl- and C1-6alkoxy-, and wherein one or more carbon in a cycloalkyl, cycloalkenyl or aryl may be substituted with one or more heteroatoms selected from O, N or S. 5. The process according to claim 4, wherein compounds of formula III are compounds of formula IV wherein n is 1 or 2, wherein R2 is selected from the group comprising C3-18alkyl- and C3-18alkenyl-,, wherein R4 or R5 is selected from the group comprising hydrogen, C1-6alkyl-, and R6 is hydrogen. 6. The process according to claim 4, wherein compounds of formula III are compounds of formula IV wherein n is 1 or 2, wherein R2 is selected from the group comprising C5-16alkyl- and C5-15alkenyl-, wherein R4 or R5 is selected from the group comprising hydrogen, C1-3alkyl-, and R6 is hydrogen. 7. The process according to claim 1, for enzymatic synthesis of amides of formula III from amines of formula I and compounds of formula IIa, wherein R1 is selected from the group comprising C1-12alkyl-, C1-12alkenyl-, C1-12alkynyl-, C1- 12alkoxy-, C1-12alkyl-O-C1-12alkyl-, C1-12alkyl-OC(O)-C1-12alkyl-, C1-12alkyl-NH-C1-12alkyl-, C1- 12alkyl-NHC(O)-C1-12alkyl-, C3-12cycloalkyl-, C3-12cycloalkenyl-, C5-12aryl-, C3-12cycloalkyl-C1- 6alkyl-, C3-12cycloalkenyl-C1-6alkyl- and C5-12aryl-C1-6alkyl-, which R1 may optionally be substituted with one or more substituent selected from the group comprising hydrogen, hydroxy, oxy, halogen, carboxy, amine, amide, C1-6hydroxyalkyl-, C1- 6haloyalkyl-, C1-6aminexyalkyl-, C1-6amideyalkyl-, C1-6carboxyalkyl-, C1-6sulfuralkyl-, C1- 6sulfidealkyl- and C1-6alkoxy-, and wherein one or more carbon in a cycloalkyl, cycloalkenyl or aryl may be substituted with one or more heteroatoms selected from O, N or S, wherein R2 is selected from the group comprising hydrogen, C1-30alkyl-, C1-30alkenyl-, C1- 30alkynyl-, C1-30alkoxy-, C1-30alkyl-O-C1-12alkyl-, C1-30alkyl-OC(O)-C1-12alkyl-, C1-30alkyl-NH-C1- 12alkyl-, C1-30alkyl-NHC(O)-C1-12alkyl-, C3-12cycloalkyl-, C3-12cycloalkenyl- and C5-12aryl-, C3- 12cycloalkyl-C1-6alkyl-, C3-12cycloalkenyl-C1-6alkyl- and C5-12aryl-C1-6alkyl-, which R2 may optionally be substituted with one or more substituent selected from the group comprising hydrogen, hydroxy, oxy, halogen, carboxy, amine, amide, C1-6hydroxyalkyl-, C1- 6haloyalkyl-, C1-6aminexyalkyl-, C1-6amideyalkyl-, C1-6carboxyalkyl-, C1-6sulfuralkyl-, C1- 6sulfidealkyl- and C1-6alkoxy-, and wherein one or more carbon in a cycloalkyl, cycloalkenyl or aryl may be substituted with one or more heteroatoms selected from O, N or S, wherein R3 is selected from the group comprising hydrogen, C1-6alkyl-, C1-6alkenyl-, C1-6alkynyl- , C1-6alkoxy-, C1-6alkyl-O-C1-6alkyl-, C1-6alkyl-OC(O)-C1-6alkyl-, C1-6alkyl-NH-C1-6alkyl-, C1-6alkyl- NHC(O)-C1-6alkyl-, C3-12cycloalkyl-, C3-12cycloalkenyl- and C5-12aryl-, C3-12cycloalkyl-C1-6alkyl-, C3- 12cycloalkenyl-C1-6alkyl- and C5-12aryl-C1-6alkyl-, which R3 may optionally be substituted with one or more substituent selected from the group comprising hydrogen, hydroxy, oxy, halogen, carboxy, amine, amide, C1-6hydroxyalkyl-, C1- 6haloyalkyl-, C1-6aminexyalkyl-, C1-6amideyalkyl-, C1-6carboxyalkyl-, C1-6sulfuralkyl-, C1- 6sulfidealkyl- and C1-6alkoxy-, and wherein one or more carbon in a cycloalkyl, cycloalkenyl or aryl may be substituted with one or more heteroatoms selected from O, N or S characterized in that the lipase is immobilized on a rotary bed reactor or on a spin-fixed-bed reactor and a Dean- Stark apparatus is used for dehydration. 8. The process according to claim 7, wherein R1 is C5-7aryl-C1-3alkyl-, which R1 may optionally be substituted with one or more substituent selected from the group comprising hydrogen, hydroxy and C1-3alkoxy-, and wherein R2 is selected from the group comprising C5-15alkyl- and C5-15alkenyl-, and wherein R3 is hydrogen, methyl or ethyl. 9. The process according to anyone of claims 1 to 8, wherein no solvent is used, or the solvent is an organic solvent selected from the group comprising methyl tert-butyl ether, diisopropylether, C1-6alkyl-O-C1-6alkyl ethers, hexane and other C5-10alkanes, cyclohexane and other C5-10cycloalkanes, benzene, toluene, xylene, tert-butanol, tert amyl alcohol, other bulky secondary or tertiary C5-10 alcohols and any esters thereof, or mixtures thereof. 10. The process according to anyone of claims 1 to 8, wherein no solvent is used, or the solvent is an organic solvent selected from the group comprising diisopropylether, cyclohexane, toluene or tert-butanol, or mixtures thereof. 11. The process according to anyone of claims 1 to 10, wherein the lipase is selected from the group comprising Candida antarctica lipase A, Candida antarctica lipase B, cross-linked Substilisin A protease, Porcine pancreas lipase, Candida cylindracea lipase, Rhizopus arrhizus, Penicillum cyclopium, Mucor miehei, Thermomyces lanuginosus lipase, Candida rugosa lipase and Pseudomonas lipoprotein lipase. 12. The process according to anyone of claims 1 to 10, wherein the lipase is Candida antarctica lipase. 13. The process according to anyone of claims 1 to 12, wherein the process temperature is between room temperature and 150°C and the pressure is between 0.900 and 0.200 MPa, or about 0.1 MPa. 14. The process according to anyone of claims 1 to 13, wherein the rotary bed reactor is loaded for 10 to 75wt% with the lipase. 15. A process according to claim 1, wherein compounds of formula II, wherein R2 is a C6-18alkyl or C6-18alkenyl, which may be straight or branched, are prepared comprising the steps of step A-1, wherein the reaction is performed without solvent or with an organic solvent, step B-1, wherein a solvent is an aprotic organic solvent, and step B-1, wherein a base a sodium or potassium alkoxides , optionally isomerization step C-1, wherein a catalyst is selected from the group comprising HNO2, HNO3 and combinations of NaNO2/HNO3, NaNO2/NaNO3/H2SO4, that can generate HNO2 or HNO3, and hydrogenation step D-1, wherein a catalyst is a heterogeneous hydrogenation catalyst and a hydrogen source is hydrogen gas. 16. The process according to claim 15, wherein the organic solvent in step A-1 is ethyl acetate, wherein the aprotic organic solvent in step B-1 is selected from the group comprising 2-methyl tetrahydrofuran, tetrahydrofuran and toluene, wherein the sodium or potassium alkoxide base in step B-1 is selected from the group comprising NaH, KH, t-BuOK, t-BuONa, and wherein the heterogeneous hydrogenation catalyst in hydrogenation step D-1 is selected from the group comprising Pd/C and Pd/Al2O3. 17. A process according to claim 1, wherein compounds of formula II, wherein R2 is 8-methyl- nonanyl, are prepared comprising the steps of step A-2, wherein the reaction is performed without solvent or with any organic solvent and a catalyst is selected from the group comprising amines and inorganic bases, step B-2, wherein the reaction is performed without solvent or with an organic solvent, and a catalyst is an acid, step C-2, wherein a catalyst is a heterogeneous hydrogenation catalyst and a hydrogen source is hydrogen gas, step D-2, wherein an oxidant is a peroxide and a catalyst is a lipase, and step E-2, wherein a reaction medium is an acidic media , and Step F-2, wherein a catalyst is a heterogeneous hydrogenation catalyst and a hydrogen source is hydrogen gas. 18. The process according to claim 17, wherein the organic solvent in step A-2 is selected from the group comprising toluene, and a catalyst is selected from the group comprising pyrrolidine and corresponding salts, NaOH and KOH, wherein the organic solvent in step B-2 is selected from the group comprising toluene, and the acid is selected from the group comprising p-TsOH, sulfuric acid and Amberlyst-15, wherein the catalyst in step C-2 is selected from the group comprising Pd/C, Pd/Al2O3, wherein the oxidant in step D-2 is selected from the group comprising aqueous H2O2 and peroxy acids and the lipase is selected from the group comprising Candida antarctica lipase A, Candida antarctica lipase B, cross-linked Substilisin A protease, Porcine pancreas lipase, Candida cylindracea lipase, Rhizopus arrhizus, Penicillum cyclopium, Mucor miehei, Thermomyces lanuginosus lipase, Candida rugosa lipase and Pseudomonas lipoprotein lipase, and wherein the reaction medium in step E-2 is selected from the group comprising aqueous sulfuric acid solution, and wherein the catalyst in step F-2 is selected from the group comprising Pd/C, Pd/Al2O3, Pd/ molecular sieves, Pt/C, Pt/Al2O3, and Pt/molecular sieves. 19. The processes according to any one of claims 1 to 18, for large scale production (> 1 kg) of compounds of formula III. |
In the process of the invention, no solvent may be used. If a solvent is used, the solvent may be an organic solvent selected from the group comprising or consisting of methyl tert-butyl ether, diisopropylether, C 1-6 alkyl-O-C 1-6 alkyl ethers, hexane and other C 5-10 alkanes, cyclohexane and other C 5-10 cycloalkanes, benzene, toluene, xylene, tert-butanol, tert amyl alcohol, other bulky secondary or tertiary C 5-10 alcohols and any esters thereof. The solvent may be toluene, diisopropylether or cyclohexane. When R 3 is not hydrogen, the solvent may be selected from the group comprising or consisting of methyl tert-butyl ether, diisopropylether, C 1-6 alkyl-O-C 1-6 alkyl ethers, hexane and other C 5- 10alkanes, cyclohexane and other C 5-10 cycloalkanes, benzene, toluene, xylene, tert-butanol, tert amyl alcohol, other bulky secondary or tertiary C 5-10 alcohols and their esters. The solvent may be toluene, diisopropylether or cyclohexane. The lipase may be selected from the group comprising or consisting of Candida antarctica lipase A, Candida antarctica lipase B, cross-linked Substilisin A protease, Porcine pancreas lipase, Candida cylindracea lipase, Rhizopus arrhizus, Penicillum cyclopium, Mucor miehei, Thermomyces lanuginosus lipase, Candida rugosa lipase and Pseudomonas lipoprotein lipase. The process may be performed at a temperature between room temperature and 150°C, or between room temperature and 115°C. The process may be performed at a pressure between 0.900 and 0.200 MPa, or about 0.1 MPa. The compounds of formula II may be prepared comprising or consisting of the steps of wherein R 2 is a C 6-18 alkyl or C 6-18 alkenyl, which may be straight or branched, step A-1, the reaction is performed without solvent or with any organic solvent, such as EtOAc, step B-1, a solvent is selected from the group comprising or consisting of 2-methyl tetrahydrofuran, tetrahydrofuran, toluene and any other aprotic organic solvent, step B-1, a base is selected from the group comprising or consisting of NaH, KH, t-BuOK, t- BuONa and another sodium or potassium alkoxides, isomerization step C-1, a catalyst is selected from the group comprising or consisting of HNO 2 , HNO 3 and any other combination that can generate HNO 2 or HNO 3 , and hydrogenation step D-1, a catalyst is selected from the group comprising or consisting of Pd/C, Pd/Al 2 O 3 and any other heterogeneous hydrogenation catalyst, a hydrogen source is hydrogen gas. The compounds of formula II may be prepared comprising or consisting of the steps of step A-2, the reaction is performed without solvent or with any organic solvents, such as toluene, a catalyst is selected from the group comprising or consisting of pyrrolidine, other amines and corresponding salts, NaOH, KOH, and other inorganic bases, step B-2, the reaction is performed without solvent or with an organic solvent, such as toluene, a catalyst is selected from the group c comprising or consisting of p-TsOH, sulfuric acid, Amberlyst-15, and other acids, step C-2 and step F-2, a hydrogen source is hydrogen gas, a catalyst is selected from the group comprising or consisting of Pd/C, Pd/Al 2 O 3 and another heterogeneous hydrogenation catalyst, step D-2, an oxidants is selected from the group comprising or consisting of aqueous H 2 O 2 , peroxyacids and another peroxides, a catalyst is selected from the group comprising or consisting of Candida antarctica lipase A, Candida antarctica lipase B, cross-linked Substilisin A protease, Porcine pancreas lipase, Candida cylindracea lipase, Rhizopus arrhizus, Penicillum cyclopium, Mucor miehei, Thermomyces lanuginosus lipase, Candida rugosa lipase and Pseudomonas lipoprotein lipase, and step E-2, a reaction medium is selected from the group comprising or consisting of aqueous sulfuric acid solution or another strong acidic media, and Step F-2, a catalyst is selected from the group comprising or consisting of Pd/C, Pd/Al 2 O 3 , Pd/ molecular sieves, Pt/C, Pt/Al 2 O 3 , and Pt/molecular sieves, a hydrogen source is hydrogen gas. The processes for the preparation of compounds of formula II may be performed at a temperature is between room temperature and 150°C, or between room temperature and 115 °C. These processes may be performed at a pressure between 0.900 and 0.200 MPa, or about 0.1 MPa. Experimental sections Preparation of vanillylamine Vanillylamine was prepared from its hydrochloride salt. The HCl salt was purchased from commercial suppliers or prepared according to literature procedures (ChemBioChem 2009, 10, 823; J. Med. Chem.2018, 61, 8225.). Example 1: 50.00 g of vanillylamine HCl salt was dissolved in 500 mL of cold water (~5 o C), and cooled with an ice-bath, 1 equivalent of 3 M NaOH (87.9 mL) was portion-wise added in 10 min while keeping vigorous stirring. The internal temperature kept about 5 o C. After addition of all bases, the milky solution was stirred for further 5 min, then filtered. The white product in the funnel was washed twice with cold water (5 o C, 100 mL×2), then dried under vacuum until the weight remains the same.37.32 g (92.4% yield) of product was obtained. Example 2: 500.0 g of vanillylamine HCl salt was dissolved in 5 L of water (10 ~ 15 o C), 1 equivalent of 3 M NaOH was portion-wise added in 20 min while keeping vigorous stirring. After addition of all bases, the milky solution was stirred for further 10 min, then filtered. The white product in the funnel was washed twice with cold water (1 L×2), then dried in a vacuum chamber at 50 o C for 24 hours.478.0 g of off-white product was obtained with 19.5wt% moisture content (determined with Kern DBS 60-3 moisture analyser). Preparation of fatty acids Preparation of fatty acids with Wittig reaction as key step Example 3: Preparation of (6-Carboxyhexyl)triphenylphosphonium bromide. In a 1 L round-bottom flask, 97.53 g 6-bromohexanoic acid and 131.15 g (1.0 equiv) triphenylphosphine (PPh 3 ) were dissolved in 500 mL EtOAc. The mixture was heated at 75-80 o C and stirred for 7 days. After filtration, the collected product was washed with EtOAc (50 mL×2) and then dried under vacuum to give 221.80 g white powder (97.0% yield). The combined filtrate was recycled as solvent for more batches. Example 4: Preparation of (Z)-8-methyl-6-nonenoic acid. In a 1 L two-necked round-bottom flask 100.00 g (6-Carboxyhexyl)triphenylphosphonium (Ph 3 PO) bromide and 49.07 g (2.0 equiv) KOtBu were dissolved in 300 mL 2-MeTHF under protection of nitrogen atmosphere and cooled using an ice water bath. The reaction mixture turned bright orange color while the compounds were dissolved. A solution of 18.92 g (1.2 equiv) isobutyraldehyde in 200 mL 2-MeTHF was slowly added to the cold reaction mixture, which quickly turned white. After the addition was completed, the reaction mixture was warmed to room temperature and stirred for 6 h. The reaction was quenched by addition of 500 mL H 2 O. The MeTHF solvent was recovered by distillation. After cooling to room temperature, most of Ph 3 PO was precipitated and collected as white powder by filtration. The filtrate was acidified with concentrated HCl to pH 2, the formed organic layer was collected, and the water phase was extracted with Et 2 O (100 mL×2). The organic phases were combined, dried with anhydrous Na 2 SO 4 , and concentrated to give 56.6 g crude product. This crude product was then distilled under reduced pressure to give (Z)-8-methyl-6-nonenoic acid (32.76 g, 88% yield, Z/E 11:1 by NMR analysis) as colorless oil product. Example 5: Preparation of 8-methyl nonanoic acid. 32 g of (Z)-8-methyl-6-nonenoic acid was dissolved in 150 mL of diisopropyl ether.0.5 mol% of Pd/C powder was then dispersed in this solution. The mixture was hydrogenated with H2 balloon at room temperature overnight. The catalyst was recovered by filtration. The solvent was recovered by distillation.8-methyl nonanoic acid was obtained as colorless oil with >99% yield. Example 6: Preparation of (E)-8-methyl-6-nonenoic acid. In a 1 L two-necked round-bottom flask 100.00 g (6-Carboxyhexyl)triphenylphosphonium bromide and 49.07 g (2.0 equiv) KOtBu were dissolved in 300 mL 2-MeTHF under protection of nitrogen atmosphere and cooled using an ice water bath. The reaction mixture turned bright orange color while the compounds were dissolved. A solution of 18.92 g (1.2 equiv) isobutyraldehyde in 200 mL 2-MeTHF was slowly added to the cold reaction mixture, which quickly turned white. After the addition was completed, the reaction mixture was warmed to room temperature and stirred for 6 h. The reaction was quenched by addition of 500 mL H 2 O. The MeTHF solvent was recovered by distillation. After cooling to room temperature, most of Ph3PO was precipitated and collected as white powder by filtration. The filtrate was acidified with concentrated HCl to pH 2, the formed organic layer was collected, and the water phase was extracted with DIPE (100 mL×2). The organic phases were combined and concentrated. This crude intermediate was then treated with concentrated HNO 3 (0.03 equiv) at 85 o C under protection of nitrogen atmosphere for 24 hours. After cooling, the mixture was washed with water (50 mL×2). The aqueous phases were combined and extracted with DIPE (50 mL×2). The organic phases were combined, dried with anhydrous Na 2 SO 4 , and concentrated to give 53.1 g crude product. This crude product was then distilled under reduced pressure to give (E)-8- methyl-6-nonenoic acid (30.2 g, 81% yield, E/Z 86:14 by NMR analysis) as colorless oil product. Preparation of 8-methyl nonanoic acid starting from cyclohexanone and isobutyraldehyde 50 g isobutyraldehyde, 102 g cyclohexanone (1.5 equiv), 5 mol% of pyrrolidine and 5 mol% AcOH were heated and stirred at 40 o C for 12 h. After cooling to room temperature, the mixture was dispersed in 200 mL of water and 100 mL of toluene and organic phase was separated. The aqueous phase was extracted with toluene (50 mL × 2). The organic phases were combined and treated with 4 mol% of p-TsOH ^H2O catalyst at refluxing condition for 2 hours with a Dean-Stark trap to collect the generated water. After cooling again to room temperature, the acid was removed by washing with 30 mL of aqueous 1 M NaOH solution. Toluene and excess cyclohexanone were recovered by distillation. The enone product (87.6 g, 83% yield, light yellow) was then distilled out under reduced pressure. Example 8: Preparation of 2-isobutylcyclohexanone 5 g of 2-(2-methylpropylidene)cyclohexan-1-one was dissolved in 10 mL of EtOAc.0.2 mol% of Pd/C was added, and the hydrogenation was conducted at room temperature with H2 balloon for 4 hours. Full conversion was achieved based on NMR analysis. The catalyst was recovered by filtration, and the filtrate was directly used in the following oxidation. Example 9: Preparation of 7-isobutyloxepan-2-one To the solution of 2-isobutylcyclohexanone in EtOAc, were added Novozym 435 (tm) (250 mg) and 30% aqueous H 2 O 2 (3 equiv). The mixture was stirred and heated at 50 o C. After 24 h, 91% conversion was achieved based on NMR analysis. After cooling to room temperature, the lipase catalyst was recovered by filtration. The filtrate was washed with 5% aqueous Na 2 S 2 O 3 solution and brine to remove excess peroxide. The organic phase was concentrated to give the crude lactone. Example 10: Preparation of 8-methyl-6-nonanoic acid The above crude lactone was dispersed in 5 M H 2 SO 4 (40 mL) and heated at 110 o C oil bath. After 20 h, the mixture was cooled to room temperature, extracted with DIPE (20 mL × 3). The organic phases were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. To the filtrate, 0.5 mol% Pd/C powder was added, and the hydrogenation was conducted at room temperature with H2 balloon for 24 hours. After filtration to recover the Pd catalyst, the filtrate was concentrated and purified by flash chromatography on silica gel to give the 8-methyl-6- nonanoic acid (2.1 g, 37% yield from 5 g of the enone product of Example 7). Preparation of capsaicinoids Example 11: Preparation of capsaicin with excess amine in DIPE. At normal atmospheric pressure (approximately 1 atm), 8-methyl-6-nonenoic acid (3.65 g), vanillyl amine (1.1 equiv.), Novozym 435 (tm) on beads (498.8 mg, 14 w/w% E/S) were refluxed (about 69 o C) in diisopropyl ether (45 mL) with a Dean-Stark trap to collect the generated water. After stirring at about 300 rpm overnight (19 h), the mixture was filtered to recover the lipase catalyst, and the filtrate was washed with 0.5 M aqueous HCl solution (10 mL). The aqueous phase was extracted with Et 2 O (10 mL×2) and the organic phase were combined, dried over anhydrous Na 2 SO 4 and concentrated to give 6.53 g product (99.7% yield, very pale yellow color). Example 12: Preparation of nonivamide with excess fatty acid in toluene. At normal atmospheric pressure (approximately 1 atm), Vanillylamine (4.89 g, 2.00 wt% water), nonanoic acid (1.01 equiv.) and Novozym 435 (tm) on beads (1 g, 20 w/w% E/S) were refluxed (about 110 o C) in toluene (50 mL) with a Dean-Stark trap to collect the generated water. After stirring at about 300 rpm overnight (16 h), the conversion of nonanoic acid was >99%. After filtration to recover enzyme catalyst, the mixture was concentrated to give 9.14 g of product (99.6% yield, white color). Example 13: Preparation of nonivamide with excess fatty acid in cyclohexane. At normal atmospheric pressure (approximately 1 atm), Vanillyl amine (4.89 g, 2.00 wt% water), nonanoic acid (1.01 equiv.) and Novozym 435 (tm) on beads (1 g, 20 w/w% E/S) were refluxed (about 81 o C) in cyclohexane (50 mL) with a Dean-Stark trap to collect the generated water. After stirring at about 300 rpm overnight (16 h), the conversion of nonanoic acid was >99%. After filtration to recover enzyme catalyst, the mixture was concentrated to give 9.10 g of product (99.1% yield, pale yellow color). Because the use of lipase on beads is not feasible for large scale production due to costs for work-up, like filtering the lipase, etc., next experiment was performed using lipase immobilized on a rotary bed reactor. Example 14: Preparation of dihydrocapsaicin in fix-bed reactor. At normal atmospheric pressure (approximately 1 atm), In a 1 L reactor equipped with a rotating fix-bed filled with 12 g of Novozym 435 (tm) (45-60 w/w% E/S), vanillylamine, slightly excess 8-methyl nonanoic acid (1.01 equiv), and diisopropyl ether (600 mL) were refluxed (about 69 o C) with a Dean-Stark trap to collect the generated water (Figure 1). During reaction, the rpm was fixed at about 300 rpm. After reaction, the hot solution was released out and cooled to room temperature. The dihydrocapsaicin product crystallized and was collected by filtration. The filtrate was directly recycled as solvent for more batches. The results are shown in Table 1. The yield of dihydrocapsaicin was 99.7% in average. Table 1. Preparation of dihydrocapsaicin in fix-bed reactor The results show good conversion rates and yields even after 6 cycles. Example 15: Preparation of capsaicin in fix-bed reactor (45w/w% E/S). The reactor system of Example 14 was cleaned by refluxing with DIPE solvent to remove residual dihydrocapsaicin. In this reactor, at normal atmospheric pressure (approximately 1 atm), vanillylamine, slightly excess 8-methyl-6-nonenoic acid (1.01 equiv), and diisopropyl ether (600 mL) were refluxed (about 69 o C) with a Dean-Stark trap to collect the generated water. During reaction, the rpm was fixed at about 300 rpm. After reaction, the hot solution was released out and cooled to room temperature. The capsaicin product crystallized and was collected by filtration. The filtrate was directly recycled as solvent for more batches. The results are shown in Table 2. The yield of capsaicin was 99.4% in average. Table 2. Preparation of capsaicin in fix-bed reactor. Amine moisture content of amine Reaction time Conversion Yield The results show good conversion rates and yields even after 5 cycles. Example 16a: Preparation of nonivamide in fix-bed reactor (15-21 w/w% E/S). The reactor system of Example 15 was cleaned by refluxing with DIPE solvent to remove residual capsaicin. In this reactor, at normal atmospheric pressure (approximately 1 atm), vanillylamine, slightly excess nonanoic acid (1.01 equiv), and diisopropyl ether (600 mL) were refluxed (about 69 o C) with a Dean-Stark trap to collect the generated water. During reaction, the rpm was fixed at about 300 rpm. After reaction, the hot solution was released out and cooled to room temperature. The nonivamide product crystallized and was collected by filtration. The filtrate was directly recycled as solvent for more batches. The results are shown in Table 3a. The yield of nonivamide was 99.8% in average. Table 3a. Preparation of nonivamide in fix-bed reactor. The results show good conversion rates and yields even after 11 cycles. Example 16b: Preparation of nonivamide in 100 L fix-bed reactor. At normal atmospheric pressure (approximately 1 atm), in a 100 L reactor equipped with a rotating fix-bed filled with 1 kg of Novozym 435 (tm) (50-100 w/w% E/S), vanillylamine, excess 8-methyl nonanoic acid (1.03 equiv), and diisopropyl ether (90 L) were refluxed (about 69 o C) with a Dean-Stark trap to collect the generated water. During reaction, the rpm was fixed at about 250 rpm. After reaction, the hot solution was released out and cooled to 15 o C. The nonivamide product crystallized and was collected by filtration. The filtrate was directly recycled as solvent for more batches. The results are shown in Table 3b. The results show that the process of the invention can be used for large scale production of amides. Table 3b. Preparation of nonivamide in 100 L fix-bed reactor The results show good conversion rates and yields even after 3 cycles when the process is used at large scale. Comparative examples: Preparation of capsaicin from fatty acid with drying agents Example 17: To a 200 mL reactor, were added in toluene (150 mL), 4 Å molecular sieves (10 g), immobilized enzyme (Novozym 435 (tm) , 0.59 g), 8-methyl-6-nonenoic acid (2.02 g), and vanillylamine (2 equiv). The reaction was conducted at 80 o C and monitored by NMR. After 6 hours, the conversion of acid was >99%. After filtration, the organic filtrate was cooled, successively washed with 1 M HCl (20 mL×2), water (20 mL×2), and brine (20 mL). After drying with anhydrous Na 2 SO 4 , the solvent was removed under vacuum. 3.07 g (84.7% yield) of capsaicin was obtained. Example 18: To a 25 mL flask, were added in t-BuOH (8 mL), 4 Å molecular sieves (600 mg), immobilized enzyme (Novozym 435 (tm) , 75 mg), 8-methyl-6-nonenoic acid (341 g), and vanillylamine (1.06 equiv). The reaction was conducted at 80 o C and monitored by NMR. After 10 hours, the conversion of acid was about 95%. Preparation of capsaicin with ester as acyl donor: Ex ample 19: Preparation of methyl ester.4.73 g of 8-methyl-6-nonenoic acid was dissolved in 30 mL of MeOH. To this solution, 5 drops of concentrated H 2 SO 4 was added as catalyst. The resulting solution was refluxed overnight. After cooling to room temperature, most of MeOH was removed by rotary evaporator and the residue was dissolved in Et 2 O (30 mL) and washed with 5% Na 2 CO 3 solution (10 mL×2). The organic phase was dried with anhydrous Na 2 SO 4 and concentrated to give the ester product with >99% yield. Example 20: Preparation of capsaicin with ester in fix-bed reactor. In a 1 L reactor equipped with a rotating fix-bed filled with 6 g of Novozym 435 (tm) (10-20 w/w% E/S), ethyl ester of 8- methyl 6-nonenoic acid, excess vanillylamine (1.1 equiv), and diisopropyl ether (600 mL) were refluxed. After reaction, the hot solution was released out and cooled to room temperature. The solution was successively washed with 0.5 M HCl (60 mL), water (60 mL), and brine (20 mL). After drying with anhydrous Na 2 SO 4 , the solvent was recovered by rotary evaporation. The capsaicin product was obtained with light yellow color. The results are shown in Table 4. Table 4. Preparation of capsaicin with ester in fix-bed reactor. Example 21: Preparation of capsaicin from ester with distillation apparatus. To a flask equipped with short-path distillation apparatus, 923 mg of methyl ester of 8-methyl-6- nonenoic acid, 200 mg of Novozym 435 (tm) on beads and 1.1 equiv. of vanillylamine were heated at 80 o C in 20 mL of t-BuOH. After 20 hours, the conversion of ester was >99% according to NMR analysis. The results show that using esters is possible, but that the yield is lower compared to earlier examples 14, 15 and 16. An extra process step is needed because the methyl ester is prepared from the corresponding acid. Further, the work-up is tedious when up-scaling. Besides, recycling of the solvent is difficult, which is important for reducing costs and environmental impact of the process at large scale production. Example 22: Preparation of capsaicinoids in neat condition (no solvent). Experimental results are shown in Table 5. Table 5. Preparation of capsaicinoids in neat condition. The results show that the yield of the process is decreased using reduced pressure (Entry 1). Example 23: Preparation of capsaicin with lipase catalyst and without dehydration. Vanillylamine (1 mmol), 8-methyl-6-nonenoic acid (1 mmol), and Novozym 435 (tm) (45 mg) were stirred in toluene (4 mL) and heated at 80 o C for 48 h. 72% conversion was achieved based on NMR analysis. Example 24: Preparation of capsaicin without lipase catalyst and with Dean-Stark distillation. With a Dean-Stark trap to collect generated water, vanillylamine (1 mmol) and 8-methyl-6- nonenoic acid (1 mmol) were refluxed in toluene (4 mL) at 115 o C oil bath for 20 h. 19% conversion was achieved based on NMR analysis. Example 25: Preparation of capsaicin with acid chloride as acyl donor In one 1 L flask, 47.17 g of 8-methyl-6-nonenoic acid was dissolved in 400 mL of anhydrous Et 2 O.30.1 mL of SOCl 2 (1.5 equiv) was dissolved in 100 mL of anhydrous Et 2 O, and slowly added to the acid solution. The resulting solution was refluxing for 3 hours, and then the excess SOCl 2 and solvent were removed under reduced pressure. The resulting acid chloride was then dissolved in 200 mL of anhydrous Et 2 O. To a slurry of 84.7 g vanillylamine (2 equiv) in 400 mL of anhydrous Et 2 O, was added slowly the acid chloride solution in 2 hours. After addition, the refluxing was continued for 2 hours. The mixture was cooled with ice water bath, the precipitate was filtered. The organic filtrate was successively washed with 1 M HCl (50 mL×2), water (50 mL×2), and brine (50 mL). After drying with anhydrous Na 2 SO 4 , the solvent was removed under vacuum.54.3 g (64.2% yield) of capsaicin was obtained. Preparation of miscellaneous amides by the combination of enzymatic catalysis and Dean- Stark distillation. Preparation of (R)-2-methoxy-N-(1-phenylethyl)acetamide Example 26. With a Dean-Stark trap to collect generated water, 1-phenylethan-1-amine (1 mmol), ethyl 2-methoxyacetate (2 mmol), and Novozym 435 (tm) on beads (45 mg) were refluxed in diisopropryl ether (30 mL) at 90 o C oil bath for 10 h. After work up, (R)-2-methoxy- N-(1-phenylethyl)acetamide was obtained with 85% yield and 8% ee. Example 27. With a Dean-Stark trap to collect generated water, 1-phenylethan-1-amine (1 mmol), ethyl 2-methoxyacetate (2 mmol), and Novozym 435 (tm) on beads (45 mg) were refluxed in diisopropryl ether (30 mL) at 90 o C oil bath for 3 h. After work up, (R)-2-methoxy- N-(1-phenylethyl)acetamide was obtained with 75% yield and 55% ee. Example 28. With a Dean-Stark trap to collect generated water, 1-phenylethan-1-amine (1 mmol), ethyl 2-methoxyacetate (2 mmol), and Novozym 435 (tm) on beads (45 mg) were refluxed in diisopropryl ether (30 mL) at 90 o C oil bath for 1 h. After work up, (R)-2-methoxy- N-(1-phenylethyl)acetamide was obtained with 48% yield and 97% ee. Example 29. Preparation of (R)-2-methoxy-N-(1-(4-methoxyphenyl)ethyl)acetamide. With a Dean-Stark trap to collect generated water, 1-(4-methoxyphenyl)ethan-1-amine (1 mmol), ethyl 2-methoxyacetate (2 mmol), and Novozym 435 (tm) on beads (45 mg) were refluxed in diisopropryl ether (30 mL) at 90 o C oil bath for 0.83 h. After work up, (R)-2-methoxy- N-(1-(4-methoxyphenyl)ethyl)acetamide was obtained with 44% yield and 97% ee. Example 30 Preparation of N phenethylnonanamide With a Dean-Stark trap to collect generated water, 2-phenylethan-1-amine (1 mmol), nonanoic acid (1.05 mmol), and Novozym 435 (tm) on beads (45 mg) were refluxed in diisopropryl ether (30 mL) at 90 o C oil bath for 10 h. After work up, N-phenethylnonanamide was obtained with 98% yield. Example 31. Preparation of N-phenethylstearamide. With a Dean-Stark trap to collect generated water, 2-phenylethan-1-amine (1 mmol), stearic acid (1.05 mmol), and Novozym 435 (tm) on beads (45 mg) were refluxed in diisopropryl ether (30 mL) at 90 o C oil bath for 10 h. After work up, N-phenethylstearamide was obtained with 98% yield. The present invention is not limited to the embodiments disclosed but may be varied and modified within the scope of the following claims.