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JP-7855817-B2 - Process for enzymatic synthesis of amides from amines and carboxylic acids or esters

JP7855817B2JP 7855817 B2JP7855817 B2JP 7855817B2JP-7855817-B2

Inventors

  • リン、シュアンジェン
  • コルドバ、アルマンド
  • デイアナ、ルカ
  • イブラヘム、イスメイル

Assignees

  • エックスピー ケミストリーズ エービー

Dates

Publication Date
20260511
Application Date
20220428
Priority Date
20210430

Claims (20)

  1. A process for enzymatically synthesizing an amide of formula III from an amine of formula I and a compound of formula II, In the formula , R1 is selected from the group including C5-12aryl and C5-12aryl - C1-6alkyl , R1 may be optionally substituted with one or more substituents selected from the group including hydrogen, hydroxyl, and C1-6 alkoxy . In the formula, R2 is selected from the group including hydrogen, C1-30 alkyl, C1-30 alkenyl , and C1-30 alkoxy . In the formula, R3 is selected from the group including hydrogen and C1-6 alkyl groups . In the formula, R is either a bond or a C1-6 alkyl group. The process involves fixing the lipase in a rotating bed reactor or a spin-fixed bed reactor, and using a Dean-Stark apparatus for dehydration.
  2. In the formula, R1 is selected from the group including C6-7 aryl and C5-7 aryl- C1-3 alkyl. R1 may be optionally substituted with one or more substituents selected from the group including hydrogen, hydroxyl, and C1-3 alkoxy. In the formula, R2 is selected from the group comprising hydrogen, C5-15 alkyl, C5-15 alkenyl, C5-15 alkoxy , and C5-15 alkyl-O- C1-6 alkyl . In the formula, R3 is selected from the group including hydrogen and C1-3 alkyl groups . The process according to claim 1, wherein R is a bond or a C1-3 alkyl group.
  3. In the formula, R1 is C5-7aryl - C1-3alkyl , R1 may be optionally substituted with one or more substituents selected from the group including hydrogen, hydroxyl, and C1-3 alkoxy. In the formula, R2 is selected from the group including C5-16 alkyl and C5-15 alkenyl. In the formula, R3 is hydrogen, methyl, or ethyl. The process according to claim 1, wherein R is a bond.
  4. The compound of formula III is the compound of formula IV, IV In the formula, n is either 1 or 2. In the formula, R2 is selected from the group comprising hydrogen, C3-30 alkyl , and C3-30 alkenyl . In the formula, R4 or R5 is selected from the group including hydrogen and C1-6 alkyl groups . In the formula, R 6 is selected from the group comprising hydrogen, hydroxyl, oxy, halogen, carboxyl, amine, amide, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, and C5-12 aryl. The process according to claim 1, wherein R 6 may optionally be substituted with one or more substituents selected from the group comprising hydrogen, hydroxyl, and C1-6 alkoxy.
  5. The compound of formula III is the compound of formula IV, IV In the formula, n is either 1 or 2. In the formula, R2 is selected from the group including C3-18 alkyl and C3-18 alkenyl. In the formula, R4 or R5 is selected from the group including hydrogen and C1-6 alkyl groups. The process according to claim 4, wherein R6 is hydrogen.
  6. The compound of formula III is the compound of formula IV, IV In the formula, n is either 1 or 2. In the formula, R2 is selected from the group including C5-16 alkyl and C5-15 alkenyl, In the formula, R4 or R5 is selected from the group including hydrogen and C1-3 alkyl groups. The process according to claim 4, wherein R6 is hydrogen.
  7. To enzymatically synthesize the amide of formula III from the amine of formula I and the compound of formula IIa, In the formula , R1 is selected from the group including C5-12aryl and C5-12aryl - C1-6alkyl , R1 may be optionally substituted with one or more substituents selected from the group including hydrogen, hydroxyl, and C1-6 alkoxy . In the formula, R2 is selected from the group including hydrogen, C1-30 alkyl, C1-30 alkenyl , and C1-30 alkoxy . In the formula, R3 is selected from the group including hydrogen and C1-6 alkyl groups . The process according to claim 1, wherein the lipase is fixed in a rotating bed reactor or a spin-fixed bed reactor, and a Dean-Stark apparatus is used for dehydration.
  8. In the formula, R1 is C5-7aryl - C1-3alkyl , R1 may be optionally substituted with one or more substituents selected from the group including hydrogen, hydroxyl, and C1-3 alkoxy. In the formula, R2 is a C5-15 alkyl and a C5-15 alkenyl. In the formula, R3 is hydrogen, methyl, or ethyl. The process according to claim 7.
  9. The process according to claim 1, wherein no solvent is used, or the solvent is an organic solvent selected from the group comprising methyl tert-butyl ether, diisopropyl ether, C1-6 alkyl-O- C1-6 alkyl ether, hexane and other C5-10 alkanes, cyclohexane and other C5-10 cycloalkanes, benzene, toluene, xylene, tert-butanol, tert-amyl alcohol, and other bulky secondary or tertiary C5-10 alcohols and any esters thereof or mixtures thereof.
  10. The process according to claim 1, wherein no solvent is used, or the solvent is an organic solvent selected from the group comprising diisopropyl ether, cyclohexane, toluene, or tert-butanol, or mixtures thereof.
  11. The process according to claim 1, wherein the lipase is selected from the group comprising Candida antarcticalipase A, Candida antarcticalipase B, cross-linked subtilisin A protease, porcine pancreatic lipase, Candida cylindracea lipase, Rhizopus arghiz, Penicillium cyclopium, Mucormiehei, Thermomyces lanuginosa lipase, Candida rugosa lipase, and Pseudomonas lipoprotein lipase.
  12. The process according to claim 1, wherein the lipase is Candida antarcticalipase.
  13. The process according to claim 1, wherein the process temperature is between room temperature and 150°C, and the pressure is between 0.09 and 0.200 MPa, or about 0.1 MPa.
  14. The process according to claim 1, wherein the process is carried out at atmospheric pressure and a temperature below 100°C.
  15. The process according to claim 1, wherein the rotating bed reactor is loaded with 10 to 75 wt% of the lipase.
  16. In the compound of formula II, R2 is a C6-18 alkyl or C6-18 alkenyl, which may be linear or branched, and is prepared by the following steps: Step A-1: Here the reaction is carried out using no solvent or an organic solvent. Step B-1, here the solvent is an aprotic organic solvent. Step B-1, here the base is sodium or potassium alkoxide. The process according to claim 1, optionally comprising isomerization step C-1, where the catalyst is selected from the group including combinations of NaNO2 / HNO3 , NaNO2 / NaNO3 / H2SO4 , which can produce HNO2 or HNO3 , and hydrogenation step D- 1 , where the catalyst is a heterogeneous hydrogenation catalyst and the hydrogen source is hydrogen gas.
  17. The organic solvent in step A-1 is ethyl acetate. The aprotic organic solvent in step B-1 is selected from the group including 2-methyltetrahydrofuran, tetrahydrofuran, and toluene. Here, the sodium or potassium alkoxide base in step B-1 is selected from the group including NaH, KH, t-BuOK, and t-BuONa. The process according to claim 16 , wherein the heterogeneous hydrogenation catalyst in hydrogenation step D-1 is selected from the group comprising Pd/C and Pd/ Al₂O₃ .
  18. In the compound of formula II, R2 is 8-methylnonanyl, and it is prepared by the following steps: Step A-2: The reaction is carried out without a solvent or using any organic solvent, and the catalyst is selected from the group including amines and inorganic bases. Step B-2: The reaction is carried out using no solvent or an organic solvent, and the catalyst is an acid. In stage C-2, the catalyst is a heterogeneous hydrogenation catalyst, and the hydrogen source is hydrogen gas. The process according to claim 1, wherein in step D-2, the oxidizing agent is a peroxide and the catalyst is a lipase, and in step E-2, the reaction medium is an acidic solvent, and in step F-2, the catalyst is a heterogeneous hydrogenation catalyst and the hydrogen source is hydrogen gas.
  19. The organic solvent in step A-2 is selected from the group including toluene, and the catalyst is selected from the group including pyrrolidine and its corresponding salt, NaOH and KOH. The organic solvent in step B-2 is selected from the group including toluene, and the acid is selected from the group including p-TsOH, sulfuric acid, and amberlist-15. The catalyst in step C-2 is selected from the group including Pd/C and Pd/ Al₂O₃ . The oxidizing agent in step D-2 is selected from the group comprising H₂O₂ aqueous solution and peracids, and the lipase is selected from the group comprising Candida antarcticalipase A, Candida antarcticalipase B, cross-linked subtilisin A protease, porcine pancreatic lipase, Candida cylindracea lipase, Rhizopus arghiz, Penicillium cyclopium, Mucormiehei, Thermomyces lanuginosa lipase, Candida rugosa lipase, and Pseudomonas lipoprotein lipase. The reaction medium in step E-2 is selected from the group including aqueous sulfuric acid solution. The process according to claim 18 , wherein the catalyst in step F-2 is selected from the group comprising Pd/C, Pd/ Al₂O₃ , Pd/molecular sieve, Pt/C, Pt/ Al₂O₃ , and Pt /molecular sieve.
  20. The process according to claim 1 for large-scale production (>1 kg) of the compound of formula III.

Description

This invention relates to a process for enzymatically synthesizing amides from amines and carboxylic acids or esters using lipase. Amide bonds are crucial in the development of many compounds, including pharmaceuticals and polymers. Several processes for direct catalytic amidation have been developed over the years. In thermal amidation, a catalyst may not be necessary. This process is carried out at high temperatures (>140°C), and the yield depends on the temperature used, the substrate concentration, the solvent used, and other parameters. Metal-based amidation is carried out using boron-based or palladium-based catalysts. Compared to thermal amidation, higher yields can be obtained, but the process is expensive and time-consuming. Catalyst and solvent recycling presents challenges. Thermal or metal-based amidation is not an environmentally friendly process. Several attempts have been made to improve process efficiency and reduce costs and carbon footprint. In the amidation process, water must be removed to improve the process yield. Therefore, most amidation processes are carried out under reduced pressure. This increases costs and therefore makes large-scale amidation more difficult. Molecular sieves can also be used, but they are still expensive for large-scale use. Dean-Stark apparatuses can also be used to remove water from the amidation process. Enzymatic amidation has been developed over many years using different types of enzymes, such as lipases. These so-called biocatalysts are available at low temperatures and exhibit good selectivity. However, modern techniques exhibit a very limited substrate range and frequently require long reaction times (several days). Combining enzymatic amidation with a palladium catalyst can yield approximately 70% yield, as demonstrated by Palo-Nieto et al., ACS Catal., 2016, 6, 3932-3940. Another drawback of biocatalysts is cost. To reduce costs and improve the efficiency of the amidation process, enzymes can be immobilized, for example, on the reaction bead during the reaction. This allows for enzyme recycling. The use of flow reactors has further improved the biocatalytic amidation process. However, lipase recycling is inefficient in terms of both time and cost. To date, no environmentally friendly catalytic amidation process exists that is sufficiently efficient, cost-effective, and suitable for large-scale production. This is a top priority at the American Chemical Society's Green Chemistry Pharmaceutical Roundtable (https://www.acsgcipr.org). Currently, most methods utilize stoichiometric amounts of toxic activating reagents (Dunetz et al. Org. Process. Res. Dev. 2016, 20, 140). Therefore, a more environmentally friendly and cost-effective amidation process suitable for large-scale use is still needed. Capsaicinoids are commonly used in environmentally friendly foods. Capsaicin is also widely used in the pharmaceutical industry. For example, capsaicin is used as an analgesic in topical ointments and skin patches to relieve mild muscle and joint pain and soreness associated with arthritis, back pain, bruises, and sprains, or to alleviate symptoms of peripheral neuropathy. Capsaicinoids can be isolated from natural sources (e.g., the fruit of the Capsicum genus), but this mainly produces capsaicin and dihydrocapsaicin because many other capsaicinoids are present only in trace amounts. Therefore, chemical synthesis is useful for obtaining rarer capsaicinoids such as nonibamide and for producing non-natural capsaicinoids. Capsaicinoids can be prepared from vanillin by first reducing vanillin oxime under reflux using a mixture of excess metal (Zn) and ammonium formate in methanol to obtain vanillylamine. Alternatively, amide bond formation can be achieved by enzymatic catalytic conversion between vanillylamine and various fatty acid derivatives. WO2015/144902A1 discloses a multi-catalyst cascade relay sequence that includes an enzyme cascade system that, when integrated with other catalytic systems such as heterogeneous metal catalysts and organic catalysts, sequentially or in a one-pot manner converts alcohols to amines and amides. US2017081277A1 discloses an amidation using a dialkylamine as a substrate. Novozyme 435 ™ , immobilized on a bead, is used. A Dean-Stark apparatus may be used to remove ethanol from the reaction mixture. The reaction is carried out under reduced pressure. For large-scale production, the bead is unsuitable because separating the bead from the reaction mixture is costly and time-consuming. Furthermore, for large-scale production, pressure reduction is preferable to avoid in order to reduce the overall cost and time of the process. US6022718 discloses a process for preparing capsaicin analogs using hydrolysis and capsaicin as starting materials. Pithani S., *Using spinchem rotation bed reactor technology for immobilized enzyme reactions: a case study*, Org. Process Res. Dev., 2019, vol. 23, pages 1926–1931, discloses the advantages of using