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CA-3208364-C - METHOD FOR MANUFACTURING HETEROCYCLE-CONTAINING AMINO ACID COMPOUND

CA3208364CCA 3208364 CCA3208364 CCA 3208364CCA-3208364-C

Abstract

Provided is a simple method for manufacturing a heterocycle-containing amino acid compound. This heterocycle-containing amino acid compound is manufactured by a method including a step A wherein a compound represented by the formula (2) below [in which R4 is a hydrogen atom or a protective group of a carboxyl group; and n is an integer of 1 to 3] or a salt thereof, acrolein, a cyanating agent, and a compound represented by the formula (3) below [in which R1a is a hydrogen atom or CO2R1b; R1b is a hydrogen atom or a protective group of a carboxyl group; R2a is a hydrogen atom or OR2b; R2b is a hydrogen atom or a protective group of a hydroxyl group; and R3 is a hydrogen atom or a protective group of an amino group] or a salt thereof are reacted.

Inventors

  • Kosuke Namba
  • Akane MERA
  • Motofumi Suzuki

Assignees

  • AICHI STEEL CORPORATION
  • TOKUSHIMA UNIVERSITY

Dates

Publication Date
20260505
Application Date
20211008
Priority Date
20210115

Claims (9)

  1. CLAIMS [Claim 1] A method for producing a compound represented by the following formula (1) or a salt thereof: C02R4 CN R1a (d~N~R2a n I R3 ( 1) wherein: Rla is a hydrogen atom or C02R1b, Rlb is a hydrogen atom or a carboxyl-protecting group, R2a is a hydrogen atom or OR2b, R2b is a hydrogen atom or a hydroxyl-protecting group, R3 is a hydrogen atom or an amino-protecting group, R4 is a hydrogen atom or a carboxyl-protecting group, and n is an integer of 1 to 3, the method comprising: step A of reacting a compound represented by the following formula (2) or a salt thereof: wherein R4 and n are as defined above, acrolein, a cyanating agent, and a compound represented by the following formula (3) or a salt thereof: Date Re9ue/Date Received 2023-07-14 (3) wherein R1a, R2a, and R3 are as defined above.
  2. [Claim 2] A method for producing a compound represented by the following formula (4) or a salt thereof: wherein: R1c is a hydrogen atom or a carboxyl group, R2c is a hydrogen atom or a hydroxyl group, and n is an integer of 1 to 3, the method comprising: step B of converting the cyano group of a compound represented by the following formula (1) or a salt thereof: C02R4 CN R1a ( d~N ~ R2a n I R3 ( 1) wherein: Date Re9ue/Date Received 2023-07-14 Rla is a hydrogen atom or C02R1b, Rlb is a hydrogen atom or a carboxyl-protecting group, R2a is a hydrogen atom or OR2b, R2b is a hydrogen atom or a hydroxyl-protecting group, R3 is a hydrogen atom or an amino-protecting group, R4 is a hydrogen atom or a carboxyl-protecting group, and n is as defined above, into a carboxyl group by hydrolysis.
  3. [Claim 3] The method according to claim 2, wherein the step Bis performed in the presence of an acid.
  4. [Claim 4] The method according to claim 3, wherein the acid is an inorganic acid.
  5. [Claim 5] The method according to claim 3 or 4, wherein the acid is at least one member selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, and nitric acid.
  6. [Claim 6] The method according to any one of claims 2 to 5, wherein: the carboxyl-protecting group is an alkyl group, an alkenyl group, or an aralkyl group, the hydroxyl-protecting group is an alkyl group, an aralkyl group, a silyl group, or a trialkylsilyl group, and the amino-protecting group is an alkoxycarbonyl group, an alkenyloxycarbonyl group, or an aralkyloxycarbonyl group.
  7. [Claim 7] The method according to any one of claims 2 to 6, further Date Re9ue/Date Received 2023-07-14 comprising step A of reacting a compound represented by the following formula (2) or a salt thereof: wherein R4 and n are as defined above, acrolein, a cyanating agent, and a compound represented by the following formula (3) or a salt thereof: (3) wherein R1a, R2a, and R3 are as defined above, to obtain the compound represented by formula (1).
  8. [Claim 8] A compound represented by the following formula (1) or a salt thereof: ( 1) , wherein: Rla is a hydrogen atom or C02R1b, Rlb is a hydrogen atom or a carboxyl-protecting group, Date Re9ue/Date Received 2023-07-14 R2a is a hydrogen atom or OR2b, R2b is a hydrogen atom or a hydroxyl-protecting group, R3 is a hydrogen atom or an amino-protecting group, R4 is a hydrogen atom or a carboxyl-protecting group, and n is an integer of 1 to 3.
  9. [Claim 9] The compound or a salt thereof according to claim 8, wherein: the carboxyl-protecting group is an alkyl group, an alkenyl group, or an aralkyl group, the hydroxyl-protecting group is an alkyl group, an aralkyl group, a silyl group, or a trialkylsilyl group, and the amino-protecting group is an alkoxycarbonyl group, an alkenyloxycarbonyl group, or an aralkyloxycarbonyl group. Date Re9ue/Date Received 2023-07-14

Description

DESCRIPTION Title of Invention: METHOD FOR MANUFACTURING HETEROCYCLE-CONTAINING AMINO ACID COMPOUND Technical Field [0001] The present invention relates to, for example, a method for producing a heterocycle-containing amino acid compound. Background Art [0002] Various trace metal elements are involved in the growth of plants and the maintenance of their functions, and 15 deficiencies of these trace metal elements make normal plant growth impossible. For example, iron is an element necessary for respiration, photosynthesis, DNA synthesis, and the like, and is an active center metal of, in particular, an enzyme that is essential for biosynthesis of chlorophyll. Accordingly, iron 20 deficiency causes chlorosis (iron deficiency chlorosis), in which the leaves turn yellow. [0003] On the other hand, poor soils, which are considered unsuitable for agriculture, account for about 67% of the total 25 land area in the world, and half of such soils is alkaline. In such alkaline soils, iron is present in the form of trivalent ferric hydroxide (Fe(OH)3), which is insoluble in water; plants are thus unable to sufficiently absorb iron from their roots, resulting in iron deficiency. 30 [0004] It is known that graminaceous plants, such as barley, rice, wheat, and corn, secrete from their roots mugineic acids (chelating agents), such as a mugineic acid represented by the following formula (A) and 2'-deoxymugineic acid (DMA) represented 35 by the following formula (B), that the chelating agent forms a Date Rei;:ue/Date Received 2023-07-14 complex with iron to dissolve iron, and that the complex is taken into the plant body via a specific transporter. (H) [0005] This makes it possible to absorb iron ions from alkaline soils. However, since the ability to secrete mugineic acids is typically low, there are also many graminaceous plants that cannot grow in alkaline soils, such as rice and corn. [0006] Accordingly, the present inventors have proposed a heterocycle-containing amino acid compound useful as a chelating agent with iron uptake ability that can be supplied as a fertilizer in order to enable agriculture even in poor alkaline soils (Patent Literature (PTL) 1 and PTL 2). Citation List Patent Literature [0007] PTL 1: Japanese Patent PTL 2: Japanese Patent Summary of Invention Technical Problem [0008] No. 634 7396 No. 6744530 The heterocycle-containing amino acid compound described in PTL 1 and PTL 2 are synthesized by a method comprising the following steps 1 to 4: Step 1: oxidatively cleaving the vinyl group of a compound having a vinyl group at one end and an amino group protected by a 30 protecting group at the other end to give an aldehyde, and reacting the aldehyde with a heterocycle-containing amino acid Date Rei;:ue/Date Received 2023-07-14 (reductive amination reaction); Step 2: protecting the carboxyl group in the reaction product of step 1 and deprotecting the protecting group of the amino group; Step 3: reacting the reaction product of step 2 with a compound 5 having a formyl group at one end and a hydroxyl group protected by a protecting group at the other end; and Step 4: deprotecting the protecting group etc. of the hydroxyl group in the reaction product of step 3. [0009] The above method requires four steps; however, if the synthesis is possible with a smaller number of steps using readily available starting materials, the industrial utility value of the method would be very high. Accordingly, a primary object of the present invention is to provide a simple method for 15 producing a heterocycle-containing amino acid compound. Solution to Problem [0010] As a result of extensive research to achieve the above 20 object, the present inventors have found that a heterocyclecontaining amino acid compound can be simply produced by a method comprising the following steps A and B: step (A) of reacting a compound represented by the following formula (2) or a salt thereof: (wherein R4 is a hydrogen atom or a carboxyl-protecting group, and n is an integer of 1 to 3), acrolein, a cyanating agent, and a compound represented by the 30 following formula (3) or a salt thereof: Date Rei;:ue/Date Received 2023-07-14 (3) (wherein Rla is a hydrogen atom or C02R1b, Rlb is a hydrogen atom or a carboxyl-protecting group, R2a is a hydrogen atom or OR2b, R2b is a hydrogen atom or a hydroxyl-protecting group, and R3 is a hydrogen atom or an amino-protecting group); and step (B) of converting the cyano group of a compound represented by formula (1) or a salt thereof obtained in step A: C02R4 CN R1a (ci~N~R2a n I R3 ( 1) (wherein Rla is a hydrogen atom or C02R1b, Rlb is a hydrogen atom or a carboxyl-protecting group, R2a is a hydrogen atom or OR2b, R2b is a hydrogen atom or a hydroxyl-protecting group, R3 is a hydrogen atom or an amino-protecting group, R4 is a hydrogen atom or a carboxyl-protecting group, and n is as defined above), into a carboxyl group by hydrolysis. 20 The present inventors have conducted further research based on this