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Aromatic Compound Containing Specific Branch

Abstract: The present invention provides an aromatic compound containing a sOecinc branch hi s aromatic compound containing a specific branch i s easily soluble in isopropyl acetate, which is excellent for separating liquids, and can be used for a method for producing peptides etc. that lead to the final product through extraction and separation only, without crystallization and isolation of each intermediate in each step.

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Patent Information

Application #
Filing Date
01 March 2013
Publication Number
44/2014
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application
Patent Number
Legal Status
Grant Date
2023-03-03
Renewal Date

Applicants

AJINOMOTO CO. INC.
15 1 Kyobashi 1 chome Chuo ku Tokyo 1048315

Inventors

1. TAKAHASHI Daisuke
c/o AJINOMOTO CO. INC. 1730 Oaza hinaga Yokkaichi shi Mie 5100885

Specification

DESCRIPTION AROMATIC COMPOUND CONTAINING SPECIFIC BRANCH Technical Field [0001] 5 The present invention relates to an aromatic compound containing a particular branched chain. The present invention further relates to a protecting reagent containing the compound or an adduct thereof. The present invention also relates to a production method of peptide by using the 10 compound, and further relates to an organic synthesis method including the production method of the peptide. Background Art [0002] The production methods of peptide are generally divided 15 into solid phase methods and liquid phase methods. The solid phase methods are advantageous since isolation and purification after reaction can be performed by only washing resin. However, they are associated with problems in that the reaction is essentially that of heterogeneous phases, reaction 20 agents and reagents need to be used in excess to compensate for the low reactivity, and tracing of reaction and analysis of reaction product supported by carrier are difficult. On the other hand, the liquid phase method is advantage since it shows good reactivity, and intermediate peptide can be 25 purified by extraction and washing, isolation and the like after condensation reaction. However, the method is associated with problems since the production step is complicated due to an extraction and washing step with a nonpolar organic solvent and an acidic or basic aqueous solution to remove residual 30 reagents and/or byproducts in each step of coupling reaction and deprotection, and/or an isolation and purification step such as crystallization and the like, and the like. [0003] In recent years, approaches to improve the problems of 35 the aforementioned two methods have been ongoing. 1 Patent document 1 and non-patent document 1 each disclose a method using a 3,4,5-tris(n-octadecyloxy)benzyl alcohol type compound as a protecting reagent of carboxyl group and the like. Patent documents 2 - 4 each disclose a 3,5- 5 di(docosyloxy)benzyl alcohol type compound, a 2,4- di(docosyloxy)benzyl alcohol type compound, a trityl type compound and the like as protecting reagents. Using these protecting reagents, the reaction can be performed in a homogeneous liquid phase, a precipitate can be produced by 10 changing the solvent composition after the reaction, which can be isolated and purified by filtration and washing alone. However, use of these protecting reagents is associated with problems in that a reaction solvent evaporation step for precipitation is required, a long time is necessary for a 15 precipitate filtration step, and these protecting reagents are insoluble or slightly-soluble in acetate ester or toluene. Therefore, the methods disclosed in the above-mentioned documents are not entirely industrially universal methods. [0004] 20 Patent document 5 introduces an example of a peptide synthesis reaction using a 3,4,5-tris(n-octadecyloxy)benzyl alcohol type compound as a protecting reagent. However, the document only discloses an example of a specific layerseparating separation of organic solvents under dilute 25 conditions, and this example is not entirely an industrially universal method. [Document List] [patent documents] [0005] 30 patent document 1: JP-A-2000-44493 patent document 2: WO2006/104166 patent document 3: WO2007/034812 patent document 4: WO2007/122847 patent document 5: WO2003/018188 35 [non-patent document] 2 [0006] non-patent document 1: Bull. Chem. Soc. Jpn 74, 733-738(2001) [SUMMARY OF THE INVENTION] Problems to be Solved by the Invention 5 [0007] The problem of the present invention is to provide a novel compound which is easily-soluble in isopropyl acetate superior in liquid-separating operability, and usable for a production method of peptide and the like which leads to a 10 final product simply by extraction separation without crystallization and isolation of each intermediate in each step (one-pot synthesis method). Means of Solving the Problems [0008] 15 The present inventors have conducted intensive studies and found that the aforementioned problems can be solved by a particular branched chain-containing aromatic compound, which resulted in the completion of the present invention. The present invention includes the following embodiments. 20 [0009] [1] A branched chain-containing aromatic compound represented by the formula (I): [0010] 25 [0011] wherein Q in the number of k are each a single bond, or -0-, -S-, - C(=0)0-, -C(=0)NH- or -NH-; Ra in the number of k are each independently an organic group 30 having at least one aliphatic hydrocarbon group having one or more branched chains, a total number of the branched chain of 3 not less than 3 and a total carbon number of not less than 14 and not more than 300; k is an integer of 1 - 4; Ri is a hydrogen atom or, when Z is a group represented by the 5 following formula (a), it optionally shows a single bond together with R2 to form a fluorene ring together with ring B; ring A optionally further has, in addition to Ri, QRa in the number of k, and C(X)(Y)Z, substituent(s) selected from the group consisting of a halogen atom, a Ci-g alkyl group 10 optionally substituted by one or more halogen atoms, and a Ci-g alkoxy group optionally substituted by one or more halogen atoms; X is a hydrogen atom or a phenyl group; Y is a hydroxyl group or an -NHR group (R is a hydrogen atom, 15 an alkyl group or an aralkyl group); and Z is a hydrogen atom or a group represented by the formula (a): [0012] * r ^ (a) 20 [0013] wherein * shows a bonding position; m is an integer of 0 - 4; Q in the number of m are as defined above; Rb in the number of m are each independently an organic group 25 having at least one aliphatic hydrocarbon group having one or more branched chains, a total number of the branched chain of not less than 3 and a total carbon number of not less than 14 and not more than 300; R2 is a hydrogen atom, or optionally shows a single bond 30 together with Ri to form a fluorene ring together with ring A; and ring B optionally further has, in addition to QRb in the number of m, and R2, substituent(s) selected from the group consisting 4 of a halogen atom, a Ci-s alkyl group optionally substituted by one or more halogen atoms, and a Ci-e alkoxy group optionally substituted by one or more halogen atoms); the organic group having at least one aliphatic hydrocarbon 5 group having one or more branched chains, a total number of the branched chain of not less than 3 and a total carbon number of not less than 14 and not more than 300 for the aforementioned Ra and Rb is a group having 3 or more the same or different divalent groups, which is represented by the 10 formula (b): [0014] R3 R4 (b) [0015] wherein * shows a bonding position with the adjacent atom; 15 R3 and R4 are each independently a hydrogen atom or a C1-4 alkyl group; Xi is a single bond, a C1-4 alkylene group or an oxygen atom, provided that R3 and R4 are not hydrogen atoms at the same time. [2] The branched chain-containing aromatic compound of the 20 aforementioned [1], wherein the organic group having at least one aliphatic hydrocarbon group having one or more branched chains, a total number of the branched chain of not less than 3 and a total carbon number of not less than 14 and not more than 300 for the aforementioned Ra and Rb is a group 25 represented by the formula (c): [0016] R7 1' R5—C-^ "~ ^^^^^-"""^Rio (c) RB RB [0017] wherein * shows a bonding position to Q; 30 R5 and Re are both hydrogen atoms, or taken together to show =0; 5 no is an integer of 2 - 40; R7 and Rg in the number of no are each independently a hydrogen atom or a Ci_4 alkyl group; X2 in the number of no are each independently a single bond or . 5 a Ci-4 alkylene group; and R9 is a hydrogen atom or a C1-4 alkyl group; Rio is a Ci-4 alkyl group or the formula (I'): [0018] A' ^ ^ ik (I') ^^/^ Q* 10 [0019] wherein * shows a bonding position; other symbols are as defined above, and ring A' optionally has, in addition to Ri, Q, and C(X) (Y)Z, substituent (s) selected from the group consisting of a halogen atom, a Ci-e alkyl group 15 optionally substituted by one or more halogen atoms, and a Ci-e alkoxy group optionally substituted by one or more halogen atoms, provided that R7 and Re are not hydrogen atoms at the same time, and when no is 2, Rg is a C1-4 alkyl group. 20 [3] The branched chain-containing aromatic compound of the aforementioned [2], wherein, in the aforementioned formula (c), R5 and Re are both hydrogen atoms; R7 and Rs in the number of no are each independently a hydrogen atom, a methyl group or an ethyl group; 25 X2 in the number of no are each independently a single bond, a methylene group or an ethylene group; and R9 is a hydrogen atom, a methyl group or an ethyl group. [4] The branched chain-containing aromatic compound of the aforementioned [1], wherein the organic group having at least 30 one aliphatic hydrocarbon group having one or more branched chains, a total number of the branched chain of not less than 6 3 and a total carbon number of not less than 14 and not more than 300 for the aforementioned Ra and Rb is a group represented by the formula (d): [0020] 5 \^^~(QRll)m1 [0021] wherein * shows a bonding position to Q; ORii in the number of mi is a hydroxyl group substituted by a group represented by the formula (c'): 10 [0022] r R 1 ^^ R5—,0^"^^^"^ ^^~~^^ R10 (C) Re Rs [0023] wherein * shows a bonding position to 0; R5 and Rg are both hydrogen atoms, or taken together show =0; 15 no is an integer of 2 - 40; R7 and Rs in the number of no are each independently a hydrogen atom or a C1-4 alkyl group; X2 in the number of no are each independently a single bond or a Ci-4 alkylene group; and 20 R9 is a hydrogen atom or a C1-4 alkyl group; Rio is a Ci-4 alkyl group or a group represented by the formula (I'): [0024] X A' \l ^^/''"^ Q 25 [0025] wherein * shows a bonding position; other symbols are as defined above, and ring A' optionally has, in addition to Ri, Q, and C(X) (Y)Z, substituent (s) selected from the group consisting of a halogen atom, a Ci-6 alkyl group 7 optionally substituted by one or more halogen atoms, and a Ci-e alkoxy group optionally substituted by one or more halogen atoms, provided that R7 and Rs are not hydrogen atoms at the same time, 5 and when no is 2, R9 is a C1-4 alkyl group; and mi is an integer of 1 - 3. [5] The branched chain-containing aromatic compound of the aforementioned [1], wherein the organic group having at least one aliphatic hydrocarbon group having one or more branched 10 chains, a total number of the branched chain of not less than 3 and a total carbon number of not less than 14 and not more than 300 for the aforementioned Ra and Rb is a group represented by the formula (e): [0026] R r '^isn r p -, Ri9 K12 Kl7 [0027] wherein * shows a bonding position to Q; ni is an integer of 1 - 10; n2 is an integer of 1 - 10; 20 Ri5 and Rie in the number of ni are each independently a hydrogen atom or a C1-4 alkyl group; X3 in the number of ni is a single bond or a C1-4 alkylene group; Ri7 and Ris in the number of n2 are each independently a 25 hydrogen atom or a C1-4 alkyl group; X5 in the number of n2 is a single bond or a C1-4 alkylene group; X4 is a single bond or a C1-4 alkylene group; and RI2A Ri3f Ri4f Ri9, R20 and R21 are each independently a hydrogen 30 atom or a C1-4 alkyl group, provided when R15 and Rie, and/or R17 and Ris are not hydrogen atoms at the same time, and when ni+n2 is 2, then two or more of R12, Ri3 and R14 are each independently a C1-4 alkyl group, or 8 two or more of Rig, R20 and R21 are each independently a C1-4 alkyl group. [6] The branched chain-containing aromatic compound of the aforementioned [5], wherein, in the aforementioned formula (e), 5 ni is an integer of 1 - 5; n2 is an integer of 1 - 5; Ri5 and Rie in the number of ni are each independently a hydrogen atom, a methyl group or an ethyl group; X3 in the number of ni is a single bond, a methylene group or 10 an ethylene group; Ri7 and Ris in the number of na are each independently a hydrogen atom, a methyl group or an ethyl group; X5 in the number of n2 is a single bond, a methylene group or an ethylene group; and 15 X4 is a single bond, a methylene group or an ethylene group. [7] The branched chain-containing aromatic compound of the aforementioned [6], wherein, in the aforementioned formula (e), Ri5 and Rig in the number of ni are each independently a hydrogen atom or a methyl group; 20 X3 in the number of ni is a single bond or a methylene group; Ri7 and Ris in the number of n2 are each independently a hydrogen atom or a methyl group; X5 in the number of n2 is a single bond or a methylene group; X4 is a single bond or a methylene group; and 25 RI2A RI3/ Ri4f RI9A R20 and R21 are each a methyl group. [8] The branched chain-containing aromatic compound of the aforementioned [1], wherein Ra and Rb are each independently a 3,7,11,15-tetramethylhexadecyl group, a 3,7,11- trimethyldodecyl group, a 2,2,4,8,10,lO-hexamethyl-5- 30 dodecanoyl group, a 3,4,5-tri(3',7',11',15'- tetramethylhexadecyloxy)benzyl group, a 3,5-di(3',7',11',15'- tetramethylhexadecyloxy)benzyl group, a group represented by the formula (f): [0028] 9 * [ L Rio (f^ [0029] wherein * shows a bonding position to Q, nio is 23 - 34, Rio is a group represented by the formula (I'): 5 [0030] X [0031] wherein * shows a bonding position; and other symbols are as defined above, wherein ring A' optionally has, in addition to 10 Ri, Q, and C(X)(Y)Z, substituent(s) selected from the group consisting of a halogen atom, a Ci-g alkyl group optionally substituted by one or more halogen atoms, and a Ci-e alkoxy group optionally substituted by one or more halogen atoms, a group represented by the formula (g): 15 [0032] L J "11 [0033] wherein * shows a bonding position to Q, and nn is 1 - 10, a group represented by the formula (h): 20 [0034] U Jni2 (h) [0035] 10 wherein * shows a bonding position to Q, and ni2 is 2 - 10, a group represented by the formula (i): [0036] * k ^ o ^ ^ / ^ 0 J X ^ J ^ * (i) "13 "14' 5 [0037] wherein * shows a bonding position to Q, and ni3 and ni4 are each independently 1 - 10, or a group represented by the formula (j): [0038] JLJ L J "15 (j) •J.Q CgHig [0039] wherein * shows a bonding position to Q, and nis is 2 - 20. [9] The branched chain-containing aromatic compound of any one of the aforementioned [1] - [8], wherein X and Z are both 15 hydrogen atoms, and Ri is a hydrogen atom. [10] The branched chain-containing aromatic compound of any one of the aforementioned [1] - [8], wherein X is a hydrogen atom, Ri is a hydrogen atom, k is 1, and Z is a group represented by the formula (a) {R2 is a hydrogen atom, and m is 20 0) . [11] The branched chain-containing aromatic compound of any one of the aforementioned [1] - [8], wherein X is a phenyl group, k is 1, Z is a group represented by the formula (a) (m is 0) , and R2 is a single bond together with Ri to form a 25 fluorene ring with ring A. [12] The branched chain-containing aromatic compound of any one of the aforementioned [1] - [11], wherein Q is -0-. [13] The branched chain-containing aromatic compound of any one of the aforementioned [1] - [12], wherein Y is a hydroxyl 30 group. 11 [14] The branched chain-containing aromatic compound of any one of the aforementioned [1] - [12], wherein Y is an -NHR group. [15] The branched chain-containing aromatic compound of the 5 aforementioned [1], which is selected from the group consisting of 2,4-di(2',3'-dihydrophytyloxy)benzyl alcohol; 3,5-di(2',3'-dihydrophytyloxy)benzyl alcohol; 4-(2',3'-dihydrophytyloxy)benzyl alcohol; 1-[(2-chloro-5-(2',3'-dihydrophytyloxy)phenyl)]-1- 10 phenylmethanamine; 3,4,5-tri(2',3'-dihydrophytyloxy)benzyl alcohol; 3,4,5-tri(2',3'-dihydrophytyloxy)benzylamine; 4-(2',3'-dihydrophytyloxy)benzylamine; 2-[3',4',5'-tri(2",3"-dihydrophytyloxy)benzyloxy]-4- 15 methoxybenzyl alcohol; 4-(2',3'-dihydrophytyloxy)-2-methoxybenzyl alcohol; 4-(2',3'-dihydrophytyloxy)-2-methoxybenzylamine; 4-(2',3'-dihydrophytyloxy)-2-methylbenzyl alcohol; 4-(2',3'-dihydrophytyloxy)-2-methylbenzylamine; 20 2,2,4,8,10,lO-hexamethyl-5-dodecanoic acid (4- hydroxymethyl)phenylamide; 4-(3,7,11-trimethyldodecyloxy)benzyl alcohol; 2-(3,7,11-trimethyldodecyloxy)-9-phenylfluoren-9-ol; a compound represented by the formula: 25 [0040] OMe OMe [0041] wherein nie is 23 or 34; a compound represented by the formula: 30 [0042] 12 [0043] wherein ni7 is 23 or 34; a compound represented by the formula: 5 [0044] •J "18 1^ OH [0045] wherein nig is 5 - 7; and a compound represented by the formula: 10 [0046] O U J2 [0047] [16] The branched chain-containing aromatic compound of any one of the aforementioned [1] - [15], which shows a saturation 15 solubility in isopropyl acetate (100 g) at 20°C of 1 - 95 wt%. [17] The branched chain-containing aromatic compound of any one of the aforementioned [1] - [15], which shows a saturation solubility in isopropyl acetate (100 g) at 20°C of 10 - 95 wt%. [18] A protecting reagent for a carboxyl group or an amido 20 group of amino acid or peptide, comprising the branched chaincontaining aromatic compound of any one of the aforementioned [1] - [17]. [19] The protecting reagent of the aforementioned [18], wherein the amino acid or peptide is protected at the C- 13 terminus. [20] A branched chain-containing aromatic compound adduct which is protected by the branched chain-containing aromatic compound of any one of the aforementioned [1] - [17]. 5 [21] A method of producing a peptide comprising steps (1) - (4); (1) a step of condensing the branched chain-containing aromatic compound of any one of the aforementioned [1] - [17] with a C-terminus of an N-protected amino acid or an N- 10 protected peptide in a solvent solubilizing the compound to give an N-protected C-protected amino acid or N-protected Cprotected peptide having a C-terminus protected with an anchor which is a protecting group derived from the compound, (2) a step of removing the N-terminal protecting group from 15 the obtained N-protected C-protected amino acid or N-protected C-protected peptide to give a C-protected amino acid or Cprotected peptide, (3) a step of condensing an N-protected amino acid or Nprotected peptide with the N-terminus of the obtained C- 20 protected amino acid or C-protected peptide to give an Nprotected C-protected peptide, and (4) a step of removing the N-terminal protecting group and the C-terminal anchor from the obtained N-protected C-protected peptide to give a peptide. 25 [22] The method of the aforementioned [21] , further comprising one or more repetitions of steps (5) - (7); (5) a step of removing the N-terminal protecting group of the obtained N-protected C-protected peptide to give a C-protected peptide, 30 (6) a step of condensing N-protected amino acid or N-protected peptide with the N-terminus of the obtained C-protected peptide to give an N-protected C-protected peptide, and (7) a step of adding water to the reaction system after step (6), and separating the impurity by extraction into an aqueous 35 layer. 14 [23] The method of the aforementioned [21], further comprising one or more repetitions of steps (5) - [!')} (5) a step of removing the N-terminal protecting group of the obtained N-protected C-protected peptide to give a C-protected 5 peptide, (6) a step of condensing N-protected amino acid or N-protected peptide with the N-terminus of the obtained C-protected peptide to give an N-protected C-protected peptide, and (7') a step of adding a hydrophilic organic solvent to the 10 reaction system after step (6), and separating the impurity by extraction into a hydrophilic organic solvent layer. [24] An organic synthesis method comprising the peptide production method of any one of the aforementioned [21] - [23]. [25] A branched chain-containing aromatic compound represented 15 by the formula (I): [0048] [0049] wherein 20 Q in the number of k are each a single bond, or -0-, -S-, - C(=0)0-, -C(=0)NH- or -NH-; Ra in the number of k are each independently an organic group having at least one aliphatic hydrocarbon group having one or more branched chains, a total number of the branched chain of 25 not less than 3 and a total carbon number of not less than 14 and not more than 300; k is an integer of 1 - 4; Ri is a hydrogen atom or, when Z is a group represented by the following formula (a), it optionally shows a single bond 30 together with R2 to form a fluorene ring together with ring B; ring A optionally further has, in addition to Ri, QRa in the number of k, and C(X)(Y)Z, substituent(s) selected from the 15 group consisting of a halogen atom, a Ci-e alkyl group optionally substituted by one or more halogen atoms, and a Ci-g alkoxy group optionally substituted by one or more halogen atoms; 5 X is a hydrogen atom or a phenyl group; Y is a hydroxyl group, an -NHR group (wherein R is a hydrogen atom, an alkyl group, or an aralkyl group), or a halogen atom (preferably halogen atom); and Z is a hydrogen atom or a group represented by the formula 10 (a) : [0050] [0051] wherein * shows a bonding position; 15 m is an integer of 0 - 4; Q in the number of m are as defined above; Rb in the number of m are each independently an organic group having at least one aliphatic hydrocarbon group having one or more branched chains, a total number of the branched chain of 20 not less than 3 and a total carbon number of not less than 14 and not more than 300; R2 is a hydrogen atom, or optionally shows a single bond together with Ri to form a fluorene ring together with ring A; and 25 ring B optionally further has, in addition to QRb in the niomber of m, and R2, substituent(s) selected from the group consisting of a halogen atom, a Ci-e alkyl group optionally substituted by one or more halogen atoms, and a Ci-e alkoxy group optionally substituted by one or more halogen atoms); 30 the organic group having at least one aliphatic hydrocarbon group having one or more branched chains, a total number of the branched chain of not less than 3 and a total carbon number of not less than 14 and not more than 300 for the 16 aforementioned Ra and Rb is a group having 3 or more the same or different divalent groups, which is represented by the formula (b): [0052] R3 5 R4 (b) [0053] wherein * shows a bonding position with the adjacent atom; R3 and R4 are each independently a hydrogen atom or a C1-4 alkyl group; 10 Xi is a single bond, a C1-4 alkylene group or an oxygen atom, provided that R3 and R4 are not hydrogen atoms at the same time. [26] A protecting reagent for a carboxyl group or an amido group of amino acid or peptide, comprising the branched chaincontaining aromatic compound of the aforementioned [25]. 15 [27] A branched chain-containing aromatic compound adduct which is protected by the branched chain-containing aromatic compound of the aforementioned [25]. [28] A method of producing a peptide comprising steps (1) - (4); 20 (1) a step of condensing the branched chain-containing aromatic compound of the aforementioned [25] with a C-terminus of an N-protected amino acid or an N-protected peptide in a solvent solubilizing the compound to give an N-protected Cprotected amino acid or N-protected C-protected peptide having 25 a C-terminus protected with an anchor which is a protecting group derived from the compound, (2) a step of removing the N-terminal protecting group from the obtained N-protected C-protected amino acid or N-protected C-protected peptide to give a C-protected amino acid or C- 30 protected peptide, (3) a step of condensing an N-protected amino acid or Nprotected peptide with the N-terminus of the obtained Cprotected amino acid or C-protected peptide to give an N- 17 protected C-protected peptide, and (4) a step of removing the N-terminal protecting group and the C-terminal anchor from the obtained N-protected C-protected peptide to give a peptide. 5 [29] The method of the aforementioned [28], further comprising one or more repetitions of steps (5) - (7); (5) a step of removing the N-terminal protecting group of the obtained N-protected C-protected peptide to give a C-protected peptide, 10 (6) a step of condensing N-protected amino acid or N-protected peptide with the N-terminus of the obtained C-protected peptide to give an N-protected C-protected peptide, and (7) a step of adding water to the reaction system after step (6), and separating the impurity by extraction into an agueous 15 layer. [30] The method of the aforementioned [28], further comprising one or more repetitions of steps (5) - [1')} (5) a step of removing the N-terminal protecting group of the obtained N-protected C-protected peptide to give a C-protected 20 peptide, (6) a step of condensing N-protected amino acid or N-protected peptide with the N-terminus of the obtained C-protected peptide to give an N-protected C-protected peptide, and (7') a step of adding a hydrophilic organic solvent to the 25 reaction system after step (6), and separating the impurity by extraction into a hydrophilic organic solvent layer. [31] An organic synthesis method comprising the peptide production method of any one of the aforementioned [28] - [30]. 30 Effect of the Invention [0054] The branched chain-containing aromatic compound of the present invention is easily-soluble in isopropyl acetate superior in liquid-separating operability. Using the branched 35 chain-containing aromatic compound of the present invention, 18 therefore, a production method of peptide and the like comprising leading to a final product via extraction separation alone, without crystallization and isolation of each intermediate in each step, can be performed. 5 [Description of Embodiments] [0055] Unless otherwise specified in the sentences, any technical terms and scientific terms used in the present specification, have the same meaning as those generally 10 understood by those of ordinary skill in the art the present invention belongs to. Any methods and materials similar or equivalent to those described in the present specification can be used for practicing or testing the present invention, and preferable methods and materials are described in the 15 following. All publications and patents referred to in the present specification are hereby incorporated by reference so as to describe and disclose constructed products and methodology described in, for example, publications usable in relation to the described invention. 20 [0056] [The compound of the present invention] The branched chain-containing aromatic compound of the present invention (hereinafter sometimes to be abbreviated as the compound of the present invention) is represented by the 25 following formula (I). The compound of the present invention encompasses a particular benzyl compound (in the formula (I), X and Z are both hydrogen atoms, and Ri is a hydrogen atom); a particular diphenylmethane compound (in the formula (I), X is a hydrogen atom, Ri is a hydrogen atom, k is 1, and Z is a 30 group represented by the formula (a) wherein R2 is a hydrogen atom and m is 0; and a particular fluorene compound (in the formula (I), X is a phenyl group, k is 1, Z is a group represented by the formula (a) wherein m is 0, and R2 is a single bond together with Ri to form a fluorene ring with ring 35 A) . 19 The formula (I): [0057] X [0058] 5 wherein Q in the number of k are each a single bond, or -0-, -S-, - C(=0)0-, -C(=0)NH- or -NH-; Ra in the number of k are each independently an organic group having at least one aliphatic hydrocarbon group having one or 10 more branched chains, a total number of the branched chain of not less than 3 and a total carbon number of not less than 14 and not more than 300; k is an integer of 1 - 4; Ri is a hydrogen atom or, when Z is a group represented by the 15 following formula (a), it optionally shows a single bond together with R2 to form a fluorene ring together with ring B; ring A optionally further has, in addition to Ri, QRa in the number of k, and C(X)(Y)Z, substituent(s) selected from the group consisting of a halogen atom, a Ci-e alkyl group 20 optionally substituted by one or more halogen atoms, and a Ci-e alkoxy group optionally substituted by one or more halogen atoms; X is a hydrogen atom or a phenyl group; Y is a hydroxyl group, an -NHR group (R is a hydrogen atom, an 25 alkyl group or an aralkyl group) or a halogen atom; and Z is a hydrogen atom or a group represented by the formula (a): [0059] 30 [0060] 20 wherein * shows a bonding position; m is an integer of 0 - 4; Q in the number of m are as defined above; Rb in the number of m are each independently an organic group 5 having at least one aliphatic hydrocarbon group having one or more branched chains, a total number of the branched chain of not less than 3 and a total carbon number of not less than 14 and not more than 300; R2 is a hydrogen atom, or optionally shows a single bond 10 together with Ri to form a fluorene ring together with ring A; and ring B optionally further has, in addition to QRb in the number of m, and R2, substituent(s) selected from the group consisting of a halogen atom, a Ci-g alkyl group optionally substituted by 15 one or more halogen atoms, and a Ci-e alkoxy group optionally substituted by one or more halogen atoms). [0061] The compound represented by the formula (I) of the present invention and compounds intended to protect are bonded 20 by a condensation reaction of a hydroxyl group, an NHR group or a halogen atom for Y group with a carboxyl group of a compound to be protected or the like. [0062] In the present specification, examples of the "alkyl 25 group" for R include a Ci-30 alkyl group, preferably a Ci-10 alkyl group, more preferably a Ci-e alkyl group. Preferable examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and the like, and particularly preferred are methyl and ethyl. 30 [0063] In the present specification, examples of the "aralkyl group" for R include a C7-30 aralkyl group. Preferred is a C7-20 aralkyl group, more preferred is a C7-16 aralkyl group (a Ce-io aryl-Ci-6 alkyl group). Preferable examples include benzyl, 1- 35 phenylethyl, 2-phenylethyl, 1-phenylpropyl, a-naphthylmethyl, 21 1-(a-naphthyl)ethyl, 2-(a-naphthyl)ethyl, 1-(a-naphthyl)propyl, p-naphthylmethyl, 1-(p-naphthyl)ethyl, 2-(P-naphthyl)ethyl, 1- (P-naphthyl)propyl and the like, and particularly preferred is benzyl. 5 [0064] As R, a hydrogen atom, a Ci-e alkyl group or a C7-16 aralkyl group is preferable, a hydrogen atom, methyl, ethyl or benzyl is more preferable, and a hydrogen atom is particularly preferable. 10 [0065] In the present specification, the "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferred as the ''^halogen atom" for Y is a chlorine atom, a bromine atom or an iodine atom, and more preferred is a 15 bromine atom. [0066] In the present specification, the "organic group having at least one aliphatic hydrocarbon group having one or more branched chains, a total number of the branched chain of not 20 less than 3 and a total carbon number of not less than 14 and not more than 300" for Ra and Rb is an organic group having at least one aliphatic hydrocarbon group having one or more branched chains in a molecular structure thereof, a total number of the branched chain of not less than 3 and a total 25 carbon number of not less than 14 and not more than 300. The "branched chain" of the "aliphatic hydrocarbon group having one or more branched chains" is a straight or branched saturated aliphatic hydrocarbon group. Preferred is a Ci-g alkyl group, more preferred is a C1-4 alkyl group, and still 30 more preferred is a methyl group or an ethyl group. In addition, the "branched chain" is optionally substituted by one or more halogen atoms. The "aliphatic hydrocarbon group" of the "aliphatic hydrocarbon group having one or more branched chains" is a 35 straight saturated or unsaturated aliphatic hydrocarbon group, 22 a C2-C300 alkyl group (preferably, a C3-C100 alkyl group, more preferably, a C3-C60 alkyl group) , a C2-C300 alkenyl group (preferably, a C3-C100 alkenyl group, more preferably, a C3-C60 alkenyl group) or a C2-C300 alkynyl group (preferably, a C3-C100 5 alkynyl group, more preferably, a C3-C60 alkynyl group). The moiety of the "aliphatic hydrocarbon group having one or more branched chains" of the "organic group having at least one aliphatic hydrocarbon group having one or more branched chains, a total number of the branched chain of not less than 10 3 and a total carbon nuinber of not less than 14 and not more than 300" is not particularly limited, and it may be present at the terminal (monovalent group), or other site (e.g., divalent group). Specific examples of the "aliphatic hydrocarbon group 15 having one or more branched chains" include a monovalent group having one or more branched chain(s) of a branched isomer of a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group (a lauryl group), a tridecyl 20 group, a myristyl group, a cetyl group, a stearyl group, an arachyl group, a behenyl group, an oleyl group, a linolyl group, a lignoceryl group and the like, and a divalent group derived therefrom, preferably, a 3,7,11-trimethyldodecyl group, a 3,7,11,15-tetramethylhexadecyl group (hereinafter sometimes 25 to be referred to as a 2,3-dihydrophytyl group), a 2,2,4,8,10,lO-hexamethylundecan-5-yl group, a group represented by the formula: [0067] \. L ^- J n n=23-34 30 [0068] wherein * shows a bonding position to Q, and the like. [0069] When plural "aliphatic hydrocarbon groups having one or 23 more branched chains" are in the "organic group having at least one aliphatic hydrocarbon group having one or more branched chains, a total number of the branched chain of not less than 3 and a total carbon number of not less than 14 and 5 not more than 300", each may be same or different. [0070] The moiety other than the "aliphatic hydrocarbon group having one or more branched chains" of the "organic group having at least one aliphatic hydrocarbon group having one or 10 more branched chains, a total number of the branched chain of not less than 3 and a total carbon number of not less than 14 and not more than 300" can be set freely. For example, the group optionally has moieties such as -0-, -S-, -CO-, -NH-, - C00-, -OCONH-, -CONH-, -NHCO-, hydrocarbon group (monovalent 15 group or divalent group) and the like. Examples of the "hydrocarbon group" include an aliphatic hydrocarbon group, an aromatic aliphatic hydrocarbon group, a monocyclic saturated hydrocarbon group, an aromatic hydrocarbon group and the like. Specifically, for example, monovalent groups such as an alkyl 20 group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, an aralkyl group and the like, and divalent groups derived therefrom are used. As the "alkyl group", a Ci_6 alkyl group and the like are preferable and, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, 25 tert-butyl, pentyl, hexyl and the like can be mentioned. As the "alkenyl group", a C2-6 alkenyl group and the like are preferable and, for example, vinyl, 1-propenyl, allyl, isopropenyl, butenyl, isobutenyl and the like can be mentioned. As the "alkynyl group", a C2-6 alkynyl group and the like are 30 preferable and, for example, ethynyl, propargyl, 1-propynyl and the like can be mentioned. As the "cycloalkyl group", a C3-6 cycloalkyl group and the like are preferable and, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl can be mentioned. As the "aryl group", for example, a C6-14 35 aryl group and the like are preferable and, for example, 24 phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl and the like can be mentioned. Of these, a Ce-io aryl group is more preferable, and phenyl is particularly preferable. As the "aralkyl group", a C7-20 aralkyl group is preferable and, for 5 example, benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, naphthylmethyl, 1-naphthylethyl, 1-naphthylpropyl and the like can be mentioned. Of these, a C7-16 aralkyl group (Cs-io aryl-Ci-s alkyl group) is more preferable, and benzyl is particularly preferable. The "hydrocarbon group" is optionally substituted 10 by a substituent selected from a halogen atom (a chlorine atom, a bromine atom, a fluorine atom, an iodine atom), an 0x0 group and the like. [0071] The compound of the present invention has a QRa group in 15 the number of k. Here, Q is a single bond, or -0-, -S-, - C(=0)0-, -C(=0)NH- or -NH-, preferably 0. The QRa group in the niomber of k may be the same or different. [0072] In the compound of the present invention, the "organic 20 group having at least one aliphatic hydrocarbon group having one or more branched chains, a total number of the branched chain of not less than 3 and a total carbon number of not less than 14 and not more than 300" for Rg and Rb preferably has a total carbon number of not less than 14, preferably not less 25 than 16, more preferably not less than 18. The "organic group having at least one aliphatic hydrocarbon group having one or more branched chains, and an aliphatic hydrocarbon group having a total number of the branched chain of not less than 3" for Ra and Rb preferably has a total carbon number of not 30 more than 300, preferably not more than 200, more preferably not more than 160. In addition, in the compound of in the present invention, the "organic group having at least one aliphatic hydrocarbon group having one or more branched chains, and an aliphatic hydrocarbon group having a total number of 35 the branched chain of not less than 3" for Ra and Rb preferably 25 has a total number of the branched chain of not less than 3, preferably not less than 4, more preferably not less than 8, further preferably not less than 10. When the total number of the branched chain is higher, a compound protected by the 5 compound of the present invention becomes an oil showing good solubility in various organic solvents even when the peptide chain becomes long. [0073] As the "organic group having at least one aliphatic 10 hydrocarbon group having one or more branched chains, a total number of the branched chain of not less than 3 and a total carbon number of not less than 14 and not more than 300" for Ra and Rb, a group having 3 or more, the same or different divalent groups represented by the formula (b): 15 [0074] R3 R4 (b) [0075] wherein * shows a bonding position with the adjacent atom; R3 and R4 are each independently a hydrogen atom or a Ci_4 alkyl 20 group; Xi is a single bond, a C1-4 alkylene group or an oxygen atom, provided that R3 and R4 are not hydrogen atoms at the same time, is preferable and, for example, a group represented by any of the following formulas (c) - (e) can be mentioned. 25 [0076] The carbon number, repeat unit number (mi, no - ng) and the like in the definition of each symbol in the formulas (c) - (e) are shown for convenience, and can be changed as appropriate within the range defined above, so that the total 30 number of the carbon will be not less than 14 (preferably not less than 16, more preferably not less than 18) and not more than 300 (preferably not more than 200, more preferably not more than 160). In the following, the formulas (c) - (e) are 26 explained in this order. [0077] The formula (c) is as described below. [0078] Rr 1 i' Rg—C'^'~~~ ^ ^ 2 ~ ^ — " " ^ R i o (c) / •- -'"0 5 Re Rs [0079] wherein* shows a bonding position to Q; Rs and Rg are both hydrogen atoms, or show =0 in combination; no is an integer of 2 - 4 0; 10 R? and Re in the number of no are each independently a hydrogen atom or a C1-4 alkyl group; X2 in the number of no are each independently a single bond or a Ci-4 alkylene group; and R9 is a hydrogen atom or a C1-4 alkyl group; 15 Rio is a Ci-4 alkyl group or the formula (I'): [0080] X A' •\l [0081] wherein * shows a bonding position; 20 other symbols are as defined above, and ring A' optionally has, in addition to Ri, Q, and C(X) {Y)Z, substituent (s) selected from the group consisting of a halogen atom, a Ci-e alkyl group optionally substituted by one or more halogen atoms, and a Ci-e alkoxy group optionally substituted by one or more halogen 25 atoms, provided that R7 and Re are not hydrogen atoms at the same time, and when no is 2, Rg is a Ci_4 alkyl group. [0082] In the group of the formula (c), a group wherein 30 R5 and Re are both hydrogen atoms; 27 no is an integer of 2 - 40; R7 and Rs in the number of no are each independently a hydrogen atom, a methyl group or an ethyl group; X2 in the number of no are each independently a single bond, a 5 methylene group or an ethylene group; and Rg is a hydrogen atom, a methyl group or an ethyl group is preferable, provided that R7 and Rs are not hydrogen atoms at the same time, and when no is 2, Rg is methyl or an ethyl group. 10 [0083] More preferable group of the formula (c) is a group of a branched isomer having a carbon number of 14 to 160, of a myristyl group, a cetyl group, a stearyl group, an arachyl group, a behenyl group and the like, wherein the total number 15 of the branched chain is not less than 3. Of these, a 2,3- dihydrophytyl group, a 3,7,11-trimethyldodecyl group and a 2,2,4,8,10,lO-hexamethyl-5-dodecanoyl group are particularly preferable. [0084] 20 The formula (d) is as described below. [0085] \_J7^QRll)m1 [0086] wherein * shows a bonding position to Q; 25 ORii in the number of mi is hydroxyl group substituted by a group represented by the formula (c') or a hydroxyl group substituted by a group having a polyalkyleneglycol group wherein the total number of the branched chain is not less than 3 (e.g., a polypropylene glycol group, a 30 polyneopentylglycol group); and mi is an integer of 1 - 3. The explanation of the group represented by the abovementioned formula (c') is the same as the explanation of a group represented by the above-mentioned formula (c) except 28 that * does not show a bonding position to Q but shows a bonding position to 0. [0087] In the group of the formula (d), Rn is more preferably a 5 group of a branched isomer having a carbon number of 14 to 30 of a myristyl group, a cetyl group, a stearyl group, an arachyl group, a behenyl group and the like, wherein the total number of the branched chain is not less than 3. Of these, a 2,3-dihydrophytyl group and a 3,7,11-trimethyldodecyl group 10 are particularly preferable. [0088] The formula (e) is as described below. [0089] Ki2 r "l R,0 "^1 HQ (Q'=0, S, CO2, NH) step(d-2)y^^ (l-b) step (a) / 1 r^ ^°^Ki / step(cl-5) O N ^ ^ : = = ^ \ ^ ^ \ step(d-1) ^ ; ; = ^ = \ ^ ^ ^ ,<:;^=^\^--^T ^c ^ I T Re \ \ ^3 RaQ („a) ""^ RaQ (,,3) Rad ^1 \ step(b) step(d^)/ (I'-c) \ (R,=ORdOrH) /^ ri^^y^^Qy^ step (6-3) r^:==^^^\'-''''^YiStep(d-6) f^^^^^^Y^^^^^ »- »- A-^^R S<^= ?

Documents

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Section Controller Decision Date

Application Documents

# Name Date
1 1903-DELNP-2013.pdf 2013-03-10
2 1903-delnp-2013-GPA.pdf 2013-08-20
3 1903-delnp-2013-Form-5.pdf 2013-08-20
4 1903-delnp-2013-Form-3.pdf 2013-08-20
5 1903-delnp-2013-Form-2.pdf 2013-08-20
6 1903-delnp-2013-Form-1.pdf 2013-08-20
7 1903-delnp-2013-Description(Complete).pdf 2013-08-20
8 1903-delnp-2013-Correspondence-Others.pdf 2013-08-20
9 1903-delnp-2013-Claims.pdf 2013-08-20
10 1903-delnp-2013-Abstract.pdf 2013-08-20
11 1903-delnp-2013-Form-3-(26-08-2013).pdf 2013-08-26
12 1903-delnp-2013-Correspondence Others-(26-08-2013).pdf 2013-08-26
13 1903-delnp-2013-Form-3-(18-02-2014).pdf 2014-02-18
14 1903-delnp-2013-Correspondence-Others-(18-02-2014).pdf 2014-02-18
15 marked up_20141029145536.pdf 2014-11-13
16 form-13_20141029145507.pdf 2014-11-13
17 clean copy_20141029145615.pdf 2014-11-13
18 12388--4_20141029145928.pdf 2014-11-13
19 1903-delnp-2013-Correspondance Others-(25-02-2015).pdf 2015-02-25
20 Form 3 [18-01-2017(online)].pdf 2017-01-18
21 1903-DELNP-2013-FORM 3 [13-09-2017(online)].pdf 2017-09-13
22 1903-DELNP-2013-FER.pdf 2018-07-06
23 1903-DELNP-2013-certified copy of translation (MANDATORY) [01-10-2018(online)].pdf 2018-10-01
24 1903-DELNP-2013-OTHERS-041018.pdf 2018-10-09
25 1903-DELNP-2013-Correspondence-041018.pdf 2018-10-09
26 1903-DELNP-2013-Information under section 8(2) (MANDATORY) [28-12-2018(online)].pdf 2018-12-28
27 1903-DELNP-2013-FORM 4(ii) [28-12-2018(online)].pdf 2018-12-28
28 1903-DELNP-2013-FORM 3 [28-12-2018(online)].pdf 2018-12-28
29 1903-DELNP-2013-MARKED COPIES OF AMENDEMENTS [04-03-2019(online)].pdf 2019-03-04
30 1903-DELNP-2013-FORM 13 [04-03-2019(online)].pdf 2019-03-04
31 1903-DELNP-2013-AMMENDED DOCUMENTS [04-03-2019(online)].pdf 2019-03-04
32 1903-DELNP-2013-OTHERS [03-04-2019(online)].pdf 2019-04-03
33 1903-DELNP-2013-FER_SER_REPLY [03-04-2019(online)].pdf 2019-04-03
34 1903-DELNP-2013-COMPLETE SPECIFICATION [03-04-2019(online)].pdf 2019-04-03
35 1903-DELNP-2013-CLAIMS [03-04-2019(online)].pdf 2019-04-03
36 1903-DELNP-2013-Information under section 8(2) (MANDATORY) [05-04-2019(online)].pdf 2019-04-05
37 1903-DELNP-2013-Information under section 8(2) (MANDATORY) [30-05-2019(online)].pdf 2019-05-30
38 1903-DELNP-2013-Information under section 8(2) (MANDATORY) [31-10-2019(online)].pdf 2019-10-31
39 1903-DELNP-2013-Information under section 8(2) [25-02-2020(online)].pdf 2020-02-25
40 1903-DELNP-2013-FORM 3 [25-02-2020(online)].pdf 2020-02-25
41 1903-DELNP-2013-Information under section 8(2) [25-08-2020(online)].pdf 2020-08-25
42 1903-DELNP-2013-FORM 3 [25-08-2020(online)].pdf 2020-08-25
43 1903-DELNP-2013-Information under section 8(2) [20-11-2020(online)].pdf 2020-11-20
44 1903-DELNP-2013-FORM 3 [20-11-2020(online)].pdf 2020-11-20
45 1903-DELNP-2013-US(14)-HearingNotice-(HearingDate-27-12-2022).pdf 2022-12-16
46 1903-DELNP-2013-REQUEST FOR ADJOURNMENT OF HEARING UNDER RULE 129A [22-12-2022(online)].pdf 2022-12-22
47 1903-DELNP-2013-FORM-26 [22-12-2022(online)].pdf 2022-12-22
48 1903-DELNP-2013-GPA-261222.pdf 2022-12-27
49 1903-DELNP-2013-Correspondence-261222.pdf 2022-12-27
50 1903-DELNP-2013-US(14)-ExtendedHearingNotice-(HearingDate-20-02-2023).pdf 2023-01-23
51 1903-DELNP-2013-Correspondence to notify the Controller [24-01-2023(online)].pdf 2023-01-24
52 1903-DELNP-2013-Written submissions and relevant documents [28-02-2023(online)].pdf 2023-02-28
53 1903-DELNP-2013-PatentCertificate03-03-2023.pdf 2023-03-03
54 1903-DELNP-2013-IntimationOfGrant03-03-2023.pdf 2023-03-03

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