公开(公告)号：US20120041172A1

公开(公告)日：2012-02-16

申请号：US13265402

申请日：2010-04-26

Applicant: Haixiang Zhang ,  Jens Fomsgaard ,  Gunnar Staerkaer

Inventor： Haixiang Zhang ,  Jens Fomsgaard ,  Gunnar Staerkaer

IPC: C07K7/06 ,  C07K1/107 ,  C07K1/14 ,  C07K1/06

CPC classification number: C07K7/23

Abstract: In a step-wise synthesis of degarelix comprising 0.3% by weight or less of 4-([2(5-hydantoyl)]acetylamino)-phenylalanine analog on (solid support)-NH2 a step comprises providing a solution of an amino acid or peptide of which the α-amino group is protected by Fmoc; contacting the support with the solution in the presence of reagent for forming a peptide bond between a carboxyl group of the amino acid or peptide and (solid support)-NH2; removing Fmoc by contacting the support with an organic base, in particular piperidine, in an organic solvent. Also disclosed is degarelix of high purity prepared by the method of the invention and the use of Fmoc in the synthesis of degarelix.

Abstract translation: 在逐步合成包含0.3重量％或更少的（固体支持物）-NH 2上的4 - （[2（5-乙酰基）]乙酰氨基） - 苯丙氨酸类似物的地加瑞克，步骤包括提供氨基酸或 α-氨基被Fmoc保护的肽; 在用于在氨基酸或肽的羧基与（固体支持物）-NH 2之间形成肽键的试剂存在下使载体与溶液接触; 通过使载体与有机碱，特别是哌啶在有机溶剂中接触来除去Fmoc。 还公开了通过本发明的方法制备的高纯度的地加瑞克，以及在地加瑞克合成中使用Fmoc。

公开(公告)号：US08173770B2

公开(公告)日：2012-05-08

申请号：US12189925

申请日：2008-08-12

Applicant: Jon H. Rasmussen ,  Palle H. Rasmussen ,  Wolfgang O. Wachs ,  Stefan Hansen ,  Jens Fomsgaard

Inventor： Jon H. Rasmussen ,  Palle H. Rasmussen ,  Wolfgang O. Wachs ,  Stefan Hansen ,  Jens Fomsgaard

IPC: A61K38/06 ,  A61K38/08 ,  A61K38/24 ,  C07K1/06

CPC classification number: C07K7/23 ,  C07K1/02 ,  C07K5/0827

Abstract: The peptides Ac-D-2Nal-D-4ClPhe-D-3Pal-OH and Boc-D-2Nal-D-4ClPhe-D-3Pal-OH are intermediates useful in the synthesis of LHRH analogs by coupling with suitable heptapeptides, in particular with the heptapeptides P1-Ser(P2)-MMeTry(P3)-D-Lys(Nic)-Leu-Lys(iPr,P4)-Pro-D-AlaNH2 and P1-Ser(P2)-NMeTry(P3)-D-Asn-Leu-Lys(iPr,P4)-Pro-D-AlaNH2.

Abstract translation: 肽Ac-D-2Nal-D-4ClPhe-D-3Pal-OH和Boc-D-2Nal-D-4ClPhe-D-3Pal-OH是通过与合适的七肽偶合合成LHRH类似物的中间体，特别是 与七肽P1-Ser（P2）-MeTry（P3）-D-Lys（Nic）-Leu-Lys（iPr，P4）-Pro-D-AlaNH2和P1-Ser（P2）-NMeTry（P3）-D -Asn-Leu-Lys（iPr，P4）-Pro-D-AlaNH 2。

公开(公告)号：US20080306242A1

公开(公告)日：2008-12-11

申请号：US12189925

申请日：2008-08-12

Applicant: Jon H. Rasmussen ,  Palle H. Rasmussen ,  Wolfgang O. Wachs ,  Stefan Hansen ,  Jens Fomsgaard

Inventor： Jon H. Rasmussen ,  Palle H. Rasmussen ,  Wolfgang O. Wachs ,  Stefan Hansen ,  Jens Fomsgaard

IPC: C07K7/23 ,  C07K1/00 ,  C07K5/00

CPC classification number: C07K7/23 ,  C07K1/02 ,  C07K5/0827

Abstract: The peptides Ac-D-2Nal-D-4ClPhe-D-3Pal-OH and Boc-D-2Nal-D-4ClPhe-D-3Pal-OH are intermediates useful in the synthesis of LHRH analogs by coupling with suitable heptapeptides, in particular with the heptapeptides P1-Ser(P2)-MMeTry(P3)-D-Lys(Nic)-Leu-Lys(iPr,P4)-Pro-D-AlaNH2 and P1-Ser(P2)-NMeTry(P3)-D-Asn-Leu-Lys(iPr,P4)-Pro-D-AlaNH2.

Abstract translation: 肽Ac-D-2Nal-D-4ClPhe-D-3Pal-OH和Boc-D-2Nal-D-4ClPhe-D-3Pal-OH是通过与合适的七肽偶合合成LHRH类似物的中间体，特别是 与七肽P1-Ser（P2）-MeTry（P3）-D-Lys（Nic）-Leu-Lys（iPr，P4）-Pro-D-AlaNH2和P1-Ser（P2）-NMeTry（P3）-D -Asn-Leu-Lys（iPr，P4）-Pro-D-AlaNH 2。

公开(公告)号：US07057014B2

公开(公告)日：2006-06-06

申请号：US10500302

申请日：2002-12-23

Applicant: Jon H. Rasmussen ,  Palle H. Rasmussen

Inventor： Jon H. Rasmussen ,  Palle H. Rasmussen

IPC: A61K38/08

CPC classification number: C07K7/06 ,  C07K1/30

Abstract: A nona- or decapeptide is purified from residual organic solvent by dissolving in a solvent comprising water and at least one C1–C3 alcohol followed by precipitation into a vigorously stirred solvent consisting of an alkyl ester of a carboxylic acid, the ester comprising from 3 to 6 carbon atoms, and one or several non-polar compounds selected from hexane, heptane, octane, cyclohexane, methylcyclohexane, and, optionally, of up to 5% of acetic or propionic acid, isolating the precipitated nona- or decapeptide, followed by washing with a mixture of C3–C5 esters and drying, with the provisio that the water content of the solvent comprising water and the at least one alcohol is below 8% (v/v), and that the volume ratio of the dissolution solvent mixture and the precipitation solvent mixture is 1:10 or higher. Also described is the monoacetate of Ac-D-2Nal-D-4ClPhe-D-3Pal-Ser-MeTyr-D-Asn-Leu-Lys(iPr)-Pro-D-Ala-NH2.

Abstract translation: 通过将溶解在包含水和至少一种C 1 -C 3 - 醇的溶剂中，然后沉淀到剧烈搅拌的溶剂中，从残留的有机溶剂中纯化非肽或十肽 由羧酸的烷基酯，包含3至6个碳原子的酯和选自己烷，庚烷，辛烷，环己烷，甲基环己烷中的一种或几种非极性化合物，和任选地至多5％ 乙酸或丙酸，分离沉淀的非 - 或十肽，然后用C 3 -C 5 - 酯的混合物洗涤并干燥，条件是水含量 包含水和至少一种醇的溶剂的含量低于8％（v / v），溶解溶剂混合物和沉淀溶剂混合物的体积比为1:10或更高。 还描述了Ac-D-2Nal-D-4ClPhe-D-3Pal-Ser-MeTyr-D-Asn-Leu-Lys（iPr）-Pro-D-Ala-NH 2 。

公开(公告)号：US08828938B2

公开(公告)日：2014-09-09

申请号：US13265402

申请日：2010-04-26

Applicant: Haixiang Zhang ,  Jens Fomsgaard ,  Gunnar Staerkaer

Inventor： Haixiang Zhang ,  Jens Fomsgaard ,  Gunnar Staerkaer

IPC: C07K7/23

CPC classification number: C07K7/23

Abstract: In a step-wise synthesis of degarelix comprising 0.3% by weight or less of 4-([2-(5-hydantoyl)]acetylamino)-phenylalanine analog on (solid support)-NH2 a step comprises providing a solution of an amino acid or peptide of which the α-amino group is protected by Fmoc; contacting the support with the solution in the presence of reagent for forming a peptide bond between a carboxyl group of the amino acid or peptide and (solid support)-NH2; removing Fmoc by contacting the support with an organic base, in particular piperidine, in an organic solvent. Also disclosed is degarelix of high purity prepared by the method of the invention and the use of Fmoc in the synthesis of degarelix.

Abstract translation: 在（在固体支持物）-NH 2上包含0.3重量％或更少的4 - （[2-（5-乙酰基）]乙酰氨基） - 苯丙氨酸类似物的地加瑞克的逐步合成步骤包括提供氨基酸 或其α-氨基被Fmoc保护的肽; 在用于形成氨基酸或肽的羧基与（固体支持物）-NH 2之间的肽键的试剂存在下使载体与溶液接触; 通过使载体与有机碱，特别是哌啶在有机溶剂中接触来除去Fmoc。 还公开了通过本发明的方法制备的高纯度的地加瑞克，以及在地加瑞克合成中使用Fmoc。