TW201718462A - Process for the manufacture of organic compounds and intermediates - Google Patents

Process for the manufacture of organic compounds and intermediates Download PDF

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TW201718462A
TW201718462A TW105127037A TW105127037A TW201718462A TW 201718462 A TW201718462 A TW 201718462A TW 105127037 A TW105127037 A TW 105127037A TW 105127037 A TW105127037 A TW 105127037A TW 201718462 A TW201718462 A TW 201718462A
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大衛 霍克
庫杰
周建光
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瑞士商諾華公司
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    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
    • C07D207/452—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Abstract

The invention relates to a novel process, novel process steps and novel intermediates useful in the synthesis of pharmaceutically active compounds, in particular neutral endopeptidase (NEP) inhibitors and prodrugs thereof.

Description

用於製備有機化合物及中間物的方法Method for preparing organic compounds and intermediates

本發明係關於一種適用於合成醫藥上活性化合物，特定言之中性肽鏈內切酶(NEP)抑制劑或其前藥之新穎方法、新穎方法步驟及新穎中間物。The present invention relates to a novel method, novel method steps and novel intermediates suitable for the synthesis of a pharmaceutically active compound, specifically a neutral endopeptidase (NEP) inhibitor or a prodrug thereof.

本發明係關於一種製備於合成醫藥上活性化合物，特定言之中性肽鏈內切酶(NEP)抑制劑(諸如描述於美國專利號4,722,810、美國專利號5,223,516、美國專利號4,610,816、美國專利號4,929,641、南非專利申請案84/0670、UK 69578、美國專利號5,217,996、EP 00342850、GB 02218983、WO 92/14706、EP 0034391 1、JP 06234754、EP 00361365、WO 90/09374、JP 07157459、WO 94/15908、美國專利號5,273,990、美國專利號5,294,632、美國專利號5,250,522、EP 00636621、WO 93/09101、EP 00590442、WO 93/10773、WO2008/031567及美國專利號5,217,996中之彼等)，特定言之於製備N -(3-羧基-1-側氧基丙基)-(4S )-(對苯基苯基甲基)-4-胺基-(2R )-甲基丁酸乙酯或其鹽中之關鍵中間物的方法。 在哺乳動物中，內源性心房利尿鈉肽(ANP)，亦稱為心房利尿鈉因子(ANF)，具有利尿劑、利尿鈉劑及血管舒張劑功能。天然ANF肽係代謝上失活的，特定言之藉由降解酶而失活，該酶已被識別為對應於酶中性肽鏈內切酶(NEP，EC 3.4.24.11)，其亦負責例如腦啡肽之代謝失活。 在相關技術中，已知經二芳基取代之膦酸衍生物，其可用作中性肽鏈內切酶(NEP)抑制劑，例如作為哺乳動物中之ANF-降解酶之抑制劑，以便藉由抑制其降解為較低活性之代謝產物來延長並增強哺乳動物中ANF之利尿劑、利尿鈉劑及血管舒張劑性質。因而NEP抑制劑特別適用於治療回應於中性肽鏈內切酶(EC 3.4.24.11)之抑制之病況及病症，特別係心血管病症諸如高血壓、腎功能不足(包括水腫及鹽滯留)、肺水腫及充血性心臟衰竭。 用於製備NEP-抑制劑之方法為已知。 US 5,217,996描述經二芳基取代之4-胺基丁酸醯胺衍生物，其適用作中性肽鏈內切酶(NEP)抑制劑，例如，作為哺乳動物中之ANF-降解酶之抑制劑。作為一較佳實施例，US 5,217,996揭示N-(3-羧基-1-側氧基丙基)-(4S)-(對苯基苯基甲基)-4-胺基-(2R)-甲基丁酸乙酯及其製備方法。 若干種二羧酸二肽中性肽鏈內切酶(NEP)抑制劑係由G.M.Ksander等人在J. Med.Chem. 1995 ,38 , 1689-1700, 「Dicarboxylic Acid Dipeptide Neutral Endopeptidase Inhibitors」中進一步描述。尤其揭示N-(3-羧基-1-側氧基丙基)-(4S)-(對苯基苯基甲基)-4-胺基-(2R)-甲基丁酸乙酯及其製備方法。 WO2008/083967描述一種用於生產NEP抑制劑或其前藥，特定言之N-(3-羧基-1-側氧基丙基)-(4S)-(對苯基苯基甲基)-4-胺基-(2R)-甲基丁酸乙酯或其鹽之方法，該方法經由中間物，諸如： -根據式(2*)之化合物或其互變異構體或鹽，(2*) 其中R1為氫或氮保護基； -式(3*)化合物或其鹽，(3*) 其中R1及R2彼此獨立地為氫或氮保護基，且R5為氫或C1 -C7 -烷基；及特定言之， -式(1d*)化合物(1d*) 或其鹽。 式(1d)化合物至N-(3-羧基-1-側氧基丙基)-(4S)-(對苯基苯基甲基)-4-胺基-(2R)-甲基丁酸乙酯(相關技術中已知為AHU377)或其鹽之轉化已描述於例如WO2008/083967中之子節B-3中。 本發明之一目標為提供一種製備NEP抑制劑或其前藥之方法的替代反應路徑。特定言之，一目標為提供一種製備根據式(1c)之N-(3-羧基-1-側氧基丙基)-(4S)-(對苯基苯基甲基)-4-胺基-(2R)-甲基丁酸乙酯或其鹽之方法的替代反應路徑，(1c)。The present invention relates to a synthetic pharmaceutically active compound, specifically a neutral endopeptidase (NEP) inhibitor (such as that described in U.S. Patent No. 4,722,810, U.S. Patent No. 5,223,516, U.S. Patent No. 4,610,816, U.S. Patent No. 4, 929, 641, South African Patent Application No. 84/0670, UK 69578, U.S. Patent No. 5,217,996, EP 00342850, GB 02218983, WO 92/14706, EP 0034391 1, JP 06234754, EP 00361365, WO 90/09374, JP 07157459, WO 94/ 15908, U.S. Patent No. 5,273,990, U.S. Patent No. 5,294,632, U.S. Patent No. 5,250,522, EP 00636621, WO 93/09101, EP 00590442, WO 93/10773, WO 2008/031567, and U.S. Patent No. 5,217,996. For the preparation of ethyl N- (3-carboxy-1-oxopropyl)-(4 S )-(p-phenylphenylmethyl)-4-amino-( 2R )-methylbutanoate or A method of key intermediates in its salt. In mammals, endogenous atrial natriuretic peptide (ANP), also known as atrial natriuretic factor (ANF), has diuretic, diuretic, and vasodilator functions. The natural ANF peptide is metabolically inactive, in particular by inactivation by a degrading enzyme, which has been identified as corresponding to the enzyme neutral endopeptidase (NEP, EC 3.4.24.11), which is also responsible for example Metabolism of enkephalin is inactivated. In the related art, a diaryl-substituted phosphonic acid derivative which is useful as a neutral endopeptidase (NEP) inhibitor, for example, as an inhibitor of ANF-degrading enzyme in mammals, is known. The properties of diuretics, diuretics, and vasodilators of ANF in mammals are prolonged and enhanced by inhibiting their degradation to less active metabolites. Thus, NEP inhibitors are particularly useful for the treatment of conditions and conditions that are responsive to inhibition by neutral endopeptidase (EC 3.4.24.11), particularly cardiovascular conditions such as hypertension, renal insufficiency (including edema and salt retention), Pulmonary edema and congestive heart failure. Methods for preparing NEP-inhibitors are known. No. 5,217,996 describes diaryl substituted 4-aminobutyric acid decylamine derivatives which are useful as neutral endopeptidase (NEP) inhibitors, for example, as inhibitors of ANF-degrading enzymes in mammals . As a preferred embodiment, US 5,217,996 discloses N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-A Ethyl butyrate and its preparation method. Several dicarboxylic acid dipeptide neutral endopeptidase (NEP) inhibitors are further described by GM Ksander et al . , J. Med. Chem. 1995 , 38 , 1689-1700, "Dicarboxylic Acid Dipeptide Neutral Endopeptidase Inhibitors". . In particular, N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutyric acid ethyl ester and preparation thereof are disclosed method. WO 2008/083967 describes a process for the production of NEP inhibitors or prodrugs thereof, in particular N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4 a method of -amino-(2R)-methylbutyric acid ethyl ester or a salt thereof, the method being via an intermediate such as: - a compound according to formula (2*) or a tautomer or salt thereof, (2*) wherein R1 is a hydrogen or nitrogen protecting group; - a compound of the formula (3*) or a salt thereof, (* 3) wherein R1 and R2 are each independently hydrogen or a nitrogen protecting group, and R5 is hydrogen or C 1 -C 7 - alkyl; and specific words, - of formula (1D *) compound (1d*) or its salt. Compound of formula (1d) to N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutyric acid B The conversion of an ester (known as AHU377 in the related art) or a salt thereof has been described, for example, in subsection B-3 of WO 2008/083967. It is an object of the present invention to provide an alternative reaction pathway for a method of preparing a NEP inhibitor or a prodrug thereof. In particular, one objective is to provide an N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino group according to formula (1c). An alternative reaction pathway for the method of -(2R)-methylbutyrate or its salt, (1c).

本發明提供用於製備根據式(1)之化合物或其鹽之新穎方法，(1) 其較佳地具有根據式(1a)或(1b)，更佳(1a)之組態，(1a)；(1b)； 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代， R3為氫或C1 -C7 -烷基；較佳氫或乙基，且 R8為C1 -C7 -烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基。 根據本發明之用於生產根據式(1)之化合物之新穎方法係匯總於以下反應圖1至5中。反應圖 1 ：形成醯胺 / 烷基化醯胺 / 水解為 (1-A) 反應圖 2 ：形成酯 / 烷基化酯 / 水解為 (1) ： 反應圖 3 ：形成醯氯 / 醯胺 / 烷基化醯胺 / 水解為 (1) ： 反應圖 4 ：形成硫酯 / 烷基化硫酯 / 水解為 (1) ： 反應圖 5 ：形成硫酯 / 烷基化硫酯 / 水解為 (1) ： 如上所述之式(1)化合物或其鹽(特定言之其中R1為H，R2為第三丁氧基羰基，R8為甲基且R3為乙基)至NEP抑制劑或其前藥(特定言之N-(3-羧基-1-側氧基丙基)-(4S)-(對苯基苯基甲基)-4-胺基-(2R)-甲基丁酸乙酯或其鹽)之轉化已經由例如G.M.Ksander等人在J. Med.Chem. 1995 ,38 , 1689-1700及前文中引述之專利文件中進行描述，各文件中之揭示內容以引用的方式併入本文中。 在以上反應圖中，在式(1)化合物中之R3為H的情況下，對應的化合物亦稱為式(1-A)化合物。式(3-I*)化合物為其中R5*為氫、C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基之式(3-I)化合物。 此外，本發明亦主張新穎中間物，特定言之式(10)化合物，或其鹽，(10)； 其較佳地具有根據式(10-a)之組態，(10-a)； 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R10係選自 •X，其中X為鹵基，較佳氯； •基團–NR5”R6”，其中R5”及R6”彼此獨立地為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基、C3 -C7 -環烷基，或者R5”及R6”與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，較佳地R5”及R6”與其所連接之氮一起形成對掌性部分； •基團–O-Rx，其中Rx與其所連接之氧一起形成對掌性部分；及 •基團–S-R5，其中R5為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基； R11為氫或基團R8，R8為C1 -C7 -烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基。 在一其實施例中，本發明係關於一種式(10)化合物或其鹽，(10)； 其較佳地具有根據式(10-a)之組態，(10-a)； 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R10係選自 •X，其中X為鹵基，較佳氯； •基團–NR5”R6”，其中R5”及R6”彼此獨立地為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基、C3 -C7 -環烷基，或者R5”及R6”與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，較佳地R5”及R6”與其所連接之氮一起形成對掌性部分； •基團–O-Rx，其中Rx與其所連接之氧一起形成對掌性部分；及 •基團–S-R5，其中R5為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基； 且R11為氫。 在另一實施例中，本發明係關於一種式(10)化合物或其鹽，(10)； 較佳地具有根據式(10-a)之組態，(10-a)； 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R10係選自 •基團–NR5”R6”，其中R5”及R6”彼此獨立地為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基、C3 -C7 -環烷基，或者R5”及R6”與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，較佳地R5”及R6”與其所連接之氮一起形成對掌性部分； •基團–O-Rx，其中Rx與其所連接之氧一起形成對掌性部分；及 •基團–S-R5，其中R5為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基； 且R11為基團R8，R8為C1 -C7 -烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基。 該等化合物及部分較佳係如下文中所指示般定義。The present invention provides a novel method for preparing a compound according to formula (1) or a salt thereof, (1) It preferably has a configuration according to formula (1a) or (1b), more preferably (1a), (1a); (1b); wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, which may be Is saturated or unsaturated and optionally contains one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from hydroxyl groups, C 1 Substituted by a substituent of -C 7 -alkyl, C 1 -C 7 -alkoxy, halo, carboxy and pendant oxy, R 3 being hydrogen or C 1 -C 7 -alkyl; preferably hydrogen or ethyl, And R8 is C 1 -C 7 -alkyl or C 6 -C 10 -aryl-C 1 -C 7 -alkyl, preferably methyl. The novel process for producing a compound according to formula (1) according to the present invention is summarized in the following reaction schemes 1 to 5. Reaction Figure 1 : Formation of decylamine / alkylated decylamine / hydrolysis to (1-A) Reaction Figure 2 : Formation of ester / alkylated ester / hydrolysis to (1) : Reaction Figure 3 : Formation of hydrazine / decylamine / alkylated decylamine / hydrolysis to (1) : Reaction Figure 4 : Formation of thioester / alkylated thioester / hydrolysis to (1) : Reaction Scheme 5 : Formation of thioester / alkylated thioester / hydrolysis to (1) : A compound of the formula (1) or a salt thereof (specifically, wherein R1 is H, R2 is a third butoxycarbonyl group, R8 is a methyl group and R3 is an ethyl group) to a NEP inhibitor or a prodrug thereof (specific N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutyric acid ethyl ester or a salt thereof The transformations have been described, for example, by GM Ksander et al . , J. Med. Chem. 1995 , 38 , 1689-1700, and the patents cited above, the disclosures of each of which are hereby incorporated by reference. In the above reaction scheme, in the case where R3 in the compound of the formula (1) is H, the corresponding compound is also referred to as a compound of the formula (1-A). A compound of the formula (3-I*) wherein R5* is hydrogen, C 1 -C 7 -alkyl, C 6 -C 10 -aryl or C 6 -C 10 -aryl-C 1 -C 7 -alkyl A compound of the formula (3-I). Furthermore, the present invention also contemplates novel intermediates, in particular compounds of formula (10), or salts thereof, (10); preferably having a configuration according to formula (10-a), (10-a); wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from the group consisting of hydroxyl groups, Substituting a C 1 -C 7 -alkyl group, a C 1 -C 7 -alkoxy group, a halogen group, a carboxyl group and a pendant oxy group, and R 10 is selected from the group consisting of X, wherein X is a halogen group, preferably chlorine; • a group -NR5 "R6", wherein R5 "and R6" independently of one another C 1 -C 7 - alkyl, C 6 -C 10 - aryl, C 6 -C 10 - aryl, -C 1 -C 7 -Alkyl, C 3 -C 7 -cycloalkyl, or R 5" and R 6" together with the nitrogen to which they are attached form a 3 to 10 member, preferably 4 to 7 membered monocyclic or bicyclic ring, which may be Saturated or unsaturated and optionally containing one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from hydroxy, C 1 - C 7 - alkyl, C 1 -C 7 - alkoxy, halo, carboxyl group and Substituted by a substituent of an oxy group, preferably R5" and R6" together with the nitrogen to which they are attached form a palm-like moiety; - a group -O-Rx, wherein Rx forms a palm-like moiety with the oxygen to which it is attached; • a group -S-R5, wherein R5 is C 1 -C 7 -alkyl, C 6 -C 10 -aryl or C 6 -C 10 -aryl-C 1 -C 7 -alkyl; R 11 is hydrogen Or the group R8, R8 is C 1 -C 7 -alkyl or C 6 -C 10 -aryl-C 1 -C 7 -alkyl, preferably methyl. In one embodiment, the invention relates to a compound of formula (10) or a salt thereof, (10); preferably having a configuration according to formula (10-a), (10-a); wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from the group consisting of hydroxyl groups, Substituting a C 1 -C 7 -alkyl group, a C 1 -C 7 -alkoxy group, a halogen group, a carboxyl group and a pendant oxy group, and R 10 is selected from the group consisting of X, wherein X is a halogen group, preferably chlorine; • a group -NR5 "R6", wherein R5 "and R6" independently of one another C 1 -C 7 - alkyl, C 6 -C 10 - aryl, C 6 -C 10 - aryl, -C 1 -C 7 -Alkyl, C 3 -C 7 -cycloalkyl, or R 5" and R 6" together with the nitrogen to which they are attached form a 3 to 10 member, preferably 4 to 7 membered monocyclic or bicyclic ring, which may be Saturated or unsaturated and optionally containing one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from hydroxy, C 1 - C 7 - alkyl, C 1 -C 7 - alkoxy, halo, carboxyl group and Substituted by a substituent of an oxy group, preferably R5" and R6" together with the nitrogen to which they are attached form a palm-like moiety; - a group -O-Rx, wherein Rx forms a palm-like moiety with the oxygen to which it is attached; • a group -S-R5, wherein R5 is C 1 -C 7 -alkyl, C 6 -C 10 -aryl or C 6 -C 10 -aryl-C 1 -C 7 -alkyl; and R 11 is hydrogen. In another embodiment, the invention relates to a compound of formula (10) or a salt thereof, (10); preferably having a configuration according to formula (10-a), (10-a); wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from the group consisting of hydroxyl groups, a substituent of a C 1 -C 7 -alkyl group, a C 1 -C 7 -alkoxy group, a halogen group, a carboxyl group and a pendant oxy group, and R 10 is selected from a group -NR 5 "R 6 ", wherein R 5"R6" independently of each other is C 1 -C 7 -alkyl, C 6 -C 10 -aryl, C 6 -C 10 -aryl-C 1 -C 7 -alkyl, C 3 -C 7 -cycloalkane a group, or R5" and R6", together with the nitrogen to which they are attached, form a 3 to 10 member, preferably a 4 to 7 member, single or double ring, which ring may be saturated or unsaturated and may optionally contain one, two or Three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from hydroxy, C 1 -C 7 -alkyl, C 1 -C 7 -alkane Substituted by a substituent of an oxy group, a halogen group, a carboxyl group and a pendant oxy group, preferably R 5" and R6" together with the nitrogen to which they are attached form a palm-like moiety; • a group -O-Rx, wherein Rx forms a pair of palms with the oxygen to which it is attached; and • a group -S-R5, wherein R5 Is C 1 -C 7 -alkyl, C 6 -C 10 -aryl or C 6 -C 10 -aryl-C 1 -C 7 -alkyl; and R 11 is a group R 8 and R 8 is C 1 -C 7 -Alkyl or C 6 -C 10 -aryl-C 1 -C 7 -alkyl, preferably methyl. These compounds and moieties are preferably as defined below.

在下文中，呈現本發明之具體實施例。製備式 (3-I) 化合物： 一種式(3-I)化合物或其鹽，(3-I)； 其較佳地具有根據式(3-I-a)之組態，(3-I-a)； 其中R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代， 且R5’為氫，或者另外C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基(則其為式3-I*化合物，其中存在R5*來代替R5’)， 其係藉由以下製備：使式(2)化合物或其互變異構體或鹽，(2)； 其較佳地具有根據式(2-a)之組態，(2-a)； 其中R1為氫或氮保護基， 與開環劑反應。 開環劑之實例係選自 -金屬氫氧化物，例如鹼金屬或鹼土金屬氫氧化物(例如，氫氧化鋰、氫氧化鈉)； -氫過氧化物，例如鹼金屬氫過氧化物(例如，氫過氧化鋰)； -式MOR5之金屬醇化物，其中M為鹼金屬或鹼土金屬，且R5為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基(例如，乙醇鋰、甲醇鈉、乙醇鈉)； -礦物酸，諸如硫酸、氫溴酸、高氯酸及鹽酸，在親核試劑或親核溶劑(例如水)之存在下； -磺酸，諸如對甲苯磺酸，在親核試劑或親核溶劑(例如水)之存在下；及 -聚合物鍵結酸，諸如Amberlyst® ，在親核試劑或親核溶劑(例如水)之存在下。 在一實施例中，該開環劑係選自乙醇鈉或氫氧化鋰。較佳地，在存在水、醇，諸如甲醇或乙醇或THF下，使用金屬氫氧化物或金屬醇化物。 在另一實施例中，該開環劑係鹽酸。較佳地，在存在水或醇(諸如甲醇或乙醇)下，使用酸。 可以催化量或理想配比量使用該開環劑。較佳地，以1至10當量之量使用內醯胺開環劑。較佳地，低於1當量，更佳地0.1當量或低於0.1當量。 或者，如WO2008/083967中所述製備式(3-I)化合物，較佳地具有根據式(3-I-a)之組態。節 A. 製備醯基鹵中間物： 在一實施例中，本發明係關於一種用於製備式(4)化合物或其鹽之方法，(4) 其中R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 X為鹵基，諸如氯， 該方法包括使式(3-I)化合物或其鹽與醯基鹵生成試劑反應以提供式(4)化合物，(3-I) 其中R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5’為氫。 在一較佳實施例中，本發明係關於一種用於製備式(4-a)化合物或其鹽之方法，(4-a) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 X為鹵基，諸如氯， 該方法包括使式(3-I-a)化合物或其鹽與醯基鹵生成試劑反應以提供式(4-a)化合物，(3-I-a) 其中R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代， 且R5’為氫。 合適的醯基鹵生成試劑為例如乙烯基鹵、C1 -C7 -烷基鹵及鹵化膦。合適的醯基鹵生成試劑係例如選自亞硫醯氯、亞硫醯溴、PCl3 、PCl5 、草醯氯、Me2 C=C(Cl)NMe2 、CCl4 Ph3 P、PhCOCl、PBr3 、PBr5 、Ph3 PBr2 、草醯溴或Me2 C=C(Br)NMe2 。 醯基鹵生成反應條件係相關技術中已熟知且係例如由Allen, C.、Barker W.在Organic Syntheses , Coll.第2卷, 1943, 第156頁 (反應式1之產物)；由Adams, R.、Jenkins, R.在Organic Syntheses , Coll.第1卷, 1941, 第394頁 (反應式1之產物)；由Newcomb, M.、Burchill, M.、Deeb, T.在J. Am. Chem.Soc. 1988 ,110 , 6528–6535 (反應式1之中間物，在第6529頁)；由Devos, A.、Remion, J.、Frisque-Hesbain, A.、Colens, A.、Ghosez, L.在Chem.Commun. 1979 , 1180 (化合物2)； 由Lee, J.在J. Am. Chem.Soc. 1966 ,88 , 3440–3441 (反應式1之產物，在第3340頁)；由Brown, H.在J. Am. Chem.Soc. 1938 ,60 , 1325–1328 (表I及表II，在第1326頁)；由Adams, R.、Ulich, L.在J. Am. Chem.Soc. 1920 , 599–611 (反應式3之產物，在第601頁，反應式1之產物，在第602頁)；由Jesus Mari, A.、Palomo, C.在Synthesis 1982 , 684-687 (化合物2，在第684頁，化合物10及11，在表1中，在第685頁)中進行描述。節 B. 製備用於烷基化步驟之起始物質： 節 B.1. 製備式 (3-II-A) 之醯胺中間物： 在另一實施例中，本發明係關於一種用於製備式(3-II-A)化合物或其鹽之方法，(3-II-A) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5”及R6”彼此獨立地為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基、C3 -C7 -環烷基，或者R5”及R6”與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，較佳地R5”及R6”與其所連接之氮一起形成對掌性部分， 該方法包括使式(4)化合物或其鹽，(4) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 X為鹵基，諸如氯， 與式HNR5”R6”之胺，其中R5”及R6”係如針對式(3-II-A)化合物所定義， 視情況在存在胺偶聯試劑下反應， 以提供式(3-II-A)化合物。 在一較佳實施例中，本發明係關於一種用於製備式(3-II-A-a)化合物或其鹽之方法，(3-II-A-a) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5”及R6”彼此獨立地為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基、C3 -C7 -環烷基，或者R5”及R6”與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，較佳地R5”及R6”與其所連接之氮一起形成對掌性部分， 該方法包括使式(4-a)化合物或其鹽，(4-a) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 X為鹵基，諸如氯， 與式HNR5”R6”之胺，其中R5”及R6”係如針對式(3-II-A)化合物所定義， 視情況在存在胺偶聯試劑下反應， 以提供式(3-II-A-a)化合物。 偶聯試劑通常係用於自羧酸製備醯胺、酯及酸酐。合適的胺偶聯試劑之典型實例可以在Valeur, E.、Bradley, M.Chem.Soc.Rev. 2009 ,38 , 606-631中找到。合適的偶聯試劑之較佳實例係選自DCC (N ,N '-二環己基碳二亞胺)、EDC (N -(3-二甲基胺基丙基)-N -乙基碳二亞胺)、CDI (1,1'-羰基二咪唑)、HATU (六氟磷酸N ,N ,N ',N '-四甲銨)、HOBt (6-氯-1-羥基苯并三唑)及其混合物。節 B.2. 製備式 (3-II-A) 之醯胺中間物： 在另一實施例中，本發明係關於一種用於製備式(3-II-A)化合物或其鹽之方法，(3-II-A) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5”及R6”彼此獨立地為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基、C3 -C7 -環烷基，或者R5”及R6”與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，較佳地R5”及R6”與其所連接之氮一起形成對掌性部分， 該方法包括使式(3-I)化合物或其鹽，(3-I) 其中R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5’為氫 與式HNR5”R6”之胺，其中R5”及R6”係如針對式(3-II-A)化合物所定義， 在存在胺偶聯試劑下反應， 以提供式(3-II-A)化合物。 在一較佳實施例中，本發明係關於一種用於製備式(3-II-A-a)化合物或其鹽之方法，(3-II-A-a) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5”及R6”彼此獨立地為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基、C3 -C7 -環烷基，或者R5”及R6”與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，較佳地R5”及R6”與其所連接之氮一起形成對掌性部分， 該方法包括使式(3-I-a)化合物或其鹽，(3-I-a) 其中R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5’為氫 與式HNR5”R6”之胺，其中R5”及R6”係如針對式(3-II-A)化合物所定義， 在存在胺偶聯試劑下反應， 以提供式(3-II-A-a)化合物。 合適的胺偶聯試劑之典型實例可以在Valeur, E.、Bradley, M.Chem.Soc.Rev .2009 ,38 , 606-631中找到。合適的偶聯試劑之較佳實例係選自DCC (N ,N '-二環己基碳二亞胺)、EDC (N -(3-二甲基胺基丙基)-N -乙基碳二亞胺)、CDI (1,1'-羰基二咪唑)、HATU(六氟磷酸N ,N ,N ',N '-四甲銨)、HOBt (6-氯-1-羥基苯并三唑)及其混合物。節 B.3. 製備式 (3-II-A) 之醯胺中間物： 在另一實施例中，本發明係關於一種用於製備式(3-II-A)化合物或其鹽之方法，(3-II-A) 其中 其中R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5”及R6”彼此獨立地為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基、C3 -C7 -環烷基，或者R5”及R6”與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，較佳地R5”及R6”與其所連接之氮一起形成對掌性部分， 該方法包括使式(2)化合物或其互變異構體或鹽，(2)； 與式HNR5”R6”之胺，其中R5”及R6”係如針對式(3-II-A)化合物所定義，且其中R1為氫或氮保護基， 在存在離子性鹽下反應，以提供式(3-II-A)化合物。 在一較佳實施例中，本發明係關於一種用於製備式(3-II-A-a)化合物或其鹽之方法，(3-II-A-a) 其中 其中R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5”及R6”彼此獨立地為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基、C3 -C7 -環烷基，或者R5”及R6”與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，較佳地R5”及R6”與其所連接之氮一起形成對掌性部分， 該方法包括使式(2-a)化合物(其亦為式2化合物)或其互變異構體或鹽，(2-a)； 與式HNR5”R6”之胺，其中R5”及R6”係如針對式(3-II-A)化合物所定義， 在存在離子性鹽下反應，以提供式(3-II-A-a)化合物。 離子性鹽之較佳實例為鹼金屬烷醇鹽諸如甲醇鈉或乙醇鈉、或鹼金屬六氟磷酸鹽諸如六氟磷酸鋰。 較佳地，該反應係在極性、非質子性有機溶劑，較佳THF中，在0至40℃，較佳10至30℃，更佳15至25℃範圍內之溫度下進行。 較佳地，該反應係在有機溶劑中，在室溫下進行，例如該反應係在四氫呋喃中在室溫下進行。 在一實施例中，該離子性鹽(為金屬烷醇鹽)係以催化量使用，較佳地使用0.1當量之甲醇鈉。 在一實施例中，式HNR5”R6”之胺係例如吡咯啶、嗎啉或二甲胺。 在提及對掌性部分之處，其等係基於在本說明中任何地方所述之對掌性分子。 在本發明之一較佳實施例中，式HNR5”R6”之胺係對掌性胺，例如具有下式：其中Ra’、Ra、Rb、Rb’、Rc、Rc’及X係例如如以下中所述：Evans, D. A.Aldrichimica Acta 1982 ,15 , 23-32，特定言之如以下中所述：其中第25頁之反應圖VI，其係以引用的方式併入本文中；或Kawanami, Y.、Ito, Y.、Kitagawa, T.、Taniguchi, Y.、Katsuki, T.、Yamaguchi, M.Tetrahedron Lett. 1984 ,25 , 857-860，特定言之如以下中所述：其中第858頁之表1，其係以引用的方式併入本文中；或Askin, D.、Wallace, M.、Vacca, J.、Reamer, R.、Volante, R.、Shinkai, I.J. Org.Chem .1992 ,57 , 2771-2773，特定言之如以下中所述：其中第2771頁之實例1，其係以引用的方式併入本文中。 具體而言，可使用(S)-脯胺醇或(R)-脯胺醇作為對掌性胺。 在另一較佳實施例中，該對掌性胺具有下式：其中R、R’及R”係例如如以下中所述： Blaser, H.-U.Chem.Rev .1992 ,92 , 935-952，特定言之如以下中所述：其中第937頁表4，其係以引用的方式併入本文中；Myers, A. G.、Yang, B. H.、Chen, H.、McKinstry, L.、Kopecky, D. J.、Gleason, J. L.J. Am. Chem.Soc. 1997 ,119 , 6496-6511，特定言之如以下中所述：其中第6498頁表2，其係以引用的方式併入本文中；Jullian, V.、Quirion, J.、Husson, H.Synthesis 1997 , 1091-1097，特定言之如以下中所述：其中第109頁實例1a-b， 其係以引用的方式併入本文中。例如，R為Me，R’為Me且R”為Ph或C(OH)Ph；或者R為甲基，R’為苯基且R”為CH2 OH。 在一實施例中，該對掌性胺具有下式：其中Rb、Rb’、Rc及Rc’係例如如以下中所述：Evans, D. A.Aldrichimica Acta 1982 ,15 , 23-32，特定言之如以下中所述：其中第27頁反應圖X及XI， 其係以引用的方式併入本文中；Davies, S.、Sanganee, H.Tetrahedron Asymmetry 1995 ,6 , 671-674，特定言之如以下中所述：其中第672頁實例3a-d，其係以引用的方式併入本文中。例如，Rb為CH2 Ph、i Pr或Me且Rb’= Rc’= 氫且Rc為氫或Ph；或Rb為甲基、苯基或CH2 Ph、i Pr，Rb’為氫，Rc = Rc’=甲基；或Rb為CH2 Ph、i Pr或Me且Rb’= Rc’= Rc = 氫。較佳地，Rb為CH2 Ph、i Pr或Me且Rb’= Rc’ = Rc =氫。特別合適的係(R)-4-苄基-噁唑啶-2-酮或(R)-4-異丙基-噁唑啶-2-酮。 特別佳的係插入下式部分NR5”R6”的對掌性胺。在一實施例中，該對掌性胺具有下式：其中Ra*、Ra’*、Rb*、Rb’*係例如如以下中所述： Oppolzer, W.、Poli, G.、Kingma, A.、Starkemann, C.、Bernardinelli, G.Helv.Chim.Acta 1987 ,70 , 2201-2214，特定言之如以下中所述：其中第2204頁實例8， 其係以引用的方式併入本文中。額外的實例係如以下中所述：Lee, A.W.M.、Chan, W.H.、Zhang, S-J.、Zhang, H-K.,Cur.Org.Chem 2007 , 11, 213-228及其中引用之參考文獻。 或者，特別佳的係插入下式部分NR5”R6”的對掌性胺。在一實施例中，該對掌性胺為(S)-甲基-(1-苯基乙基)胺、(R)-甲基-(1-苯基乙基)胺或(1R,2R)-偽麻黃鹼。 在一較佳實施例中，該對掌性胺為(1R ,2R )-偽麻黃鹼。節 B.4. 製備式 (3-III-A) 之酯中間物： 在另一實施例中，本發明係關於一種用於製備式(3-III-A)化合物或其鹽之方法，(3-III-A) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 Rx為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基，或(較佳地)Rx與其所連接之氧一起形成對掌性部分， 該方法包括使式(4)化合物或其鹽，(4) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 X為鹵基，諸如氯， 與式HORx之醇，其中Rx係如針對式(3-III-A)化合物所定義， 視情況在存在偶聯試劑下反應，以提供式(3-III-A)化合物。 在一較佳實施例中，本發明係關於一種用於製備式(3-III-A-a)化合物或其鹽之方法，(3-III-A-a) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 Rx為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基，或(較佳地)Rx與其所連接之氧一起形成對掌性部分， 該方法包括使式(4-a)化合物或其鹽，(4-a) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 X為鹵基，諸如氯， 與式HORx之醇，其中Rx係如針對式(3-III-A-a)化合物所定義， 視情況在存在偶聯試劑下反應，以提供式(3-III-A-a)化合物。 偶聯試劑(亦參見以上定義)通常係用於自羧酸製備醯胺、酯及酸酐。合適的偶聯試劑之典型實例可以在Valeur, E.、Bradley, M.Chem.Soc.Rev. 2009 ,38 , 606-631中找到。合適的偶聯試劑之較佳實例係選自DCC (N ,N '-二環己基碳二亞胺)、EDC (N -(3-二甲基胺基丙基)-N -乙基碳二亞胺)、CDI (1,1'-羰基二咪唑)、HATU (六氟磷酸N ,N ,N ',N '-四甲銨)、HOBt (6-氯-1-羥基苯并三唑)及其混合物。節 B.5. 製備式 (3-III-A) 之酯中間物： 在另一實施例中，本發明係關於一種用於製備式(3-III-A)化合物或其鹽之方法，(3-III-A) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 Rx為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基，或(較佳地)Rx與其所連接之氧一起形成對掌性部分， 該方法包括使式(3-I)化合物或其鹽，(3-I) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5’為氫 與式HORx之醇或與式Rx-X之鹵化物，其中Rx係如針對式(3-III-A)化合物所定義，且其中X係如以上式(4)中所定義，諸如溴或氯， 視情況在存在偶聯試劑下反應，以提供式(3-III-A)化合物。 在一較佳實施例中，本發明係關於一種用於製備式(3-III-A-a)化合物或其鹽之方法，(3-III-A-a) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 Rx為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基，或Rx與其所連接之氧一起形成對掌性部分， 該方法包括使式(3-I-a)化合物或其鹽，(3-I-a) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代， 且R5’為氫 與式HORx之醇或與式Rx-X之鹵化物，其中Rx係如針對式(3-III-A)化合物所定義，且其中X係如以上式(4)中所定義，諸如溴或氯， 視情況在存在偶聯試劑下反應， 以提供式(3-III-A)化合物。 偶聯試劑通常係用於自羧酸製備醯胺、酯及酸酐。合適的偶聯試劑之典型實例可以在Valeur, E.、Bradley, M.Chem.Soc.Rev .2009 ,38 , 606-631中找到。合適的偶聯試劑之較佳實例係選自DCC (N ,N '-二環己基碳二亞胺)、EDC (N -(3-二甲基胺基丙基)-N -乙基碳二亞胺)、CDI (1,1'-羰基二咪唑)、HATU (六氟磷酸N ,N ,N ',N '-四甲銨)、HOBt (6-氯-1-羥基苯并三唑)及其混合物。 酯之形成係相關技術中已熟知之反應。節 B.6. 製備式 (3-III-A) 之酯中間物： 在另一實施例中，本發明係關於一種用於製備式(3-III-A)化合物或其鹽之方法，(3-III-A) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 Rx為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基，或Rx與其所連接之氧一起形成對掌性部分， 該方法包括使式(3’-III)化合物或其鹽，(3’-III) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5”為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基，條件為 R5”為非Rx 與式HORx之醇，其中Rx係如針對式(3-III-A)化合物所定義，視情況在存在酸或鹼下反應， 以提供式(3-III-A)化合物。 在一較佳實施例中，本發明係關於一種用於製備式(3-III-A-a)化合物或其鹽之方法，(3-III-A-a) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 Rx為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基，或Rx與其所連接之氧一起形成對掌性部分， 該方法包括使式(3’-III-a)化合物或其鹽，(3’-III-a) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代， R5”為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基，條件為 R5”為非Rx 與式HORx之醇，其中Rx係如針對式(3-III-A)化合物所定義，視情況在存在酸或鹼下反應， 以提供式(3-III-A-a)化合物。 相關技術中已熟知轉酯化反應。較佳地，藉由在醇中，在存在催化量之酸或鹼下，加熱酯來進行轉酯化反應。轉酯化反應之典型條件係例如由Riemenschneider, W.；Bolt, H. M.在Ullmann's Encyclopedia of Industrial Chemistry 2012 , 245-266中進行描述。 在一實施例中，該醇具有式HORx，其中Rx為甲基、乙基、對甲基苯基或苄基。 在一實施例中，鹵化物Rx-X之Rx為甲基、乙基、對甲基苯基或苄基。較佳地，Rx-X為苄基溴。 在本發明之一較佳實施例中，式HORx之醇係對掌性醇，例如具有下式：其中R’及R”係例如如以下中所述： Blaser, H.-U.Chem.Rev. 1992 ,92 , 935-952，特定言之如以下中所述：其中第937頁之表3，其係以引用的方式併入本文中；Oertling, H.、Reckziegel, A.、Surburg, H.、Bertram, H.在Chem.Rev. 2007 ,107 , 2136-2164中，特定言之如以下中所述：其中第2138頁之實例1a-e，其係以引用的方式併入本文中；Hultin, P.、Earle, M.、Sudharshan, M.在Tetrahedron 1997 ,53 , 14823-14870中，特定言之如以下中所述：其中第14843-14844頁之實例111及117，其係以引用的方式併入本文中；及Kunz, H., Ruck, K.在Angew.Chem.Int. Ed.Engl. 1993 ,32 , 336-358中，特定言之如以下中所述：其中第339頁實例17， 其係以引用的方式併入本文中。例如，R’為Me且R”為Ph (參考 (a) Leemhuis, M.；Van Steenis, J. H.；Van Uxem, M. J.；Van Nostrum, C. F.；Hennink, W. E. Eur.J. Org.Chem.2003, 3344-3349；(b) Neradovic；Van Steenbergen；Vansteelant；Meijer；Van Nostrum；Hennink Macromolecules 2003, 36, 7491-7498)。或者，特定言之，式HORx之醇為L-薄荷醇或D-薄荷醇(參見(a) Zheng, S.-L.；Yu, W.-Y.；Che, C.-M. Org.Lett.2002, 889-892；(b) Maegawa, Y.；Agura, K.；Hayashi, Y.；Ohshima, T.；Mashima, K. Synlett 2012, 137-141；(c) Iwasaki, T.；Maegawa, Y.；Hayashi, Y.；Ohshima, T.；Mashima, K. J. org.Chem.2008, 5147-5150；(d) Meth-Cohn, O. J. Chem.Soc.Chem.Comm.1986, 695-697)。另外，特定言之，該反應係在有機溶劑諸如四氫呋喃中，在室溫下進行。由Rx與鍵結氧形成之對掌性部分較佳係彼等，其中Rx因而對應於對映異構體薄荷基或2-苯基乙基部分。節 B.7. 製備式 (3-IV) 之硫酯中間物： 在另一實施例中，本發明係關於一種用於製備式(3-IV)化合物或其鹽之方法，(3-IV)， 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基，較佳地對掌性部分， 該方法包括使式(4)化合物或其鹽，(4) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 X為鹵基，諸如氯， 與式HSR5之硫醇，其中R5係如針對式(3-IV)化合物所定義，視情況在存在偶聯試劑下反應， 以提供式(3-IV)化合物。 在一較佳實施例中，本發明係關於一種用於製備式(3-IV-a)化合物或其鹽之方法，(3-IV-a)， 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基， 該方法包括使式(4-a)化合物或其鹽，(4-a) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 X為鹵基，諸如氯，或為羥基 與式HSR5之硫醇，其中R5係如針對式(3-IV-a)化合物所定義，視情況在存在偶聯試劑下反應， 以提供式(3-IV-a)化合物。 在一實施例中，該硫醇具有式HSR5，其中R5為4-甲基苄基。 較佳地，該式HSR5之硫醇為對掌性硫醇，例如具有下式：其中R’及R”係例如如以下中所述： Blaser, H.-U.在Chem.Rev. 1992 ,92 , 935-952，特定言之如以下中所述：其中第937頁之表3，其係以引用的方式併入本文中；Oertling, H.、Reckziegel, A.、Surburg, H.、Bertram, H.在Chem.Rev. 2007 ,107 , 2136-2164中，特定言之如以下中所述：其中第2138頁之實例1a-e，其係以引用的方式併入本文中；Hultin, P.、Earle, M.、Sudharshan, M.在Tetrahedron 1997 ,53 , 14823-14870中，特定言之如以下中所述：其中第14843-14844頁之實例111及117，其係以引用的方式併入本文中；及Kunz, H., Ruck, K.在Angew.Chem.Int. Ed.Engl. 1993 ,32 , 336-358中，特定言之如以下中所述：其中第339頁實例17， 其係以引用的方式併入本文中。例如，R’為Me且R”為Ph (參考(a) Alajarin, M.； Ortin, M.-M.；Sanchez-Andrada, P.；Vidal, A.；Bautista, D. Org.Lett.2005, 7, 5281-5284；(b) EP1264547 A1, 2002；(c) Corey, E. J.；Cimprich, K. A. Tet.Lett.1992, 33, 4099-4102)。或者，特定言之，該式HSRx之醇為L-薄荷醇或D-薄荷醇之硫醇基類似物。由Rx與鍵結硫形成之對掌性部分較佳係彼等，其中Rx因而對應於對映異構體薄荷基或2-苯基乙基部分。節 B.8. 製備式 (3-IV) 之硫酯中間物： 在另一實施例中，本發明係關於一種用於製備式(3-IV)化合物或其鹽之方法，(3-IV) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基，較佳地對掌性部分， 該方法包括使式(3-III)化合物或其鹽，(3-III) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基， 與式MSR5化合物反應，其中R5為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基且M為金屬， 例如，鹼金屬或鋁，以提供式(3-IV)化合物。 在一較佳實施例中，本發明係關於一種用於製備式(3-IV-a)化合物或其鹽之方法，(3-IV-a) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基， 該方法包括使式(3-III-a)化合物或其鹽，(3-III-a) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基， 與式MSR5化合物反應，其中R5為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基且M為鹼金屬，以提供式(3-IV-a)化合物。 藉由轉酯化反應形成硫酯係相關技術熟知(參考例如(a) US5948917 A1；(b) Gennari, C.；Carcano, M.；Donghi, M.；Mongelli, N.；Vanotti, E.；Vulpetti, A.J. Org.Chem. 1997 ,62 , 4746-4755；(c) Trost, B. M.；O'Boyle, B. M.Org.Lett. 2008 ,10 , 1369-1372。 式MSR5之(例如對掌性)部分及化合物較佳係如針對式HSR5化合物中之部分所述般。節 B.9. 製備式 (3-IV) 之硫酯中間物： 在另一實施例中，本發明係關於一種用於製備式(3-IV)化合物或其鹽之方法，(3-IV) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基，較佳地對掌性部分， 該方法包括使式(3-I)化合物或其鹽，(3-I) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5’為氫 與式HSR5之硫醇，其中R5係如針對式(3-IV)化合物所定義，視情況在存在偶聯試劑下反應， 以提供式(3-IV)化合物。 在一較佳實施例中，本發明係關於一種用於製備式(3-IV-a)化合物或其鹽之方法，(3-IV-a) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基，較佳地對掌性部分， 該方法包括使式(3-I-a)化合物或其鹽，(3-I-a) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5’為氫 與式HSR5之硫醇，其中R5係如針對式(3-IV)化合物所定義，視情況在存在偶聯試劑下反應， 以提供式(3-IV-a)化合物。 偶聯試劑通常係用於自羧酸製備醯胺、酯及酸酐。合適的偶聯試劑之典型實例可以在Valeur, E.、Bradley, M.Chem.Soc.Rev. 2009 ,38 , 606-631中找到。合適的偶聯試劑之較佳實例係選自DCC (N ,N '-二環己基碳二亞胺)、EDC (N -(3-二甲基胺基丙基)-N -乙基碳二亞胺)、CDI (1,1'-羰基二咪唑)、HATU (六氟磷酸N ,N ,N ',N '-四甲銨)、HOBt (6-氯-1-羥基苯并三唑)及其混合物。 硫酯之形成係相關技術中已熟知之反應(參考例如，針對硫代薄荷醇(a) Porto, S.；Seco, J. M.；Ortiz, A.；Quinoa, E.；Riguera, R.Org.Lett. 2007 ,9 , 5015-5018；(b) Louzao, I.；Seco, J. M.；Quinoa, E.；Riguera, R.Chem.Comm. 2010 ,46 , 7903-7905；針對1-苯基硫代乙醇)：Shoda, S.-i.；Mukaiyama, T.Chem.Lett. 1980 , 391-392)。較佳地，式HSR5硫醇之R5為4-甲基苯基，藉以與根據式(3-I-a)之化合物(藉以R1及R2為苄基)反應係在有機溶劑諸如二氯甲烷中，在室溫下，在存在合適偶聯試劑諸如CDI下進行。節 C. 烷基化步驟： 節 C.1. 醯胺中間物之烷基化： 在另一實施例中，本發明係關於一種用於製備式(5-II-A)化合物或其鹽之方法，(5-II-A) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代， R5”及R6”彼此獨立地為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基、C3 -C7 -環烷基，或者R5”及R6”與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，較佳地R5”及R6”與其所連接之氮一起形成對掌性部分，且 R8為C1-C7-烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基， 該方法包括使式(3-II-A)化合物或其鹽，(3-II-A) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5”及R6”彼此獨立地為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基、C3 -C7 -環烷基，或者R5”及R6”與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，較佳地R5”及R6”與其所連接之氮一起形成對掌性部分， 與鹼及選自以下之C1 -C7 -烷基化試劑： -(R8)3 O+ Z− ，其中R8為C1 -C7 -烷基(諸如甲基或乙基)或C6 -C10 -芳基-C1 -C7 -烷基，且Z− 為陰離子(諸如四氟硼酸根)； -R8X，其中R8為C1 -C7 -烷基(諸如甲基或乙基)或C6 -C10 -芳基-C1 -C7 -烷基，且X為離去基團諸如鹵基(諸如氯離子、溴離子、碘離子)或磺酸根(例如三氟甲磺酸根、甲苯磺酸根或甲磺酸根)；及 -(R8)2 SO4 ，其中R8為C1 -C7 -烷基(諸如甲基或乙基)或C6 -C10 -芳基-C1 -C7 -烷基， 視情況在存在添加劑下反應， 以提供式(5-II-A)化合物。 在一較佳實施例中，本發明係關於一種用於製備式(5-II-A-a)化合物或其鹽之方法，(5-II-A-a) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代， R5”及R6”彼此獨立地為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基、C3 -C7 -環烷基，或者R5”及R6”與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，較佳地R5”及R6”與其所連接之氮一起形成對掌性部分，且 R8為C1 -C7 -烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基， 該方法包括使式(3-II-A-a)化合物或其鹽，(3-II-A-a) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5”及R6”彼此獨立地為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基、C3 -C7 -環烷基，或者R5”及R6”與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，較佳地R5”及R6”與其所連接之氮一起形成對掌性部分， 與鹼及選自以下之烷基化試劑： -(R8)3 O+ Z− ，其中R8為C1 -C7 -烷基(諸如甲基或乙基)或C6 -C10 -芳基-C1 -C7 -烷基，且Z− 為陰離子(諸如四氟硼酸根)； -R8X，其中R8為C1 -C7 -烷基(諸如甲基或乙基)或C6 -C10 -芳基-C1 -C7 -烷基，且X為離去基團諸如鹵基(諸如氯離子、溴離子、碘離子)或磺酸根(例如三氟甲磺酸根、甲苯磺酸根或甲磺酸根)；及 -(R8)2 SO4 ，其中R8為C1 -C7 -烷基(諸如甲基或乙基)或C6 -C10 -芳基-C1 -C7 -烷基， 視情況在存在添加劑下反應， 以提供式(5-II-A-a)化合物。 較佳地，該烷基化試劑為甲基碘、磺酸二甲酯、苄基溴或異丙基碘，最佳地甲基碘或磺酸二甲酯。 合適的添加劑係會改良所形成產物之溶解度或有助於使鹼解聚，藉此使其更具反應性的化合物，例如，如Carey, F. A.、Sundberg, R. J.Organische Chemie , VCH, Weinheim, 1995中之相關章節中所述，諸如六甲基磷醯胺(HMPA)、N ,N ’-二甲基伸丙基脲(DMPU)、四甲基乙二胺(TMEDA)、二甲基亞碸(DMSO)、NMP (N -甲基吡咯啶酮)或其混合物。冠醚或對掌性冠醚，例如如由Shirakawa, S.、Yamamoto, K.、Kitamura, M.、Ooi, T.、Maruoka, K.在Angew.Chem.Int. Ed. 2005 ,44 , 625-628中，特定言之如其中第626頁反應圖1所述，其以引用的方式併入本文中；由Weber, B.、Seebach, D.在Tetrahedron 1994 ,50 , 7473-7484中所述，特定言之如第7476頁表1所述，其以引用的方式併入本文中，亦適用於此目的。 合適的鹼為例如選自下式 -RmRnNM，其中Rm及Rn獨立地選自C1 -C7 -烷基、環烷基、雜環基或甲矽烷基且M為鹼金屬諸如Na、Li或K；例如，雙(三甲基甲矽烷基)醯胺鋰(LHMDS)、雙(三甲基甲矽烷基)醯胺鈉(NaHMDS)、雙(三甲基甲矽烷基)醯胺鉀(KHMDS)、二異丙基醯胺鋰(LDA)或二異丙胺基鉀； -RmM，其中Rm係選自C1 -C7 -烷基或芳基且M為鹼金屬諸如Na、Li或K；例如，甲基鋰、正丁基鋰、第二丁基鋰、第三丁基鋰或苯基鋰； -MH，其中M為鹼金屬諸如Na、Li或K；例如，氫化鈉或氫化鉀； -或其混合物。 較佳地，該鹼為NaHMDS、LDA或KHMDS。 該烷基化反應可在存在溶劑下進行。合適的溶劑包括醚諸如乙醚、第三丁基甲基醚、四氢呋喃或2-甲基四氫呋喃；芳族溶劑，諸如甲苯或二甲苯或脂族烴諸如戊烷、己烷或庚烷。兩種或更多種該等溶劑之任何混合物亦係在本發明之範疇內。較佳地，該烷基化反應係在低於室溫下，較佳在-10℃下或低於-10℃進行。更佳地，該烷基化反應係在介於-10℃與-78℃之間之溫度下進行。最佳地，該烷基化反應係在介於-60℃與-78℃之間之溫度下進行。 對掌性部分係如上針對NR5”R6”所定義。節 C.2. 酯中間物之烷基化： 在另一實施例中，本發明係關於一種用於製備式(5-III-A)化合物或其鹽之方法，(5-III-A) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代， Rx為C1 -C7 -烷基或C6 -C10 -芳基-C1 -C7 -烷基，或(較佳地)Rx與其所連接之氧一起形成對掌性部分，且 R8為C1 -C7 -烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基， 該方法包括使式(3-III-A)化合物或其鹽，(3-III-A) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 Rx為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基，或(較佳地)Rx與其所連接之氧一起形成對掌性部分， 與鹼及選自以下之烷基化試劑： -(R8)3 O+ Z− ，其中R8為C1 -C7 -烷基(諸如甲基或乙基)或C6 -C10 -芳基-C1 -C7 -烷基，且Z− 為陰離子(諸如四氟硼酸根)； -R8X，其中R8為C1 -C7 -烷基(諸如甲基或乙基)或C6 -C10 -芳基-C1 -C7 -烷基，且X為離去基團諸如鹵基(諸如氯離子、溴離子、碘離子)或磺酸根(例如三氟甲磺酸根、甲苯磺酸根或甲磺酸根)；及 -(R8)2 SO4 ，其中R8為C1 -C7 -烷基(諸如甲基或乙基)或C6 -C10 -芳基-C1 -C7 -烷基， 視情況在存在添加劑下反應， 以提供式(5-III-A)化合物。 在另一實施例中，本發明係關於一種用於製備式(5-III-A-a)化合物或其鹽之方法，(5-III-A-a) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代， Rx為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基，或(較佳地)Rx與其所連接之氧一起形成對掌性部分， R8為C1 -C7 -烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基， 該方法包括使式(3-III-A-a)化合物或其鹽，(3-III-A-a) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 Rx為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基，或(較佳地)Rx與其所連接之氧一起形成對掌性部分， 與鹼及選自以下之烷基化試劑： -(R8)3 O+ Z− ，其中R8為C1 -C7 -烷基(諸如甲基或乙基)或C6 -C10 -芳基-C1 -C7 -烷基，且Z− 為陰離子(諸如四氟硼酸根)； -R8X，其中R8為C1 -C7 -烷基(諸如甲基或乙基)或C6 -C10 -芳基-C1 -C7 -烷基，且X為離去基團諸如鹵基(諸如氯離子、溴離子、碘離子)或磺酸根(例如三氟甲磺酸根、甲苯磺酸根或甲磺酸根)；及 -(R8)2 SO4 ，其中R8為C1 -C7 -烷基(諸如甲基或乙基)或C6 -C10 -芳基-C1 -C7 -烷基， 視情況在存在添加劑下反應， 以提供式(5-III-A-a)化合物。 合適的烷基化試劑係例如如本文以上之節C.1中所定義。 合適的添加劑係例如如本文以上之節C.1中所定義。 合適的鹼係例如如本文以上之節C.1中所定義。 合適的溶劑係例如如本文以上之節C.1中所定義。節 C.3 及 C4. 硫酯中間物之烷基化： 在另一實施例中，本發明係關於一種用於製備式(5-IV)化合物或其鹽之方法，(5-IV)， 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代， R5為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基，較佳地對掌性部分，且 R8為C1 -C7 -烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基， 該方法包括使式(3-IV)化合物或其鹽，(3-IV)， 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基，較佳地對掌性部分， 與鹼及選自以下之烷基化試劑： -(R8)3 O+ Z− ，其中R8為C1 -C7 -烷基(諸如甲基或乙基)或C6 -C10 -芳基-C1 -C7 -烷基，且Z− 為陰離子(諸如四氟硼酸根)； -R8X，其中R8為C1 -C7 -烷基(諸如甲基或乙基)或C6 -C10 -芳基-C1 -C7 -烷基，且X為離去基團諸如鹵基(諸如氯離子、溴離子、碘離子)或磺酸根(例如三氟甲磺酸根、甲苯磺酸根或甲磺酸根)；及 -(R8)2 SO4 ，其中R8為C1 -C7 -烷基(諸如甲基或乙基)或C6 -C10 -芳基-C1 -C7 -烷基， 視情況在存在添加劑下反應， 以提供式(5-IV)化合物。 在一較佳實施例中，本發明係關於一種用於製備式(5-IV-a)化合物或其鹽之方法，(5-IV-a)， 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代， R5為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基，且 R8為C1 -C7 -烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基， 該方法包括使式(3-IV-a)化合物或其鹽，(3-IV-a)， 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基，較佳地對掌性部分， 與鹼及選自以下之烷基化試劑： -(R8)3 O+ Z− ，其中R8為C1 -C7 -烷基(諸如甲基或乙基)或C6 -C10 -芳基-C1 -C7 -烷基，且Z− 為陰離子(諸如四氟硼酸根)； -R8X，其中R8為C1 -C7 -烷基(諸如甲基或乙基)或C6 -C10 -芳基-C1 -C7 -烷基，且X為離去基團諸如鹵基(諸如氯離子、溴離子、碘離子)或磺酸根(例如三氟甲磺酸根、甲苯磺酸根或甲磺酸根)；及 -(R8)2 SO4 ，其中R8為C1 -C7 -烷基(諸如甲基或乙基)或C6 -C10 -芳基-C1 -C7 -烷基， 視情況在存在添加劑下反應， 以提供式(5-IV-a)化合物。 合適的烷基化試劑係例如如本文以上之節C.1中所定義。 合適的添加劑係例如如本文以上之節C.1中所定義。 合適的鹼係例如如本文以上之節C.1中所定義。 合適的溶劑係例如如本文以上之節C.1中所定義。 對掌性部分較佳係如上針對式HSR5化合物所定義。 在本發明之一態樣中，利用鹼(較佳NaHMDS)及烷基化劑(較佳甲基碘)，在存在溶劑(較佳四氫呋喃)下處理根據式3-II-A-a之化合物，以得到根據式5-II-A-a之化合物及式5-II-A-b之其相應的非對映異構體。較佳地，5-II-A-a比5-II-A-b之比率為77:23，更佳地84:16，甚至更佳地90:10，還更佳地97:3。最佳地，5-II-A-a比5-II-A-b之比率為99:1。在本發明之另一態樣中，利用鹼(較佳KHMDS)及烷基化劑(較佳甲基碘)，在存在溶劑(較佳四氫呋喃)下處理根據式3-II-A-a之化合物，以得到根據式5-II-A-a之化合物及式5-II-A-b之其相應的非對映異構體。較佳地，5-II-A-a比5-II-A-b之比率為41:59，更佳地23:77，最佳地5-II-A-a比5-II-A-b之比率為＞1:99。 在本發明之另一態樣中，利用鹼(較佳LDA)及烷基化劑(較佳乙基碘)，在存在溶劑(較佳四氫呋喃)下處理根據式3-II-A-a之化合物，以得到根據式5-II-A-a之化合物及式5-II-A-b之其相應的非對映異構體。較佳地，5-II-A-a比5-II-A-b之比率為79:21或更高。 在本發明之還有另一態樣中，利用鹼(較佳LDA)及烷基化劑(較佳異丙基碘)，在存在溶劑(較佳四氫呋喃)下處理根據式3-II-A-a之化合物，以得到根據式5-II-A-a之化合物及式5-II-A-b之其相應的非對映異構體。較佳地，5-II-A-a比5-II-A-b之比率為72:28或更高。 在本發明之還有另一態樣中，利用鹼(較佳NaHMDS)及烷基化劑(較佳苄基溴)，在存在溶劑(較佳四氫呋喃)下處理根據式3-II-A-a之化合物，以得到根據式5-II-A-a之化合物及式5-II-A-b之其相應的非對映異構體。較佳地，5-II-A-a比5-II-A-b之比率為＞99:1。節 D. 本發明中間物轉化為式 (1) 化合物 ( 已知中間物描述於 WO 2008/083967 中 ) ： 節 D.1. 烷基化之醯胺中間物： 在另一實施例中，本發明係關於一種用於製備式(1A)化合物或其鹽之方法，(1A) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R8為C1 -C7 -烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基， 該方法包括使式(5-II-A)化合物或其鹽，(5-II-A) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代， R8為C1 -C7 -烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基，且 R5”及R6”彼此獨立地為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基、C3 -C7 -環烷基，或者R5”及R6”與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，較佳地R5”及R6”與其所連接之氮一起形成對掌性部分， 與無機酸反應，以提供式(1A)化合物。 在一較佳實施例中，本發明係關於一種用於製備式(1A-a)化合物或其鹽之方法，(1A-a) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R8為C1 -C7 -烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基， 該方法包括使式(5-II-A-a)化合物或其鹽，(5-II-A-a) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代， R8為C1 -C7 -烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基，且 R5”及R6”彼此獨立地為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基、C3 -C7 -環烷基，或者R5”及R6”與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，較佳地R5”及R6”與其所連接之氮一起形成對掌性部分， 與無機酸反應，以提供式(1A-a)化合物。 合適的無機酸為例如礦物酸或布朗斯特酸，諸如鹽酸、硫酸或磷酸。通常，使用HCl係例如如由Kawanami, Y.、Ito, Y.、Kitagawa, T.、Taniguchi, Y.、Katsuki, T.、Yamaguchi, M.在Tetrahedron Lett. 1984 ,25 , 857-860第860頁第3行中所述。 對掌性部分NR5”R6”較佳係如本文以上所定義。節 D.2. 烷基化酯中間物： 在另一實施例中，本發明係關於一種用於製備式(1A)化合物或其鹽之方法，(1A) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R8為C1 -C7 -烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基， 該方法包括使式(5-IIIA)化合物或其鹽，(5-III-A) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代， R8為C1 -C7 -烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基，且 Rx為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基，或(較佳地)Rx與其所連接之氧一起形成對掌性部分， 與無機酸反應，以提供式(1A)化合物。 在一較佳實施例中，本發明係關於一種用於製備式(1A-a)化合物或其鹽之方法，(1A-a) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R8為C1 -C7 -烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基， 該方法包括使式(5-III-A-a)化合物或其鹽，(5-III-A-a) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代， R8為C1 -C7 -烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基，且 Rx為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基，或(較佳地)Rx與其所連接之氧一起形成對掌性部分， 與無機酸反應，以提供式(1A-a)化合物。 合適的無機酸為例如礦物酸或布朗斯特酸，諸如鹽酸、硫酸或磷酸。通常，HCl之使用係例如如由Ullrich, A.、Chai, Y.、Pistorius, D.、Elnakady, Y.、Herrmann, J.、Weissman, K.、Kazmaier, U.、Muller, R.在Angew.Chem.Int. Ed.Engl. 2009 ,48 , 4422-4425中第4424頁反應圖3中所述。 由Rx連同鍵結氧所形成之對掌性部分較佳係如本文以上所定義。節 D.3 及 D.4. 烷基化之硫酯中間物： 在另一實施例中，本發明係關於一種用於製備式(1A)化合物或其鹽之方法，(1A) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R8為C1 -C7 -烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基， 該方法包括使式(5-IV)化合物或其鹽，(5-IV)， 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代， R5為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基，較佳地對掌性部分，且 R8為C1 -C7 -烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基， 在氧化條件下反應，以提供式(1A)化合物。 在一較佳實施例中，本發明係關於一種用於製備式(1A-a)化合物或其鹽之方法，(1A-a) 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R8為C1 -C7 -烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基， 該方法包括使式(5-IV-a)化合物或其鹽，(5-IV-a)， 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代， R5為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基，較佳地對掌性部分，且 R8為C1 -C7 -烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基， 在氧化條件下反應，以提供式(1A)化合物。 合適的氧化條件係指例如使用氧化劑諸如H2 O2 ，在鹼性條件下(例如，在存在鹼金屬鹼諸如NaOH、LiOH或KOH下)。通常，氧化條件係例如如由Gierasch, T；Shi, Z.；Verdine, G.在Org. Lett. 2003 ,5 , 621-624中之第622頁反應圖2中所述。 對掌性部分較佳係如上針對式HSR5硫醇或使用式HSR5硫醇所得結果所定義。 可以根據已熟知酯化條件，例如，如WO 2008/083967中例如於實例51、43、44或42中所述，達成式I化合物之形成(利用R3-OH酯化，其中R3係如針對式I化合物所定義且非氫)(尤其係R3 =乙基)。節 E ：在先前節且尤其在實例中出現之新穎且本發明化合物 在以上所示之方法中，涉及若干種新穎且本發明化合物。因此，本發明之其他目標係以下顯示之化合物。 一種式(4)化合物或其鹽，(4)； 其較佳地具有根據式(4-a)之組態，(4-a)； 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 X為鹵基，諸如氯。 一種式(3-II-A)化合物或其鹽，(3-II-A)； 其較佳地具有根據式(3-II-A-a)之組態，(3-II-A-a)； 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5”及R6”彼此獨立地為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基、C3 -C7 -環烷基，或者R5”及R6”與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，較佳地R5”及R6”與其所連接之氮一起形成對掌性部分，尤其係如本文其他地方所定義。 一種式(3-III-A)化合物或其鹽，(3-III-A) 其較佳地具有根據式(3-III-A-a)之組態，(3-III-A-a)； 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 Rx與其所連接之氧一起形成對掌性部分，較佳地如本文其他地方所定義。 一種式(3-IV)化合物或其鹽，(3-IV)； 其較佳地具有根據式(3-IV-a)之組態，(3-IV-a)； 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基，較佳地對掌性部分，較佳地如本文其他地方所定義。 一種式(5-II-A)化合物或其鹽，(5-II-A)； 其較佳地具有根據式(5-II-A-a)之組態，(5-II-A-a)； 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代， R5”及R6”彼此獨立地為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基、C3 -C7 -環烷基，或者R5”及R6”與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，較佳地R5”及R6”與其所連接之氮一起形成對掌性部分，尤其係如本文其他地方所定義，且 R8為C1 -C7 -烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基。 一種式(5-III-A)化合物或其鹽，(5-III-A)， 其較佳地具有根據式(5-III-A-a)之組態，(5-III-A-a)， 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 Rx與其所連接之氧一起形成對掌性部分，較佳地如本文其他地方所定義。 一種式(5-IV)化合物或其鹽，(5-IV)， 其較佳地具有根據式(5-IV-a)之組態，(5-IV-a)， 其中 R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代， R5為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基，較佳地對掌性部分如本文其他地方所定義，且 R8為C1 -C7 -烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基。 ((參考反應圖1))在另一態樣，本發明係關於一種用於將如本文所定義之式(3-I)化合物，較佳地式(3-I-a)化合物或其鹽轉化為如本文所定義之式(1-A)化合物，較佳地式(1-A-a)化合物或其鹽之方法，該方法包括 i)節B.2中之方法，以將如本文所定義之式(3-I)化合物，較佳地式(3-I-a)化合物或其鹽轉化為如本文所定義之式(3-II-A)化合物，較佳地式(3-II-A-a)化合物或其鹽； ii)節C.1中之方法，以將如本文所定義之式(3-II-A)化合物，較佳地式(3-II-A-a)化合物或其鹽轉化為如本文所定義之式(5-II-A)化合物，較佳地式(5-II-A-a)化合物或其鹽； iii)節D.1中之方法，以將如本文所定義之式(5-II-A)化合物，較佳地式(5-II-A-a)化合物或其鹽轉化為如本文所定義之式(1-A)化合物，較佳地式(1-A-a)化合物或其鹽； ((參考反應圖3))在另一態樣，本發明係關於一種用於將如本文所定義之式(3-I)化合物，較佳地式(3-I-a)化合物或其鹽轉化為如本文所定義之式(1-A)化合物，較佳地式(1-A-a)化合物或其鹽之方法，該方法包括 i)節A中之方法，以將如本文所定義之式(3-I)化合物，較佳地式(3-I-a)化合物或其鹽轉化為如本文所定義之式(4)化合物，較佳地式(4-a)化合物或其鹽； ii)節B.1中之方法，以將如本文所定義之式(4)化合物，較佳地式(4-a)化合物或其鹽轉化為如本文所定義之式(3-II-A)化合物，較佳地式(3-II-A-a)化合物或其鹽； iii)節C.1中之方法，以將如本文所定義之式(3-II-A)化合物，較佳地式(3-II-A-a)化合物或其鹽轉化為如本文所定義之式(5-II-A)化合物，較佳地式(5-II-A-a)化合物或其鹽； iv)節D.1中之方法，以將如本文所定義之式(5-II-A)化合物，較佳地式(5-II-A-a)化合物或其鹽轉化為如本文所定義之式(1-A)化合物，較佳地式(1-A-a)化合物或其鹽； ((參考反應圖1))在另一態樣，本發明係關於一種用於將如本文所定義之式(2)化合物，較佳地式(2-a)化合物或其鹽轉化為如本文所定義之式(1-A)化合物，較佳地式(1-A-a)化合物或其鹽之方法，該方法包括 i)節B.3中之方法，以將如本文所定義之式(2)化合物，較佳地式(2-a)化合物或其鹽轉化為如本文所定義之式(3-II-A)化合物，較佳地式(3-II-A-a)化合物或其鹽； ii)節C.1中之方法，以將如本文所定義之式(3-II-A)化合物，較佳地式(3-II-A-a)化合物或其鹽轉化為如本文所定義之式(5-II-A)化合物，較佳地式(5-II-A-a)化合物或其鹽； iii)節D.1中之方法，以將如本文所定義之式(5-II-A)化合物，較佳地式(5-II-A-a)化合物或其鹽轉化為如本文所定義之式(1-A)化合物，較佳地式(1-A-a)化合物或其鹽； ((參考反應圖2))在另一態樣，本發明係關於一種用於將如本文所定義之式(3-I)化合物，較佳地式(3-I-a)化合物或其鹽轉化為如本文所定義之式(1-A)化合物，較佳地式(1-A-a)化合物或其鹽之方法，該方法包括 i)節B.5中之方法，以將如本文所定義之式(3-I)化合物，較佳地式(3-I-a)化合物或其鹽轉化為如本文所定義之式(3-III-A)化合物，較佳地式(3-III-A-a)化合物或其鹽； ii)節C.2中之方法，以將如本文所定義之式(3-III-A)化合物，較佳地式(3-III-A-a)化合物或其鹽轉化為如本文所定義之式(5-III-A)化合物，較佳地式(5-III-A-a)化合物或其鹽； iii)節D.2中之方法，以將如本文所定義之式(5-III-A)化合物，較佳地式(5-III-A-a)化合物或其鹽轉化為如本文所定義之式(1-A)化合物，較佳地式(1-A-a)化合物或其鹽； ((參考反應圖1變型，包括節A)在另一態樣，本發明係關於一種用於將如本文所定義之式(3-I)化合物，較佳地式(3-I-a)化合物或其鹽轉化為如本文所定義之式(1-A)化合物，較佳地式(1-A-a)化合物或其鹽之方法，該方法包括 i)節A中之方法，以將如本文所定義之式(3-I)化合物，較佳地式(3-I-a)化合物或其鹽轉化為如本文所定義之式(4)化合物，較佳地式(4-a)化合物或其鹽； ii)節B.1中之方法，以將如本文所定義之式(4)化合物，較佳地式(4-a)化合物或其鹽轉化為如本文所定義之式(3-II-A)化合物，較佳地式(3-II-A-a)化合物或其鹽； iii)節C.1中之方法，以將如本文所定義之式(3-II-A)化合物，較佳地式(3-II-A-a)化合物或其鹽轉化為如本文所定義之式(5-II-A)化合物，較佳地式(5-III-A-a)化合物或其鹽； iv)節D.1中之方法，以將如本文所定義之式(5-II-A)化合物，較佳地式(5-II-A-a)化合物或其鹽轉化為如本文所定義之式(1-A)化合物，較佳地式(1-A-a)化合物或其鹽； ((參考反應圖2))在另一態樣，本發明係關於一種用於將如本文所定義之式(3’-III)化合物，較佳地式(3’-III-a)化合物或其鹽轉化為如本文所定義之式(1-A)化合物，較佳地式(1-A-a)化合物或其鹽之方法，該方法包括 i)節B.6中之方法，以將如本文所定義之式(3’-III)化合物，較佳地式(3’-III-a)化合物或其鹽轉化為如本文所定義之式(3-III-A)化合物，較佳地式(3-III-A-a)化合物或其鹽； ii)節C.2中之方法，以將如本文所定義之式(3-III-A)化合物，較佳地式(3-III-A-a)化合物或其鹽轉化為如本文所定義之式(5-III-A)化合物，較佳地式(5-III-A-a)化合物或其鹽； iii)節D.2中之方法，以將如本文所定義之式(5-III-A)化合物，較佳地式(5-III-A-a)化合物或其鹽轉化為如本文所定義之式(1-A)化合物，較佳地式(1-A-a)化合物或其鹽； ((參考反應圖1+反應圖4))在另一態樣，本發明係關於一種用於將如本文所定義之式(3-I)化合物，較佳地式(3-I-a)化合物或其鹽轉化為如本文所定義之式(1-A)化合物，較佳地式(1-A-a)化合物或其鹽之方法，該方法包括 i)節A中之方法，以將如本文所定義之式(3-I)化合物，較佳地式(3-I-a)化合物或其鹽轉化為如本文所定義之式(4)化合物，較佳地式(4-a)化合物或其鹽； ii)節B.7中之方法，以將如本文所定義之式(4)化合物，較佳地式(4-a)化合物或其鹽轉化為如本文所定義之式(3-IV)化合物，較佳地式(3-IVI-a)化合物或其鹽； iii)節C.3中之方法，以將如本文所定義之式(3-IV)化合物，較佳地式(3-IV-a)化合物或其鹽轉化為如本文所定義之式(5-IV)化合物，較佳地式(5-IV-a)化合物或其鹽； iv)節D.3中之方法，以將如本文所定義之式(5-IV)化合物，較佳地式(5-IV-a)化合物或其鹽轉化為如本文所定義之式(1-A)化合物，較佳地式(1-A-a)化合物或其鹽； ((參考反應圖5))在另一態樣，本發明係關於一種用於將如本文所定義之式(3-III)化合物，較佳地式(3-III-a)化合物或其鹽轉化為如本文所定義之式(1-A)化合物，較佳地式(1-A-a)化合物或其鹽之方法，該方法包括 i)節B.8中之方法，以將如本文所定義之式(3-III)化合物，較佳地式(3-III-a)化合物或其鹽轉化為如本文所定義之式(3-IV)化合物，較佳地式(3-IV-a)化合物或其鹽； ii)節C.4中之方法，以將如本文所定義之式(3-IV)化合物，較佳地式(3-IV-a)化合物或其鹽轉化為如本文所定義之式(5-IV)化合物，較佳地式(5-IV-a)化合物或其鹽； iii)節D.4中之方法，以將如本文所定義之式(5-IV)化合物，較佳地式(5-IV-a)化合物或其鹽轉化為如本文所定義之式(1-A)化合物，較佳地式(1-A-a)化合物或其鹽； ((參考反應圖5))在另一態樣，本發明係關於一種用於將如本文所定義之式(3-I)化合物，較佳地式(3-I-a)化合物或其鹽轉化為如本文所定義之式(1-A)化合物，較佳地式(1-A-a)化合物或其鹽之方法，該方法包括 i)節B.9中之方法，以將如本文所定義之式(3-I)化合物，較佳地式(3-I-a)化合物或其鹽轉化為如本文所定義之式(3-IV)化合物，較佳地式(3-IV-a)化合物或其鹽； ii)節C.4中之方法，以將如本文所定義之式(3-IV)化合物，較佳地式(3-IV-a)化合物或其鹽轉化為如本文所定義之式(5-IV)化合物，較佳地式(5-IV-a)化合物或其鹽； iii)節D.4中之方法，以將如本文所定義之式(5-IV)化合物，較佳地式(5-IV-a)化合物或其鹽轉化為如本文所定義之式(1-A)化合物，較佳地式(1-A-a)化合物或其鹽； 本發明特別係關於在各節中所述之方法中之任一者。本發明同樣獨立地係關於在相應節中之方法順序中所述之每個單一步驟。因此，由一系列本文所述之步驟所組成之任何方法之各個及每個單一步驟本身係本發明之一實施例。因此，本發明亦係關於該方法之彼等實施例，根據該等實施例，在該方法之任何步驟中作為中間物可獲得之化合物係用作起始物質。 尤佳的係任何反應(方法步驟)，其中如針對本文之各自化合物所定義之部分R8係在該分子之其餘處存在對掌性部分(例如，NR5”R6”、ORx或OR5)之情況下引入，因為此允許立體化學上選擇性合成。 本發明方法之產物可以用於合成NEP抑制劑或其前藥，特定言之，其可用於合成包括γ-胺基-δ-聯苯基-α-甲基烷醇酸或酸酯主鏈之NEP抑制劑。 在一實施例中，本發明方法之產物可以用於合成NEP抑制劑前藥N-(3-羧基-1-側氧基丙基)-(4S)-(對苯基苯基甲基)-4-胺基-(2R)-甲基丁酸乙酯或其活性代謝產物，NEP抑制劑N-(3-羧基-1-側氧基丙基)-(4S)-(對苯基苯基甲基)-4-胺基-(2R)-甲基丁酸。 術語「NEP抑制劑」描述會抑制酶中性肽鏈內切酶(NEP，EC 3.4.24.11)之活性的化合物。在本發明中，術語「NEP-抑制劑」(其在所有實施例中亦可包括前藥)或「NEP-抑制劑前藥」係指物質本身或其鹽，較佳地其醫藥上可接受之鹽。實例為鈉鹽、鉀鹽、鎂鹽、鈣鹽或銨鹽。鈣鹽較佳。 術語「前藥」描述以非活性(或較低活性)形式投與之藥理學無助。一旦投與，前藥在體內活體內代謝為活性化合物。 本發明方法之一實施例包括一或多個額外步驟，其中根據式(1-A)之化合物或其鹽進一步反應，以獲得NEP-抑制劑或其前藥，特定言之包括γ-胺基-δ-聯苯基-α-甲基烷醇酸或酸酯主鏈之NEP-抑制劑或其前藥。 較佳地，根據式(1-A)之化合物或其鹽進一步反應，以獲得NEP-抑制劑或其前藥，特定言之包括γ-胺基-δ-聯苯基-α-甲基烷醇酸或酸酯主鏈之NEP-抑制劑或其前藥。 在一較佳實施例中，如本文所定義之根據式(1-A)之化合物，較佳地式(1-A-a)化合物或其鹽進一步反應，以獲得NEP抑制劑前藥N-(3-羧基-1-側氧基丙基)-(4S)-(對苯基苯基甲基)-4-胺基-(2R)-甲基丁酸乙酯(在相關技術中已知為AHU377)或其鹽。一般而言，本發明包括N-(3-羧基-1-側氧基丙基)-(4S)-(對苯基苯基甲基)-4-胺基-(2R)-甲基丁酸乙酯之任何醫藥上可接受之鹽。 NEP抑制劑前藥N-(3-羧基-1-側氧基丙基)-(4S)-(對苯基苯基甲基)-4-胺基-(2R)-甲基丁酸乙酯視情況進一步反應，以獲得活性 NEP抑制劑N-(3-羧基-1-側氧基丙基)-(4S)-(對苯基苯基甲基)-4-胺基-(2R)-甲基丁酸。一般術語： 以下所列的係用於描述本發明之各種術語之定義。此等定義，或藉由取代一個、超過一個或所有本發明中所使用之一般表達或符號且因此產生本發明之較佳實施例，較佳地適用於該等術語，因為除非在具體情況中另外限制，否則其係在整篇說明書中個別地或作為較大基團之一部分使用。 在本申請案中，術語「氮保護基」一般包括能夠可逆地保護氮官能度，較佳地胺基及/或醯胺官能度之任何基團。 較佳地，氮保護基係胺保護基及/或醯胺保護基。合適的氮保護基係習知上用於肽化學中且係描述於例如標準參考著作之相關章節中，該等著作諸如J. F. W. McOmie, 「Protective Groups in Organic Chemistry」, Plenum Press, London and New York 1973，在T. W. Greene及P. G. M. Wuts, 「Protective Groups in Organic Synthesis」, 第三版, Wiley, New York 1999,在「The Peptides」；第3卷(編輯者：E. Gross及J. Meienhofer), Academic Press, London and New York 1981，及在「Methoden der organischen Chemie 」(Methods of Organic Chemistry), Houben Weyl, 第4版，第15/I卷, Georg Thieme Verlag, Stuttgart 1974中。 較佳的氮保護基一般包括： -C1 -C6 -烷基，較佳地C1 -C4 -烷基，更佳地C1 -C2 -烷基，最佳地C1 -烷基，其視情況經三-C1 -C7 -烷基甲矽烷基-C1 -C7 -烷氧基(例如，三甲基甲矽烷及乙氧基) C6 -C10 -芳基，較佳苯基，或雜環基，較佳吡咯啶基單-、二-或三-取代，其中該芳基環或雜環基係未經取代或經一個或多個(例如，兩個或三個)例如選自由C1 -C7 -烷基、羥基、C1 -C7 -烷氧基、C2 -C8 -醯基-氧、鹵素、硝基、氰基及CF3 組成之群之殘基取代；或 -C6 -C10 -芳基-C1 -C2 -烷氧基羰基 (較佳地，苯基-C1 -C2 -烷氧基羰基，例如苄氧基羰基)；C1 -C10 -烯氧基羰基；C1 -C6 -烷基羰基 (例如，乙醯基或新戊醯基)；C6 -C10 -芳基羰基；C1 -C6 -烷氧基羰基 (例如，第三丁氧基羰基)；C6 -C10 -芳基-C1 -C6 -烷氧基羰基；烯丙基或肉桂基；磺醯基或硫基；琥珀醯亞胺基、根據式之甲矽烷基SiRA RA* RA** ，其中RA 、RA* 及RA** 彼此獨立地為C1 -C7 -烷基、C6 -C10 -芳基-C1 -C2 -烷基或C6 -C10 -芳基。RA 、RA* 及RA** 之較佳實例為甲基、乙基、異丙基、第三丁基或苯基。 較佳的氮保護基之實例為乙醯基、苄基、異丙苯基、二苯甲基、三苯甲基、苄氧基羰基(Cbz)、9-芴甲氧基羰基(Fmoc)、苄氧基甲基(BOM)、新戊醯基-氧-甲基(POM)、三氯乙氧基羰基(Troc)、1-金剛烷氧基羰基(Adoc)、烯丙基、烯丙基氧羰基、三甲基甲矽烷基、第三丁基-二甲基甲矽烷基、三乙基甲矽烷基(TES)、三異丙基甲矽烷基、三甲基甲矽烷基乙氧基甲基(SEM)、第三丁氧基羰基(BOC)、第三丁基、1-甲基-1,1-二甲基苄基、(苯基)甲苯、吡咯啶基及新戊醯基。最佳的氮保護基為乙醯基、苄基、苄基氧羰基(Cbz)、三乙基甲矽烷基(TES)、三甲基甲矽烷基乙氧基甲基(SEM)、第三丁氧基羰基(BOC)、吡咯啶基甲基及新戊醯基。較佳的氮保護基為苄基、鄰苯二甲醯基及第三丁氧基羰基BOC。 較佳的氮保護基之其他實例為新戊醯基、吡咯啶基甲基、第三丁氧基羰基、苄基及甲矽烷基，特別係甲矽烷基(例如三乙基甲矽烷基)。 若一個實施例要求移除如上所定義之氮保護基，則該移除通常可藉由使用已知方法進行。較佳地，如上所定義之氮保護基係藉由使用酸性或鹼性條件而移除。酸性條件之實例為鹽酸、三氟乙酸、硫酸。鹼性條件之實例為氫氧化鋰、乙醇鈉。可使用親核試劑，諸如硼氫化鈉。 就N -苄基作為氮保護基而言，其可藉由氫化或藉由使用某些合適的氧化劑，例如硝酸銨鈰(CAN)或2,3-二氯-5,6-二氰基-對苯并醌(DDQ)而移除。 烷基(為自由基或自由基諸如芳烷基或烷氧基之一部分)係直鏈或分支鏈(一次，或若需要且可行多次)碳鏈，且尤其係C1 -C7 -烷基或C1 -C6 -烷基諸如C1 -C4 -烷基，特定言之分支鏈C1 -C4 -烷基，諸如異丙基。術語「低碳數」或「C1 -C7 -」定義具有至多且包括最大7，尤其係至多且包括最大4個碳原子之部分，該部分為分支鏈(一次或多次)或直鏈且經由末端或非末端碳鍵結。低碳數或C1 -C7 -烷基為例如正戊基、正己基或正庚基或較佳地C1 -C4 -烷基，諸如甲基、乙基、正丙基、第二丙基、正丁基、異丁基、第二丁基、第三丁基，特定言之甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基。特定言之，C1 -C7 -烷基為甲基、乙基、丙基或異丙基。在一實施例中，C1 -C7 -烷基為甲基或乙基。 芳基(例如，作為自由基或自由基諸如芳烷基之一部分)係具有6至10個碳原子之單環或雙環經取代或未經取代之芳基，諸如苯基、茚基、二氫茚基或萘基，特定言之苯基。經取代之C6-10 芳基為例如經一或多個獨立選自例如C1 -C7 -烷基、C1 -C7 -烷氧基-C1 -C7 -烷基、C1 -C7 -烷氧基及鹵基之取代基(例如一至三個取代基)取代之C6-10 芳基。在一實施例中，經取代之C6-10 芳基為經鹵基取代之C6-10 芳基，諸如對氯苯基。在一實施例中，芳基為未經取代之C6-10 芳基。 環烷基為例如C3 -C7 -環烷基且為例如環丙基、環丁基、環戊基、環己基及環庚基。環戊基及環己基為較佳。 醯基(作為自由基或自由基之一部分)係例如未經取代或經取代之C6-10 芳基羰基、未經取代或經取代之C6-10 芳基磺醯基、未經取代或經取代之雜環基羰基或未經取代或經取代之雜環基磺醯基；其中較佳的取代基為選自由以下組成之群：鹵基、C1 -C7 -烷基、鹵基-C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基-C1 -C7 -烷氧基，諸如三氟甲氧基及C1 -C7 -烷氧基-C1 -C7 -烷氧基。較佳地，醯基係未經取代或經取代之C6-10 芳基羰基；或未經取代或經取代之雜環基羰基；其中較佳的取代基為選自由以下組成之群：鹵基、C1 -C7 -烷基、鹵基-C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基-C1 -C7 -烷氧基，諸如三氟甲氧基及C1 -C7 -烷氧基-C1 -C7 -烷氧基。 術語芳基烷基係指C6 -C10 -芳基-C1 -C7 -烷基，其中芳基係如本文所定義。在一實施例中，芳基烷基為例如苄基。 術語羧基係指–CO2 R，其中R為氫或C1 -C7 -烷基。 芳氧基係指芳基-O-，其中芳基係如上所定義。 雜環基係單環或多環，較佳地單環、二環或三環，最佳地單環不飽和、部分飽和、飽和或芳族環體系，較佳具有3至14(更佳5至14)個環原子且具有一個或多個，較佳一至四個獨立選自氮、氧、硫、S(=O)-或S-(=O)2 之雜原子。 烷氧基(作為自由基或自由基之一部分)為例如C1 -C7 -烷氧基且為例如甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基、第三丁氧基且亦包括對應的戊氧基、己氧基及庚氧基自由基。C1 -C4 烷氧基為較佳。 在提及「環」的情況下，例如就由R1及R2與鍵結氮一起所形成之環而言，此包括單環或二環環部分，例如苯并稠合之環體系。在提及環之情況下，例如於其所連接之氮一起，該環可為飽和或不飽和且可視情況包含一個或多個，較佳一個、兩個或三個額外的雜原子，諸如氮、硫或硫，藉以該環含有3至10，較佳地4至7個環原子；此等環亦可攜帶一個或多個取代基，較佳一個、兩個或三個取代基，該等取代基獨立地選自諸如羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基。 在提及「一個或多個」之情況下，例如就雜原子而言，此較佳係指1至4(1、2、3、4)、1至3 (1、2、3)或1或2個。然後該等各自取代基或雜原子可係彼此獨立地選擇且無需為相同。 鹵基或鹵素較佳為氟、氯、溴或碘，最佳地溴或尤其氯。 術語「鹼金屬」係指周期表第一行中的金屬，諸如Li、Na或K。 在本申請案之式中，在C-sp3 上之術語「」指示絕對立體化學，(R )或(S )。 在本申請案之式中，在C-sp3 上之術語「」指示絕對立體化學，(R )或(S )。 在本申請案之式中，在C-sp3 上之術語「」代表立體化學(例如外消旋)混合物，因此其意指對掌性中心，其中(S )立體異構體及(R )立體異構體均存在，例如以50:50比率。 如本文使用，術語「對掌性」係指與其鏡像搭檔具有非疊加性之分子，而術語「非對掌性」係指與其鏡像搭檔為可疊加的分子。任何可行純對映異構體或對映異構體混合物、純非對映異構體或非對映異構體混合物係包括在本發明內。在一實施例中，術語對掌性係指對映異構體之對映異構上富集混合物。如本文使用，術語「對映異構上富集」係指其中一種對映異構體之含量高於50%之對映異構體混合物。在另一實施例中，術語對掌性係指非對映異構體之非對映異構上富集混合物。如本文使用，術語「非對映異構上富集」係指其中一種非對映異構體之含量高於50%之非對映異構體混合物。 術語「回流」係指反應混合物沸騰時之溫度，較佳地上至實際回流溫度或180℃，較佳地上至140℃之溫度。 如本文使用，術語「室溫」或「環境溫度」意指20至35℃，諸如20至25℃之溫度。 鑑於以游離形式及以其鹽形式之化合物及中間物之間的密切關係，包括彼等可用作於例如純化或鑑定化合物或其鹽之中間物的鹽，前文及後文中任何提及「化合物」、「起始物質」及「中間物」時應理解為亦係指一或多種其鹽或相應游離化合物、中間物或起始物質及一或多種其鹽之混合物，其各者旨在亦包括任何溶劑合物、代謝前驅物諸如酯或醯胺或此等之任一者或多者之鹽，按適當及權宜且在不另外明確提及之情況下。不同的晶型可係可獲得的則亦包括在內。 在存在可以例如在4至10之pH範圍內至少部分解離形式存在於水性溶液中，或可尤其以固體，尤其係結晶形式單離之成鹽基團(諸如鹼性或酸性基團)之情況下，可形成鹽。 在存在鹼性基團(例如亞胺基或胺基)下，可較佳地利用有機或無機酸形成鹽。合適的無機酸為例如氫鹵酸，諸如鹽酸、硫酸或磷酸。合適的有機酸為例如羧酸、膦酸、磺酸或胺基磺酸，例如乙酸、丙酸、乳酸、富馬酸、琥珀酸、檸檬酸、胺基酸，諸如穀胺酸或天冬胺酸、馬來酸、羥基馬來酸、甲基馬來酸、苯甲酸、甲磺酸或乙磺酸、乙烷-1,2-二磺酸、苯磺酸、2-萘磺酸、1,5-萘-二磺酸、N -環己基胺基磺酸、N -甲基-、N -乙基-或N -丙基-胺基磺酸、或其他有機質子酸，諸如抗壞血酸。 在存在帶負電荷之游離根，諸如羧基或磺酸基下，可以利用鹼，例如金屬或銨鹽，諸如鹼金屬或鹼土金屬鹽，例如，鈉鹽、鉀鹽、鎂鹽或鈣鹽，或利用氨或合適的有機胺，諸如第三單胺，例如三乙胺或三(2-羥基乙基)胺形成銨鹽或雜環鹼，例如N -乙基-哌啶或N ,N '-二甲基哌嗪，形成鹽。 當在相同分子中存在鹼性基團及酸基團時，亦可形成內鹽。 特別有用的鹽包括本發明化合物之鹽酸鹽、氫溴酸鹽、硫酸鹽、硝酸鹽、磷酸鹽、乳酸鹽、富馬酸鹽、琥珀酸鹽、草酸鹽、蘋果酸鹽、丙二酸鹽、酒石酸鹽、甲苯基酒石酸鹽、苯甲基酒石酸鹽、乳清酸鹽、菸鹼酸鹽、甲磺酸鹽或4-甲基苯磺酸鹽及由與以上試劑之反應所形成之類似物。用於製備酸加成鹽之方法係描述於文獻中，例如以下之相關章節中：「CRC Handbook of Optical Resolutions via Diasteromeric Salt Formation」, D. Kozma, CRC Press 2002, 在Acta Cryst .2006 , B62, 498-505中及在Synthesis 2003 ,13 , 1965-1967中。 在針對化合物、起始物質、中間物、鹽、醫藥製劑、疾病、病症等等使用複數形式之情況下，此旨在意指一(較佳的)或多種單一化合物、鹽、醫藥製劑、疾病、病症等等，在使用單數或不定冠詞(「一」、「一個」)之情況下，此不旨在排除複數，但是僅較佳地意指「一個」。 如本文使用，術語「前藥」代表特定言之在活體內例如藉由在血液中水解轉化為親本化合物之化合物，例如，如以下中所述：T. Higuchi及V. Stella, Pro-drugs as Novel Delivery Systems, A.C.S. Symposium Series的第14卷，Edward B. Roche編輯，Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987；H Bundgaard編輯， Design of Prodrugs, Elsevier, 1985；及Judkins等人，Synthetic Communications 1996 ,26, 4351-4367，及「The Organic Chemistry of Drug Design and Drug Action」, 第2版，R B Silverman (特別係章節8，第497至557頁 )， Elsevier Academic Press, 2004。 因此，前藥包括具有已經轉化為其可逆衍生物之官能基之藥物。通常，此等前藥係藉由水解轉化為活性藥物。可提及以下作為實例： 前藥亦包括可藉由氧化或還原反應轉化為活性藥物之化合物。可提及以下作為實例： 上述反應及/或反應步驟之每一者可以個別地或以組合用於製備NEP-抑制劑或其前藥，諸如包括γ-胺基-δ-聯苯基-α-甲基烷醇酸或酸酯諸如烷基酯主鏈之NEP-抑制劑或其前藥的方法中。特定言之，該NEP-抑制劑為N-(3-羧基-1-側氧基丙基)-(4S)-(對苯基苯基甲基)-4-胺基-(2R)-甲基丁酸或其鹽或其前藥。實例部分 本發明之特定實施例係提供於以下實例中。此等實例用於說明本發明而不限制其範疇，同時在另一方面其代表本發明反應步驟、中間物及/或方法之較佳實施例。 縮寫： δ                 化學位移 μl                     微升 μm              微米 AcOH          乙酸 aliph            脂族 arom                 芳族 Bn               苄基 Boc             第三丁氧基羰基 br. s.            基於回收之起始物質 n-BuLi         正丁基鋰 BOC2 O        碳酸二-第三丁酯 CDCl3 氘化氯仿 CDIN ,N -羰基二咪唑 CH2 Cl2 二氯甲烷 (COCl)2 草醯氯 d                 雙峰 dd               雙峰之雙峰 DCM           二氯甲烷 DMF            二甲基甲醯胺 de                非對映異構體超量 dr                     非對映異構體比率 EDC·HClN -(3-二甲基胺基丙基)-N -乙基碳化二亞胺鹽酸鹽 DEA            二乙胺 DMF = dmfN ,N -二甲基甲醯胺 DMSO         二甲基亞碸 DMSO-d 6 二甲基亞碸氘化 d6 -DMSO     二甲基亞碸氘化 ee                對映異構體超量 ES               電噴霧 ESI              電噴霧電離 Et                乙基 EtOAc         乙酸乙酯 EtOH           乙醇 FTIR           傅立葉變換紅外 h                 小時 HCl             鹽酸 H2 SO4 硫酸 HOBt           6-氯-1-羥基苯并三唑 HNMR         質子核磁共振 HPLC          高效液相層析 H3 PO4 磷酸 iPr               異丙基 iPrOAc        乙酸異丙酯 iPrOH          異丙醇 IR                紅外線J 偶聯常數 K2 CO3 碳酸鉀 KHMDS       雙(三甲基甲矽烷基)醯胺鉀 L                 公升 LDA            二異丙基醯胺鋰 LiOH           氫氧化鋰 LC-MS        液相層析-質譜 LHMDS       雙（三甲基甲矽烷基）醯胺鋰 M                莫耳濃度 m                多重峰 m/e              質量對電荷比 m/z              質量對電荷比 Me               甲基 MeOH         甲醇 mg               毫克 min             分鐘 MeI             甲基碘 ml               毫升 mmol(s)       毫莫耳 mol(s)         莫耳 MS               質譜 N                 氮原子 N2 氮氣 nm               奈米 NaH             氫化鈉 NaOH          氫氧化鈉 NaHCO3 碳酸氫鈉 NaHMDS     雙(三甲基甲矽烷基)醯胺鈉 NH4 Cl          氯化銨 nm               奈米 NMR           核磁共振 Ph               苯基 pH               氫離子濃度 ppm             每百萬份數 q                 四重峰 RT = rt        室溫 s                  單峰 SM              起始物質 t                  三重峰 TBME          第三丁基甲醚 TEA            三乙胺 TFA             三氟乙酸 THF             四氫呋喃 TLC             薄層層析法 Tol              甲苯 tR 滯留時間實例 1 ： (S )-4- 胺基 -5- 聯苯 -4- 基 - 戊酸鹽酸鹽 將(S)-5-聯苯-4-基甲基-吡咯啶-2-酮(40.0 g，0.159 mol)懸浮於6N HCl (250 mL)中，使混合物回流2小時，然後允許冷卻至室溫。過濾後，收集固體並乾燥，得到(S)-4-胺基-5-聯苯-4-基-戊酸鹽酸鹽。1 H NMR (DMSO)：1.80 (2H, m), 2.45 (2H, m), 2.81(1H, m), 3.05 (1H, m), 3.57 (1H, m), 7.36~7.71 (9H, m, 芳族), 8.21 (2H, s), 12.23 (1H, s)。實例 2 ： (S)-5-( 聯苯 -4- 基 )-4-( 第三丁氧基羰基胺基 ) 戊酸 向四氫呋喃(150 ml)及水(50 ml)之混合物添加(S)-2-聯苯-4-基甲基-5-側氧基-吡咯啶-1-甲酸第三丁酯(20 g，56 mmol)。然後，將溶於水(100 ml)中之氫氧化鋰(6 g)之溶液添加至該混合物。然後，劇烈攪拌所得混合物14小時。添加1M鹽酸溶液至該混合物，直至達成小於7之pH。然後在減壓下自該混合物移除四氫呋喃溶劑。然後添加乙酸乙酯(100 ml)，且兩相分離。用1M鹽酸溶液(40 ml)及鹽水溶液(40 ml)清洗有機相。經無水硫酸鈉乾燥有機層，過濾並在減壓下濃縮，得到(S)-5-(聯苯-4-基)-4-(第三丁氧基羰基胺基)戊酸。1 H NMR (400 MHz, DMSO-d 6 )δ ppm 1.3 (s, 9 H) 1.4 - 1.8 (m, 2 H) 2.1 - 2.3 (m, 2 H) 2.7 (d,J =7.0 Hz, 2 H) 3.5 - 3.7 (m, 1 H) 6.7 (d,J =8.8 Hz, 1 H) 7.2 - 7.7 (m, 9 H) 12.0 (br. s., 1 H)；ESI+ MSm/z 369.5 ([M+H]+ , 370.5)。實例 3 ： (S)-4- 胺基 -5-( 聯苯 -4- 基 ) 戊酸 將(S)-5-(聯苯-4-基)-4-(第三丁氧基羰基胺基)戊酸(6.512 g，17 mmol)添加至二氯甲烷(20 ml)。將三氟乙酸(10 ml)添加至該混合物。在室溫下攪拌該混合物直至起泡停止，然後在50℃下再攪拌該混合物40分鐘。然後在減壓下濃縮該混合物。然後添加乙酸乙酯(120 ml)。用水(3×40 ml)及鹽水溶液(40 ml)清洗該混合物。經無水硫酸鈉乾燥有機層，過濾並在減壓下移除揮發物，得到(S)-4-胺基-5-(聯苯-4-基)戊酸。1 H NMR (400 MHz, DMSO-d 6 )δ ppm 1.7 - 1.9 (m, 2 H) 2.3 - 2.5 (m, 2 H) 2.8 - 3.0 (m, 2 H) 3.4 - 3.6 (m, 1 H) 7.3 (d,J =8.0 Hz, 3 H) 7.4 (t,J =7.6 Hz, 2 H) 7.6 (dd,J =7.6, 4.4 Hz, 4 H) 7.9 (br. s., 3 H)；ESI+ MSm/z 269.3 ([M+H]+ , 270.3)。實例 4 ： (S)-5-( 聯苯 -4- 基 )-4-(2,5- 二側氧基 -2,5- 二氫 -1H- 吡咯 -1- 基 ) 戊酸 將馬來酸酐(820 mg，8.3 mmol)添加至四氫呋喃(40 ml)。然後添加(S)-4-胺基-5-(聯苯-4-基)戊酸 (2.131 g，6.9 mmol)含於四氫呋喃(8 ml)中之混合物。在室溫下攪拌該反應混合物3小時。然後將該混合物濃縮至乾燥並添加甲苯(50 ml)。然後，以一份式添加溴化鋅(II)(1.550 g，6.9 mmol)且嚴格地攪拌所得混合物並加熱至80℃。分三個獨立份歷時30分鐘添加六甲基二矽氮烷(2.6 ml，12.4 mmol)含於甲苯(15 ml)中之溶液。在80℃下攪拌該反應過夜。將反應混合物蒸發至乾燥。用飽和碳酸鈉溶液(2×20 ml)及鹽水溶液(40 ml)清洗所得油。添加乙酸乙酯(40 ml)。經無水硫酸鈉乾燥有機層，過濾並在減壓下移除溶劑，得到(S)-5-(聯苯-4-基)-4-(2,5-二側氧基-2,5-二氫-1H-吡咯-1-基)戊酸。1 H NMR (400 MHz, DMSO-d 6 )δ ppm 1.9 - 2.0 (m, 1 H) 2.1 - 2.3 (m, 3 H) 2.9 - 3.2 (m, 2 H) 4.1 - 4.3 (m, 1 H) 6.8 (s, 2 H) 7.0 - 7.7 (m, 9 H) 12.1 (br. s., 1 H)；ESI+ MSm/z 349.4 ([M+H]+ , 350.4)。實例 5 ： (S)-5- 聯苯 -4- 基 -4- 第三丁氧基羰基胺基 - 戊酸乙酯 在室溫下，向(S)-2-聯苯-4-基甲基-5-側氧基-吡咯啶-1-甲酸第三丁酯(5.9 g)含於乙醇(10 mL)中之溶液添加乙醇鈉(1.14 g)。30分鐘後，將該溶液倒入鹽水中並用TBME萃取。乾燥並濃縮合併的有機萃取物，得到(S)-5-聯苯-4-基-4-第三丁氧基羰基胺基-戊酸乙酯。1 H NMR (CDCl3 )：1.22~1.26 (3H, t), 1.40 (9H, s), 1.62~1.68 (1H, m), 1.86~1.94 (1H, m), 2.36~2.41 (2H, m), 2.76~2.87 (2H, m), 3.86 (1H, s), 4.11~4.23 (2H, q), 3.38~3.41 (1H, m), 7.24 ~7.58 (9H, m, 芳族)。實例 6 ： (S)-4- 胺基 -5-( 聯苯 -4- 基 ) 戊酸乙酯 將(S)-5-(聯苯-4-基)-4-(第三丁氧基羰基胺基)戊酸乙酯(5 g，12.6 mmol)溶解於二氯甲烷(20 ml)中。將三氟乙酸(8 ml)添加至該混合物。在室溫下攪拌該混合物直至起泡停止，然後在50℃下再攪拌該混合物40分鐘。然後在減壓下濃縮該混合物。然後添加乙酸乙酯(120 ml)。用飽和碳酸鈉溶液(2×40 ml)及鹽水溶液(40 ml)清洗所得混合物。經無水硫酸鈉乾燥有機層，過濾並在減壓下移除揮發物，得到(S)-4-胺基-5-(聯苯-4-基)戊酸乙酯。1 H NMR (400 MHz, DMSO-d 6 )δ ppm 1.5 (t,J =7.1 Hz, 3 H) 2.1 - 2.3 (m, 2 H) 2.7 - 3.0 (m, 2 H) 3.2 - 3.5 (m, 2 H) 3.8 - 4.0 (m, 1 H) 4.4 (q,J =7.0 Hz, 2 H) 7.6 - 8.2 (m, 9 H) 8.5 (br. s., 3 H)；ESI+ MSm/z 297.4 ([M+H]+ , 298.4)。實例 7 ： (S)-5-( 聯苯 -4- 基 )-4-(2,5- 二側氧基 -2,5- 二氫 -1H- 吡咯 -1- 基 ) 戊酸乙酯 在室溫下，將馬來酸酐(1.28 g，13.0 mmol)添加至四氫呋喃(60 ml)。然後將(S)-4-胺基-5-(聯苯-4-基)戊酸乙酯(3.226 g，10.9 mmol)含於四氫呋喃(12 ml)添加至該混合物。在室溫下攪拌所得混合物3小時。然後將該混合物濃縮至乾燥並添加甲苯(80 ml)。然後，以一份式添加溴化鋅(II)(2.443g，10.9 mmol)且嚴格地攪拌所得混合物並加熱至80℃。分三個獨立份歷時30分鐘添加六甲基二矽氮烷(4.1 ml，19.5 mmol)含於甲苯(25 ml)中之溶液。在80℃下攪拌該反應過夜。將反應混合物蒸發至乾燥。添加乙酸乙酯(50 ml)並用飽和碳酸鈉溶液(2×40 ml)及鹽水溶液(40 ml)清洗混合物。經無水硫酸鈉乾燥有機層，過濾並在減壓下移除溶劑。藉由層析(1%甲醇含於二氯甲烷中)純化殘餘物，得到(S)-5-(聯苯-4-基)-4-(2,5-二側氧基-2,5-二氫-1H-吡咯-1-基)戊酸乙酯。1 H NMR (400 MHz, DMSO-d 6 ) 1.1 (t,J =7.1 Hz, 3 H) 1.9 - 2.4 (m, 4 H) 2.9 - 3.2 (m, 2 H) 4.0 (q,J =7.1 Hz, 2 H) 4.1 - 4.3 (m, 1 H) 6.9 (s, 2 H) 7.0 - 7.7 (m, 9 H)；ESI+ MSm/z 377.4 ([M+H]+ , 378.4)；IR (FTIR) cm-1 3454 (C=O), 3099 (CH. arom), 2977 (CH. aliph), 1728, 1702 (C=O 醯亞胺 + 酯), 1400, 1371 (C-N)。實例 8 ： [(S)-1- 聯苯 -4- 基甲基 -4-((S)-2- 羥基甲基 - 吡咯啶 -1- 基 )-4- 側氧基 - 丁基 ]- 胺基甲酸第三丁酯 將甲醇鈉(54 mg，1 mmol)添加至(S)-2-聯苯-4-基甲基-5-側氧基-吡咯啶-1-甲酸第三丁酯(3.5 g，10 mmol)及(S)-(+)-脯胺醇(1.11 g，11 mmol)含於50mL無水THF中之混合物並攪拌3小時。然後添加氯化銨水溶液，用乙酸乙酯萃取該混合物並合併有機萃取物並乾燥。藉由管柱層析純化殘餘物，得到[(S)-1-聯苯-4-基甲基-4-((S)-2-羥基甲基-吡咯啶-1-基)-4-側氧基-丁基]-胺基甲酸第三丁酯。1 H NMR (CDCl3 )：1.40 (9H, s, (CH3 )3 ), 1.80 (2H, m, 3-CH2 ), 1.90 (4H, m, CH2 CH2 ), 2.36 (2H, m, 2- CH2 ), 2.85 (2H, m, 5-CH2 ), 3.42 (1H, m, 4-CH), 3.45 (2H, m, CH2 ), 3.58 (2H, m, CH2 ), 4.18 (1H, m, CH), 4.93 (1H, s, OH), 7.40~7.60 (9H, m, 芳族)。 HPLC方法：管柱：Eclipse XDB-C18；150×4.6mm；5 μm。流動相A (0.1 % H3 PO4 )含於水中；流動相B (乙腈)。梯度：0 min (90 % B)；10 min (95 % B)；15 min (95 % B)。流速：0.7 ml min-1 。波長：210 nm。溫度：30℃。滯留時間：11.2 min實例 9 ： [(S)-1- 聯苯 -4- 基甲基 -4- 側氧基 -4- 吡咯啶 -1- 基 - 丁基 ]- 胺基甲酸第三丁酯 將甲醇鈉(16 mg，0.3 mmol)添加至(S)-2-聯苯-4-基甲基-5-側氧基-吡咯啶-1-甲酸第三丁酯(1.05 g，3 mmol)及吡咯啶(0.23 g，3.3 mmol)含於15 mL無水THF中之混合物並攪拌3小時。添加氯化銨水溶液，用乙酸乙酯萃取該混合物並合併有機層並濃縮。藉由管柱層析純化殘餘物，得到[(S)-1-聯苯-4-基甲基-4-側氧基-4-吡咯啶-1-基-丁基]-胺基甲酸第三丁酯。1 H NMR (CDCl3 )：1.40 (9H, s, (CH3 )3 ), 1.82 (2H, m, 3-CH2 ), 1.90 (4H, m, CH2 CH2 ), 2.32 (2H, m, 2- CH2 ), 2.78 (2H, m, 5-CH2 ), 2.90 (1H, m, 4-CH), 3.36 (2H, t, CH2 ), 3.44 (2H, t, CH2 ), 7.20~7.60 (9H, m, 芳族)。 HPLC方法：管柱：Eclipse XDB-C18；150×4.6 mm；5 μm。流動相A (0.1 % H3 PO4 )含於水中；流動相B (乙腈)。梯度：0 min (90 % B)；10 min (95 % B)；15 min (95 % B)。流速：0.7ml min-1 。波長：210 nm。溫度：30℃。滯留時間：13.2 min實例 10 ： (S)-1-( 聯苯 -4- 基 )-5-( 二甲基胺基 )-5- 側氧基戊 -2- 基胺基甲酸第三丁酯 向(S)-2-聯苯-4-基甲基-5-側氧基-吡咯啶-1-甲酸第三丁基酯(351 mg，1 mmol)及六氟磷酸鋰(152 mg，1 mmol)含於四氫呋喃(5 ml)中之混合物添加二甲胺(2M THF溶液) (5 ml，10 mmol)。在室溫下攪拌所得混合物30分鐘。然後在真空下濃縮該混合物並添加乙酸乙酯(20 ml)。用飽和碳酸鈉溶液(2×20 ml)接著鹽水溶液(20 ml)清洗混合物。經無水硫酸鈉乾燥有機層，過濾並在減壓下移除揮發性物質。藉由管柱層析純化所得殘餘物，得到(S)-1-(聯苯-4-基)-5-(二甲基胺基)-5-側氧基戊-2-基胺基甲酸第三丁酯。1 H NMR (400 MHz, d6 -DMSO)：1.3 (s, 9 H) 1.5 - 1.8 (m, 2 H) 2.3 (t,J =7.5 Hz, 2 H) 2.7 (d,J =5.8 Hz, 2 H) 2.8 (s, 3 H) 2.9 (s, 3 H) 3.6 (br. s., 1 H) 6.8 (d,J =8.8 Hz, 1 H) 7.2 - 7.7 (m, 9 H)；ESI+ MSm/z 369.5 ([M+H]+ , 370.5)；IR (FTIR) cm-1 3255 (N-H), 3005, 2981 (CH. arom), 2968, 2944 (CH. aliph), 1714 (C=O. Boc), 1619 (C=O. 醯胺)。實例 11 ： (S)-5- 聯苯 -4- 基 -4-(1,3- 二側氧基 -1,3- 二氫 - 異吲哚 -2- 基 )- 戊酸 向(S)-4-胺基-5-聯苯-4-基-戊酸鹽酸鹽(30.0 g，98 mmol)含於THF (300 mL)中之溶液添加三乙胺(27.4 mL，197 mmol)，接著添加1,3-二側氧基-1,3-二氫-異吲哚-2-甲酸乙酯(25.2 g，103 mmol)。使反應混合物回流12小時。然後在真空下移除溶劑，添加200 mL 2N HCl，攪拌0.5小時，過濾，用2N HCl及正庚烷清洗濾餅，然後乾燥，獲得(S)-5-聯苯-4-基-4-(1,3-二側氧基-1,3-二氫-異吲哚-2-基)-戊酸，如藉由HPLC所測定。1 H NMR (CDCl3 )：2.15(1H, m, 3-CH), 2.36 (2H, m, 2-CH2 ), 2.54 (1H, m, 3- CH), 4.56 (1H, m, 4-CH), 7.20~7.80 (13H, m, 芳族)。 HPLC方法：管柱：Eclipse XDB-C18；150×4.6 mm；5 μm。流動相A (0.1 % H3 PO4 )含於水中；流動相B (乙腈)。梯度：0 min (30 % B)；8 min (95 % B)；15 min (95 % B)。流速：1.0 ml min-1 。波長：210 nm。溫度：30℃。滯留時間：7.8 min。實例 12 ： 2-((S)-1- 聯苯 -4- 基甲基 -4- 側氧基 -4- 吡咯啶 -1- 基 - 丁基 )- 異吲哚 -1,3- 二酮 在室溫下，向2-((S)-1-聯苯-4-基甲基-4-嗎啉-4-基-4-側氧基-丁基)-異吲哚-1,3-二酮(5 g，12.52 mmol)含於無水THF (30 mL)中之溶液添加EDC·HCl (2.88 g，15.03 mmol)、HOBt (2.03 g，15.03 mmol)、TEA (7 mL，50.08 mmol)及吡咯啶(0.98 g，13.77 mmol)。劇烈攪拌反應混合物12小時，然後將乙酸乙酯(100 mL)添加至該反應混合物。分離有機相，依序利用1N HCl(50 mL)、飽和NaHCO3 溶液(50 mL)及鹽水(50 mL)清洗，乾燥並濃縮。藉由急驟管柱層析純化所得殘餘物，得到2-((S)-1-聯苯-4-基甲基-4-側氧基-4-吡咯啶-1-基-丁基)-異吲哚-1,3-二酮。1 H NMR (CDCl3 )：1.78 (2H, m), 1.85 (2H, m), 2.23 (2H, m), 2.63 (1H, m), 3.30 (6H, m), 4.72 (1H, m), 7.20~7.78  (13H, m, 芳族)。MS (ESI, m/e) 453 (MH+)。 2-((S)-1-聯苯-4-基甲基-4-側氧基-4-吡咯啶-1-基-丁基)-異吲哚-1,3-二酮為結晶固體且可藉由X-射線粉末圖譜表徵。X-射線繞射圖譜中之最強反射顯示以下晶格間平面間隔(平均2θ以[o ]計係以±0.2之誤差限值指示)：2θ以[o ]計：3.7、9.6、10.5、11.2、14.7、15.7、16.4、19.6、20.1、21.2、26.2。使用Bruker D8高級繞射儀，使用Cu-Kα輻射採集資料。 HPLC方法：管柱：Eclipse XDB-C18；150×4.6 mm；5 μm。流動相A (0.1 % H3 PO4 )含於水中；流動相B (乙腈)。梯度：0 min (30 % B)；8 min (95 % B)；15 min (95 % B)。流速：1.0 ml min-1 。波長：210 nm。溫度：30℃。滯留時間：9.4 min實例 13 ： 2-((S)-1- 聯苯 -4- 基甲基 -4- 嗎啉 -4- 基 -4- 側氧基 - 丁基 ) 異吲哚 -1, 3- 二酮 在室溫下，向(S)-5-聯苯-4-基-4-(1,3-二側氧基-1,3-二氫-異吲哚-2-基)-戊酸(5 g，12.52 mmol)含於無水THF (30 mL)中之溶液添加EDC·HCl (2.88 g，15.03 mmol)、HOBt (2.03 g，15.03 mmol)、TEA (7 mL，50.08 mmol)及嗎啉 (1.20 g，13.77 mmol)。劇烈攪拌反應混合物12小時，然後添加乙酸乙酯(100 mL)。依序利用1N HCl(50 mL)、飽和NaHCO3 溶液(50 mL)及鹽水(50 mL)清洗有機相，乾燥並濃縮。藉由急驟管柱層析純化所得殘餘物，得到2-((S)-1-聯苯-4-基甲基-4-嗎啉-4-基-4-側氧基-丁基)-異吲哚-1,3-二酮。1 H NMR (CDCl3 )：1.24 (2H, m), 2.21~2.29 (1H, m), 2.31~2.40 (2H, m), 2.52~2.57 (1H, m), 3.18~3.21 (1H, m), 3.23(2H, m), 3.24~3.32  (2H, m), 3.53~3.57 (3H, m), 7.23 ~7.75 (13H, m, 芳族)。MS (ESI, m/e) 469 (MH+)。 2-((S)-1-聯苯-4-基甲基-4-嗎啉-4-基-4-側氧基-丁基)異吲哚-1, 3-二酮為結晶固體且可藉由X-射線粉末圖譜表徵。X-射線繞射圖譜中之最強反射顯示以下晶格間平面間隔(平均2θ以[o ]計係以±0.2之誤差限值指示)：2θ以[o ]計：3.6、9.5、10.8、12.6、13.1、14.5、15.9、16.9、18.5、19.3、20.4、22.5、23.1、24.1、25.9、27.2、27.9。使用Bruker D8高級繞射儀，使用Cu-Kα輻射採集資料。 HPLC方法：管柱：Eclipse XDB-C18；150×4.6 mm；5 μm。流動相A (0.1 % H3 PO4 )含於水中；流動相B (乙腈)。梯度：0 min (30 % B)；8 min (95 % B)；15 min (95 % B)。流速：1.0 ml min-1 。波長：210 nm。溫度：30℃。滯留時間：7.9 min實例 14 ： 2-[(S)-4-((R)-4- 苄基 -2- 側氧基 - 噁唑啶 -3- 基 )-1- 聯苯 -4- 基甲基 -4- 側氧基 - 丁基 ]- 異吲哚 -1,3- 二酮 向(S)-5-聯苯-4-基-4-(1,3-二側氧基-1,3-二氫-異吲哚-2-基)戊酸(1.00 g，2.95 mmol)含於10 mL無水DCM中之溶液添加1滴DMF，冷卻至0℃，然後滴加(COCl)2 (0.75 g，5.89 mmol)。攪拌混合物1小時，然後蒸餾過量(COCl)2 。在獨立的燒瓶中，將NaH (142 mg，3.24 mmol)懸浮於10 mL無水THF中，冷卻至0℃，添加(R)-4-苄基-噁唑啶-2-酮(0.57 g，3.24 mmol)，在0℃下攪拌1小時，然後添加預製的醯氯。在0℃下攪拌反應混合物30分鐘，然後添加飽和NH4 Cl，用DCM萃取並用水清洗，用5% NaHCO3 及鹽水清洗有機萃取物，乾燥並濃縮。使所得粗物質結晶，得到2-[(S)-4-((R)-4-苄基-2-側氧基-噁唑啶-3-基)-1-聯苯-4-基甲基-4-側氧基-丁基]-異吲哚-1,3-二酮。1 H NMR (CDCl3 )：2.28 (1H, m), 2.25 (1H, m), 2.67 (1H, m), 2.95 (2H, m), 3.27 (2H, m), 3.50 (1H, m),4.15 (1H, m), 4.23 (1H, m), 7.15 ~7.80 (18H, m, 芳族)。m/z：559 (MH+ )。 2-[(S)-4-((R)-4-苄基-2-側氧基-噁唑啶-3-基)-1-聯苯-4-基甲基-4-側氧基-丁基]-異吲哚-1,3-二酮為結晶固體且可藉由X-射線粉末圖譜表徵。X-射線繞射圖譜中之最強反射顯示以下晶格間平面間隔(平均2θ以[o ]計係以±0.2之誤差限值指示)：2θ以[o ]計：4.4、8.6、9.4、10.7、12.3、14.2、14.6、15.9、16.9、18.1、19.6、20.4、20.7、21.3、21.7、22.1、23.2、23.7、24.2、24.8、25.1 、26.4。使用Bruker D8高級繞射儀，使用Cu-Kα輻射採集資料。 HPLC方法：管柱：Eclipse XDB-C18；150×4.6 mm；5 μm。流動相A (0.1 % H3 PO4 )含於水中；流動相B (乙腈)。梯度：0 min (10 % B)；10 min (95 % B)；15 min (95 % B)。流速：1.0 ml min-1 。波長：210 nm。溫度：30℃。滯留時間：11.5 min實例 15 ： 2-[(S)-4-((R)-4- 異丙基 -2- 側氧基 - 噁唑啶 -3- 基 )-1- 聯苯 -4- 基甲基 -4- 側氧基 - 丁基 ]- 異吲哚 -1,3- 二酮 向(S)-5-聯苯-4-基-4-(1,3-二側氧基-1,3-二氫-異吲哚-2-基)-戊酸(1.00 g，2.95 mmol)含於10 mL無水CH2 Cl2 中之溶液添加1滴DMF，冷卻至0℃，然後滴加(COCl)2 (0.75 g，5.89 mmol)。攪拌混合物1小時，然後蒸餾過量(COCl)2 。在獨立的燒瓶中，將NaH (142 mg，3.24 mmol)懸浮於10 mL無水THF中，冷卻至0℃，添加(R)-4-異丙基-噁唑啶-2-酮(418 mg，3.24 mmol)，在0℃下攪拌1小時，然後添加預製的醯氯。在0℃下攪拌反應混合物30分鐘，然後添加飽和NH4 Cl，用DCM萃取並用水清洗，用5% NaHCO3 及鹽水清洗有機萃取物，乾燥並濃縮。藉由管柱層析純化所得粗物質，得到2-[(S)-4-((R)-4-異丙基-2-側氧基-噁唑啶-3-基)-1-聯苯-4-基甲基-4-側氧基-丁基]-異吲哚-1,3-二酮。1 H NMR (CDCl3 )：0.8 (6H, d), 2.26 (2H, m), 2.54 (1H, m), 2.90 (1H, m), 3.01 (1H, m), 3.20 (1H, m),3.45 (1H, m), 4.10 (2H, dd), 4.27 (1H,m), 4.60 (1H, m), 7.20 ~7.80 (13H, m, 芳族)。m/z：400 (MH+ )。 HPLC方法：管柱：Eclipse XDB-C18；150×4.6 mm；5 μm。流動相A (0.1 % H3 PO4 )含於水中；流動相B (乙腈)。梯度：0 min (30 % B)；8 min (95 % B)；15 min (95 % B)。流速：1.0 ml min-1 。波長：210 nm。溫度：30℃。滯留時間：9.8 min實例 16 ： (S)-5- 聯苯 -4- 基 -4- 二苄基胺基 -1-((S)-2- 羥基甲基 - 吡咯啶 -1- 基 )- 戊 -1- 酮 向(S)-5-聯苯-4-基-4-二苄基胺基-戊酸鹽酸鹽 (4.86 g，10mmol)含於100 mL CH2 Cl2 中之懸浮液依序添加(S)-(+)-脯胺醇(1.11 g，11 mmol)、EDC·HCl (2.3 g，12 mmol)、HOBt (1.62 g，12 mmol)及TEA (5 g，50 mmol)，且在室溫下攪拌混合物12小時。用水清洗反應混合物，乾燥並濃縮。藉由管柱層析(乙酸乙酯/庚烷 = 1/2)純化所得殘餘物，得到(S)-5-聯苯-4-基-4-二苄基胺基-1-((S)-2-羥基甲基-吡咯啶-1-基)-戊-1-酮。1 H NMR (CDCl3 )：1.69 ( 1H, m, 3-CH H), 1.75 (1H, m, 3-CHH ), 1.94 (4H, m, CH2 CH2 ), 2.50 (1H, m, 2- CH H), 2.55 (2H, m, 5-CH2 ), 2.79 (1H, m, 2- CHH ), 3.17 (1H, dd, 4-CH), 3.31 (2H, m, CH2 ), 3.54 (2H, d, CH2 ), 3.58 (2H, m, CH2 ), 3.88 (2H, d, CH2 ), 4.09 (1H, m, CH), 5.14 (1H, s, OH), 7.10~7.50 (19H, m, 芳族)。 HPLC方法：管柱：Eclipse XDB-C18；150×4.6 mm；5 μm。流動相A (0.1 % H3 PO4 )含於水中；流動相B (乙腈)。梯度：0 min (30 % B)；8 min (95 % B)；15 min (95 % B)。流速：1.0 ml min-1 。波長：210 nm。溫度：30℃。滯留時間：9.6 min。實例 17 ： (S)-5- 聯苯 -4- 基 -4- 二苄基胺基 -1-((R)-2- 羥基甲基 - 吡咯啶 -1- 基 )- 戊 -1- 酮 向(S)-5-聯苯-4-基-4-二苄基胺基-戊酸鹽酸鹽 (4.86 g，10 mmol)含於100 mL CH2 Cl2 中之懸浮液依序添加(R)-(－)-脯胺醇(1.11 g，11 mmol)、EDC·HCl (2.3 g，12 mmol)、HOBt (1.62 g，12 mmol)及TEA (5 g，50 mmol)，且在室溫下攪拌混合物12小時。用水清洗反應混合物，乾燥並濃縮。藉由管柱層析(乙酸乙酯/庚烷 = 1/2)純化所得殘餘物，得到(S)-5-聯苯-4-基-4-二苄基胺基-1-((R)-2-羥基甲基-吡咯啶-1-基)-戊-1-酮。1 H NMR (CDCl3 )：1.69 ( 1H, m, 3-CH H), 1.75 (1H, m, 3-CHH ), 1.94 (4H, m, CH2 CH2 ), 2.50 (1H, m, 2- CH H), 2.55 (2H, m, 5-CH2 ), 2.79 (1H, m, 2- CHH ), 3.18 (1H, dd, 4-CH), 3.31 (2H, m, CH2 ), 3.54 (2H, d, CH2 ), 3.57 (2H, m, CH2 ), 3.87 (2H, d, CH2 ), 4.12 (1H, m, CH), 5.12 (1H, d, OH), 7.10~7.50 (19H, m, 芳族)。 HPLC方法：管柱：Eclipse XDB-C18；150×4.6 mm；5 μm。流動相A (0.1 % H3 PO4 )含於水中；流動相B (乙腈)。梯度：0 min (30 % B)；8 min (95 % B)；15 min (95 % B)。流速：1.0 ml min-1 。波長：210 nm。溫度：30℃。滯留時間：9.5 min。實例 18 ： (S)-5- 聯苯 -4- 基 -4- 二苄基胺基 - 戊酸甲基 -((S)-1- 苯基 - 乙基 )- 醯胺 向(S)-5-聯苯-4-基-4-二苄基胺基-戊酸鹽酸鹽 (4.86 g，10 mmol)含於10 mL CH2 Cl2 中之懸浮液依序添加(S)-甲基-(1-苯基-乙基)-胺(0.19 g，1.36 mmol)、EDC·HCl (0.29 g，1.5 mmol)、HOBt (0.21 g，1.5 mmol)及TEA (0.63 g，6.2 mmol)，且在室溫下攪拌混合物12小時。用水清洗反應混合物，乾燥並濃縮。藉由管柱層析(乙酸乙酯/庚烷 = 1/5)純化所得殘餘物，得到(S)-5-聯苯-4-基-4-二苄基胺基-戊酸 甲基-((S)-1-苯基-乙基)-醯胺。1 H NMR (CDCl3 )：1.40 (3H, d, CH3 ), 1.74 ( 1H, m, 3-CH H), 1.90 (1H, m, 3-CHH ), 2.50 (3H, s, CH3 ), 2.60 (2H, m, 2- CH2 ), 2.80 (2H, m, 5-CH2 ), 3.20 (1H, dd, 4-CH), 3.57 (2H, d, CH2 ), 3.89 (2H, d, CH2 ), 6.02(1H, q, CH), 7.10~7.50 (24H, m, 芳族)。 HPLC方法：管柱：Eclipse XDB-C18；150×4.6 mm；5 μm。流動相A (0.1 % H3 PO4 )含於水中；流動相B (乙腈)。梯度：0 min (30 % B)；8 min (95 % B)；15 min (95 % B)。流速：1.0 ml min-1 。波長：210 nm。溫度：30℃。滯留時間：11.1 min實例 19 ： (S)-5- 聯苯 -4- 基 -4- 二苄基胺基 - 戊酸甲基 -((R)-1- 苯基 - 乙基 )- 醯胺 向(S)-5-聯苯-4-基-4-二苄基胺基-戊酸鹽酸鹽 (4.86 g，10 mmol)含於10 mL CH2 Cl2 中之懸浮液依序添加(R)-甲基-(1-苯基-乙基)-胺(0.19 g，1.36 mmol)、EDC·HCl (0.29 g，1.5 mmol)、HOBt (0.21 g，1.5 mmol)及TEA (0.63 g，6.2 mmol)，且在室溫下攪拌混合物12小時。用水清洗反應混合物，乾燥並濃縮。藉由管柱層析(乙酸乙酯/庚烷 = 1/5)純化殘餘物，得到(S)-5-聯苯-4-基-4-二苄基胺基-戊酸甲基-((S)-1-苯基-乙基)-醯胺。1 H NMR (CDCl3 )：1.45 (3H, d, CH3 ), 1.73 ( 1H, m, 3-CH H), 1.90 (1H, m, 3-CHH ), 2.51 (3H, s, CH3 ), 2.63 (2H, m, 2- CH2 ), 2.79 (2H, m, 5-CH2 ), 3.20 (1H, dd, 4-CH), 3.54 (2H, q, CH2 ), 3.87 (2H, q, CH2 ), 6.02 (1H, q, CH), 7.10~7.50 (24H, m, 芳族)。 HPLC方法：管柱：Eclipse XDB-C18；150×4.6 mm；5 μm。流動相A (0.1 % H3 PO4 )含於水中；流動相B (乙腈)。梯度：0 min (30 % B)；8 min (95 % B)；15 min (95 % B)。流速：1.0 ml min-1 。波長：210 nm。溫度：30℃。滯留時間：11.0 min。實例 20 ： 5- 聯苯 -4- 基 -(S)-4- 二苄基胺基 -1- 吡咯啶 -1- 基 - 戊 -1- 酮 向5-聯苯-4-基-(S)-4-二苄基胺基-戊酸鹽酸鹽 (1.46 g，3 mmol)含於CH2 Cl2 中之溶液添加，接著添加三乙胺(0.34 g，3.3 mmol)，接著添加CDI (0.73 g，4.5 mmol)且在室溫下攪拌混合物15分鐘，然後添加吡咯啶(0.43 g，6 mmol)。攪拌30分鐘後，用水稀釋反應混合物，並乾燥有機層並濃縮，得到5-聯苯-4-基-(S)-4-二苄基胺基-1-吡咯啶-1-基-戊-1-酮。1 H NMR (CDCl3 )：1.80 ( 2H, m, 3-CH2 ), 1.88 (2H, m, CH2 ), 1.98 (2H, m, CH2 ), 2.53 (2H, m, 2-CH2 ), 2.81 (2H, m, 5-CH2 ), 3.20 (1H, dd, 4-CH), 3.26(2H, m, CH2 ), 3.38 (2H, m, CH2 ), 3.54 (2H, d, CH2 ), 3.84 (2H, d, CH2 ), 7.10~7.4 (19H, m, 芳族)。 HPLC方法：管柱：Waters Xbridge-Phenyl；150×3.0 mm；3.5 µm。流動相A (0.1 % DEA)含於水中；流動相B (乙腈)。梯度：0 min (90 % B)；10 min (95 % B)；15 min (95 % B)。流速：0.7 ml min-1。波長：210 nm。溫度：30℃。滯留時間：11.2 min。實例 21 ： (S)-5- 聯苯 -4- 基 -4-(1,3- 二氫 - 異吲哚 -2- 基 )- 戊酸甲基 -(R-1- 苯基 - 乙基 )- 醯胺 向(S)-5-聯苯-4-基-4-(1,3-二側氧基-1,3-二氫-異吲哚-2-基)-戊酸(4.0 g，10 mmol)含於100 mL CH2 Cl2 中之溶液依序添加N-甲基-(R-1-苯基-乙基)胺(1.48g，11 mmol)、EDC·HCl (2.3g，12mmol)、HOBt (1.62 g，12 mmol)及TEA (5 g，50 mmol)，且在室溫下攪拌混合物12小時。用水清洗混合物後，乾燥並濃縮。藉由管柱層析(乙酸乙酯/庚烷 = 1/2)純化殘餘物，得到(S)-5-聯苯-4-基-4-(1,3-二氫-異吲哚-2-基)-戊酸甲基-(R-1-苯基-乙基)-醯胺。1 H NMR (CDCl3 )：1.39 ( 3H, d), 2.34 (3H, m), 2.51 (3H, s), 2.60 (1H, m), 3.24 (1H, m), 3.46 (1H, m), 4.65 (1H, m), 5.99 (1H, m), 7.20~7.80 (18H, m, 芳族)。 HPLC方法：管柱：Eclipse XDB-C18；150×4.6 mm；5 μm。流動相A (0.1% H3 PO4 )含於水中；流動相B (乙腈)。梯度：0 min (30 % B)；8 min (95 % B)；15 min (95 % B)。流速：1.0 ml/min。波長：210 nm。溫度：30℃。滯留時間：9.9 min。實例 22 ： (S)-5- 聯苯 -4- 基 -4-(1,3- 二氫 - 異吲哚 -2- 基 )- 戊酸甲基 -(S-1- 苯基 - 乙基 )- 醯胺 向(S)-5-聯苯-4-基-4-(1,3-二側氧基-1,3-二氫-異吲哚-2-基)-戊酸(4.0 g，10 mmol)含於100 mL CH2 Cl2 中之溶液依序添加N-甲基-(S-1-苯基-乙基)胺(1.48g，11 mmol)、EDC·HCl (2.3g，12mmol)、HOBt (1.62 g，12 mmol)及TEA (5 g，50 mmol)，且在室溫下攪拌混合物12小時。用水清洗混合物後，乾燥並濃縮。藉由管柱層析(乙酸乙酯/庚烷 = 1/2)純化殘餘物，得到(S)-5-聯苯-4-基-4-(1,3-二氫-異吲哚-2-基)-戊酸甲基-(S-1-苯基-乙基)-醯胺。1 H NMR (CDCl3 )：1.39 ( 3H, d), 2.34 (3H, m), 2.51 (3H, s), 2.60 (1H, m), 3.24 (1H, m), 3.46 (1H, m), 4.65 (1H, m), 5.99 (1H, m), 7.20~7.80 (18H, m, 芳族)。 HPLC方法：管柱：Eclipse XDB-C18；150×4.6 mm；5 μm。流動相A (0.1 % H3 PO4 )含於水中；流動相B (乙腈)。梯度：0 min (30 % B)；8 min (95 % B)；15 min (95 % B)。流速：1.0 ml min-1 。波長：210 nm。溫度：30℃。滯留時間：9.9 min。實例 23 ： 2-(S)-1- 聯苯 -4- 基甲基 -4(R)-2- 羥基甲基 - 吡咯啶 -1- 基 )-4- 側氧基 - 丁基 )- 異吲哚 -1,3- 二酮 向(S)-5-聯苯-4-基-4-(1,3-二側氧基-1,3-二氫-異吲哚-2-基)-戊酸(4.0 g，10 mmol)含於100 mL CH2 Cl2 中之溶液依序添加(R)-脯胺醇(1.12 g，11 mmol)、EDC·HCl (2.3 g，12mmol)、HOBt (1.62 g，12 mmol)及TEA (5 g，50 mmol)，且在室溫下攪拌混合物12小時。用水清洗反應混合物後，乾燥並濃縮。藉由管柱層析純化殘餘物，得到2-(S)-1-聯苯-4-基甲基-4(R)-2-羥基甲基-吡咯啶-1-基)-4-側氧基-丁基)-異吲哚-1,3-二酮。1 H NMR (CDCl3 )：1.57 (1H, m), 1.78 (1H, m), 1.93 (2H,m), 2.24 (1H, m), 2.30 (2H, m), 2.57 (1H, m), 3.1-3.6 (5H, m), 3.72 (1H, m), 3.95 (1H, m), 4.60 (1H, m),  7.20~7.80 (13H, m, 芳族)。 HPLC方法：管柱：Eclipse XDB-C18；150×4.6 mm；5 μm。流動相A (0.1 % H3 PO4 )含於水中；流動相B (乙腈)。梯度：0 min (30 % B)；8 min (95 % B)；15 min (95 % B)。流速：1.0 ml min-1 。波長：210 nm。溫度：30℃。滯留時間：7.6 min。實例 24 ： 2-(S)-1- 聯苯 -4- 基甲基 -4(S)-2- 羥基甲基 - 吡咯啶 -1- 基 )-4- 側氧基 - 丁基 )- 異吲哚 -1,3- 二酮 向(S)-5-聯苯-4-基-4-(1,3-二側氧基-1,3-二氫-異吲哚-2-基)-戊酸(4.0 g，10 mmol)含於100 mL CH2 Cl2 中之溶液依序添加(S)-脯胺醇(1.12 g，11 mmol)、EDC·HCl (2.3 g，12mmol)、HOBt (1.62 g，12 mmol)及TEA (5 g，50 mmol)，且在室溫下攪拌混合物12小時。然後用水清洗反應混合物，乾燥並濃縮。藉由管柱層析純化殘餘物，得到2-(S)-1-聯苯-4-基甲基-4(S)-2-羥基甲基-吡咯啶-1-基)-4-側氧基-丁基)-異吲哚-1,3-二酮。1 H NMR (CDCl3 )：1.53 ( 1H, m), 1.83 (2H, m), 1.98 (1H,m), 2.22 (1H, m), 2.32 (2H, m), 2.59 (1H, m), 3.22 (1H, dd), 3.30-3.50 (4H, m), 3.56 (1H, m), 4.13 (1H, m),  7.20~7.80 (13H, m, 芳族)。 HPLC方法：管柱：Eclipse XDB-C18；150×4.6 mm；5 μm。流動相A (0.1 % H3 PO4 )含於水中；流動相B (乙腈)。梯度：0 min (30 % B)；8 min (95 % B)；15 min (95 % B)。流速：1.0 ml min-1 。波長：210 nm。溫度：30℃。滯留時間：7.5 min。實例 25 ： (S)-5- 聯苯 -4- 基 -4- 二苄基胺基 - 戊酸苄酯 向(S)-4-胺基-5-聯苯-4-基-戊酸鹽酸鹽 (10 g，32.7mmol)含於200 mL水中之懸浮液添加苄基溴(22.4 g，130.8mmol)、K2 CO3 (18.1 g，130.8 mmol)及NaOH (3.9 g，98 mmol)並將混合物加熱至回流持續4小時。然後添加濃HCl，並將pH調整為4至5，利用乙酸乙酯萃取，並用水清洗有機層，乾燥並濃縮，得到(S)-5-聯苯-4-基-4-二苄基胺基-戊酸苄酯。1 H NMR (CDCl3 )：1.70 ( 1H, m, 3-CH H), 1.9 0 (1H, m, 3-CHH ), 2.20 (1H, m, 2- CH H), 2.46 (1H, m, 5-CH H), 2.63 (1H, m, 2- CHH ), 2.83(1H, m, 5-CHH ), 3.18 (1H, dd, 4-CH), 3.52 (2H, d, CH2 ), 3.85 (2H, d, CH2 ), 4.98 (2H, s, CH2 ), 7.10~7.50 (24H, m, 芳族)。 HPLC方法：管柱：Eclipse XDB-C18；150×4.6 mm；5 μm。流動相A (0.1 % H3 PO4 )含於水中；流動相B (乙腈)。梯度：0 min (30 % B)；8 min (95 % B)；15 min (95 % B)。流速：1.0 ml min-1 。波長：210 nm。溫度：30℃。滯留時間：12.7 min。實例 26 ： (S)-5- 聯苯 -4- 基 -4- 二苄基胺基 - 戊酸鹽酸鹽 向(S)-5-聯苯-4-基-4-二苄基胺基-戊酸苄酯(14.5 g，32.3 mmol)含於水中之懸浮液添加3.9 g NaOH，使混合物回流3小時，在冷卻至室溫之後，用庚烷萃取混合物，且用濃HCl處理水層，以將pH調整為4至5，然後用乙酸乙酯萃取混合物，並用水清洗有機層，乾燥並濃縮。利用HCl的乙酸乙酯溶液處理所得殘餘物，過濾所形成之固體並乾燥，得到(S)-5-聯苯-4-基-4-二苄基胺基-戊酸鹽酸鹽。1 H NMR (DMSO-d6 )：1.75 ( 1H, m, 3-CH H), 1.92 (1H, m, 3-CHH ), 2.21 (1H, m, 2- CH H), 2.47 (1H, m, 5-CH H), 2.65 (1H, m, 2- CHH ), 2.84(1H, m, 5-CHH ), 3.20 (1H, dd, 4-CH), 3.54 (2H, d, CH2 ), 3.86 (2H, d, CH2 ), 7.10~7.50 (19H, m, 芳族), 10.8 (1H, s, COOH)。 HPLC方法：管柱：Eclipse XDB-C18；150×4.6 mm；5 μm。流動相A (0.1 % H3 PO4 )含於水中；流動相B (乙腈)。梯度：0 min (30 % B)；8 min (95 % B)；15 min (95 % B)。流速：1.0 ml min-1 。波長：210 nm。溫度：30℃。滯留時間：10.4 min。實例 27 ： 5- 聯苯 -4- 基 -(S)-4- 二苄基胺基 - 戊酸甲酯 向4.9 g 5-聯苯-4-基-(S)-4-二苄基胺基-戊酸鹽酸鹽含於50 mL MeOH中之混合物添加濃H2 SO4 (0.1 mL)。將反應混合物加熱至回流持續12小時。在移除MeOH後，將殘餘物溶於50 mL乙酸乙酯中，用NaHCO3 、水清洗，並乾燥。移除溶劑並獲得5-聯苯-4-基-(S)-4-二苄基胺基-戊酸甲酯。1 H NMR (CDCl3 )：1.65 ( 1H, m, 3-CH H), 1.87 (1H, m, 3-CHH ), 2.13 (1H, m, 2- CH2 ), 2.46 (1H, m, 2- CH2 ), 2.60 (1H, m, 5-CH2 ), 2.81 (1H, m, 5-CH2 ), 3.19 (1H, dd, 4-CH), 3.52 (2H, d, CH2 ), 3.55 (3H, s, OCH3 ), 3.86 (2H, d, CH2 ), 7.10~7.50 (19H, m, 芳族)。 HPLC方法：管柱：Eclipse XDB-C18；150×4.6 mm；5 μm。流動相A (0.1 % H3 PO4 )含於水中；流動相B (乙腈)。梯度：0 min (90 % B)；10 min (95 % B)；15 min (95 % B)。流速：0.7 ml min-1 。波長：210 nm。溫度：30℃。滯留時間：13.9 min。實例 28 ： 5- 聯苯 -4- 基 -(S)-4- 二苄基胺基 - 戊酸 L- 薄荷酯 在N2 氛圍下，將n-BuLi (1.6M，0.9 mL，1.44 mmol)添加至L-薄荷醇含於10 mL無水THF中之溶液。然後添加含於5 mL THF中之5-聯苯-4-基-(S)-4-二苄基胺基-戊酸甲酯，在室溫下攪拌該混合物2小時。用飽和氯化銨水溶液稀釋反應混合物，以乙酸乙酯萃取。合併有機萃取物，並濃縮，藉由管柱層析(乙酸乙酯/庚烷 = 1/15)純化所得殘餘物，得到5-聯苯-4-基-(S)-4-二苄基胺基-戊酸L-薄荷酯。1 H NMR (CDCl3 )：0.67 (3H, d, CH3 ), 0.79 (3H, d, CH3 ), 0.86 (3H, d, CH3 ), 1.26 (4H, m, CH2 -CH2 ), 1.56 (2H, m, CH2 ), 1.60 (1H, m, CH), 1.71 (1H, m, CH), 1.73 (1H, m, 3-CHH ), 1.87 (1H, m, 3-CH H), 2.14 (1H, m, 2-CHH ), 2.47 (1H, m, 2-CH H), 2.59 (1H, m, 5-CHH ), 2.78 (1H, m, 5-CH H), 3.17 (1H, dd, 4-CH), 3.54 (2H, d, CH2 ), 3.87 (2H, d, CH2 ), 4.56 (3H, m, OCH), 7.10~7.50 (19H, m, 芳族)。 HPLC方法：管柱：Waters Xbridge-Phenyl; 150 × 3.0 mm；3.5 μm。流動相A (0.1 % DEA)含於水中；流動相B (乙腈)。梯度：0 min (60 % B)；30 min (95 % B)。流速：0.5 ml min-1 。波長：210 nm。溫度：35℃。滯留時間：27.3 min。實例 29 ： 5- 聯苯 -4- 基 -(S)-4- 二苄基胺基 - 戊酸 D- 薄荷酯 在N2 氛圍下，將n-BuLi (1.6M，0.9 mL，1.44 mmol)添加至D-薄荷醇含於10 mL無水THF中之混合物。然後添加含於5 mL THF中之5-聯苯-4-基-(S)-4-二苄基胺基-戊酸甲酯，在室溫下攪拌該混合物2小時。用飽和氯化銨水溶液稀釋反應混合物，以乙酸乙酯萃取。合併有機萃取物，並濃縮，藉由管柱層析(乙酸乙酯/庚烷 = 1/15)純化所得殘餘物，得到5-聯苯-4-基-(S)-4-二苄基胺基-戊酸L-薄荷酯。1 H NMR (CDCl3 )：0.71 (3H, d, CH3 ), 0.87 (6H, d, CH3 ), 1.26 (4H, m, CH2 -CH2 ), 1.55 (2H, m, CH2 ), 1.64 (1H, m, CH), 1.78 (1H, m, CH), 1.88 (2H, m, 3-CH2 ), 2.04 (1H, m, 2-CHH ), 2.46 (1H, m, 2-CH H), 2.62 (1H, m, 5-CHH ), 2.80 (1H, m, 5-CH H), 3.16 (1H, dd, 4-CH), 3.55 (2H, d, CH2 ), 3.85 (2H, d, CH2 ), 4.60 (3H, m, OCH), 7.10~7.50 (19H, m, 芳族)。 HPLC方法：管柱：Waters Xbridge-Phenyl; 150 × 3.0 mm；3.5 μm。流動相A (0.1 % DEA)含於水中；流動相B (乙腈)。梯度：0 min (60 % B)；30 min (95 % B)。流速：0.5 ml min-1 。波長：210 nm。溫度：35℃。滯留時間：22.9 min。實例 30 ： 5- 聯苯 -4- 基 -(S)-4- 二苄基胺基 - 戊酸 S- 對甲苯酯 向5-聯苯-4-基-(S)-4-二苄基胺基-戊酸鹽酸鹽 (1.46 g，3mmol)含於CH2 Cl2 中之溶液添加，接著添加三乙胺(0.34g，3.3mmol)，接著添加CDI (0.73 g，4.5 mmol)。在室溫下攪拌反應混合物15分鐘，然後添加4-甲基-苯硫醇(0.74 g，6 mmol)。30分鐘後，用水清洗反應混合物，並濃縮，藉由管柱層析(乙酸乙酯/庚烷 = 1/25)純化所得殘餘物，得到5-聯苯-4-基-(S)-4-二苄基胺基-戊酸S-對甲苯酯。1 H NMR (CDCl3 )：1.72 ( 1H, m, 3-CH H), 1.95 (1H, m, 3-CHH ), 2.34 (3H, s, CH3 ), 2.43 (2H, m, 2- CH2 ), 2.79 (1H, m, 5-CH2 ), 2.95 (1H, m, 5-CH2 ), 3.17 (1H, dd, 4-CH), 3.52 (2H, d, CH2 ), 3.86 (2H, d, CH2 ), 7.10~7.40 (23H, m, 芳族)。 HPLC方法：管柱：Eclipse XDB-C18；150×4.6 mm；5 μm。流動相A (0.1 % H3 PO4 )含於水中；流動相B (乙腈)。梯度：0 min (90 % B)；10 min (95 % B)；15 min (95 % B)。流速：0.7 ml min-1 。波長：210 nm。溫度：30℃。滯留時間：14.8 min。實例 31 ： 2-[(1S,3R)-4-((R)-4- 苄基 -2- 側氧基 - 噁唑啶 -3- 基 )-1- 聯苯 -4- 基甲基 -3- 甲基 -4- 側氧基 - 丁基 ]- 異吲哚 -1,3- 二酮 方法 1 ： 向NaHMDS (6.5 mL，6.5 mmol)含於20 mL無水THF中之-78℃溶液添加含於無水THF中之2-[(S)-4-((R)-4-苄基-2-側氧基-噁唑啶-3-基)-1-聯苯-4-基甲基-4-側氧基-丁基]-異吲哚-1,3-二酮(3.00 g，5.38 mmol)。攪拌反應混合物1小時，然後將碘甲烷(3.82 g，26.90 mmol)添加至該反應混合物。12小時後，使該反應混合物升溫至室溫，添加飽和NH4 Cl (25 ml)，用TBME萃取該混合物。用鹽水清洗合併的有機萃取物，乾燥並濃縮，使殘餘物自TBME及庚烷結晶，得到2-[(1S,3R)-4-((R)-4-苄基-2-側氧基-噁唑啶-3-基)-1-聯苯-4-基甲基-3-甲基-4-側氧基-丁基]-異吲哚-1,3-二酮，非對映異構體比率(2R, 4S) :(2S,4S) = 97 :3，如藉由HPLC所測定。此物質可自TBME及庚烷再結晶，得到(2R, 4S) :(2S, 4S) ＞99:1，如藉由HPLC所測定。1 H NMR (CDCl3 )：1.35 ( 3H, d), 2.28 (1H, m), 2.25 (1H, m), 2.67 (1H, m), 2.95 (2H, m), 3.27 (2H, m), 3.50 (1H, m),4.15 (1H, m), 4.23 (1H, m), 7.15 ~7.80 (18H, m, 芳族)。MS (ESI, m/e) 573 (MH+ )。 2-[(1S,3R)-4-((R)-4-苄基-2-側氧基-噁唑啶-3-基)-1-聯苯-4-基甲基-3-甲基-4-側氧基-丁基]-異吲哚-1,3-二酮為結晶固體且可藉由X-射線粉末圖譜表徵。X-射線繞射圖譜中之最強反射顯示以下晶格間平面間隔(平均2θ以[o ]計係以±0.2之誤差限值指示)：2θ以[o ]計：7.5、9.5、10.9、16.9、19.1、21.4、22.9、24.9、26.2、27.6、29.6、30.9。使用Bruker D8高級繞射儀，使用Cu-Kα輻射採集資料。方法 2 ： 向NaHMDS (2.1 mL，2.1 mmol)含於5 mL無水THF中之-60℃溶液添加含於無水THF中之2-[(S)-4-((R)-4-苄基-2-側氧基-噁唑啶-3-基)-1-聯苯-4-基甲基-4-側氧基-丁基]-異吲哚-1,3-二酮(1 g，1.8 mmol)。攪拌反應混合物1小時，然後將碘甲烷(1.2 g，8.5 mmol)添加至該反應混合物。12小時後，使該反應混合物升溫至室溫，添加飽和NH4 Cl (10 ml)，用TBME萃取該混合物。用鹽水清洗合併的有機萃取物，乾燥並濃縮，使殘餘物自TBME及庚烷結晶，得到2-[(1S,3R)-4-((R)-4-苄基-2-側氧基-噁唑啶-3-基)-1-聯苯-4-基甲基-3-甲基-4-側氧基-丁基]-異吲哚-1,3-二酮，非對映異構體比率(2R, 4S) :(2S, 4S) = 95 :5，如藉由HPLC所測定。方法 3 ： 向NaHMDS (2.1 mL，2.1 mmol)含於5 mL無水THF中之-40℃溶液添加含於無水THF中之2-[(S)-4-((R)-4-苄基-2-側氧基-噁唑啶-3-基)-1-聯苯-4-基甲基-4-側氧基-丁基]-異吲哚-1,3-二酮(1 g，1.8 mmol)。攪拌反應混合物1小時，然後將碘甲烷(1.2 g，8.5 mmol)添加至該反應混合物。12小時後，使該反應混合物升溫至室溫，添加飽和NH4 Cl (10 ml)，用TBME萃取該混合物。用鹽水清洗合併的有機萃取物，乾燥並濃縮，使殘餘物自TBME及庚烷結晶，得到2-[(1S,3R)-4-((R)-4-苄基-2-側氧基-噁唑啶-3-基)-1-聯苯-4-基甲基-3-甲基-4-側氧基-丁基]-異吲哚-1,3-二酮，非對映異構體比率(2R, 4S) :(2S, 4S) = 94 :6，如藉由HPLC所測定。方法 4 ： 向NaHMDS (2.1 mL，2.1 mmol)含於5 mL無水THF中之-10℃溶液添加含於無水THF中之2-[(S)-4-((R)-4-苄基-2-側氧基-噁唑啶-3-基)-1-聯苯-4-基甲基-4-側氧基-丁基]-異吲哚-1,3-二酮(1 g，1.8 mmol)。攪拌反應混合物1小時，然後將碘甲烷(1.2 g，8.5 mmol)添加至該反應混合物。12小時後，使該反應混合物升溫至室溫，添加飽和NH4 Cl (10 ml)，用TBME萃取該混合物。用鹽水清洗合併的有機萃取物，乾燥並濃縮，使殘餘物自TBME及庚烷結晶，得到2-[(1S,3R)-4-((R)-4-苄基-2-側氧基-噁唑啶-3-基)-1-聯苯-4-基甲基-3-甲基-4-側氧基-丁基]-異吲哚-1,3-二酮，非對映異構體比率(2R, 4S) :(2S, 4S) = 90 :10，如藉由HPLC所測定。方法 5 ： 向NaHMDS (2.1 mL，2.1 mmol)含於5 mL無水甲苯中之-78℃溶液添加含於無水THF中之2-[(S)-4-((R)-4-苄基-2-側氧基-噁唑啶-3-基)-1-聯苯-4-基甲基-4-側氧基-丁基]-異吲哚-1,3-二酮(1 g，1.8 mmol)。攪拌反應混合物1小時，然後將碘甲烷(1.2 g，8.5 mmol)添加至該反應混合物。12小時後，使該反應混合物升溫至室溫，添加飽和NH4 Cl (10 ml)，用TBME萃取該混合物。用鹽水清洗合併的有機萃取物，乾燥並濃縮，使殘餘物自TBME及庚烷結晶，得到2-[(1S,3R)-4-((R)-4-苄基-2-側氧基-噁唑啶-3-基)-1-聯苯-4-基甲基-3-甲基-4-側氧基-丁基]-異吲哚-1,3-二酮，非對映異構體比率(2R, 4S) :(2S, 4S) = 77 :23，如藉由HPLC所測定。方法 6 ： 向KHMDS (2.1 mL，2.1 mmol)含於5 mL無水THF中之-78℃溶液添加含於無水THF中之2-[(S)-4-((R)-4-苄基-2-側氧基-噁唑啶-3-基)-1-聯苯-4-基甲基-4-側氧基-丁基]-異吲哚-1,3-二酮(1 g，1.8 mmol)。攪拌反應混合物1小時，然後將碘甲烷(1.2 g，8.5 mmol)添加至該反應混合物。12小時後，使該反應混合物升溫至室溫，添加飽和NH4 Cl (10 ml)，用TBME萃取該混合物。用鹽水清洗合併的有機萃取物，乾燥並濃縮，使殘餘物自TBME及庚烷結晶，得到2-[(1S,3R)-4-((R)-4-苄基-2-側氧基-噁唑啶-3-基)-1-聯苯-4-基甲基-3-甲基-4-側氧基-丁基]-異吲哚-1,3-二酮，非對映異構體比率(2R,4S):(2S,4S) = 41:59，如藉由HPLC所測定。 HPLC方法：管柱：Phenomenex  Gemini C18; 150 × 3.0 mm；3.0 μm。流動相A (0.1 % H3 PO4 )含於水中；流動相B (乙腈)。梯度：0 min (30 % B)；30 min (95 % B)；35 min (95 % B)。流速：0.5 ml min-1 。波長：210或254 nm。溫度：30℃。滯留時間：SM 25.0 min，(2S,4S) 26.1 min，(2R,4S) 26.9 min。實例 32 ： 2-[(S)-4-((R)-4- 異丙基 -2- 側氧基 - 噁唑啶 -3- 基 )-1- 聯苯 -4- 基甲基 -3- 甲基 -4- 側氧基 - 丁基 ]- 異吲哚 -1,3- 二酮 向NaHMDS (6.5 mL，6.5 mmol)含於20 mL無水THF中之-78℃溶液添加含於無水THF中之2-[(S)-4-((R)-4-異丙基-2-側氧基-噁唑啶-3-基)-1-聯苯-4-基甲基-4-側氧基-丁基]-異吲哚-1,3-二酮(2.74 g，5.38 mmol)。攪拌反應混合物1小時，然後將碘甲烷(3.82 g，26.90 mmol)添加至該反應混合物。12小時後，使該反應混合物升溫至室溫，添加飽和NH4 Cl (25 ml)，用TBME萃取該混合物。用鹽水清洗合併的有機萃取物，乾燥並濃縮，得到2-[(S)-4-((R)-4-異丙基-2-側氧基-噁唑啶-3-基)-1-聯苯-4-基甲基-3-甲基-4-側氧基-丁基]-異吲哚-1,3-二酮，非對映異構體比率(2R,4S):(2S,4S) = 99.6:0.4係藉由HPLC測定。1 H NMR (CDCl3 )：0.9(6H, d),1.2 ( 3H, d), 2.31 (3H, m), 3.12 (1H, m), 3.45 (1H, m), 3.75 (1H, m), 4.17 (1H, m), 4.41 (1H, m),4.47 (1H, m), 4.54 (1H, m), 7.15 ~7.70 (13H, m, 芳族)。MS (ESI, m/e) 400 (MH+ )。 HPLC方法：管柱：Eclipse XDB-C18；150×4.6 mm；5 μm。流動相A (0.1 % H3 PO4 )含於水中；流動相B (乙腈)。梯度：0 min (10 % B)；10 min (95 % B)；15 min (95 % B)。流速：1.0 ml min-1 。波長：210 nm。溫度：30℃。滯留時間：10.5 min。實例 33 ： 5- 聯苯 -4- 基 -(S)-4- 二苄基胺基 -1-((S)-2- 羥基甲基 - 吡咯啶 -1- 基 )-(S)-2- 甲基 - 戊 -1- 酮 在N2 氛圍下，在-70℃下，將2.5 mL LDA (1.0M含於THF中)添加至5-聯苯-4-基-(S)-4-二苄基胺基-1-((S)-2-羥基甲基-吡咯啶-1-基)-戊-1-酮(0.53 g，1 mmol)含於15 mL無水THF中之混合物。再攪拌混合物1小時，然後添加MeI (0.2 g，1.4 mmol)。使所得混合物緩慢升溫至室溫並攪拌3小時，添加飽和氯化銨溶液，用乙酸乙酯萃取水層並濃縮，獲得5-聯苯-4-基-(S)-4-二苄基胺基-1-((S)-2-羥基甲基-吡咯啶-1-基)-(S)-2-甲基-戊-1-酮。藉由HPLC分析之非對映異構體之比率：(2R,4S):(2S,4S) = 23:77。1 H NMR (CDCl3 )：1.04 (3H, d, CH3 ), 1.48 ( 1H, m, 3-CH H), 1.80 (4H, m, CH2 CH2 ), 1.90 (1H, m, 3-CHH ), 2.45 (1H, m, 5-CHH ), 2.60 (1H, m, 5-CH H), 2.96 (1H, m, 2- CHH ), 3.08 (1H, m, 4-CH), 3.20 (2H, m, CH2 ), 3.62 (2H, m, CH2 ), 3.57 (2H, m, CH2 ), 3.86 (2H, d, CH2 ), 4.05 (1H, m, CH), 5.07 (1H, d, OH), 7.10~7.50 (19H, m, 芳族)。 HPLC方法：管柱：Waters Xbridge-Phenyl; 150 × 3.0 mm；3.5 μm。流動相A (0.1 % DEA)含於水中；流動相B (乙腈)。梯度：0 min (55 % B)；30 min (55 % B)；30.1 min (95 % B)；35 min (95 % B)。流速：0.5 ml min-1 。波長：210 nm。溫度：35℃。滯留時間：(2R,4S)：22.6 min；(2S,4S)：20.0 min。實例 34 ： 5- 聯苯 -4- 基 -(S)-4- 二苄基胺基 -1-((R)-2- 羥基甲基 - 吡咯啶 -1- 基 )-(R)-2- 甲基 - 戊 -1- 酮 在N2 氛圍下，在-70℃下，將2.5 mL LDA (1.0M含於THF中)添加至5-聯苯-4-基-(S)-4-二苄基胺基-1-((R)-2-羥基甲基-吡咯啶-1-基)-戊-1-酮(0.53 g，1 mmol)含於15 mL無水THF中之混合物。再攪拌混合物1小時，然後添加MeI (0.2 g，1.4 mmol)。使所得混合物緩慢升溫至室溫並攪拌3小時，添加飽和氯化銨溶液，用乙酸乙酯萃取水層並濃縮，獲得5-聯苯-4-基-(S)-4-二苄基胺基-1-((R)-2-羥基甲基-吡咯啶-1-基)-(R)-2-甲基-戊-1-酮。藉由HPLC分析之非對映異構體之比率：(2R,4S):(2S,4S) = 84:16。1 H NMR (CDCl3 )：0.99 (3H, d, CH3 ), 1.42 ( 1H, m, 3-CH H), 1.70 (4H, m, CH2 CH2 ), 1.91 (2H, m, 3-CH2 ), 2.50 (1H, m, 5-CHH ), 2.60 (1H, m, 2- CHH ), 2.92 (1H, m, 4-CH), 3.00 (2H, m, CH2 ), 3.28 (2H, m, CH2 ), 3.60 (2H, m, CH2 ), 3.71 (2H, d, CH2 ), 4.11 (1H, m, CH), 5.12 (1H, d, OH), 7.10~7.50 (19H, m, 芳族)。 HPLC方法：管柱：Waters Xbridge-Phenyl；150 × 3.0 mm；3.5 μm。流動相A (0.1 % DEA)含於水中；流動相B (乙腈)。梯度：0 min (50 % B)；20 min (50 % B)；30 min (60 % B)。流速：0.5 ml min-1 。波長：210 nm。溫度：50℃。滯留時間：(2R,4S)：30.1 min；(2S,4S)：30.8 min實例 35 ： 5- 聯苯 -4- 基 -(S)-4- 二苄基胺基 -(R)-2- 甲基 - 戊酸 (S)- 甲基 -(1- 苯基 - 乙基 )- 醯胺 在N2 氛圍下，在-70℃下，將2.5 mL LDA (1.0M含於THF中)添加至5-聯苯-4-基-(S)-4-二苄基胺基-1-((S)-2-羥基甲基-吡咯啶-1-基)-戊-1-酮(0.53 g，1 mmol)含於15 mL無水THF中之混合物。再攪拌混合物1小時，然後添加MeI (0.2 g，1.4 mmol)。使所得混合物緩慢升溫至室溫並攪拌3小時，添加飽和氯化銨溶液，用乙酸乙酯萃取水層並濃縮，獲得5-聯苯-4-基-(S)-4-二苄基胺基-(R)-2-甲基-戊酸 (S)-甲基-(1-苯基-乙基)-醯胺。藉由HPLC分析之非對映異構體之比率：(2R,4S):(2S, 4S) =63:37。1 H NMR (CDCl3 )：1.00 (3H, d, CH3 ), 1.38 (3H, d, CH3 ), 1.87 ( 2H, m, 3-CH2 ), 2.30 (3H, s, CH3 ), 2.60 (1H, m, 2-CH2 ), 2.98 (2H, m, 5-CH2 ), 3.55 (1H, dd, 4-CH), 3.58 (2H, d, CH2 ), 3.70 (2H, d, CH2 ), 6.00 (1H, m, CH), 7.10~7.50 (24H, m, 芳族)。 HPLC方法：管柱：Waters Xbridge-Phenyl; 150 × 3.0 mm；3.5 μm。流動相A (0.1 % DEA)含於水中；流動相B (乙腈)。梯度：0 min (65 % B)；30 min (65 % B)；30.1 min (95 % B)；35 min (95 % B)。流速：0.5 ml min-1 。波長：210 nm。溫度：35℃。滯留時間：(2R, 4S)：20.4 min；(2S, 4S)：19.3 min。實例 36 ： 5- 聯苯 -4- 基 -(S)-4- 二苄基胺基 -(R)-2- 甲基 - 戊酸 (R)- 甲基 -(1- 苯基 - 乙基 )- 醯胺 在N2 氛圍下，在-70℃下，將2.5 mL LDA (1.0M含於THF中)添加至5-聯苯-4-基-(S)-4-二苄基胺基-1-((R)-2-羥基甲基-吡咯啶-1-基)-戊-1-酮(0.53 g，1 mmol)含於15 mL無水THF中之混合物。再攪拌混合物1小時，然後添加MeI (0.2 g，1.4 mmol)。使所得混合物緩慢升溫至室溫並攪拌3小時，添加飽和氯化銨溶液，用乙酸乙酯萃取水層並濃縮，獲得5-聯苯-4-基-(S)-4-二苄基胺基-(R)-2-甲基-戊酸 (R)-甲基-(1-苯基-乙基)-醯胺。藉由HPLC分析之非對映異構體之比率：(2R,4S):(2S, 4S) = 75:25。1 H NMR (CDCl3 )：1.03 (3H, d, CH3 ), 1.37 (3H, d, CH3 ), 1.82 ( 1H, m, 3-CHH ), 1.92 ( 1H, m, 3-CH H), 2.41 (3H, s, CH3 ), 2.63 (1H, m, 2-CH2 ), 2.99 (2H, m, 5-CH2 ), 3.57 (1H, m, 4-CH), 3.59 (2H, m, CH2 ), 3.70 (2H, d, CH2 ), 6.00 (1H, m, CH), 7.10~7.50 (24H, m, 芳族)。 HPLC方法：管柱：Waters Xbridge-Phenyl；150 × 3.0 mm；3.5 μm。流動相A (0.1 % DEA)含於水中；流動相B (乙腈)。梯度：0 min (60 % B)；40 min (60 % B)；40.1 min (95 % B)；45 min (95 % B)。流速：0.5 ml min-1 。波長：210 nm。溫度：35℃。滯留時間：(2R, 4S)：33.4 min；(2S, 4S)：34.6 min。實例 37 ： 5- 聯苯 -4- 基 -(S)-4- 二苄基胺基 -(R)-2- 甲基戊酸 L- 薄荷酯 在N2 氛圍下，在-70℃下，將LDA (1.0M含於THF中，0.6 mL)添加至5-聯苯-4-基-(S)-4-二苄基胺基-戊酸L-薄荷酯(0.3 g，0.5 mmol)含於15 mL無水THF中之混合物。1小時後，添加MeI (0.04 mL，0.6 mmol)，並使反應混合物緩慢升溫至室溫並攪拌3小時。用飽和氯化銨水溶液稀釋混合物，然後以乙酸乙酯萃取。合併有機萃取物，並濃縮，得到5-聯苯-4-基-(S)-4-二苄基胺基-(R)-2-甲基戊酸L-薄荷酯。根據HPLC分析，非對映異構體(2R,4S):(2S, 4S)之比率為57:43。1 H NMR (CDCl3 )：0.68 (3H, d, CH3 ), 0.99 (3H, d, CH3 ), 0.80 (3H, d, CH3 ), 0.85 (3H, d, CH3 ), 1.27 (4H, m, CH2 -CH2 ), 1.55 (2H, m, CH2 ), 1.62 (1H, m, CH), 1.73 (1H, m, CH), 1.75 (1H, m, 3-CHH ), 1.86 (1H, m, 3-CH H), 2.15 (1H, m, 2-CH), 2.60 (1H, m, 5-CHH ), 2.79 (1H, m, 5-CH H), 3.18 (1H, dd, 4-CH), 3.56 (2H, d, CH2 ), 3.85 (2H, d, CH2 ), 4.57 (3H, m, OCH), 7.10~7.5 0 (19H, m, 芳族)。 HPLC方法：管柱：Waters Xbridge-Phenyl; 150 × 3.0 mm；3.5 μm。流動相A (0.1 % DEA)含於水中；流動相B (乙腈)。梯度：0 min (60 % B)；30 min (95 % B)。流速：0.5 ml min-1 。波長：210 nm。溫度：35℃。滯留時間：(2R, 4S)：32.1 min；(2S, 4S)：31.7 min。實例 38 ： 5- 聯苯 -4- 基 -(S)-4- 二苄基胺基 -(R)-2- 甲基戊酸 D- 薄荷酯 在N2 氛圍下，在-70℃下，將LDA (1.0M含於THF中，0.6 mL)添加至5-聯苯-4-基-(S)-4-二苄基胺基-戊酸D-薄荷酯(0.3 g，0.5 mmol)含於15 mL無水THF中之混合物。1小時後，添加MeI (0.04 mL，0.6 mmol)，並使反應混合物緩慢升溫至室溫並攪拌3小時。用飽和氯化銨水溶液稀釋混合物，以乙酸乙酯萃取。合併有機萃取物，並濃縮，得到5-聯苯-4-基-(S)-4-二苄基胺基-(R)-2-甲基戊酸D-薄荷酯。根據HPLC分析，非對映異構體(2R,4S):(2S,4S)之比率為64:36。1 H NMR (CDCl3 )：0.70(3H, d, CH3 ), 0.85(6H, d, CH3 ), 0.98(3H, d, CH3 ), 1.25(4H, m, CH2 -CH2 ), 1.56(2H, m, CH2 ), 1.65(1H, m, CH), 1.79(1H, m, CH), 1.89(2H, m, 3-CH2 ), 2.08(1H, m, 2-CH), 2.63 (1H, m, 5-CHH ), 2.79(1H, m, 5-CH H), 3.17(1H, dd, 4-CH), 3.57(2H, d, CH2 ), 3.86 (2H, d, CH2 ), 4.62(3H, m, OCH), 7.10~7.5 0 (19H, m, 芳族)。 HPLC方法：管柱：Waters Xbridge-Phenyl; 150 × 3.0 mm；3.5 μm。流動相A (0.1 % DEA)含於水中；流動相B (乙腈)。梯度：0 min (60 % B)；30 min (95 % B)。流速：0.5 ml min-1 。波長：210 nm。溫度：35℃。滯留時間：(2R, 4S)：23.4 min；(2S, 4S)：23.8 min。實例 39 ： 5- 聯苯 -4- 基 -(S)-4- 二苄基胺基 -(R)-2- 甲基戊酸 S- 對甲苯酯 在N2 氛圍下，在-70℃下，將LDA (1.0M含於THF中，2.8 mL)添加至5-聯苯-4-基-(S)-4-二苄基胺基-戊酸S-對甲苯酯(1.11g，2mmol)含於20 mL無水THF中之混合物。1小時後，添加MeI (0.19 mL，3 mmol)，並使混合物緩慢升溫至室溫並攪拌3小時。用氯化銨溶液稀釋混合物，以乙酸乙酯萃取。合併有機萃取物，並濃縮，得到5-聯苯-4-基-(S)-4-二苄基胺基-(R)-2-甲基戊酸S-對甲苯酯。根據HPLC分析，非對映異構體(2R,4S):(2S, 4S)之比率為66:34。1 H NMR (CDCl3 )：1.13(3H, d, CH3 ), 1.68 ( 1H, m, 3-CH H), 1.87 (1H, m, 3-CHH ), 2.34 (3H, s, CH3 ), 2.54 (1H, m, 2- CH2 ), 2.91 (1H, m, 5-CH2 ), 3.07 (1H, m, 5-CH2 ), 3.19 (1H, dd, 4-CH), 3.52 (2H, d, CH2 ), 3.86 (2H, d, CH2 ), 7.10~7.40 (23H, m, 芳族)。 HPLC方法：管柱：Waters Xbridge-Phenyl；150 × 3.0 mm；3.5 μm。流動相A (0.1 % DEA)含於水中；流動相B (乙腈)。梯度：0 min (60 % B)；30 min (95 % B)。流速：0.5 ml min-1 。波長：210 nm。溫度：35℃。滯留時間：(2R,4S)：20.1 min；(2S,4S)：20.5 min。實例 40 ： (2S,4S)-5- 聯苯 -4- 基 -4- 第三丁氧基羰基胺基 -2- 甲基 - 戊酸乙酯 在室溫下，將(S)-5-聯苯-4-基-4-第三丁氧基羰基胺基-戊酸乙酯(2 g)添加至四氫呋喃(18 ml)。然後將所得混合物冷卻至-78℃。添加雙(三甲基甲矽烷基)醯胺鋰(13.1 ml，1M溶液含於四氫呋喃中)。然後在-78℃下攪拌混合物45分鐘。然後添加甲基碘(1.56 ml)，並在-78℃下攪拌混合物2小時。添加1N鹽酸水溶液(20 ml)及乙酸乙酯(10 ml)。分離相，並用1N鹽酸水溶液(10 ml)及然後用鹽水(20 ml)清洗有機層。然後，使有機相經硫酸鎂乾燥並在減壓下濃縮，得到(2S,4S)-5-聯苯-4-基-4-第三丁氧基羰基胺基-2-甲基-戊酸乙酯。1H NMR (CDCl3 )：0.98 (3H), 1.09 (3H), 1.23 (9H), 1.38-1.43 (1H), 1.58-1.66 (1H), 2.31-2.36 (1H), 2.59-2.70 (2H), 3.76 (1H), 3.97 (2H), 4.19 (1H), 7.10 (2H), 7.17 (1H), 7.27 (2H), 7.37 (2H), 7.41 (2H)。實例 41 ： 5- 聯苯 -4- 基 -(S)-4- 二苄基胺基 -(R)-2- 乙基 -1- 吡咯啶 -1- 基 - 戊 -1- 酮 在N2 氛圍下，在-70℃下，將LDA (1.0M含於THF中，2.8 mL)添加至5-聯苯-4-基-(S)-4-二苄基胺基-1-吡咯啶-1-基-戊-1-酮(1.0 g，2 mmol)含於20 mL無水THF中之溶液。1小時後，在-70℃下添加碘乙烷(0.45 g，3 mmol)，並使反應混合物緩慢升溫至室溫。在室溫下3小時後，用氯化鈉溶液稀釋混合物，以乙酸乙酯萃取並濃縮至乾燥，獲得5-聯苯-4-基-(S)-4-二苄基胺基-(R)-2-乙基-1-吡咯啶-1-基-戊-1-酮。根據HPLC分析，非對映異構體(2R,4S):(2S, 4S)之比率為79:21。1 H NMR (CDCl3 )：0.77 (3H, m), 1.40-2.00 ( 8H, m), 2.39 (1H, m), 2.61 (1H, m), 3.04 (2H, m), 3.35 (4H, m), 3.7-3.9 (4H, m), 7.10~7.4 (19H, m, 芳族)。 HPLC方法：管柱：Waters Xbridge-Phenyl；150×3.0 mm；3.5 µm。流動相A (0.1 % DEA)含於水中；流動相B (乙腈)。梯度：0 min (60 % B)；30 min (95% B)。流速：0.5 ml min-1。波長：210 nm。溫度：35℃。滯留時間：(2R, 4S)：12.6 min；(2S, 4S)：12.2 min。實例 42 ： 5- 聯苯 -4- 基 -(S)-4- 二苄基胺基 -(R)-2- 異丙基 -1- 吡咯啶 -1- 基 - 戊 -1- 酮 在N2 氛圍下，在-70℃下，將LDA (1.0M含於THF中，2.8 mL)添加至5-聯苯-4-基-(S)-4-二苄基胺基-1-吡咯啶-1-基-戊-1-酮(1.0 g，2 mmol)含於20 mL無水THF中之溶液，在-70℃下攪拌再混合物1小時，然後添加2-碘丙烷(0.51 g，3 mmol)，並使反應混合物緩慢升溫至室溫並攪拌3小時。添加飽和氯化銨溶液，以乙酸乙酯萃取混合物並濃縮合併的有機萃取物，得到 5-聯苯-4-基-(S)-4-二苄基胺基-(R)-2-異丙基-1-吡咯啶-1-基-戊-1-酮。根據HPLC分析，非對映異構體(2R,4S):(2S,4S)之比率為72:28。1 H NMR (CDCl3 )：0.68(3H, d, CH3 ), 0.74(3H, d, CH3 ), 1.62 ( 2H, m, 3-CH2 ), 1.68 (2H, m, CH2 ), 1.78 (2H, m, CH2 ), 2.29(1H, m, CH), 2.44 (1H, m, 2- CH2 ), 2.81 (2H, m, 5-CH2 ), 3.16 (1H, dd, 4-CH), 3.26(2H, m, CH2 ), 3.47(2H, m, CH2 ), 3.57 (2H, d, CH2 ), 3.77 (2H, d, CH2 ), 7.10~7.40 (19H, m, 芳族)。 HPLC方法：管柱：Waters Xbridge-Phenyl；150×3.0 mm；3.5 µm。流動相A (0.1 % DEA)含於水中；流動相B (乙腈)。梯度：0 min (60 % B)；30 min (95 % B)。流速：0.5 ml min-1 。波長：210 nm。溫度：35℃。滯留時間：(2R,4S)：13.8 min；(2S,4S)：13.1 min。實例 43 ： 2-[(S)-4-((R)-4- 異丙基 -2- 側氧基 - 噁唑啶 -3- 基 )-1- 聯苯 -4- 基甲基 -3- 苯甲基 -4- 側氧基 - 丁基 ]- 異吲哚 -1,3- 二酮 向NaHMDS (6.5 mL，6.5 mmol)含於20 mL無水THF中之-78℃溶液添加含於無水THF中之2-[(S)-4-((R)-4-異丙基-2-側氧基-噁唑啶-3-基)-1-聯苯-4-基甲基-4-側氧基-丁基]-異吲哚-1,3-二酮(2.74 g，5.38 mmol)。攪拌反應混合物1小時，然後將苄基溴(3.82 g，22.30 mmol)添加至該反應混合物。12小時後，使該反應混合物升溫至室溫，添加飽和NH4 Cl (25 ml)，用TBME萃取該混合物。用鹽水清洗合併的有機萃取物，乾燥並濃縮，得到 2-[(1S,3R)-3-苄基-1-(聯苯-4-基甲基)4-((4R)-4-異丙基-2-側氧基-1,3-噁唑啶-3-基)-1H- -異吲哚-1,3(2H)-二酮。根據HPLC分析，非對映異構體(2R,4S):(2S, 4S)之比率為＞99:1。1H NMR (CDCl3 )：0.5-1.0 (6H, d), 2.11(1H, m), 2.31 (1H, m), 2.61(1H, m), 2.80 (3H, m), 2.91 (1H, m), 3.11 (1H, m), 3.43 (1H, m), 4.0-4.5 (5H, m), 7.05 ~7.70 (18H, m, 芳族)。MS (ESI, m/e) 400 (MH+)。 HPLC方法：管柱：Waters Xbridge-Phenyl; 150 × 3.0 mm；3.5 μm。流動相A (0.1 % DEA)含於水中；流動相B (乙腈)。梯度：0 min (60 % B)；25 min (60 % B)；30 min (95 % B)。流速：0.5 ml min-1 。波長：210 nm。溫度：35℃。滯留時間：(2R, 4S)：16.7 min；(2S, 4S)：16.0 min。實例 44 ： (2R,4S)-4- 胺基 -5- 聯苯 -4- 基 -2- 甲基 - 戊酸鹽酸鹽 向2-[(1S,3R)-4-((R)-4-苄基-2-側氧基-噁唑啶-3-基)-1-聯苯-4-基甲基-3-甲基-4-側氧基-丁基]-異吲哚-1,3-二酮(100 mg，0.175 mmol)含於10 mL THF中之溶液添加2.5 mL 0℃之水，然後添加LiOH·H2 O (15 mg，0.350 mmol)。攪拌12小時後，添加2 mL濃HCl，然後使混合物回流2小時，然後再冷卻至室溫。過濾所得沉澱，在高真空下乾燥，得到(2R,4S)-4-胺基-5-聯苯-4-基-2-甲基-戊酸鹽酸鹽(43 mg)。m/z：283 (MH+ )。光譜儀資料係如WO2008/083967中之實例7所述。實例 45 ： 5- 聯苯 -4- 基 -(S)-4- 二苄基胺基 -(R)-2- 甲基 - 戊酸 將5-聯苯-4-基-(S)-4-二苄基胺基-1-((R)-2-羥基甲基-吡咯啶-1-基)-2-甲基-戊-1-酮(0.5 g，0.9 mmol)含於10 mL 6N HCl中之混合物加熱至回流持續6小時。然後移除水，將所得殘餘物溶解於20 mL乙酸乙酯中，以NaHCO3 、水清洗。濃縮有機相，得到5-聯苯-4-基-(S)-4-二苄基胺基-(R)-2-甲基-戊酸。1 H NMR (CDCl3 )：0.88 (3H, d, CH3 ), 1.65 (1H, m, 3-CH H), 1.82 (1H, m, 3-CHH ), 2.55 (1H, m, 2-CH), 2.65 (1H, m, 4-CH), 3.14 (2H, m, 5-CH2 ), 3.59 (2H, d, CH2 ), 3.85 (2H, m, CH2 ), 7.10~7.50 (19H, m, 芳族)。 HPLC方法：管柱：Eclipse XDB-C18；150×4.6 mm；5 μm。流動相A (0.1 % H3 PO4 )含於水中；流動相B (乙腈)。梯度：0 min (90 % B)；10 min (95 % B)；15 min (95 % B)。流速：0.7 ml min-1 。波長：210 nm。溫度：30℃。滯留時間：11.2 min。實例 46 ： 5- 聯苯 -4- 基 -(S)-4- 二苄基胺基 -(R)-2- 甲基 - 戊酸 將 5-聯苯-4-基-(S)-4-二苄基胺基-(R)-2-甲基-戊酸-(S)-甲基-(1-苯基-乙基)-醯胺 (0.5 g，0.9 mmol)含於10 mL 6N HCl中之混合物加熱至回流持續6小時。然後移除水，將所得殘餘物溶解於20 mL乙酸乙酯中，以NaHCO3 、水清洗。濃縮有機相，得到5-聯苯-4-基-(S)-4-二苄基胺基-(R)-2-甲基-戊酸。1 H NMR (CDCl3 )：0.88 (3H, d, CH3 ), 1.65 (1H, m, 3-CH H), 1.82 (1H, m, 3-CHH ), 2.55 (1H, m, 2-CH), 2.65 (1H, m, 4-CH), 3.14 (2H, m, 5-CH2 ), 3.59 (2H, d, CH2 ), 3.85 (2H, m, CH2 ), 7.10~7.50 (19H, m, 芳族)。 HPLC方法：管柱：Eclipse XDB-C18；150×4.6 mm；5 μm。流動相A (0.1 % H3 PO4 )含於水中；流動相B (乙腈)。梯度：0 min (90 % B)；10 min (95 % B)；15 min (95 % B)。流速：0.7 ml min-1 。波長：210 nm。溫度：30℃。滯留時間：11.2 min。實例 47 ： 5- 聯苯 -4- 基 -(S)-4- 二苄基胺基 -(R)-2- 甲基 - 戊酸 將5-聯苯-4-基-(S)-4-二苄基胺基-(R)-2-甲基-戊酸-(R)-甲基-(1-苯基-乙基)-醯胺 (0.5 g，0.9 mmol)含於10 mL 6N HCl中之混合物加熱至回流持續6小時。然後移除水，將所得殘餘物溶解於20 mL乙酸乙酯中，以NaHCO3 、水清洗。濃縮有機相，得到0.3 g 5-聯苯-4-基-(S)-4-二苄基胺基-(R)-2-甲基-戊酸。1 H NMR (CDCl3 )：0.88 (3H, d, CH3 ), 1.65 (1H, m, 3-CH H), 1.82 (1H, m, 3-CHH ), 2.55 (1H, m, 2-CH), 2.65 (1H, m, 4-CH), 3.14 (2H, m, 5-CH2 ), 3.59 (2H, d, CH2 ), 3.85 (2H, m, CH2 ), 7.10~7.50 (19H, m, 芳族)。 HPLC方法：管柱：Eclipse XDB-C18；150×4.6 mm；5 μm。流動相A (0.1 % H3 PO4 )含於水中；流動相B (乙腈)。梯度：0 min (90 % B)；10 min (95 % B)；15 min (95 % B)。流速：0.7 ml min-1 。波長：210 nm。溫度：30℃。滯留時間：11.2 min。實例 48 ： 5- 聯苯 -4- 基 -(S)-4- 二苄基胺基 -(R)-2- 甲基 - 戊酸 向四氫呋喃(2 ml)及水(5 ml)之混合物添加5-聯苯-4-基-(S)-4-二苄基胺基-(R)-2-甲基戊酸-S-對甲苯酯(200 mg，0.35 mmol)。然後，將氫氧化鋰(20 mg)添加至該混合物。然後，在室溫下攪拌所得混合物12小時。添加1M鹽酸溶液至該混合物，變成酸性。然後自該混合物移除四氫呋喃溶劑。然後添加乙酸乙酯(5 ml)，且兩相分離。合併有機相並乾燥，得到5-聯苯-4-基-(S)-4-二苄基胺基-(R)-2-甲基-戊酸。1 H NMR (CDCl3 )：0.88 (3H, d, CH3 ), 1.65 (1H, m, 3-CH H), 1.82 (1H, m, 3-CHH ), 2.55 (1H, m, 2-CH), 2.65 (1H, m, 4-CH), 3.14 (2H, m, 5-CH2 ), 3.59 (2H, d, CH2 ), 3.85 (2H, m, CH2 ), 7.10~7.50 (19H, m, 芳族)。 HPLC方法：管柱：Eclipse XDB-C18；150×4.6 mm；5 μm。流動相A (0.1 % H3 PO4 )含於水中；流動相B (乙腈)。梯度：0 min (90 % B)；10 min (95 % B)；15 min (95 % B)。流速：0.7 ml min-1 。波長：210 nm。溫度：30℃。滯留時間：11.2 min。實例 49 ： 5- 聯苯基 -(S)-4- 胺基 -4- 基 -(R)-2- 甲基戊酸鹽酸鹽 在H2 氛圍下，將0.3 g 5-聯苯-4-基-(S)-4-二苄基胺基-(R)-2-甲基-戊酸、0.1 g碳載鈀含於10 mL AcOH中之混合物加熱至50℃並攪拌12小時。過濾反應混合物，並濃縮。向所得殘餘物添加3M HCl含於乙酸乙酯中，過濾沉澱並乾燥，得到5-聯苯基-(S)-4-胺基-4-基-(R)-2-甲基戊酸鹽酸鹽。光譜儀資料係如WO2008/083967中之實例7所述。實例 50 ： (2R,4S)-4- 胺基 -5- 聯苯 -4- 基 -2- 甲基 - 戊酸鹽酸鹽 向2-[(S)-4-((R)-4-異丙基-2-側氧基-噁唑啶-3-基)-1-聯苯-4-基甲基-3-甲基-4-側氧基-丁基]-異吲哚-1,3-二酮(102 mg，0.2 mmol)含於10 mL THF中之溶液添加2.5 mL 0℃之水，接著添加LiOH·H2 O (15 mg，0.350 mmol)。12小時後，添加2 mL濃HCl，然後使混合物回流2小時。允許反應混合物冷卻至室溫，過濾並乾燥，得到(2R, 4S)-4-胺基-5-聯苯-4-基-2-甲基-戊酸鹽酸鹽。光譜儀資料係如WO2008/083967中之實例7所述。實例 51 ： (2R,4S)-4- 胺基 -5- 聯苯 -4- 基 -2- 甲基 - 戊酸乙酯 在室溫下，攪拌(2R,4S)-4-胺基-5-聯苯-4-基-2-甲基-戊酸鹽酸鹽 (100 mg，0.32 mmol)含於10 mL 3~4M HCl / EtOH中之懸浮液12小時。在真空下濃縮反應混合物，得到(2R,4S)-4-胺基-5-聯苯-4-基-2-甲基-戊酸乙酯。光譜儀資料係如WO2008/083967中之實例9-1所述。實例 52 ： 5- 聯苯 -4- 基 -(S)-4- 二苄基胺基 -(R)-2- 甲基 - 戊酸 ((R)-2- 羥基 -(R)-1- 甲基 -2- 苯基 - 乙基 )- 甲基 - 醯胺 在N2 氛圍下，將LiCl (500 mg，0.84 mmol)懸浮於THF (3 mL)中並冷卻至-70℃，然後將二異丙胺(0.53 mL，3.8 mmol)添加至該懸浮液，接著滴加n-BuLi (2.2 mL，1.6M含於己烷中，3.50 mmol)。30分鐘後，在-70℃下，將5-聯苯-4-基-(S)-4-二苄基胺基-戊酸 ((R)-2-羥基-(R)-1-甲基-2-苯基-乙基)-甲基-醯胺 (0.99 g，1.67 mmol)含於THF (4 mL)中之溶液添加至5-聯苯-4-基-(S)-4-二苄基胺基-1-((S)-2-羥基甲基-吡咯啶-1-基)-戊-1-酮(0.53 g，1 mmol)含於無水THF (4 mL)中之溶液。1小時後，添加MeI (470 mg，3.34 mmol)，且攪拌該反應混合物30分鐘。然後添加NH4 Cl (3 mL，飽和水溶液)。使所得混合物緩慢升溫至室溫，以TBME (10 mL)萃取水層。乾燥有機層，並濃縮，得到5-聯苯-4-基-(S)-4-二苄基胺基-(R)-2-甲基-戊酸 ((R)-2-羥基-(R)-1-甲基-2-苯基-乙基)-甲基-醯胺。藉由HPLC分析之非對映異構體之比率：(2R,4S):(2S,4S) = 99:1。1 H NMR (DMSO-D6 )：0.83-.89 (3H, m), 1.23-1.29 (3 H, m), 1.43-1.65 (2 H, m), 2.62-3.07 (8 H, m), 3.47-3.69 (4 H, m), 4.38-4.58 (1 H, m), 5.39-5.42 (1 H, m) , 7.08~7.67 (24 H, m)。 HPLC方法：管柱：Waters Xbridge-Phenyl；150 × 3.0 mm；3.5 μm。流動相A (0.1 % DEA)含於水中；流動相B (乙腈)。梯度：0 min (60 % B)；20 min (95 % B)；25 min (95 % B)；35 min (95 % B)。流速：0.5 ml min-1。波長：254 nm。溫度：35℃。滯留時間：(2R, 4S)：16.7 min；(2S, 4S)：17.2 min。In the following, specific embodiments of the invention are presented.Preparation (3-I) Compound: a compound of the formula (3-I) or a salt thereof,(3-I); it preferably has a configuration according to formula (3-I-a),(3-Ia); wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from the group consisting of hydroxyl groups, C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R5' is hydrogen or otherwise C1 -C7 -alkyl, C6 -C10 -aryl or C6 -C10 -aryl-C1 -C7 An alkyl group (which is a compound of the formula 3-I* in which R5* is present instead of R5'), which is prepared by making a compound of the formula (2) or a tautomer or salt thereof,(2); preferably having a configuration according to formula (2-a),(2-a); wherein R1 is a hydrogen or nitrogen protecting group and is reacted with a ring-opening agent. Examples of the ring-opening agent are selected from the group consisting of - metal hydroxides such as alkali metal or alkaline earth metal hydroxides (for example, lithium hydroxide, sodium hydroxide); - hydroperoxides such as alkali metal hydroperoxides (for example) , lithium hydroperoxide); - a metal alkoxide of the formula MOR5, wherein M is an alkali metal or an alkaline earth metal, and R5 is C1 -C7 -alkyl, C6 -C10 -aryl or C6 -C10 -aryl-C1 -C7 - an alkyl group (for example, lithium ethoxide, sodium methoxide, sodium ethoxide); - a mineral acid such as sulfuric acid, hydrobromic acid, perchloric acid and hydrochloric acid in the presence of a nucleophile or a nucleophilic solvent such as water; Sulfonic acid, such as p-toluenesulfonic acid, in the presence of a nucleophile or nucleophilic solvent (eg, water); and - a polymeric bond acid, such as Amberlyst® In the presence of a nucleophile or a nucleophilic solvent such as water. In one embodiment, the ring opening agent is selected from the group consisting of sodium ethoxide or lithium hydroxide. Preferably, a metal hydroxide or metal alkoxide is used in the presence of water, an alcohol such as methanol or ethanol or THF. In another embodiment, the ring opening agent is hydrochloric acid. Preferably, the acid is used in the presence of water or an alcohol such as methanol or ethanol. The ring-opening agent can be used in a catalytic amount or in a stoichiometric amount. Preferably, the indoleamine ring-opening agent is used in an amount of from 1 to 10 equivalents. Preferably, it is less than 1 equivalent, more preferably 0.1 equivalent or less than 0.1 equivalent. Alternatively, the compound of formula (3-I) is prepared as described in WO 2008/083967, preferably having a configuration according to formula (3-I-a).Festival A. Preparation of sulfhydryl halide intermediates: In one embodiment, the invention relates to a process for the preparation of a compound of formula (4) or a salt thereof,(4) wherein R1 and R2 are independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, which may be Saturated or unsaturated and optionally containing one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from hydroxy, C1 -C7 -alkyl, C1 -C7 Substituting a substituent of an alkoxy group, a halogen group, a carboxyl group and a pendant oxy group, and X is a halogen group such as chlorine, the method comprising reacting a compound of the formula (3-I) or a salt thereof with a mercapto halogen generating reagent to provide a compound of formula (4),(3-I) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably 4 to 7-membered monocyclic or bicyclic ring, the ring It may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and it may be unsubstituted or one, two or three independently selected from hydroxyl groups, C.1 -C7 -alkyl, C1 -C7 Substituents of alkoxy, halo, carboxy and pendant oxy groups are substituted, and R5' is hydrogen. In a preferred embodiment, the invention relates to a process for the preparation of a compound of formula (4-a) or a salt thereof,(4-a) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably 4 to 7-membered monocyclic or bicyclic ring, the ring It may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and it may be unsubstituted or one, two or three independently selected from hydroxyl groups, C.1 -C7 -alkyl, C1 -C7 Substituting a substituent of an alkoxy group, a halogen group, a carboxyl group and a pendant oxy group, and X is a halogen group such as chlorine, the method comprising reacting a compound of the formula (3-Ia) or a salt thereof with a mercapto halogen generating reagent to provide a compound of formula (4-a),(3-Ia) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably 4 to 7-membered monocyclic or bicyclic ring, the ring It may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and it may be unsubstituted or one, two or three independently selected from hydroxyl groups, C.1 -C7 -alkyl, C1 -C7 Substituents of alkoxy, halo, carboxy and pendant oxy groups are substituted, and R5' is hydrogen. Suitable mercapto halide generating reagents are, for example, vinyl halides, C1 -C7 - alkyl halides and phosphine halides. Suitable mercapto halide generating reagents are, for example, selected from the group consisting of sulfinium chloride, sulfinium bromide, PCl3 , PCl5 , grass, chlorine, Me2 C=C(Cl)NMe2 CCl4 Ph3 P, PhCOCl, PBr3 PBr5 , Ph3 PBr2 Grasshopper bromine or Me2 C=C(Br)NMe2 . The reaction conditions for the formation of mercapto halides are well known in the art and are, for example, by Allen, C., Barker W.Organic Syntheses , Coll. Vol. 2, 1943, p. 156 (product of Reaction 1); by Adams, R., Jenkins, R.Organic Syntheses , Coll. Vol. 1, 1941, p. 394 (product of Reaction 1); by Newcomb, M., Burchill, M., Deeb, T.J. Am. Chem.Soc. 1988 ,110 , 6528–6535 (Intermediate of Reaction 1, on page 6529); by Devos, A., Remion, J., Frisque-Hesbain, A., Colens, A., Ghosez, L.Chem.Commun. 1979 , 1180 (compound 2); by Lee, J.J. Am. Chem.Soc. 1966 ,88 , 3440–3441 (product of Reaction 1 on page 3340); by Brown, H.J. Am. Chem.Soc. 1938 ,60 , 1325–1328 (Tables I and II, at page 1326); by Adams, R., Ulich, L.J. Am. Chem.Soc. 1920 , 599–611 (product of Reaction 3, on page 601, product of Reaction 1 on page 602); by Jesus Mari, A., Palomo, C.Synthesis 1982 , 684-687 (Compound 2, on page 684, compounds 10 and 11, in Table 1, on page 685).Festival B. Preparation of starting materials for the alkylation step: Festival B.1. Preparation (3-II-A) Indole intermediate: In another embodiment, the present invention relates to a process for the preparation of a compound of formula (3-II-A) or a salt thereof,(3-II-A) wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from a hydroxyl group. , C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R5" and R6" are independently of each other C1 -C7 -alkyl, C6 -C10 -aryl, C6 -C10 -aryl-C1 -C7 -alkyl, C3 -C7 a cycloalkyl group, or R5" and R6", together with the nitrogen to which they are attached, form a 3 to 10 member, preferably a 4 to 7 membered monocyclic or bicyclic ring which may be saturated or unsaturated and optionally contain one, Two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from hydroxy, C1 -C7 -alkyl, C1 -C7 Substituting a substituent of an alkoxy group, a halogen group, a carboxyl group and a pendant oxy group, preferably R5" and R6" together with the nitrogen to which they are attached form a palmitic moiety, the method comprising making a compound of the formula (4) or a salt thereof ,(4) wherein R1 and R2 are independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, which may be Saturated or unsaturated and optionally containing one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from hydroxy, C1 -C7 -alkyl, C1 -C7 a substituent substituted with an alkoxy group, a halogen group, a carboxyl group and a pendant oxy group, and X is a halogen group such as chlorine, and an amine of the formula HNR5"R6", wherein R5" and R6" are as defined for the formula (3-II) The -A) compound is defined and optionally reacted in the presence of an amine coupling reagent to provide a compound of formula (3-II-A). In a preferred embodiment, the present invention relates to a process for the preparation of a compound of the formula (3-II-A-a) or a salt thereof,(3-II-Aa) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from a hydroxyl group. , C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R5" and R6" are independently of each other C1 -C7 -alkyl, C6 -C10 -aryl, C6 -C10 -aryl-C1 -C7 -alkyl, C3 -C7 a cycloalkyl group, or R5" and R6", together with the nitrogen to which they are attached, form a 3 to 10 member, preferably a 4 to 7 membered monocyclic or bicyclic ring which may be saturated or unsaturated and optionally contain one, Two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from hydroxy, C1 -C7 -alkyl, C1 -C7 Substituting alkoxy, halo, carboxy and pendant oxy substituents, preferably R5" and R6" together with the nitrogen to which they are attached form a palmitic moiety, the process comprising formulating a compound of formula (4-a) or Its salt,(4-a) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably 4 to 7-membered monocyclic or bicyclic ring, the ring It may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and it may be unsubstituted or one, two or three independently selected from hydroxyl groups, C.1 -C7 -alkyl, C1 -C7 a substituent substituted with an alkoxy group, a halogen group, a carboxyl group and a pendant oxy group, and X is a halogen group such as chlorine, and an amine of the formula HNR5"R6", wherein R5" and R6" are as defined for the formula (3-II) The -A) compound is defined and optionally reacted in the presence of an amine coupling reagent to provide a compound of formula (3-II-Aa). Coupling reagents are typically used to prepare guanamines, esters, and anhydrides from carboxylic acids. Typical examples of suitable amine coupling reagents are available from Valeur, E., Bradley, M.Chem.Soc.Rev. 2009 ,38 Found in 606-631. Preferred examples of suitable coupling reagents are selected from DCC (N ,N '-Dicyclohexylcarbodiimide), EDC (N -(3-dimethylaminopropyl)-N -ethylcarbodiimide), CDI (1,1'-carbonyldiimidazole), HATU (hexafluorophosphoric acid)N ,N ,N ',N '-Tetraammonium), HOBt (6-chloro-1-hydroxybenzotriazole) and mixtures thereof.Festival B.2. Preparation (3-II-A) Indole intermediate: In another embodiment, the present invention relates to a process for the preparation of a compound of formula (3-II-A) or a salt thereof,(3-II-A) wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from a hydroxyl group. , C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R5" and R6" are independently of each other C1 -C7 -alkyl, C6 -C10 -aryl, C6 -C10 -aryl-C1 -C7 -alkyl, C3 -C7 a cycloalkyl group, or R5" and R6", together with the nitrogen to which they are attached, form a 3 to 10 member, preferably a 4 to 7 membered monocyclic or bicyclic ring which may be saturated or unsaturated and optionally contain one, Two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from hydroxy, C1 -C7 -alkyl, C1 -C7 Substituting a substituent of an alkoxy group, a halogen group, a carboxyl group and a pendant oxy group, preferably R5" and R6" together with the nitrogen to which they are attached form a palmitic moiety, the method comprising: or a compound of formula (3-I) or Its salt,(3-I) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably 4 to 7-membered monocyclic or bicyclic ring, the ring It may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and it may be unsubstituted or one, two or three independently selected from hydroxyl groups, C.1 -C7 -alkyl, C1 -C7 a substituent substituted with an alkoxy group, a halogen group, a carboxyl group and a pendant oxy group, and R5' is an amine of the formula HNR5"R6", wherein R5" and R6" are as for a compound of the formula (3-II-A) As defined, the reaction is carried out in the presence of an amine coupling reagent to provide a compound of formula (3-II-A). In a preferred embodiment, the present invention relates to a process for the preparation of a compound of the formula (3-II-A-a) or a salt thereof,(3-II-Aa) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from a hydroxyl group. , C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R5" and R6" are independently of each other C1 -C7 -alkyl, C6 -C10 -aryl, C6 -C10 -aryl-C1 -C7 -alkyl, C3 -C7 a cycloalkyl group, or R5" and R6", together with the nitrogen to which they are attached, form a 3 to 10 member, preferably a 4 to 7 membered monocyclic or bicyclic ring which may be saturated or unsaturated and optionally contain one, Two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from hydroxy, C1 -C7 -alkyl, C1 -C7 Substituting a substituent of an alkoxy group, a halogen group, a carboxyl group and a pendant oxy group, preferably R5" and R6" together with the nitrogen to which they are attached form a palmitic moiety, the method comprising reacting a compound of the formula (3-Ia) or Its salt,(3-Ia) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably 4 to 7-membered monocyclic or bicyclic ring, the ring It may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and it may be unsubstituted or one, two or three independently selected from hydroxyl groups, C.1 -C7 -alkyl, C1 -C7 a substituent substituted with an alkoxy group, a halogen group, a carboxyl group and a pendant oxy group, and R5' is an amine of the formula HNR5"R6", wherein R5" and R6" are as for a compound of the formula (3-II-A) As defined, the reaction is carried out in the presence of an amine coupling reagent to provide a compound of formula (3-II-Aa). Typical examples of suitable amine coupling reagents are available from Valeur, E., Bradley, M.Chem.Soc.Rev .2009 ,38 Found in 606-631. Preferred examples of suitable coupling reagents are selected from DCC (N ,N '-Dicyclohexylcarbodiimide), EDC (N -(3-dimethylaminopropyl)-N -ethylcarbodiimide), CDI (1,1'-carbonyldiimidazole), HATU (hexafluorophosphoric acid)N ,N ,N ',N '-Tetraammonium), HOBt (6-chloro-1-hydroxybenzotriazole) and mixtures thereof.Festival B.3. Preparation (3-II-A) Indole intermediate: In another embodiment, the present invention relates to a process for the preparation of a compound of formula (3-II-A) or a salt thereof,(3-II-A) wherein R1 and R2 are independently hydrogen or a nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring. The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or selected from one, two or three independently. Hydroxy, C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R5" and R6" are independently of each other C1 -C7 -alkyl, C6 -C10 -aryl, C6 -C10 -aryl-C1 -C7 -alkyl, C3 -C7 a cycloalkyl group, or R5" and R6", together with the nitrogen to which they are attached, form a 3 to 10 member, preferably a 4 to 7 membered monocyclic or bicyclic ring which may be saturated or unsaturated and optionally contain one, Two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from hydroxy, C1 -C7 -alkyl, C1 -C7 Substituting a substituent of an alkoxy group, a halogen group, a carboxyl group and a pendant oxy group, preferably R5" and R6" together with the nitrogen to which they are attached form a palmitic moiety, the method comprising reacting a compound of formula (2) or Isomer or salt,(2); an amine of the formula HNR5"R6", wherein R5" and R6" are as defined for the compound of formula (3-II-A), and wherein R1 is a hydrogen or nitrogen protecting group, in the presence of an ionic salt The reaction is carried out to provide a compound of the formula (3-II-A). In a preferred embodiment, the present invention relates to a process for the preparation of a compound of the formula (3-II-A-a) or a salt thereof,(3-II-Aa) wherein R1 and R2 are independently hydrogen or a nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring. The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or selected from one, two or three independently. Hydroxy, C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R5" and R6" are independently of each other C1 -C7 -alkyl, C6 -C10 -aryl, C6 -C10 -aryl-C1 -C7 -alkyl, C3 -C7 a cycloalkyl group, or R5" and R6", together with the nitrogen to which they are attached, form a 3 to 10 member, preferably a 4 to 7 membered monocyclic or bicyclic ring which may be saturated or unsaturated and optionally contain one, Two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from hydroxy, C1 -C7 -alkyl, C1 -C7 Substituting alkoxy, halo, carboxy and pendant oxy substituents, preferably R5" and R6" together with the nitrogen to which they are attached form a palmitic moiety, the process comprising bringing a compound of formula (2-a) ( It is also a compound of formula 2) or a tautomer or salt thereof,(2-a); an amine of the formula HNR5"R6", wherein R5" and R6" are as defined for a compound of formula (3-II-A), reacted in the presence of an ionic salt to provide a formula (3- II-Aa) compound. Preferred examples of the ionic salt are alkali metal alkoxides such as sodium methoxide or sodium ethoxide, or alkali metal hexafluorophosphates such as lithium hexafluorophosphate. Preferably, the reaction is carried out in a polar, aprotic organic solvent, preferably THF, at a temperature in the range of from 0 to 40 ° C, preferably from 10 to 30 ° C, more preferably from 15 to 25 ° C. Preferably, the reaction is carried out in an organic solvent at room temperature, for example, the reaction is carried out in tetrahydrofuran at room temperature. In one embodiment, the ionic salt (which is a metal alkoxide) is used in a catalytic amount, preferably 0.1 equivalents of sodium methoxide. In one embodiment, the amine of formula HNR5"R6" is, for example, pyrrolidine, morpholine or dimethylamine. Where reference is made to the palm portion, it is based on the palmier molecules described anywhere in this specification. In a preferred embodiment of the invention, the amine of formula HNR5"R6" is a palmitic amine, for example having the formula:Wherein Ra', Ra, Rb, Rb', Rc, Rc' and X are as described, for example, in the following: Evans, D. A.Aldrichimica Acta 1982 ,15 , 23-32, specifically as described below: wherein Figure VI of Figure 25 is incorporated herein by reference; or Kawanami, Y., Ito, Y., Kitagawa, T., Taniguchi, Y., Katsuki, T., Yamaguchi, M.Tetrahedron Lett. 1984 ,25 , 857-860, specifically as described below: Table 1 on page 858, which is incorporated herein by reference; or Askin, D., Wallace, M., Vacca, J., Reamer , R., Volante, R., Shinkai, I.J. Org.Chem .1992 ,57 , 2771-2773, specifically as described below: Example 1 on page 2771, which is incorporated herein by reference. Specifically, (S)-prolinol or (R)-guanamine can be used as the palmitic amine. In another preferred embodiment, the pair of palmitic amines have the formula:Wherein R, R' and R" are as described, for example, in the following: Blaser, H.-U.Chem.Rev .1992 ,92 , 935-952, specifically as described below: wherein Table 4 on page 937 is incorporated herein by reference; Myers, AG, Yang, BH, Chen, H., McKinstry, L., Kopecky, DJ, Gleason, JLJ. Am. Chem.Soc. 1997 ,119 6,496-6511, specifically as described below: wherein Table 2, page 6498, is incorporated herein by reference; Jullian, V., Quirion, J., Husson, H.Synthesis 1997 1091-1097, specifically as described below: wherein Examples 1a-b on page 109 are incorporated herein by reference. For example, R is Me, R' is Me and R" is Ph or C(OH)Ph; or R is a methyl group, R' is a phenyl group and R" is CH2 OH. In one embodiment, the pair of palmitic amines have the formula:Wherein Rb, Rb', Rc and Rc' are as described, for example, in the following: Evans, D. A.Aldrichimica Acta 1982 ,15 23-32, specifically as described below: wherein page 27 is a reaction diagram X and XI, which is incorporated herein by reference; Davies, S., Sanganee, H.Tetrahedron Asymmetry 1995 ,6 , 671-674, specifically as described below: wherein Examples 3a-d on page 672 are incorporated herein by reference. For example, Rb is CH2 Ph,i Pr or Me and Rb' = Rc' = hydrogen and Rc is hydrogen or Ph; or Rb is methyl, phenyl or CH2 Ph,i Pr, Rb' is hydrogen, Rc = Rc' = methyl; or Rb is CH2 Ph,i Pr or Me and Rb' = Rc' = Rc = hydrogen. Preferably, Rb is CH2 Ph,i Pr or Me and Rb' = Rc' = Rc = hydrogen. Particularly suitable are (R)-4-benzyl-oxazolidine-2-one or (R)-4-isopropyl-oxazolidine-2-one. Particularly preferred is the insertion of a palmitic amine of the formula NR5"R6".In one embodiment, the pair of palmitic amines have the formula:Wherein Ra*, Ra'*, Rb*, Rb'* are as described below, for example: Oppolzer, W., Poli, G., Kingma, A., Starkemann, C., Bernardinelli, G.Helv.Chim.Acta 1987 ,70 2201-2214, specifically as described below: wherein Example 8, page 2204, is incorporated herein by reference. Additional examples are as follows: Lee, A.W.M., Chan, W.H., Zhang, S-J., Zhang, H-K.,Cur.Org.Chem 2007 , 11, 213-228 and references cited therein. Alternatively, a particularly preferred one is inserted into the palmitic amine of the formula NR5"R6".In one embodiment, the palmitic amine is (S)-methyl-(1-phenylethyl)amine, (R)-methyl-(1-phenylethyl)amine or (1R, 2R ) - pseudoephedrine. In a preferred embodiment, the pair of palmitic amines are (1)R ,2R ) - pseudoephedrine.Festival B.4. Preparation (3-III-A) Ester intermediate: In another embodiment, the present invention relates to a process for the preparation of a compound of formula (3-III-A) or a salt thereof,(3-III-A) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from a hydroxyl group. , C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and Rx is C1 -C7 -alkyl, C6 -C10 -aryl, C6 -C10 -aryl-C1 -C7 An alkyl group, or (preferably) Rx, together with the oxygen to which it is attached, forms a palmitic moiety, the method comprising reacting a compound of formula (4) or a salt thereof,(4) wherein R1 and R2 are independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, which may be Saturated or unsaturated and optionally containing one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from hydroxy, C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and X is halo, such as chloro, and an alcohol of the formula HORx, wherein Rx is as defined for the compound of formula (3-III-A), The reaction is optionally carried out in the presence of a coupling reagent to provide a compound of formula (3-III-A). In a preferred embodiment, the present invention relates to a process for the preparation of a compound of the formula (3-III-A-a) or a salt thereof,(3-III-Aa) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from a hydroxyl group. , C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and Rx is C1 -C7 -alkyl, C6 -C10 -aryl, C6 -C10 -aryl-C1 -C7 An alkyl group, or (preferably) Rx, together with the oxygen to which it is attached, forms a palmitic moiety, the method comprising reacting a compound of formula (4-a) or a salt thereof,(4-a) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably 4 to 7-membered monocyclic or bicyclic ring, the ring It may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and it may be unsubstituted or one, two or three independently selected from hydroxyl groups, C.1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and X is halo, such as chloro, and an alcohol of the formula HORx, wherein Rx is as defined for the compound of formula (3-III-Aa), The reaction is optionally carried out in the presence of a coupling reagent to provide a compound of formula (3-III-Aa). Coupling reagents (see also definition above) are typically used to prepare guanamines, esters and anhydrides from carboxylic acids. Typical examples of suitable coupling reagents can be found in Valeur, E., Bradley, M.Chem.Soc.Rev. 2009 ,38 Found in 606-631. Preferred examples of suitable coupling reagents are selected from DCC (N ,N '-Dicyclohexylcarbodiimide), EDC (N -(3-dimethylaminopropyl)-N -ethylcarbodiimide), CDI (1,1'-carbonyldiimidazole), HATU (hexafluorophosphoric acid)N ,N ,N ',N '-Tetraammonium), HOBt (6-chloro-1-hydroxybenzotriazole) and mixtures thereof.Festival B.5. Preparation (3-III-A) Ester intermediate: In another embodiment, the present invention relates to a process for the preparation of a compound of formula (3-III-A) or a salt thereof,(3-III-A) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from a hydroxyl group. , C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and Rx is C1 -C7 -alkyl, C6 -C10 -aryl, C6 -C10 -aryl-C1 -C7 An alkyl group, or (preferably) Rx, together with the oxygen to which it is attached, forms a palmitic moiety, the method comprising reacting a compound of formula (3-I) or a salt thereof,(3-I) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably 4 to 7-membered monocyclic or bicyclic ring, the ring It may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and it may be unsubstituted or one, two or three independently selected from hydroxyl groups, C.1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R5' is hydrogen with an alcohol of the formula HORx or with a halide of the formula Rx-X, wherein Rx is as for formula (3-III-A) Compounds are defined, and wherein X is as defined in formula (4) above, such as bromine or chlorine, optionally reacted in the presence of a coupling reagent to provide a compound of formula (3-III-A). In a preferred embodiment, the present invention relates to a process for the preparation of a compound of the formula (3-III-A-a) or a salt thereof,(3-III-Aa) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from a hydroxyl group. , C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and Rx is C1 -C7 -alkyl, C6 -C10 -aryl, C6 -C10 -aryl-C1 -C7 An alkyl group, or Rx, together with the oxygen to which it is attached, forms a palmitic moiety, the method comprising reacting a compound of formula (3-I-a) or a salt thereof,(3-Ia) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably 4 to 7-membered monocyclic or bicyclic ring, the ring It may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and it may be unsubstituted or one, two or three independently selected from hydroxyl groups, C.1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R5' is hydrogen with an alcohol of the formula HORx or with a halide of the formula Rx-X, wherein Rx is as for the formula (3-III-A) Compounds are defined, and wherein X is as defined in formula (4) above, such as bromine or chlorine, optionally reacted in the presence of a coupling reagent to provide a compound of formula (3-III-A). Coupling reagents are typically used to prepare guanamines, esters, and anhydrides from carboxylic acids. Typical examples of suitable coupling reagents can be found in Valeur, E., Bradley, M.Chem.Soc.Rev .2009 ,38 Found in 606-631. Preferred examples of suitable coupling reagents are selected from DCC (N ,N '-Dicyclohexylcarbodiimide), EDC (N -(3-dimethylaminopropyl)-N -ethylcarbodiimide), CDI (1,1'-carbonyldiimidazole), HATU (hexafluorophosphoric acid)N ,N ,N ',N '-Tetraammonium), HOBt (6-chloro-1-hydroxybenzotriazole) and mixtures thereof. The formation of esters is a reaction well known in the art.Festival B.6. Preparation (3-III-A) Ester intermediate: In another embodiment, the present invention relates to a process for the preparation of a compound of formula (3-III-A) or a salt thereof,(3-III-A) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from a hydroxyl group. , C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and Rx is C1 -C7 -alkyl, C6 -C10 -aryl, C6 -C10 -aryl-C1 -C7 An alkyl group, or Rx, together with the oxygen to which it is attached, forms a palmitic moiety, the method comprising bringing a compound of formula (3'-III) or a salt thereof,(3'-III) wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from the group consisting of hydroxyl groups, C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R5" is C1 -C7 -alkyl, C6 -C10 -aryl or C6 -C10 -aryl-C1 -C7 An alkyl group, the condition R5" being an alcohol other than Rx and a formula HORx, wherein Rx is as defined for a compound of formula (3-III-A), optionally reacted in the presence of an acid or a base to provide formula (3- III-A) A compound. In a preferred embodiment, the invention relates to a process for the preparation of a compound of the formula (3-III-Aa) or a salt thereof,(3-III-Aa) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from a hydroxyl group. , C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and Rx is C1 -C7 -alkyl, C6 -C10 -aryl, C6 -C10 -aryl-C1 -C7 An alkyl group, or Rx, together with the oxygen to which it is attached, forms a palmitic moiety, the method comprising reacting a compound of formula (3'-III-a) or a salt thereof,(3'-III-a) wherein R1 and R2 are independently hydrogen or a nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered single or double ring The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or selected from one, two or three independently. Hydroxy, C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, R5" is C1 -C7 -alkyl, C6 -C10 -aryl or C6 -C10 -aryl-C1 -C7 An alkyl group, the condition R5" being an alcohol other than Rx and a formula HORx, wherein Rx is as defined for a compound of formula (3-III-A), optionally reacted in the presence of an acid or a base to provide formula (3- III-Aa) Compounds The transesterification reaction is well known in the art. Preferably, the transesterification reaction is carried out by heating the ester in an alcohol in the presence of a catalytic amount of an acid or a base. Typical conditions are for example by Riemenschneider, W.; Bolt, HMUllmann's Encyclopedia of Industrial Chemistry 2012 , described in 245-266. In one embodiment, the alcohol has the formula HORx wherein Rx is methyl, ethyl, p-methylphenyl or benzyl. In one embodiment, the Rx of the halide Rx-X is methyl, ethyl, p-methylphenyl or benzyl. Preferably, Rx-X is benzyl bromide. In a preferred embodiment of the invention, the alcohol of formula HORx is a palmitic alcohol, for example having the formula:Wherein R' and R" are as described, for example, in the following: Blaser, H.-U.Chem.Rev. 1992 ,92 , 935-952, specifically as described below: wherein Table 3 on page 937 is incorporated herein by reference; Oertling, H., Reckziegel, A., Surburg, H., Bertram, H. atChem.Rev. 2007 ,107 , 2136-2164, specifically as described below: Example 1a-e on page 2138, which is incorporated herein by reference; Hultin, P., Earle, M., Sudharshan, M. inTetrahedron 1997 ,53 , 14823-14870, specifically as described below: Examples 111 and 117 of pages 14843-14844, which are incorporated herein by reference; and Kunz, H., Ruck, K.Angew.Chem.Int. Ed.Engl. 1993 ,32 , 336-358, specifically as described below: wherein Example 17, page 339, is incorporated herein by reference. For example, R' is Me and R" is Ph (reference (a) Leemhuis, M.; Van Steenis, JH; Van Uxem, MJ; Van Nostrum, CF; Hennink, WE Eur. J. Org. Chem. 2003, 3344 -3349; (b) Neradovic; Van Steenbergen; Vansteelant; Meijer; Van Nostrum; Hennink Macromolecules 2003, 36, 7491-7498). Or, specifically, the alcohol of the formula HORx is L-menthol or D-menthol ( See (a) Zheng, S.-L.; Yu, W.-Y.; Che, C.-M. Org. Lett. 2002, 889-892; (b) Maegawa, Y.; Agura, K.; Hayashi, Y.; Ohshima, T.; Mashima, K. Synlett 2012, 137-141; (c) Iwasaki, T.; Maegawa, Y.; Hayashi, Y.; Ohshima, T.; Mashima, KJ org.Chem .2008, 5147-5150; (d) Meth-Cohn, OJ Chem. Soc. Chem. Comm. 1986, 695-697). In addition, specifically, the reaction is carried out in an organic solvent such as tetrahydrofuran at room temperature. Preferably, the palmitic moiety formed by Rx and the bonding oxygen is such that Rx thus corresponds to the enantiomeric menthyl or 2-phenylethyl moiety.Festival B.7. Preparation (3-IV) Thioester intermediates: In another embodiment, the present invention is directed to a process for the preparation of a compound of formula (3-IV) or a salt thereof,(3-IV), wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring. The ring may be saturated or unsaturated and optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from the group consisting of hydroxyl groups, C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R5 is C1 -C7 -alkyl, C6 -C10 -aryl or C6 -C10 -aryl-C1 -C7 An alkyl group, preferably a palmitic moiety, the process comprising reacting a compound of formula (4) or a salt thereof,(4) wherein R1 and R2 are independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, which may be Saturated or unsaturated and optionally containing one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from hydroxy, C1 -C7 -alkyl, C1 -C7 a substituent substituted with an alkoxy group, a halogen group, a carboxyl group and a pendant oxy group, and X is a halogen group such as chlorine, and a thiol of the formula HSR5 wherein R5 is as defined for the compound of the formula (3-IV), The reaction is carried out in the presence of a coupling reagent to provide a compound of formula (3-IV). In a preferred embodiment, the present invention relates to a process for the preparation of a compound of formula (3-IV-a) or a salt thereof,(3-IV-a), wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered single or double ring The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or selected from one, two or three independently. Hydroxy, C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R5 is C1 -C7 -alkyl, C6 -C10 -aryl or C6 -C10 -aryl-C1 -C7 An alkyl group, the method comprising the compound of the formula (4-a) or a salt thereof,(4-a) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably 4 to 7-membered monocyclic or bicyclic ring, the ring It may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and it may be unsubstituted or one, two or three independently selected from hydroxyl groups, C.1 -C7 -alkyl, C1 -C7 a substituent substituted with an alkoxy group, a halogen group, a carboxyl group and a pendant oxy group, and X is a halogen group such as chlorine, or a hydroxy group of the formula HSR5, wherein R5 is as defined for the formula (3-IV-a) The compound is defined and optionally reacted in the presence of a coupling reagent to provide a compound of formula (3-IV-a). In one embodiment, the thiol has the formula HSR5 wherein R5 is 4-methylbenzyl. Preferably, the thiol of the formula HSR5 is a palmitic thiol, for example having the formula:Wherein R' and R" are as described, for example, in the following: Blaser, H.-U.Chem.Rev. 1992 ,92 , 935-952, specifically as described below: wherein Table 3 on page 937 is incorporated herein by reference; Oertling, H., Reckziegel, A., Surburg, H., Bertram, H. atChem.Rev. 2007 ,107 , 2136-2164, specifically as described below: Example 1a-e on page 2138, which is incorporated herein by reference; Hultin, P., Earle, M., Sudharshan, M. inTetrahedron 1997 ,53 , 14823-14870, specifically as described below: Examples 111 and 117 of pages 14843-14844, which are incorporated herein by reference; and Kunz, H., Ruck, K.Angew.Chem.Int. Ed.Engl. 1993 ,32 , 336-358, specifically as described below: wherein Example 17, page 339, is incorporated herein by reference. For example, R' is Me and R" is Ph (reference (a) Alajarin, M.; Ortin, M.-M.; Sanchez-Andrada, P.; Vidal, A.; Bautista, D. Org. Lett. 2005 , 7, 5281-5284; (b) EP1264547 A1, 2002; (c) Corey, EJ; Cimprich, KA Tet. Lett. 1992, 33, 4099-4102). Or, specifically, the alcohol of the formula HSRx is a thiol-based analog of L-menthol or D-menthol. Preferably, the palmitic moiety formed by Rx and bonded sulfur is such that Rx thus corresponds to the enantiomer of menthyl or 2-benzene. Base ethyl moiety.Festival B.8. Preparation (3-IV) Thioester intermediates: In another embodiment, the present invention is directed to a process for the preparation of a compound of formula (3-IV) or a salt thereof,(3-IV) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably 4 to 7-membered monocyclic or bicyclic ring, the ring It may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and it may be unsubstituted or one, two or three independently selected from hydroxyl groups, C.1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R5 is C1 -C7 -alkyl, C6 -C10 -aryl or C6 -C10 -aryl-C1 -C7 An alkyl group, preferably a palmitic moiety, the process comprising reacting a compound of formula (3-III) or a salt thereof,(3-III) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably 4 to 7-membered monocyclic or bicyclic ring, the ring It may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and it may be unsubstituted or one, two or three independently selected from hydroxyl groups, C.1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R5 is C1 -C7 -alkyl, C6 -C10 -aryl or C6 -C10 -aryl-C1 -C7 -alkyl, reacted with a compound of the formula MSR5 wherein R5 is C1 -C7 -alkyl, C6 -C10 -aryl or C6 -C10 -aryl-C1 -C7 - alkyl and M is a metal, for example an alkali metal or aluminum, to provide a compound of formula (3-IV). In a preferred embodiment, the present invention relates to a process for the preparation of a compound of formula (3-IV-a) or a salt thereof,(3-IV-a) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from a hydroxyl group. , C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R5 is C1 -C7 -alkyl, C6 -C10 -aryl or C6 -C10 -aryl-C1 -C7 An alkyl group, the method comprising the compound of the formula (3-III-a) or a salt thereof,(3-III-a) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from a hydroxyl group. , C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R5 is C1 -C7 -alkyl, C6 -C10 -aryl or C6 -C10 -aryl-C1 -C7 -alkyl, reacted with a compound of the formula MSR5 wherein R5 is C1 -C7 -alkyl, C6 -C10 -aryl or C6 -C10 -aryl-C1 -C7 - alkyl and M is an alkali metal to provide a compound of formula (3-IV-a). It is well known in the art for the formation of thioesters by transesterification (see, for example, (a) US 5,948,917 A1; (b) Gennari, C.; Carcano, M.; Donghi, M.; Mongelli, N.; Vanotti, E.; Vulpetti, A.J. Org.Chem. 1997 ,62 , 4746-4755; (c) Trost, B. M.; O'Boyle, B. M.Org.Lett. 2008 ,10 , 1369-1372. The (e.g., palmitic) moiety and compound of formula MSR5 are preferably as described for the portion of the compound of formula HSR5.Festival B.9. Preparation (3-IV) Thioester intermediates: In another embodiment, the present invention is directed to a process for the preparation of a compound of formula (3-IV) or a salt thereof,(3-IV) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably 4 to 7-membered monocyclic or bicyclic ring, the ring It may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and it may be unsubstituted or one, two or three independently selected from hydroxyl groups, C.1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R5 is C1 -C7 -alkyl, C6 -C10 -aryl or C6 -C10 -aryl-C1 -C7 An alkyl group, preferably a palmitic moiety, the process comprising reacting a compound of formula (3-I) or a salt thereof,(3-I) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably 4 to 7-membered monocyclic or bicyclic ring, the ring It may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and it may be unsubstituted or one, two or three independently selected from hydroxyl groups, C.1 -C7 -alkyl, C1 -C7 a substituent substituted with an alkoxy group, a halogen group, a carboxyl group and a pendant oxy group, and R5' is hydrogen and a thiol of the formula HSR5, wherein R5 is as defined for the compound of the formula (3-IV), optionally in the presence of The reaction is carried out under a reagent to provide a compound of the formula (3-IV). In a preferred embodiment, the present invention relates to a process for the preparation of a compound of formula (3-IV-a) or a salt thereof,(3-IV-a) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from a hydroxyl group. , C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R5 is C1 -C7 -alkyl, C6 -C10 -aryl or C6 -C10 -aryl-C1 -C7 An alkyl group, preferably a palmitic moiety, the process comprising bringing a compound of formula (3-I-a) or a salt thereof,(3-Ia) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably 4 to 7-membered monocyclic or bicyclic ring, the ring It may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and it may be unsubstituted or one, two or three independently selected from hydroxyl groups, C.1 -C7 -alkyl, C1 -C7 a substituent substituted with an alkoxy group, a halogen group, a carboxyl group and a pendant oxy group, and R5' is hydrogen and a thiol of the formula HSR5, wherein R5 is as defined for the compound of the formula (3-IV), optionally in the presence of The reaction is carried out under a reagent to provide a compound of the formula (3-IV-a). Coupling reagents are typically used to prepare guanamines, esters, and anhydrides from carboxylic acids. Typical examples of suitable coupling reagents can be found in Valeur, E., Bradley, M.Chem.Soc.Rev. 2009 ,38 Found in 606-631. Preferred examples of suitable coupling reagents are selected from DCC (N ,N '-Dicyclohexylcarbodiimide), EDC (N -(3-dimethylaminopropyl)-N -ethylcarbodiimide), CDI (1,1'-carbonyldiimidazole), HATU (hexafluorophosphoric acid)N ,N ,N ',N '-Tetraammonium), HOBt (6-chloro-1-hydroxybenzotriazole) and mixtures thereof. The formation of thioesters is a reaction well known in the art (see, for example, for thiomenthol (a) Porto, S.; Seco, J. M.; Ortiz, A.; Quinoa, E.; Riguera, R.Org.Lett. 2007 ,9 , 5015-5018; (b) Louzao, I.; Seco, J. M.; Quinoa, E.; Riguera, R.Chem.Comm. 2010 ,46 , 7903-7905; for 1-phenylthioethanol): Shoda, S.-i.; Mukaiyama, T.Chem.Lett. 1980 , 391-392). Preferably, R5 of the formula HSR5 thiol is 4-methylphenyl, whereby the reaction with a compound according to formula (3-Ia) (by which R1 and R2 are benzyl) is carried out in an organic solvent such as dichloromethane. It is carried out at room temperature in the presence of a suitable coupling reagent such as CDI.Festival C. Alkylation step: Festival C.1. Alkylation of the indole intermediate: In another embodiment, the present invention relates to a process for the preparation of a compound of formula (5-II-A) or a salt thereof,(5-II-A) wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from a hydroxyl group. , C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, R5" and R6" are independently of each other C1 -C7 -alkyl, C6 -C10 -aryl, C6 -C10 -aryl-C1 -C7 -alkyl, C3 -C7 a cycloalkyl group, or R5" and R6", together with the nitrogen to which they are attached, form a 3 to 10 member, preferably a 4 to 7 membered monocyclic or bicyclic ring which may be saturated or unsaturated and optionally contain one, Two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from hydroxy, C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, preferably R5" and R6" together with the nitrogen to which they are attached form a palmitic moiety, and R8 is C1-C7-alkyl or C6 -C10 -aryl-C1 -C7 An alkyl group, preferably a methyl group, which comprises a compound of the formula (3-II-A) or a salt thereof,(3-II-A) wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from a hydroxyl group. , C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R5" and R6" are independently of each other C1 -C7 -alkyl, C6 -C10 -aryl, C6 -C10 -aryl-C1 -C7 -alkyl, C3 -C7 a cycloalkyl group, or R5" and R6", together with the nitrogen to which they are attached, form a 3 to 10 member, preferably a 4 to 7 membered monocyclic or bicyclic ring which may be saturated or unsaturated and optionally contain one, Two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from hydroxy, C1 -C7 -alkyl, C1 -C7 Substituted with a substituent of an alkoxy group, a halogen group, a carboxyl group and a pendant oxy group, preferably R5" and R6" together with the nitrogen to which they are attached form a palmitic moiety, with a base and C selected from1 -C7 -alkylating reagent: -(R8)3 O+ Z− , where R8 is C1 -C7 -alkyl (such as methyl or ethyl) or C6 -C10 -aryl-C1 -C7 -alkyl, and Z− An anion (such as tetrafluoroborate); -R8X, where R8 is C1 -C7 -alkyl (such as methyl or ethyl) or C6 -C10 -aryl-C1 -C7 -alkyl, and X is a leaving group such as a halo group (such as chloride, bromide, iodide) or a sulfonate (such as triflate, tosylate or mesylate); and - (R8)2 SO4 , where R8 is C1 -C7 -alkyl (such as methyl or ethyl) or C6 -C10 -aryl-C1 -C7 - an alkyl group, optionally reacted in the presence of an additive to provide a compound of formula (5-II-A). In a preferred embodiment, the present invention relates to a process for the preparation of a compound of the formula (5-II-A-a) or a salt thereof,(5-II-Aa) wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from a hydroxyl group. , C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, R5" and R6" are independently of each other C1 -C7 -alkyl, C6 -C10 -aryl, C6 -C10 -aryl-C1 -C7 -alkyl, C3 -C7 a cycloalkyl group, or R5" and R6", together with the nitrogen to which they are attached, form a 3 to 10 member, preferably a 4 to 7 membered monocyclic or bicyclic ring which may be saturated or unsaturated and optionally contain one, Two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from hydroxy, C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, preferably R5" and R6" together with the nitrogen to which they are attached form a palmitic moiety, and R8 is C1 -C7 -alkyl or C6 -C10 -aryl-C1 -C7 An alkyl group, preferably a methyl group, which comprises a compound of the formula (3-II-A-a) or a salt thereof,(3-II-Aa) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from a hydroxyl group. , C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R5" and R6" are independently of each other C1 -C7 -alkyl, C6 -C10 -aryl, C6 -C10 -aryl-C1 -C7 -alkyl, C3 -C7 a cycloalkyl group, or R5" and R6", together with the nitrogen to which they are attached, form a 3 to 10 member, preferably a 4 to 7 membered monocyclic or bicyclic ring which may be saturated or unsaturated and optionally contain one, Two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from hydroxy, C1 -C7 -alkyl, C1 -C7 Substituting alkoxy, halo, carboxy and pendant oxy substituents, preferably R5" and R6" together with the nitrogen to which they are attached form a palmitic moiety, with a base and an alkylating agent selected from the group consisting of: -(R8)3 O+ Z− , where R8 is C1 -C7 -alkyl (such as methyl or ethyl) or C6 -C10 -aryl-C1 -C7 -alkyl, and Z− An anion (such as tetrafluoroborate); -R8X, where R8 is C1 -C7 -alkyl (such as methyl or ethyl) or C6 -C10 -aryl-C1 -C7 -alkyl, and X is a leaving group such as a halo group (such as chloride, bromide, iodide) or a sulfonate (such as triflate, tosylate or mesylate); and - (R8)2 SO4 , where R8 is C1 -C7 -alkyl (such as methyl or ethyl) or C6 -C10 -aryl-C1 -C7 - an alkyl group, optionally reacted in the presence of an additive to provide a compound of formula (5-II-A-a). Preferably, the alkylating agent is methyl iodide, dimethyl sulfonate, benzyl bromide or isopropyl iodide, most preferably methyl iodide or dimethyl sulfonate. Suitable additives are compounds which modify the solubility of the product formed or which contribute to the depolymerization of the base, thereby making it more reactive, for example, as Carey, F. A., Sundberg, R. J.Organische Chemie , VCH, Weinheim, 1995, related sections, such as hexamethylphosphonium (HMPA),N ,N '-Dimethyl propyl propyl urea (DMPU), tetramethylethylene diamine (TMEDA), dimethyl hydrazine (DMSO), NMP (N -methylpyrrolidone) or a mixture thereof. Crown ether or palmitic crown ether, for example as by Shirakawa, S., Yamamoto, K., Kitamura, M., Ooi, T., Maruoka, K.Angew.Chem.Int. Ed. 2005 ,44 , 625-628, as specified in the reaction diagram 1 on page 626, which is incorporated herein by reference; by Weber, B., Seebach, D.Tetrahedron 1994 ,50 , 7473-7484, specifically as described in Table 1 on page 7476, which is incorporated herein by reference, and also for this purpose. Suitable bases are, for example, selected from the group -RmRnNM, wherein Rm and Rn are independently selected from C1 -C7 An alkyl group, a cycloalkyl group, a heterocyclic group or a germyl group and M is an alkali metal such as Na, Li or K; for example, lithium bis(trimethylmethane alkyl) guanamine (LHMDS), bis(trimethyl) Methyl decyl) sodium amide (NaHMDS), bis(trimethylmethyl decyl) potassium amide (KHMDS), lithium diisopropyl guanamine (LDA) or potassium diisopropylamide; -RmM, where Rm is From C1 -C7 -alkyl or aryl and M is an alkali metal such as Na, Li or K; for example, methyl lithium, n-butyl lithium, second butyl lithium, tert-butyl lithium or phenyl lithium; -MH, wherein M Is an alkali metal such as Na, Li or K; for example, sodium hydride or potassium hydride; or a mixture thereof. Preferably, the base is NaHMDS, LDA or KHMDS. The alkylation reaction can be carried out in the presence of a solvent. Suitable solvents include ethers such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran or 2-methyltetrahydrofuran; aromatic solvents such as toluene or xylene or aliphatic hydrocarbons such as pentane, hexane or heptane. Any mixture of two or more such solvents is also within the scope of the invention. Preferably, the alkylation reaction is carried out below room temperature, preferably at -10 ° C or below -10 ° C. More preferably, the alkylation reaction is carried out at a temperature between -10 ° C and -78 ° C. Most preferably, the alkylation reaction is carried out at a temperature between -60 ° C and -78 ° C. The palm part is as defined above for NR5 "R6".Festival C.2. Alkylation of ester intermediates: In another embodiment, the present invention relates to a process for the preparation of a compound of formula (5-III-A) or a salt thereof,(5-III-A) wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from a hydroxyl group. , C1 -C7 -alkyl, C1 -C7 Substituted by alkoxy, halo, carboxy and pendant oxy groups, Rx is C1 -C7 -alkyl or C6 -C10 -aryl-C1 -C7 - an alkyl group, or (preferably) Rx together with the oxygen to which it is attached form a palmitic moiety, and R8 is C1 -C7 -alkyl or C6 -C10 -aryl-C1 -C7 An alkyl group, preferably a methyl group, which comprises a compound of the formula (3-III-A) or a salt thereof,(3-III-A) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from a hydroxyl group. , C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and Rx is C1 -C7 -alkyl, C6 -C10 -aryl, C6 -C10 -aryl-C1 -C7 - an alkyl group, or (preferably) Rx together with the oxygen to which it is attached form a palmitic moiety, with a base and an alkylating agent selected from the group consisting of: -(R8)3 O+ Z− , where R8 is C1 -C7 -alkyl (such as methyl or ethyl) or C6 -C10 -aryl-C1 -C7 -alkyl, and Z− An anion (such as tetrafluoroborate); -R8X, where R8 is C1 -C7 -alkyl (such as methyl or ethyl) or C6 -C10 -aryl-C1 -C7 -alkyl, and X is a leaving group such as a halo group (such as chloride, bromide, iodide) or a sulfonate (such as triflate, tosylate or mesylate); and - (R8)2 SO4 , where R8 is C1 -C7 -alkyl (such as methyl or ethyl) or C6 -C10 -aryl-C1 -C7 - an alkyl group, optionally reacted in the presence of an additive to provide a compound of formula (5-III-A). In another embodiment, the present invention relates to a process for the preparation of a compound of formula (5-III-A-a) or a salt thereof,(5-III-Aa) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from a hydroxyl group. , C1 -C7 -alkyl, C1 -C7 Substituted by alkoxy, halo, carboxy and pendant oxy groups, Rx is C1 -C7 -alkyl, C6 -C10 -aryl, C6 -C10 -aryl-C1 -C7 - an alkyl group, or (preferably) Rx together with the oxygen to which it is attached forms a palmitic moiety, R8 is C1 -C7 -alkyl or C6 -C10 -aryl-C1 -C7 An alkyl group, preferably a methyl group, which comprises a compound of the formula (3-III-A-a) or a salt thereof,(3-III-Aa) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from a hydroxyl group. , C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and Rx is C1 -C7 -alkyl, C6 -C10 -aryl, C6 -C10 -aryl-C1 -C7 - an alkyl group, or (preferably) Rx together with the oxygen to which it is attached form a palmitic moiety, with a base and an alkylating agent selected from the group consisting of: -(R8)3 O+ Z− , where R8 is C1 -C7 -alkyl (such as methyl or ethyl) or C6 -C10 -aryl-C1 -C7 -alkyl, and Z− An anion (such as tetrafluoroborate); -R8X, where R8 is C1 -C7 -alkyl (such as methyl or ethyl) or C6 -C10 -aryl-C1 -C7 -alkyl, and X is a leaving group such as a halo group (such as chloride, bromide, iodide) or a sulfonate (such as triflate, tosylate or mesylate); and - (R8)2 SO4 , where R8 is C1 -C7 -alkyl (such as methyl or ethyl) or C6 -C10 -aryl-C1 -C7 - an alkyl group, optionally reacted in the presence of an additive to provide a compound of formula (5-III-A-a). Suitable alkylating agents are for example as defined in Section C.1 above. Suitable additives are for example as defined in Section C.1 above. Suitable bases are for example as defined in Section C.1 above. Suitable solvents are, for example, as defined in Section C.1 above herein.Festival C.3 and C4. Alkylation of thioester intermediates: In another embodiment, the present invention relates to a process for the preparation of a compound of formula (5-IV) or a salt thereof,(5-IV), wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from the group consisting of hydroxyl groups, C1 -C7 -alkyl, C1 -C7 Substituted by alkoxy, halo, carboxy and pendant oxy groups, R5 is C1 -C7 -alkyl, C6 -C10 -aryl or C6 -C10 -aryl-C1 -C7 - an alkyl group, preferably a palmitic moiety, and R8 is C1 -C7 -alkyl or C6 -C10 -aryl-C1 -C7 An alkyl group, preferably a methyl group, which comprises a compound of the formula (3-IV) or a salt thereof,(3-IV), wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring. The ring may be saturated or unsaturated and optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from the group consisting of hydroxyl groups, C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R5 is C1 -C7 -alkyl, C6 -C10 -aryl or C6 -C10 -aryl-C1 -C7 An alkyl group, preferably a palmitic moiety, with a base and an alkylating agent selected from the group consisting of: -(R8)3 O+ Z− , where R8 is C1 -C7 -alkyl (such as methyl or ethyl) or C6 -C10 -aryl-C1 -C7 -alkyl, and Z− An anion (such as tetrafluoroborate); -R8X, where R8 is C1 -C7 -alkyl (such as methyl or ethyl) or C6 -C10 -aryl-C1 -C7 -alkyl, and X is a leaving group such as a halo group (such as chloride, bromide, iodide) or a sulfonate (such as triflate, tosylate or mesylate); and - (R8)2 SO4 , where R8 is C1 -C7 -alkyl (such as methyl or ethyl) or C6 -C10 -aryl-C1 -C7 - an alkyl group, optionally reacted in the presence of an additive to provide a compound of formula (5-IV). In a preferred embodiment, the present invention relates to a process for the preparation of a compound of the formula (5-IV-a) or a salt thereof,(5-IV-a), wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered single or double ring The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or selected from one, two or three independently. Hydroxy, C1 -C7 -alkyl, C1 -C7 Substituted by alkoxy, halo, carboxy and pendant oxy groups, R5 is C1 -C7 -alkyl, C6 -C10 -aryl or C6 -C10 -aryl-C1 -C7 -alkyl, and R8 is C1 -C7 -alkyl or C6 -C10 -aryl-C1 -C7 An alkyl group, preferably a methyl group, which comprises a compound of the formula (3-IV-a) or a salt thereof,(3-IV-a), wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered single or double ring The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or selected from one, two or three independently. Hydroxy, C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R5 is C1 -C7 -alkyl, C6 -C10 -aryl or C6 -C10 -aryl-C1 -C7 An alkyl group, preferably a palmitic moiety, with a base and an alkylating agent selected from the group consisting of: -(R8)3 O+ Z− , where R8 is C1 -C7 -alkyl (such as methyl or ethyl) or C6 -C10 -aryl-C1 -C7 -alkyl, and Z− An anion (such as tetrafluoroborate); -R8X, where R8 is C1 -C7 -alkyl (such as methyl or ethyl) or C6 -C10 -aryl-C1 -C7 -alkyl, and X is a leaving group such as a halo group (such as chloride, bromide, iodide) or a sulfonate (such as triflate, tosylate or mesylate); and - (R8)2 SO4 , where R8 is C1 -C7 -alkyl (such as methyl or ethyl) or C6 -C10 -aryl-C1 -C7 - an alkyl group, optionally reacted in the presence of an additive to provide a compound of formula (5-IV-a). Suitable alkylating agents are for example as defined in Section C.1 above. Suitable additives are for example as defined in Section C.1 above. Suitable bases are for example as defined in Section C.1 above. Suitable solvents are, for example, as defined in Section C.1 above herein. Preferably, the palmitic moiety is as defined above for the compound of formula HSR5. In one aspect of the invention, the compound according to formula 3-II-Aa is treated with a base (preferably NaHMDS) and an alkylating agent (preferably methyl iodide) in the presence of a solvent (preferably tetrahydrofuran). The compound according to formula 5-II-Aa and the corresponding diastereomer of formula 5-II-Ab are obtained. Preferably, the ratio of 5-II-A-a to 5-II-A-b is 77:23, more preferably 84:16, even more preferably 90:10, still more preferably 97:3. Most preferably, the ratio of 5-II-A-a to 5-II-A-b is 99:1.In another aspect of the invention, the compound according to formula 3-II-Aa is treated with a base (preferably KHMDS) and an alkylating agent (preferably methyl iodide) in the presence of a solvent, preferably tetrahydrofuran. The compound according to formula 5-II-Aa and the corresponding diastereomer of formula 5-II-Ab are obtained. Preferably, the ratio of 5-II-Aa to 5-II-Ab is 41:59, more preferably 23:77, and optimally the ratio of 5-II-Aa to 5-II-Ab is >1:99 . In another aspect of the invention, the compound according to formula 3-II-Aa is treated with a base (preferably LDA) and an alkylating agent (preferably ethyl iodide) in the presence of a solvent, preferably tetrahydrofuran. The compound according to formula 5-II-Aa and the corresponding diastereomer of formula 5-II-Ab are obtained. Preferably, the ratio of 5-II-A-a to 5-II-A-b is 79:21 or higher. In still another aspect of the invention, the treatment with a base (preferably LDA) and an alkylating agent (preferably isopropyl iodide) in the presence of a solvent (preferably tetrahydrofuran) according to formula 3-II-Aa a compound to give a corresponding diastereomer of the compound according to formula 5-II-Aa and formula 5-II-Ab. Preferably, the ratio of 5-II-A-a to 5-II-A-b is 72:28 or higher. In still another aspect of the invention, the base (preferably NaHMDS) and an alkylating agent (preferably benzyl bromide) are treated in the presence of a solvent (preferably tetrahydrofuran) according to formula 3-II-Aa. a compound to give a compound according to formula 5-II-Aa and its corresponding diastereomer of formula 5-II-Ab. Preferably, the ratio of 5-II-A-a to 5-II-A-b is >99:1.Festival D. The intermediate of the invention is converted into a formula (1) Compound ( Known intermediates are described in WO 2008/083967 in ) : Festival D.1. Alkylated guanamine intermediates: In another embodiment, the present invention relates to a process for the preparation of a compound of formula (1A) or a salt thereof,(1A) wherein R1 and R2 are independently hydrogen or a nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, which may be Saturated or unsaturated and optionally containing one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from hydroxy, C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R8 is C1 -C7 -alkyl or C6 -C10 -aryl-C1 -C7 An alkyl group, preferably a methyl group, which comprises a compound of the formula (5-II-A) or a salt thereof,(5-II-A) wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from a hydroxyl group. , C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, R8 is C1 -C7 -alkyl or C6 -C10 -aryl-C1 -C7 -alkyl, preferably methyl, and R5" and R6" are independently of each other C1 -C7 -alkyl, C6 -C10 -aryl, C6 -C10 -aryl-C1 -C7 -alkyl, C3 -C7 a cycloalkyl group, or R5" and R6", together with the nitrogen to which they are attached, form a 3 to 10 member, preferably a 4 to 7 membered monocyclic or bicyclic ring which may be saturated or unsaturated and optionally contain one, Two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from hydroxy, C1 -C7 -alkyl, C1 -C7 Substituting alkoxy, halo, carboxy and pendant oxy substituents, preferably R5" and R6" together with the nitrogen to which they are attached form a palmitic moiety, which is reacted with a mineral acid to provide a compound of formula (1A) . In a preferred embodiment, the present invention relates to a process for the preparation of a compound of formula (1A-a) or a salt thereof,(1A-a) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably 4 to 7-membered monocyclic or bicyclic ring, the ring It may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and it may be unsubstituted or one, two or three independently selected from hydroxyl groups, C.1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R8 is C1 -C7 -alkyl or C6 -C10 -aryl-C1 -C7 An alkyl group, preferably a methyl group, which comprises a compound of the formula (5-II-A-a) or a salt thereof,(5-II-Aa) wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from a hydroxyl group. , C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, R8 is C1 -C7 -alkyl or C6 -C10 -aryl-C1 -C7 -alkyl, preferably methyl, and R5" and R6" are independently of each other C1 -C7 -alkyl, C6 -C10 -aryl, C6 -C10 -aryl-C1 -C7 -alkyl, C3 -C7 a cycloalkyl group, or R5" and R6", together with the nitrogen to which they are attached, form a 3 to 10 member, preferably a 4 to 7 membered monocyclic or bicyclic ring which may be saturated or unsaturated and optionally contain one, Two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from hydroxy, C1 -C7 -alkyl, C1 -C7 Substituting alkoxy, halo, carboxy and pendant oxy substituents, preferably R5" and R6" together with the nitrogen to which they are attached form a palmitic moiety, reacting with a mineral acid to provide formula (1A-a) ) compound. Suitable inorganic acids are, for example, mineral acids or Bronsted acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Usually, HCl is used, for example, as by Kawanami, Y., Ito, Y., Kitagawa, T., Taniguchi, Y., Katsuki, T., Yamaguchi, M.Tetrahedron Lett. 1984 ,25 , 857-860, page 860, line 3. Preferably, the palmitic moiety NR5"R6" is as defined herein above.Festival D.2. Alkylated ester intermediates: In another embodiment, the present invention relates to a process for the preparation of a compound of formula (1A) or a salt thereof,(1A) wherein R1 and R2 are independently hydrogen or a nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, which may be Saturated or unsaturated and optionally containing one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from hydroxy, C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R8 is C1 -C7 -alkyl or C6 -C10 -aryl-C1 -C7 An alkyl group, preferably a methyl group, which comprises a compound of the formula (5-IIIA) or a salt thereof,(5-III-A) wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from a hydroxyl group. , C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, R8 is C1 -C7 -alkyl or C6 -C10 -aryl-C1 -C7 -alkyl, preferably methyl, and Rx is C1 -C7 -alkyl, C6 -C10 -aryl, C6 -C10 -aryl-C1 -C7 An alkyl group, or (preferably) Rx, together with the oxygen to which it is attached, forms a palmitic moiety, which is reacted with a mineral acid to provide a compound of formula (1A). In a preferred embodiment, the present invention relates to a process for the preparation of a compound of formula (1A-a) or a salt thereof,(1A-a) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably 4 to 7-membered monocyclic or bicyclic ring, the ring It may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and it may be unsubstituted or one, two or three independently selected from hydroxyl groups, C.1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R8 is C1 -C7 -alkyl or C6 -C10 -aryl-C1 -C7 An alkyl group, preferably a methyl group, which comprises a compound of the formula (5-III-A-a) or a salt thereof,(5-III-Aa) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from a hydroxyl group. , C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, R8 is C1 -C7 -alkyl or C6 -C10 -aryl-C1 -C7 -alkyl, preferably methyl, and Rx is C1 -C7 -alkyl, C6 -C10 -aryl, C6 -C10 -aryl-C1 -C7 An alkyl group, or (preferably) Rx, together with the oxygen to which it is attached, forms a palmitic moiety, which is reacted with a mineral acid to provide a compound of formula (1A-a). Suitable inorganic acids are, for example, mineral acids or Bronsted acids such as hydrochloric acid, sulfuric acid or phosphoric acid. In general, the use of HCl is, for example, as by Ullrich, A., Chai, Y., Pistorius, D., Elnakady, Y., Herrmann, J., Weissman, K., Kazmaier, U., Muller, R.Angew.Chem.Int. Ed.Engl. 2009 ,48 , page 4424 of 4422-4425, the reaction is described in Figure 3. The palm-forming portion formed by Rx along with the bonding oxygen is preferably as defined herein above.Festival D.3 and D.4. Alkylated thioester intermediates: In another embodiment, the present invention relates to a process for the preparation of a compound of formula (1A) or a salt thereof,(1A) wherein R1 and R2 are independently hydrogen or a nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, which may be Saturated or unsaturated and optionally containing one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from hydroxy, C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R8 is C1 -C7 -alkyl or C6 -C10 -aryl-C1 -C7 An alkyl group, preferably a methyl group, which comprises a compound of the formula (5-IV) or a salt thereof,(5-IV), wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from the group consisting of hydroxyl groups, C1 -C7 -alkyl, C1 -C7 Substituted by alkoxy, halo, carboxy and pendant oxy groups, R5 is C1 -C7 -alkyl, C6 -C10 -aryl or C6 -C10 -aryl-C1 -C7 - an alkyl group, preferably a palmitic moiety, and R8 is C1 -C7 -alkyl or C6 -C10 -aryl-C1 -C7 An alkyl group, preferably a methyl group, is reacted under oxidizing conditions to provide a compound of formula (1A). In a preferred embodiment, the present invention relates to a process for the preparation of a compound of formula (1A-a) or a salt thereof,(1A-a) wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably 4 to 7-membered monocyclic or bicyclic ring, the ring It may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and it may be unsubstituted or one, two or three independently selected from hydroxyl groups, C.1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R8 is C1 -C7 -alkyl or C6 -C10 -aryl-C1 -C7 An alkyl group, preferably a methyl group, which comprises a compound of the formula (5-IV-a) or a salt thereof,(5-IV-a), wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered single or double ring The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or selected from one, two or three independently. Hydroxy, C1 -C7 -alkyl, C1 -C7 Substituted by alkoxy, halo, carboxy and pendant oxy groups, R5 is C1 -C7 -alkyl, C6 -C10 -aryl or C6 -C10 -aryl-C1 -C7 - an alkyl group, preferably a palmitic moiety, and R8 is C1 -C7 -alkyl or C6 -C10 -aryl-C1 -C7 An alkyl group, preferably a methyl group, is reacted under oxidizing conditions to provide a compound of formula (1A). Suitable oxidizing conditions mean, for example, the use of an oxidizing agent such as H2 O2 Under alkaline conditions (for example, in the presence of an alkali metal base such as NaOH, LiOH or KOH). Usually, the oxidation conditions are, for example, as by Gierasch, T; Shi, Z.; Verdine, G.Org. Lett. 2003 ,5 , page 622 of 621-624, is described in Figure 2. Preferably, the palmitic moiety is as defined above for the HSR5 thiol or the use of the HSR5 thiol. The formation of a compound of formula I can be achieved according to well-known esterification conditions, for example as described in, for example, in WO 2008/083967, for example, in Examples 51, 43, 44 or 42 (with R3-OH esterification, wherein R3 is as directed I compounds are defined and non-hydrogen) (especially R3 = ethyl).Festival E : novel and inventive compounds appearing in the previous section and especially in the examples In the methods indicated above, several novel and inventive compounds are involved. Accordingly, other objects of the invention are the compounds shown below. a compound of the formula (4) or a salt thereof,(4); preferably having a configuration according to formula (4-a),(4-a); wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from the group consisting of hydroxyl groups, C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and X is halo, such as chloro. a compound of the formula (3-II-A) or a salt thereof,(3-II-A); it preferably has a configuration according to formula (3-II-A-a),(3-II-Aa); wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered single or double ring The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or selected from one, two or three independently. Hydroxy, C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R5" and R6" are independently of each other C1 -C7 -alkyl, C6 -C10 -aryl, C6 -C10 -aryl-C1 -C7 -alkyl, C3 -C7 a cycloalkyl group, or R5" and R6", together with the nitrogen to which they are attached, form a 3 to 10 member, preferably a 4 to 7 membered monocyclic or bicyclic ring which may be saturated or unsaturated and optionally contain one, Two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from hydroxy, C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, preferably R5" and R6" together with the nitrogen to which they are attached form a palmitic moiety, especially as defined elsewhere herein. a compound of the formula (3-III-A) or a salt thereof,(3-III-A) which preferably has a configuration according to formula (3-III-A-a),(3-III-Aa); wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered single or double ring The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or selected from one, two or three independently. Hydroxy, C1 -C7 -alkyl, C1 -C7 Substituents of alkoxy, halo, carboxy and pendant oxy groups are substituted, and Rx, together with the oxygen to which they are attached, form a palmitic moiety, preferably as defined elsewhere herein. a compound of the formula (3-IV) or a salt thereof,(3-IV); it preferably has a configuration according to formula (3-IV-a),(3-IV-a); wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered single or double ring The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or selected from one, two or three independently. Hydroxy, C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, and R5 is C1 -C7 -alkyl, C6 -C10 -aryl or C6 -C10 -aryl-C1 -C7 An alkyl group, preferably a palmitic moiety, preferably as defined elsewhere herein. a compound of the formula (5-II-A) or a salt thereof,(5-II-A); it preferably has a configuration according to formula (5-II-A-a),(5-II-Aa); wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered single or double ring The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or selected from one, two or three independently. Hydroxy, C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, R5" and R6" are independently of each other C1 -C7 -alkyl, C6 -C10 -aryl, C6 -C10 -aryl-C1 -C7 -alkyl, C3 -C7 a cycloalkyl group, or R5" and R6", together with the nitrogen to which they are attached, form a 3 to 10 member, preferably a 4 to 7 membered monocyclic or bicyclic ring which may be saturated or unsaturated and optionally contain one, Two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from hydroxy, C1 -C7 -alkyl, C1 -C7 Substituted with alkoxy, halo, carboxy and pendant oxy groups, preferably R5" and R6" together with the nitrogen to which they are attached form a palmitic moiety, especially as defined elsewhere herein, and R8 is C1 -C7 -alkyl or C6 -C10 -aryl-C1 -C7 - an alkyl group, preferably a methyl group. a compound of the formula (5-III-A) or a salt thereof,(5-III-A), which preferably has a configuration according to formula (5-III-A-a),(5-III-Aa), wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered single or double ring The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or selected from one, two or three independently. Hydroxy, C1 -C7 -alkyl, C1 -C7 Substituents of alkoxy, halo, carboxy and pendant oxy groups are substituted, and Rx, together with the oxygen to which they are attached, form a palmitic moiety, preferably as defined elsewhere herein. a compound of the formula (5-IV) or a salt thereof,(5-IV), which preferably has a configuration according to formula (5-IV-a),(5-IV-a), wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered single or double ring The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or selected from one, two or three independently. Hydroxy, C1 -C7 -alkyl, C1 -C7 Substituted by alkoxy, halo, carboxy and pendant oxy groups, R5 is C1 -C7 -alkyl, C6 -C10 -aryl or C6 -C10 -aryl-C1 -C7 - an alkyl group, preferably a palmitic moiety as defined elsewhere herein, and R8 is C1 -C7 -alkyl or C6 -C10 -aryl-C1 -C7 - an alkyl group, preferably a methyl group. ((Reference Reaction Scheme 1)) In another aspect, the present invention relates to a compound for converting a compound of the formula (3-I), preferably a compound of the formula (3-Ia) or a salt thereof, as defined herein A method of a compound of formula (1-A), preferably a compound of formula (1-Aa) or a salt thereof, as defined herein, comprising i) a method of Section B.2, to formulate a formula as defined herein (3-I) a compound, preferably a compound of the formula (3-Ia) or a salt thereof, is converted to a compound of the formula (3-II-A) as defined herein, preferably a compound of the formula (3-II-Aa) or a salt thereof; ii) a method of Section C.1, wherein a compound of formula (3-II-A), preferably a compound of formula (3-II-Aa), or a salt thereof, as defined herein, is converted as herein A compound of formula (5-II-A), preferably a compound of formula (5-II-Aa) or a salt thereof; iii) a method of Section D.1, which will have formula (5-II) as defined herein -A) a compound, preferably a compound of the formula (5-II-Aa) or a salt thereof, converted to a compound of the formula (1-A), preferably a compound of the formula (1-Aa) or a salt thereof; (Refer to Reaction Scheme 3)) In another aspect, the invention relates to a compound of formula (3-I) as defined herein, A method of converting a compound of the formula (3-Ia) or a salt thereof to a compound of the formula (1-A), preferably a compound of the formula (1-Aa) or a salt thereof, which comprises i) Section A A method of converting a compound of formula (3-I), preferably a compound of formula (3-Ia), or a salt thereof, as defined herein, to a compound of formula (4), as defined herein, preferably 4-a) a compound or a salt thereof; ii) a method of Section B.1, wherein a compound of formula (4), preferably a compound of formula (4-a) or a salt thereof, as defined herein, is converted as herein A compound of formula (3-II-A), preferably a compound of formula (3-II-Aa) or a salt thereof; iii) a method of Section C.1, which will have a formula (3-II as defined herein) -A) a compound, preferably a compound of the formula (3-II-Aa) or a salt thereof, is converted to a compound of the formula (5-II-A) as defined herein, preferably a compound of the formula (5-II-Aa) or a salt thereof; iv) a method of Section D.1, wherein a compound of formula (5-II-A), preferably a compound of formula (5-II-Aa) or a salt thereof, as defined herein, is converted as herein A compound of the formula (1-A), preferably a compound of the formula (1-Aa) or a salt thereof; ((Reference Reaction Figure 1)) in another aspect, The invention relates to a compound of formula (1-A), preferably a compound of formula (2), preferably a compound of formula (2-a), or a salt thereof, as defined herein, A method of (1-Aa) a compound or a salt thereof, the method comprising i) the method of Section B.3, wherein a compound of formula (2), preferably a compound of formula (2-a), or Conversion of a salt to a compound of formula (3-II-A) as defined herein, preferably a compound of formula (3-II-Aa) or a salt thereof; ii) a method of Section C.1, as defined herein A compound of the formula (3-II-A), preferably a compound of the formula (3-II-Aa) or a salt thereof, is converted to a compound of the formula (5-II-A) as defined herein, preferably a formula (5- a compound of the formula (II-Aa) or a salt thereof; iii) a compound of the formula (5-II-A), preferably a compound of the formula (5-II-Aa), or a compound thereof, or Conversion of a salt to a compound of formula (1-A) as defined herein, preferably a compound of formula (1-Aa) or a salt thereof; ((Reference Scheme 2)) In another aspect, the invention relates to Converting a compound of formula (3-I), preferably a compound of formula (3-Ia) or a salt thereof, as defined herein, to A method of formula (1-A), preferably a compound of formula (1-Aa) or a salt thereof, which method comprises i) the method of Section B.5, wherein the formula is as defined herein ( 3-I) a compound, preferably a compound of the formula (3-Ia) or a salt thereof, converted to a compound of the formula (3-III-A), preferably a compound of the formula (3-III-Aa), or Salt; ii) the method of Section C.2, wherein a compound of formula (3-III-A), preferably a compound of formula (3-III-Aa) or a salt thereof, as defined herein, is converted as defined herein a compound of the formula (5-III-A), preferably a compound of the formula (5-III-Aa) or a salt thereof; iii) a method of Section D.2, which will have the formula (5-III- as defined herein) A) a compound, preferably a compound of the formula (5-III-Aa) or a salt thereof, is converted to a compound of the formula (1-A) as defined herein, preferably a compound of the formula (1-Aa) or a salt thereof; With reference to a variant of Figure 1, including Section A) in another aspect, the invention relates to a compound of formula (3-I), preferably a compound of formula (3-Ia), or a salt thereof, as defined herein a method of converting a compound of formula (1-A), preferably a compound of formula (1-Aa) or a salt thereof, as defined herein, The method comprises i) the method of Section A, wherein a compound of formula (3-I), preferably a compound of formula (3-Ia) or a salt thereof, as defined herein, is converted to a compound of formula (4) as defined herein Preferred is a compound of the formula (4-a) or a salt thereof; ii) a method of Section B.1, wherein a compound of the formula (4), preferably a compound of the formula (4-a), or a compound thereof, or The salt is converted to a compound of formula (3-II-A) as defined herein, preferably a compound of formula (3-II-Aa) or a salt thereof; iii) a method of Section C.1, as defined herein A compound of the formula (3-II-A), preferably a compound of the formula (3-II-Aa) or a salt thereof, is converted to a compound of the formula (5-II-A) as defined herein, preferably a formula (5- a compound of the formula (5-II-A), preferably a compound of the formula (5-II-Aa), or a compound thereof, or a compound thereof, or a compound of the formula (5-II-Aa), or Conversion of a salt to a compound of formula (1-A) as defined herein, preferably a compound of formula (1-Aa) or a salt thereof; ((Reference Scheme 2)) In another aspect, the invention relates to Converting a compound of formula (3'-III), preferably a compound of formula (3'-III-a) or a salt thereof, as defined herein, to A method of formulating a compound of formula (1-A), preferably a compound of formula (1-Aa) or a salt thereof, the process comprising i) the method of Section B.6, to formula (3' as defined herein -III) a compound, preferably a compound of the formula (3'-III-a) or a salt thereof, converted to a compound of the formula (3-III-A) as defined herein, preferably a compound of the formula (3-III-Aa) Or a salt thereof; ii) a method of Section C.2, wherein a compound of the formula (3-III-A), preferably a compound of the formula (3-III-Aa) or a salt thereof, as defined herein, is converted as herein A compound of the formula (5-III-A), preferably a compound of the formula (5-III-Aa) or a salt thereof; iii) a method of Section D.2, which will have a formula (5- as defined herein) A compound of the formula III-A), preferably a compound of the formula (5-III-Aa) or a salt thereof, is converted to a compound of the formula (1-A), preferably a compound of the formula (1-Aa) or a salt thereof; ((Reference Reaction Figure 1 + Reaction Figure 4)) In another aspect, the invention relates to a compound of formula (3-I), preferably a compound of formula (3-Ia), or a method of converting a salt thereof to a compound of the formula (1-A), preferably a compound of the formula (1-Aa) or a salt thereof, as defined herein, The method comprises i) the method of Section A, wherein a compound of formula (3-I), preferably a compound of formula (3-Ia) or a salt thereof, as defined herein, is converted to a compound of formula (4) as defined herein Preferred is a compound of the formula (4-a) or a salt thereof; ii) a method of Section B.7, wherein a compound of the formula (4), preferably a compound of the formula (4-a), or a compound thereof, or Conversion of a salt to a compound of formula (3-IV) as defined herein, preferably a compound of formula (3-IVI-a) or a salt thereof; iii) a method of Section C.3, to formulate a formula as defined herein A compound of formula (3-IV), preferably a compound of formula (3-IV-a) or a salt thereof, is converted to a compound of formula (5-IV), preferably a compound of formula (5-IV-a), or a salt thereof; iv) a method of Section D.3, wherein a compound of formula (5-IV), preferably a compound of formula (5-IV-a) or a salt thereof, as defined herein, is converted as defined herein a compound of the formula (1-A), preferably a compound of the formula (1-Aa) or a salt thereof; ((Reference Reaction Figure 5)) In another aspect, the invention relates to a formula as defined herein (3-III) a compound, preferably a compound of the formula (3-III-a) or a salt thereof, is converted to the formula (1-A) as defined herein And a method of the compound of the formula (1-Aa) or a salt thereof, which comprises the method of i) Section B.8, to formulate a compound of the formula (3-III) as defined herein, preferably The compound of the formula (3-III-a) or a salt thereof is converted into a compound of the formula (3-IV) as defined herein, preferably a compound of the formula (3-IV-a) or a salt thereof; ii) in the section C.4 A method of converting a compound of formula (3-IV), preferably a compound of formula (3-IV-a) or a salt thereof, as defined herein, to a compound of formula (5-IV) as defined herein, preferably Or a compound of the formula (5-IV), or a salt thereof; Or a salt thereof is converted to a compound of the formula (1-A) as defined herein, preferably a compound of the formula (1-Aa) or a salt thereof; ((Reference Reaction Figure 5)) In another aspect, the present invention relates to A compound of formula (3-I), preferably a compound of formula (3-Ia), or a salt thereof, as defined herein, is converted to a compound of formula (1-A) as defined herein, preferably 1-Aa) A method of a compound or a salt thereof, the method comprising i) the method of Section B.9, wherein the formula is as defined herein ( 3-I) a compound, preferably a compound of the formula (3-Ia) or a salt thereof, converted to a compound of the formula (3-IV) as defined herein, preferably a compound of the formula (3-IV-a) or a salt thereof; Ii) the method of Section C.4, wherein a compound of formula (3-IV), preferably a compound of formula (3-IV-a) or a salt thereof, as defined herein, is converted to formula (5 as defined herein) -IV) a compound, preferably a compound of the formula (5-IV-a) or a salt thereof; iii) a method of Section D.4, to give a compound of the formula (5-IV) as defined herein, preferably The compound of the formula (5-IV-a) or a salt thereof is converted into a compound of the formula (1-A), preferably a compound of the formula (1-Aa) or a salt thereof; the invention is particularly relevant in each section Any of the methods described. The invention is also independently independent of each single step described in the sequence of methods in the respective section. Thus, each and every single step of any method consisting of a series of steps described herein is an embodiment of the invention. Accordingly, the invention is also directed to such embodiments of the process, according to which the compounds obtainable as intermediates in any of the steps of the process are used as starting materials. Particularly preferred are any reactions (method steps) in which a portion of the R8 as defined for the respective compounds herein has a palmitic moiety (eg, NR5 "R6", ORx or OR5) in the remainder of the molecule. Introduced as this allows for stereochemically selective synthesis. The product of the method of the invention can be used to synthesize NEP inhibitors or prodrugs thereof, in particular, which can be used to synthesize γ-amino-δ-biphenyl-α-methylalkanolic acid or acid ester backbones NEP inhibitor. In one embodiment, the product of the method of the invention can be used to synthesize a NEP inhibitor prodrug N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)- Ethyl 4-amino-(2R)-methylbutanoate or its active metabolite, NEP inhibitor N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenyl) Methyl)-4-amino-(2R)-methylbutyric acid. The term "NEP inhibitor" describes a compound that inhibits the activity of an enzyme neutral endopeptidase (NEP, EC 3.4.24.11). In the present invention, the term "NEP-inhibitor" (which may also include prodrugs in all embodiments) or "NEP-inhibitor prodrug" means the substance itself or a salt thereof, preferably pharmaceutically acceptable Salt. Examples are sodium, potassium, magnesium, calcium or ammonium salts. Calcium salts are preferred. The term "prodrug" describes a pharmacologically unhelpful administration in an inactive (or less active) form. Once administered, the prodrug is metabolized in vivo to the active compound. An embodiment of the method of the present invention comprises one or more additional steps, wherein the compound according to formula (1-A) or a salt thereof is further reacted to obtain a NEP-inhibitor or a prodrug thereof, specifically including a γ-amino group A NEP-inhibitor or a prodrug thereof of a delta-biphenyl-α-methylalkanolic acid or acid ester backbone. Preferably, the compound according to formula (1-A) or a salt thereof is further reacted to obtain a NEP-inhibitor or a prodrug thereof, specifically including γ-amino-δ-biphenyl-α-methylalkane. A NEP-inhibitor of an alkyd or acid ester backbone or a prodrug thereof. In a preferred embodiment, a compound according to formula (1-A), preferably a compound of formula (1-Aa) or a salt thereof, is further reacted to obtain a NEP inhibitor prodrug N-(3) -Carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutyrate (known in the art as AHU377) ) or its salt.In general, the invention includes N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutyric acid Any pharmaceutically acceptable salt of ethyl ester. NEP inhibitor prodrug N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutyrate Further reacting as appropriate to obtain the active NEP inhibitor N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- Methyl butyric acid.General terms: The following list is used to describe the definition of various terms of the invention. These definitions, or by substitution of one, more than one or all of the general expressions or symbols used in the present invention, and thus the preferred embodiments of the invention, are preferably applied to such terms, as in the specific case Further restrictions, otherwise they are used individually or as part of a larger group throughout the specification. In the present application, the term "nitrogen protecting group" generally includes any group capable of reversibly protecting the nitrogen functionality, preferably the amine group and/or the guanamine functionality. Preferably, the nitrogen protecting group is an amine protecting group and/or a guanamine protecting group. Suitable nitrogen protecting groups are conventionally used in peptide chemistry and are described, for example, in relevant sections of standard reference works such as JFW McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973. In TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", Third Edition, Wiley, New York 1999, in "The Peptides"; Volume 3 (Editor: E. Gross and J. Meienhofer), Academic Press , London and New York 1981, and atMethoden der organischen Chemie (Methods of Organic Chemistry), Houben Weyl, 4th edition, Vol. 15/I, Georg Thieme Verlag, Stuttgart 1974. Preferred nitrogen protecting groups generally include: -C1 -C6 -alkyl, preferably C1 -C4 -alkyl, more preferably C1 -C2 -alkyl, optimally C1 -alkyl, which is optionally 3-C1 -C7 -alkylmethylalkyl-C1 -C7 - alkoxy (for example, trimethylmethane and ethoxy) C6 -C10 An aryl group, preferably a phenyl group, or a heterocyclic group, preferably a pyrrolidinyl mono-, di- or tri-substituted group, wherein the aryl ring or heterocyclic group is unsubstituted or one or more (for example , two or three) for example selected from C1 -C7 -alkyl, hydroxy, C1 -C7 -alkoxy, C2 -C8 - mercapto-oxygen, halogen, nitro, cyano and CF3 Substituted by the group of residues; or -C6 -C10 -aryl-C1 -C2 - alkoxycarbonyl (preferably, phenyl-C1 -C2 - alkoxycarbonyl group, such as benzyloxycarbonyl); C1 -C10 -alkenyloxycarbonyl; C1 -C6 -alkylcarbonyl (for example, ethenyl or neopentyl);6 -C10 -arylcarbonyl; C1 -C6 - alkoxycarbonyl (for example, a third butoxycarbonyl group);6 -C10 -aryl-C1 -C6 - alkoxycarbonyl; allyl or cinnamyl; sulfonyl or thio; amber quinone imine, according to the formulaA RA* RA** , where RA , RA* And RA** Independent of each other for C1 -C7 -alkyl, C6 -C10 -aryl-C1 -C2 -alkyl or C6 -C10 -Aryl. RA , RA* And RA** Preferred examples are methyl, ethyl, isopropyl, tert-butyl or phenyl. Examples of preferred nitrogen protecting groups are ethenyl, benzyl, cumyl, benzhydryl, trityl, benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), Benzyloxymethyl (BOM), neopentyl-oxy-methyl (POM), trichloroethoxycarbonyl (Troc), 1-adamantyloxycarbonyl (Adoc), allyl, allyl Oxycarbonyl, trimethylmethanyl, tert-butyl-dimethylformamidin, triethylmethyl decyl (TES), triisopropylmethyl decyl, trimethyl methacrylate alkyl ethoxy Base (SEM), tert-butoxycarbonyl (BOC), tert-butyl, 1-methyl-1,1-dimethylbenzyl, (phenyl)toluene, pyrrolidinyl and neopentyl. The most suitable nitrogen protecting groups are ethyl hydrazino, benzyl, benzyloxycarbonyl (Cbz), triethylmethyl decyl (TES), trimethyl decyl ethoxymethyl (SEM), third butyl Oxycarbonyl (BOC), pyrrolidinylmethyl and neopentyl. Preferred nitrogen protecting groups are benzyl, phthalic acid and third butoxycarbonyl BOC. Further examples of preferred nitrogen protecting groups are neopentyl, pyrrolidinylmethyl, tert-butoxycarbonyl, benzyl and germyl, especially methoxyalkyl (e.g., triethylformamidin). If an embodiment requires removal of a nitrogen protecting group as defined above, the removal can generally be carried out by using known methods. Preferably, the nitrogen protecting group as defined above is removed by the use of acidic or basic conditions. Examples of acidic conditions are hydrochloric acid, trifluoroacetic acid, and sulfuric acid. Examples of alkaline conditions are lithium hydroxide and sodium ethoxide. A nucleophile such as sodium borohydride can be used. onN - benzyl as a nitrogen protecting group, which can be hydrogenated or by using some suitable oxidizing agent, such as ammonium cerium nitrate (CAN) or 2,3-dichloro-5,6-dicyano-p-benzene And remove (DDQ). An alkyl group (which is a free radical or a free radical such as an arylalkyl or a part of an alkoxy group) is a linear or branched chain (once, or if necessary and feasible multiple times) carbon chain, and especially C1 -C7 -alkyl or C1 -C6 -alkyl such as C1 -C4 -alkyl, specifically branched chain C1 -C4 - an alkyl group such as isopropyl. The term "low carbon number" or "C1 -C7 -" defines a moiety having up to and including a maximum of 7, especially up to and including a maximum of 4 carbon atoms, which moiety is a branched chain (one or more times) or linear and bonded via a terminal or non-terminal carbon. Low carbon number or C1 -C7 - an alkyl group is, for example, n-pentyl, n-hexyl or n-heptyl or preferably C1 -C4 -alkyl, such as methyl, ethyl, n-propyl, second propyl, n-butyl, isobutyl, t-butyl, t-butyl, specifically methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, t-butyl, tert-butyl. In particular, C1 -C7 - The alkyl group is a methyl group, an ethyl group, a propyl group or an isopropyl group. In an embodiment, C1 -C7 - The alkyl group is a methyl group or an ethyl group. An aryl group (for example, as a radical or a radical such as a part of an aralkyl group) is a monocyclic or bicyclic substituted or unsubstituted aryl group having 6 to 10 carbon atoms, such as a phenyl group, a fluorenyl group, a dihydrogen group. Mercapto or naphthyl, specifically phenyl. Substituted C6-10 An aryl group is, for example, one or more independently selected from, for example, C1 -C7 -alkyl, C1 -C7 -alkoxy-C1 -C7 -alkyl, C1 -C7 Substituting C for alkoxy and halo substituents (eg one to three substituents)6-10 Aryl. In an embodiment, substituted C6-10 The aryl group is substituted by a halogen group6-10 An aryl group such as p-chlorophenyl. In one embodiment, the aryl group is unsubstituted C6-10 Aryl. A cycloalkyl group is, for example, C3 -C7 a cycloalkyl group and is, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group. Cyclopentyl and cyclohexyl are preferred. A thiol group (as part of a free radical or a free radical) is, for example, unsubstituted or substituted C6-10 Arylcarbonyl, unsubstituted or substituted C6-10 An arylsulfonyl group, an unsubstituted or substituted heterocyclic carbonyl group or an unsubstituted or substituted heterocyclylsulfonyl group; wherein preferred substituents are selected from the group consisting of halo, C1 -C7 -alkyl, halo-C1 -C7 -alkyl, C1 -C7 -alkoxy,halo-C1 -C7 - alkoxy groups such as trifluoromethoxy and C1 -C7 -alkoxy-C1 -C7 - alkoxy. Preferably, the fluorenyl group is unsubstituted or substituted C6-10 An arylcarbonyl group; or an unsubstituted or substituted heterocyclic carbonyl group; wherein preferred substituents are selected from the group consisting of halo, C1 -C7 -alkyl, halo-C1 -C7 -alkyl, C1 -C7 -alkoxy,halo-C1 -C7 - alkoxy groups such as trifluoromethoxy and C1 -C7 -alkoxy-C1 -C7 - alkoxy. The term arylalkyl means C6 -C10 -aryl-C1 -C7 An alkyl group wherein the aryl group is as defined herein. In one embodiment, the arylalkyl group is, for example, a benzyl group. The term carboxy means –CO2 R, where R is hydrogen or C1 -C7 -alkyl. Aryloxy means aryl-O- wherein aryl is as defined above. The heterocyclic group is monocyclic or polycyclic, preferably monocyclic, bicyclic or tricyclic, most preferably monocyclic unsaturated, partially saturated, saturated or aromatic ring systems, preferably having from 3 to 14 (better 5). Up to 14) ring atoms and having one or more, preferably one to four independently selected from nitrogen, oxygen, sulfur, S(=O)- or S-(=O)2 Hetero atom. An alkoxy group (as part of a radical or a radical) is, for example, C1 -C7 Alkoxy and is, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, second butoxy, third butoxy and also includes The pentyloxy, hexyloxy and heptoxy radicals. C1 -C4 Alkoxy groups are preferred. In the case of a "ring", for example, in the case of a ring formed by the combination of R1 and R2 with a nitrogen bond, this includes a monocyclic or bicyclic ring moiety, such as a benzofused ring system. Where a ring is mentioned, for example together with the nitrogen to which it is attached, the ring may be saturated or unsaturated and may optionally comprise one or more, preferably one, two or three additional heteroatoms, such as nitrogen. Sulfur or sulfur, whereby the ring contains from 3 to 10, preferably from 4 to 7 ring atoms; such rings may also carry one or more substituents, preferably one, two or three substituents, such Substituents are independently selected from, for example, hydroxyl, C1 -C7 -alkyl, C1 -C7 a substituent of an alkoxy group, a halogen group, a carboxyl group and a pendant oxy group. In the case of "one or more", for example, in the case of a hetero atom, this preferably means 1 to 4 (1, 2, 3, 4), 1 to 3 (1, 2, 3) or 1 Or 2. The respective substituents or heteroatoms can then be selected independently of each other and need not be identical. The halo or halogen is preferably fluorine, chlorine, bromine or iodine, most preferably bromine or especially chlorine. The term "alkali metal" refers to a metal such as Li, Na or K in the first row of the periodic table. In the formula of this application, in C-sp3 The term "Indicating absolute stereochemistry, (R )or(S ). In the formula of this application, in C-sp3 The term "Indicating absolute stereochemistry, (R )or(S ). In the formula of this application, in C-sp3 The term "Represents a mixture of stereochemistry (such as racemic), so it means the center of the palm, whereS ) stereoisomers andR The stereoisomers are present, for example, in a 50:50 ratio. As used herein, the term "pivot" refers to a molecule that has non-superimposability with its mirror partner, and the term "non-pivoting" refers to a molecule that is superimposable with its mirror partner. Any viable pure enantiomeric or enantiomeric mixture, pure diastereomer or mixture of diastereomers is included in the present invention. In one embodiment, the term palm to palm refers to an enantiomerically enriched mixture of enantiomers. As used herein, the term "enantiomeric enrichment" refers to a mixture of enantiomers in which one enantiomer is present in an amount greater than 50%. In another embodiment, the term palm to palm refers to a diastereomeric enriched mixture of diastereomers. As used herein, the term "diastereomeric enrichment" refers to a mixture of diastereomers in which the content of one diastereomer is greater than 50%. The term "reflux" means the temperature at which the reaction mixture boils, preferably up to the actual reflux temperature or 180 ° C, preferably up to 140 ° C. As used herein, the term "room temperature" or "ambient temperature" means 20 to 35 ° C, such as a temperature of 20 to 25 ° C. In view of the close relationship between the compound and the intermediate in free form and in its salt form, including those salts which can be used, for example, to purify or identify an intermediate of a compound or a salt thereof, any of the foregoing and the following "compounds" " "Starting substances" and "intermediate substances" are understood to mean also one or more of their salts or corresponding free compounds, intermediates or starting substances and mixtures of one or more of them, each of which is intended to be Salts including any solvate, metabolic precursor such as an ester or guanamine or any one or more of these are suitably and expediently and not explicitly mentioned otherwise. Different crystal forms that are available are also included. In the presence of a salt-forming group (such as a basic or acidic group) which may be present in an aqueous solution at least partially dissociated, for example in the pH range of 4 to 10, or may be isolated, in particular in solid, especially crystalline form. Underneath, a salt can be formed. In the presence of a basic group such as an imido group or an amine group, it is preferred to form a salt using an organic or inorganic acid. Suitable inorganic acids are, for example, hydrohalic acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Suitable organic acids are, for example, carboxylic acids, phosphonic acids, sulfonic acids or aminosulfonic acids, such as acetic acid, propionic acid, lactic acid, fumaric acid, succinic acid, citric acid, amino acids, such as glutamic acid or aspartame. Acid, maleic acid, hydroxymaleic acid, methyl maleic acid, benzoic acid, methanesulfonic acid or ethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1 , 5-naphthalene-disulfonic acid,N -cyclohexylaminosulfonic acid,N -methyl-,N -ethyl- orN -propyl-aminosulfonic acid, or other organic protic acid such as ascorbic acid. In the presence of a negatively charged free radical, such as a carboxyl or sulfonic acid group, a base such as a metal or ammonium salt such as an alkali metal or alkaline earth metal salt such as a sodium, potassium, magnesium or calcium salt, or Forming an ammonium salt or a heterocyclic base using ammonia or a suitable organic amine such as a third monoamine such as triethylamine or tris(2-hydroxyethyl)amine, for exampleN -ethyl-piperidine orN ,N '-Dimethylpiperazine, forming a salt. When a basic group and an acid group are present in the same molecule, an internal salt can also be formed. Particularly useful salts include the hydrochloride, hydrobromide, sulfate, nitrate, phosphate, lactate, fumarate, succinate, oxalate, malate, malonic acid of the compounds of the invention. Salt, tartrate, tolyl tartrate, benzyl tartrate, orotate, nicotinic acid, methanesulfonate or 4-methylbenzenesulfonate and similar to those formed by reaction with the above reagents Things. Methods for the preparation of acid addition salts are described in the literature, for example in the relevant sections below: "CRC Handbook of Optical Resolutions via Diasteromeric Salt Formation", D. Kozma, CRC Press 2002,Acta Cryst .2006 , B62, 498-505 andSynthesis 2003 ,13 , 1965-1967. Where a plural form is used for a compound, a starting substance, an intermediate, a salt, a pharmaceutical preparation, a disease, a condition, or the like, this is intended to mean a (preferred) or a plurality of single compounds, salts, pharmaceutical preparations, diseases, In the case of a singular or indefinite article ("one", "one"), it is not intended to exclude plural, but only preferably means "one". As used herein, the term "prodrug" means a compound which is specifically converted to a parent compound in vivo, for example by hydrolysis in blood, for example, as described below: T. Higuchi and V. Stella, Pro-drugs As Novel Delivery Systems, Volume 14 of the ACS Symposium Series, edited by Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; H Bundgaard, ed., Design of Prodrugs, Elsevier, 1985; and Judkins et al. ,Synthetic Communications 1996 ,26, 4351-4367, and "The Organic Chemistry of Drug Design and Drug Action", 2nd ed., R B Silverman (Special Section 8, pages 497 to 557), Elsevier Academic Press, 2004. Thus, prodrugs include drugs having functional groups that have been converted to their reversible derivatives. Typically, such prodrugs are converted to the active drug by hydrolysis. The following can be mentioned as an example: Prodrugs also include compounds which can be converted to the active drug by oxidation or reduction. The following can be mentioned as an example: Each of the above reactions and/or reaction steps may be used individually or in combination for the preparation of a NEP-inhibitor or a prodrug thereof, such as including gamma-amino-delta-biphenyl-α-methylalkanol or An acid ester such as a NEP-inhibitor of an alkyl ester backbone or a method of a prodrug thereof. In particular, the NEP-inhibitor is N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- Butyric acid or a salt thereof or a prodrug thereof.Instance section Specific embodiments of the invention are provided in the following examples. These examples are intended to illustrate the invention without limiting its scope, and on the other hand, represent preferred embodiments of the reaction steps, intermediates and/or methods of the invention. Abbreviations: δ chemical shift μl microliter μm micron AcOH acetic acid aliph aliphatic arom aromatic Bn benzyl Boc tert-butoxycarbonyl br. s. based on recovered starting material n-BuLi n-butyl lithium BOC2 O Di-tert-butyl carbonate CDCl3 Deuterated chloroform CDIN ,N -carbonyldiimidazole CH2 Cl2 Dichloromethane (COCl)2 Grasshopper chlorine d double peak dd double peak double peak DCM dichloromethane DMF dimethylformamide de diastereomer excess dr diastereomer ratio EDC·HClN -(3-dimethylaminopropyl)-N -ethylcarbodiimide hydrochloride DEA diethylamine DMF = dmfN ,N - dimethylformamide DMSO dimethyl hydrazine DMSO-d 6 Dimethyl sulfonation d6 -DMSO dimethyl hydrazide ee enantiomer excess ES electrospray ESI electrospray ionization Et ethyl EtOAc ethyl acetate EtOH ethanol FTIR Fourier transform infrared h hour HCl hydrochloric acid H2 SO4 Sulfuric acid HOBt 6-chloro-1-hydroxybenzotriazole HNMR proton nuclear magnetic resonance HPLC high performance liquid chromatography3 PO4 Phosphoric acid iPr isopropyl iPrOAc isopropyl acetate iPrOH isopropanol IR infraredJ Coupling constant K2 CO3 Potassium carbonate KHMDS bis(trimethylmethane alkyl) decylamine potassium L liter LDA diisopropyl guanamine lithium LiOH lithium hydroxide LC-MS liquid chromatography-mass spectrometry LHMDS bis(trimethylmethyl decyl) decylamine Lithium M molar concentration m multiple peak m/e mass to charge ratio m/z mass to charge ratio Me methyl MeOH methanol mg mg min min MeI methyl iodide ml ml mmol(s) millimoles mol(s) molar MS mass spectrometry N nitrogen atom N2 Nitrogen nm nano NaH sodium hydride NaOH sodium hydroxide NaHCO3 Sodium bicarbonate NaHMDS bis(trimethylmethane alkyl) guanamine sodium NH4 Cl ammonium chloride nm nano NMR nuclear magnetic resonance Ph phenyl pH hydrogen ion concentration ppm per million parts q quadruple peak RT = rt room temperature s unimodal SM starting material t triplet TBME third butyl methyl ether TEA three Amine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography Tol toluene tR Residence timeInstance 1 : ( S )-4- Amine -5- Biphenyl -4- base - Palladium hydrochloride (S)-5-Biphenyl-4-ylmethyl-pyrrolidin-2-one (40.0 g, 0.159 mol) was suspended in 6N HCl (250 mL) and the mixture was refluxed for 2 hr then allowed to cool to room temperature. After filtration, the solid was collected and dried to give (S)-4-amino-5-biphenyl-4-yl-pentanoic acid salt.1 H NMR (DMSO): 1.80 (2H, m), 2.45 (2H, m), 2.81 (1H, m), 3.05 (1H, m), 3.57 (1H, m), 7.36~7.71 (9H, m, fang Family), 8.21 (2H, s), 12.23 (1H, s).Instance 2 : (S)-5-( Biphenyl -4- base )-4-( Third butoxycarbonylamino group ) Valeric acid Add (S)-2-biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (20 g, to a mixture of tetrahydrofuran (150 ml) and water (50 ml). 56 mmol). Then, a solution of lithium hydroxide (6 g) dissolved in water (100 ml) was added to the mixture. Then, the resulting mixture was vigorously stirred for 14 hours. A 1 M hydrochloric acid solution was added to the mixture until a pH of less than 7 was reached. The tetrahydrofuran solvent was then removed from the mixture under reduced pressure. Then ethyl acetate (100 ml) was added and the two phases were separated. The organic phase was washed with a 1M aqueous solution of hydrochloric acid (40 ml) and brine (40 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated, evaporated,]]]]]]]1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 1.3 (s, 9 H) 1.4 - 1.8 (m, 2 H) 2.1 - 2.3 (m, 2 H) 2.7 (d,J =7.0 Hz, 2 H) 3.5 - 3.7 (m, 1 H) 6.7 (d,J =8.8 Hz, 1 H) 7.2 - 7.7 (m, 9 H) 12.0 (br. s., 1 H); ESI+ MSm/z 369.5 ([M+H]+ , 370.5).Instance 3 : (S)-4- Amine -5-( Biphenyl -4- base ) Valeric acid (S)-5-(Biphenyl-4-yl)-4-(t-butoxycarbonylamino)pentanoic acid (6.512 g, 17 mmol) was added to dichloromethane (20 ml). Trifluoroacetic acid (10 ml) was added to the mixture. The mixture was stirred at room temperature until foaming stopped, and then the mixture was stirred at 50 ° C for another 40 minutes. The mixture was then concentrated under reduced pressure. Then ethyl acetate (120 ml) was added. The mixture was washed with water (3 x 40 ml) and brine (40 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated, evaporated.1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 1.7 - 1.9 (m, 2 H) 2.3 - 2.5 (m, 2 H) 2.8 - 3.0 (m, 2 H) 3.4 - 3.6 (m, 1 H) 7.3 (d,J =8.0 Hz, 3 H) 7.4 (t,J =7.6 Hz, 2 H) 7.6 (dd,J =7.6, 4.4 Hz, 4 H) 7.9 (br. s., 3 H); ESI+ MSm/z 269.3 ([M+H]+ , 270.3).Instance 4 : (S)-5-( Biphenyl -4- base )-4-(2,5- Bis-oxy -2,5- Dihydrogen -1H- Pyrrole -1- base ) Valeric acid Maleic anhydride (820 mg, 8.3 mmol) was added to tetrahydrofuran (40 ml). Then, a mixture of (S)-4-amino-5-(biphenyl-4-yl)pentanoic acid (2.131 g, 6.9 mmol) in tetrahydrofuran (8 ml) was added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was then concentrated to dryness and toluene (50 mL). Then, zinc (II) bromide (1.550 g, 6.9 mmol) was added in one portion and the resulting mixture was stirred strictly and heated to 80 °C. A solution of hexamethyldioxane (2.6 ml, 12.4 mmol) in toluene (15 ml) was added in three separate portions over 30 minutes. The reaction was stirred at 80 ° C overnight. The reaction mixture was evaporated to dryness. The resulting oil was washed with a saturated sodium carbonate solution (2×20 ml) and brine (40 ml). Ethyl acetate (40 ml) was added. The organic layer was dried over anhydrous sodium sulfate, filtered, and then evaporated and evaporated.]]]~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Dihydro-1H-pyrrol-1-yl)pentanoic acid.1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 1.9 - 2.0 (m, 1 H) 2.1 - 2.3 (m, 3 H) 2.9 - 3.2 (m, 2 H) 4.1 - 4.3 (m, 1 H) 6.8 (s, 2 H) 7.0 - 7.7 ( m, 9 H) 12.1 (br. s., 1 H); ESI+ MSm/z 349.4 ([M+H]+ , 350.4).Instance 5 : (S)-5- Biphenyl -4- base -4- Third butoxycarbonylamino group - Ethyl valerate To the (S)-2-biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (5.9 g) in ethanol (10 mL) at room temperature Sodium ethoxide (1.14 g) was added to the solution. After 30 minutes, the solution was poured into brine and extracted with TBME. The combined organic extracts were dried and concentrated to give (S)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-acetic acid ethyl ester.1 H NMR (CDCl3 ): 1.22~1.26 (3H, t), 1.40 (9H, s), 1.62~1.68 (1H, m), 1.86~1.94 (1H, m), 2.36~2.41 (2H, m), 2.76~2.87 (2H , m), 3.86 (1H, s), 4.11~4.23 (2H, q), 3.38~3.41 (1H, m), 7.24 ~7.58 (9H, m, aromatic).Instance 6 : (S)-4- Amine -5-( Biphenyl -4- base ) Ethyl valerate Ethyl (S)-5-(biphenyl-4-yl)-4-(t-butoxycarbonylamino)pentanoate (5 g, 12.6 mmol) was dissolved in dichloromethane (20 ml). Trifluoroacetic acid (8 ml) was added to the mixture. The mixture was stirred at room temperature until foaming stopped, and then the mixture was stirred at 50 ° C for another 40 minutes. The mixture was then concentrated under reduced pressure. Then ethyl acetate (120 ml) was added. The resulting mixture was washed with a saturated sodium carbonate solution (2×40 ml) and brine (40 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated, evaporated]]]]1 H NMR (400 MHz, DMSO-d 6 )δ ppm 1.5 (t,J =7.1 Hz, 3 H) 2.1 - 2.3 (m, 2 H) 2.7 - 3.0 (m, 2 H) 3.2 - 3.5 (m, 2 H) 3.8 - 4.0 (m, 1 H) 4.4 (q,J =7.0 Hz, 2 H) 7.6 - 8.2 (m, 9 H) 8.5 (br. s., 3 H); ESI+ MSm/z 297.4 ([M+H]+ , 298.4).Instance 7 : (S)-5-( Biphenyl -4- base )-4-(2,5- Bis-oxy -2,5- Dihydrogen -1H- Pyrrole -1- base ) Ethyl valerate Maleic anhydride (1.28 g, 13.0 mmol) was added to tetrahydrofuran (60 ml) at room temperature. Then ethyl (S)-4-amino-5-(biphenyl-4-yl)pentanoate (3.226 g, 10.9 mmol) was added to tetrahydrofuran (12 ml). The resulting mixture was stirred at room temperature for 3 hours. The mixture was then concentrated to dryness and toluene (80 mL). Then, zinc (II) bromide (2.443 g, 10.9 mmol) was added in one portion and the resulting mixture was stirred strictly and heated to 80 °C. A solution of hexamethyldioxane (4.1 ml, 19.5 mmol) in toluene (25 ml) was added in three separate portions over 30 minutes. The reaction was stirred at 80 ° C overnight. The reaction mixture was evaporated to dryness. Ethyl acetate (50 ml) was added and the mixture was washed with saturated sodium carbonate (2×40 ml) and brine (40 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by chromatography (1% MeOH in dichloromethane) to afford (S)-5-(biphenyl-4-yl)-4-(2,5-di- oxy-2,5 -Dihydro-1H-pyrrol-1-yl)pentanoic acid ethyl ester.1 H NMR (400 MHz, DMSO-d 6 ) 1.1 (t,J =7.1 Hz, 3 H) 1.9 - 2.4 (m, 4 H) 2.9 - 3.2 (m, 2 H) 4.0 (q,J =7.1 Hz, 2 H) 4.1 - 4.3 (m, 1 H) 6.9 (s, 2 H) 7.0 - 7.7 (m, 9 H); ESI+ MSm/z 377.4 ([M+H]+ , 378.4);IR (FTIR) cm-1 3454 (C=O), 3099 (CH. arom), 2977 (CH. aliph), 1728, 1702 (C=O phthalimide + ester), 1400, 1371 (C-N).Instance 8 : [(S)-1- Biphenyl -4- Methyl -4-((S)-2- Hydroxymethyl - Pyrrolidine -1- base )-4- Side oxy - Butyl ]- Tert-butyl carbamic acid Sodium methoxide (54 mg, 1 mmol) was added to (S)-2-biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3.5 g, 10 mmol) And a mixture of (S)-(+)-prolinol (1.11 g, 11 mmol) in 50 mL of dry THF and stirred for 3 hr. Aqueous ammonium chloride solution was then added, the mixture was extracted with ethyl acetate and the organic extracts were combined and dried. The residue was purified by column chromatography to give [(S)-1-biphenyl-4-ylmethyl-4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-4- Tributyl butyl-butyl]-carbamic acid.1 H NMR (CDCl3 ): 1.40 (9H, s, (CH3 )3 ), 1.80 (2H, m, 3-CH)2 ), 1.90 (4H, m, CH2 CH2 ), 2.36 (2H, m, 2- CH2 ), 2.85 (2H, m, 5-CH)2 ), 3.42 (1H, m, 4-CH), 3.45 (2H, m, CH2 ), 3.58 (2H, m, CH2 ), 4.18 (1H, m, CH), 4.93 (1H, s, OH), 7.40~7.60 (9H, m, aromatic). HPLC method: column: Eclipse XDB-C18; 150 x 4.6 mm; 5 μm. Mobile phase A (0.1 % H3 PO4 ) contained in water; mobile phase B (acetonitrile). Gradient: 0 min (90% B); 10 min (95% B); 15 min (95% B). Flow rate: 0.7 ml min-1 . Wavelength: 210 nm. Temperature: 30 ° C. Residence time: 11.2 minInstance 9 : [(S)-1- Biphenyl -4- Methyl -4- Side oxy -4- Pyrrolidine -1- base - Butyl ]- Tert-butyl carbamic acid Sodium methoxide (16 mg, 0.3 mmol) was added to (S)-2-biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (1.05 g, 3 mmol) And a mixture of pyrrolidine (0.23 g, 3.3 mmol) in 15 mL of anhydrous THF and stirred for 3 hours. Aqueous ammonium chloride solution was added, the mixture was extracted with ethyl acetate. The residue was purified by column chromatography to give [(S)-1-biphenyl-4-ylmethyl-4- oxo-4-pyrrolidin-1-yl-butyl]-carbamic acid Tributyl ester.1 H NMR (CDCl3 ): 1.40 (9H, s, (CH3 )3 ), 1.82 (2H, m, 3-CH)2 ), 1.90 (4H, m, CH2 CH2 ), 2.32 (2H, m, 2- CH2 ), 2.78 (2H, m, 5-CH)2 ), 2.90 (1H, m, 4-CH), 3.36 (2H, t, CH2 ), 3.44 (2H, t, CH2 ), 7.20~7.60 (9H, m, aromatic). HPLC method: column: Eclipse XDB-C18; 150 x 4.6 mm; 5 μm. Mobile phase A (0.1 % H3 PO4 ) contained in water; mobile phase B (acetonitrile). Gradient: 0 min (90% B); 10 min (95% B); 15 min (95% B). Flow rate: 0.7ml min-1 . Wavelength: 210 nm. Temperature: 30 ° C. Residence time: 13.2 minInstance 10 : (S)-1-( Biphenyl -4- base )-5-( Dimethylamino group )-5- Oxylo-pentyl -2- Tert-butyl carbamic acid To (S)-2-biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (351 mg, 1 mmol) and lithium hexafluorophosphate (152 mg, 1 mmol) To a mixture of tetrahydrofuran (5 ml) was added dimethylamine (2M in THF) (5 ml, 10 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The mixture was then concentrated in vacuo and ethyl acetate (20 mL) was evaporated. The mixture was washed with a saturated sodium carbonate solution (2×20 ml) and then brine (20 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated and evaporated. The obtained residue was purified by column chromatography to give (S)-1-(biphenyl-4-yl)-5-(dimethylamino)-5-oxoxypentan-2-ylaminocarboxylic acid Third butyl ester.1 H NMR (400 MHz, d6 -DMSO): 1.3 (s, 9 H) 1.5 - 1.8 (m, 2 H) 2.3 (t,J =7.5 Hz, 2 H) 2.7 (d,J =5.8 Hz, 2 H) 2.8 (s, 3 H) 2.9 (s, 3 H) 3.6 (br. s., 1 H) 6.8 (d,J =8.8 Hz, 1 H) 7.2 - 7.7 (m, 9 H); ESI+ MSm/z 369.5 ([M+H]+ , 370.5);IR (FTIR) cm-1 3255 (N-H), 3005, 2981 (CH. arom), 2968, 2944 (CH. aliph), 1714 (C=O. Boc), 1619 (C=O. decylamine).Instance 11 : (S)-5- Biphenyl -4- base -4-(1,3- Bis-oxy -1,3- Dihydrogen - Different -2- base )- Valeric acid To a solution of (S)-4-amino-5-biphenyl-4-yl-pentanoic acid hydrochloride (30.0 g, 98 mmol) in THF (300 mL), triethylamine (27.4 mL, 197 Methyl) 1,3-dihydro-1,3-dihydro-isoindole-2-carboxylic acid ethyl ester (25.2 g, 103 mmol). The reaction mixture was refluxed for 12 hours. The solvent was then removed under vacuum, 200 mL of 2N HCl was added, stirred for 0.5 h, filtered, and the filter cake was washed with 2N HCl and n-heptane and then dried to give (S)-5-biphenyl-4-yl-4- (1,3-Di-oxy-1,3-dihydro-isoindol-2-yl)-pentanoic acid, as determined by HPLC.1 H NMR (CDCl3 ): 2.15 (1H, m, 3-CH), 2.36 (2H, m, 2-CH2 ), 2.54 (1H, m, 3-CH), 4.56 (1H, m, 4-CH), 7.20~7.80 (13H, m, aromatic). HPLC method: column: Eclipse XDB-C18; 150 x 4.6 mm; 5 μm. Mobile phase A (0.1 % H3 PO4 ) contained in water; mobile phase B (acetonitrile). Gradient: 0 min (30% B); 8 min (95% B); 15 min (95% B). Flow rate: 1.0 ml min-1 . Wavelength: 210 nm. Temperature: 30 ° C. Residence time: 7.8 min.Instance 12 : 2-((S)-1- Biphenyl -4- Methyl -4- Side oxy -4- Pyrrolidine -1- base - Butyl )- Different -1,3- Diketone To 2-((S)-1-biphenyl-4-ylmethyl-4-morpholin-4-yl-4-yloxy-butyl)-isoindole-1,3 at room temperature a solution of diketone (5 g, 12.52 mmol) in dry THF (30 mL) EtOAc (EtOAc: EtOAc (EtOAc: EtOAc) And pyrrolidine (0.98 g, 13.77 mmol). The reaction mixture was stirred vigorously for 12 h then ethyl acetate (100 mL) was added to the mixture. Separate the organic phase, using 1N HCl (50 mL), saturated NaHCO3 The solution (50 mL) and brine (50 mL) were washed, dried and concentrated. The obtained residue was purified by flash column chromatography to give 2-((s)-1-biphenyl-4-ylmethyl-4- oxo-4-pyrrolidin-1-yl-butyl)- Isoindole-1,3-dione.1 H NMR (CDCl3 ): 1.78 (2H, m), 1.85 (2H, m), 2.23 (2H, m), 2.63 (1H, m), 3.30 (6H, m), 4.72 (1H, m), 7.20~7.78 (13H, m, aromatic). MS (ESI, m/e) 453 (MH+). 2-((S)-1-Biphenyl-4-ylmethyl-4-oxo-4-pyrrolidin-1-yl-butyl)-isoindole-1,3-dione is a crystalline solid And can be characterized by X-ray powder pattern. The strongest reflection in the X-ray diffraction pattern shows the following interplanar plane spacing (average 2θ to [o The meter is indicated by an error limit of ±0.2): 2θ to [o ]: 3.7, 9.6, 10.5, 11.2, 14.7, 15.7, 16.4, 19.6, 20.1, 21.2, 26.2. Data were collected using Cu-Kα radiation using a Bruker D8 advanced diffractometer. HPLC method: column: Eclipse XDB-C18; 150 x 4.6 mm; 5 μm. Mobile phase A (0.1 % H3 PO4 ) contained in water; mobile phase B (acetonitrile). Gradient: 0 min (30% B); 8 min (95% B); 15 min (95% B). Flow rate: 1.0 ml min-1 . Wavelength: 210 nm. Temperature: 30 ° C. Residence time: 9.4 minInstance 13 : 2-((S)-1- Biphenyl -4- Methyl -4- Morpholine -4- base -4- Side oxy - Butyl ) Different -1, 3- Diketone To (S)-5-biphenyl-4-yl-4-(1,3-di- oxy-1,3-dihydro-isoindol-2-yl)-pentanoic acid at room temperature ( 5 g, 12.52 mmol) of the solution in anhydrous THF (30 mL) was added EDC·HCl (2.88 g, 15.03 mmol), HOBt (2.03 g, 15.03 mmol), TEA (7 mL, 50.08 mmol) and morpholine ( 1.20 g, 13.77 mmol). The reaction mixture was stirred vigorously for 12 h then ethyl acetate (100 mL). 1N HCl (50 mL), saturated NaHCO3 The organic phase was washed with a solution (50 mL) and brine (50 mL), dried and concentrated. The obtained residue was purified by flash column chromatography to give 2-((s)-1-biphenyl-4-ylmethyl-4-morpholin-4-yl-4-yloxy-butyl)- Isoindole-1,3-dione.1 H NMR (CDCl3 ): 1.24 (2H, m), 2.21~2.29 (1H, m), 2.31~2.40 (2H, m), 2.52~2.57 (1H, m), 3.18~3.21 (1H, m), 3.23(2H, m ), 3.24~3.32 (2H, m), 3.53~3.57 (3H, m), 7.23 ~ 7.75 (13H, m, aromatic). MS (ESI, m/e) 469 (MH+). 2-((S)-1-Biphenyl-4-ylmethyl-4-morpholin-4-yl-4-yloxy-butyl)isoindole-1,3-dione is a crystalline solid and It can be characterized by X-ray powder pattern. The strongest reflection in the X-ray diffraction pattern shows the following interplanar plane spacing (average 2θ to [o The meter is indicated by an error limit of ±0.2): 2θ to [o ]: 3.6, 9.5, 10.8, 12.6, 13.1, 14.5, 15.9, 16.9, 18.5, 19.3, 20.4, 22.5, 23.1, 24.1, 25.9, 27.2, 27.9. Data were collected using Cu-Kα radiation using a Bruker D8 advanced diffractometer. HPLC method: column: Eclipse XDB-C18; 150 x 4.6 mm; 5 μm. Mobile phase A (0.1 % H3 PO4 ) contained in water; mobile phase B (acetonitrile). Gradient: 0 min (30% B); 8 min (95% B); 15 min (95% B). Flow rate: 1.0 ml min-1 . Wavelength: 210 nm. Temperature: 30 ° C. Residence time: 7.9 minInstance 14 : 2-[(S)-4-((R)-4- Benzyl -2- Side oxy - Oxazolidine -3- base )-1- Biphenyl -4- Methyl -4- Side oxy - Butyl ]- Different -1,3- Diketone To (S)-5-biphenyl-4-yl-4-(1,3-di-oxo-1,3-dihydro-isoindol-2-yl)pentanoic acid (1.00 g, 2.95 mmol) Add 1 drop of DMF to the solution containing 10 mL of anhydrous DCM, cool to 0 ° C, then add (COCl)2 (0.75 g, 5.89 mmol). The mixture was stirred for 1 hour and then distilled in excess (COCl)2 . In a separate flask, NaH (142 mg, 3.24 mmol) was suspended in 10 mL anhydrous THF, cooled to 0 ° C, and (R)-4-benzyl-oxazolidin-2-one (0.57 g, 3.24) Methyl), stirred at 0 ° C for 1 hour, then added pre-formed ruthenium chloride. The reaction mixture was stirred at 0 ° C for 30 minutes and then saturated NH was added.4 Cl, extracted with DCM and washed with water, 5% NaHCO3 The organic extract was washed with brine, dried and concentrated. The obtained crude material was crystallized to give 2-[(S)-4-((R)-4-benzyl-2-yloxy-oxazolidine-3-yl)-1-biphenyl-4-yl-methyl Keto-4-oxo-butyl]-isoindole-1,3-dione.1 H NMR (CDCl3 ): 2.28 (1H, m), 2.25 (1H, m), 2.67 (1H, m), 2.95 (2H, m), 3.27 (2H, m), 3.50 (1H, m), 4.15 (1H, m) , 4.23 (1H, m), 7.15 ~ 7.80 (18H, m, aromatic). m/z: 559 (MH+ ). 2-[(S)-4-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-1-biphenyl-4-ylmethyl-4-yloxy - Butyl]-isoindole-1,3-dione is a crystalline solid and can be characterized by X-ray powder pattern. The strongest reflection in the X-ray diffraction pattern shows the following interplanar plane spacing (average 2θ to [o The meter is indicated by an error limit of ±0.2): 2θ to [o ]: 4.4, 8.6, 9.4, 10.7, 12.3, 14.2, 14.6, 15.9, 16.9, 18.1, 19.6, 20.4, 20.7, 21.3, 21.7, 22.1, 23.2, 23.7, 24.2, 24.8, 25.1, 26.4. Data were collected using Cu-Kα radiation using a Bruker D8 advanced diffractometer. HPLC method: column: Eclipse XDB-C18; 150 x 4.6 mm; 5 μm. Mobile phase A (0.1 % H3 PO4 ) contained in water; mobile phase B (acetonitrile). Gradient: 0 min (10% B); 10 min (95% B); 15 min (95% B). Flow rate: 1.0 ml min-1 . Wavelength: 210 nm. Temperature: 30 ° C. Residence time: 11.5 minInstance 15 : 2-[(S)-4-((R)-4- Isopropyl -2- Side oxy - Oxazolidine -3- base )-1- Biphenyl -4- Methyl -4- Side oxy - Butyl ]- Different -1,3- Diketone To (S)-5-biphenyl-4-yl-4-(1,3-di-oxo-1,3-dihydro-isoindol-2-yl)-pentanoic acid (1.00 g, 2.95 mmol ) contained in 10 mL of anhydrous CH2 Cl2 Add 1 drop of DMF to the solution, cool to 0 ° C, then add (COCl)2 (0.75 g, 5.89 mmol). The mixture was stirred for 1 hour and then distilled in excess (COCl)2 . In a separate flask, NaH (142 mg, 3.24 mmol) was suspended in 10 mL anhydrous THF, cooled to 0 ° C, and (R)-4-isopropyl-oxazolidin-2-one (418 mg, 3.24 mmol), stir at 0 °C for 1 hour, then add pre-formed ruthenium chloride. The reaction mixture was stirred at 0 ° C for 30 minutes and then saturated NH was added.4 Cl, extracted with DCM and washed with water, 5% NaHCO3 The organic extract was washed with brine, dried and concentrated. The crude material was purified by column chromatography to give 2-[(S)-4-((R)-4-isopropyl-2-oxo-oxazolidine-3-yl)-1- Benz-4-ylmethyl-4-oxo-butyl]-isoindole-1,3-dione.1 H NMR (CDCl3 ): 0.8 (6H, d), 2.26 (2H, m), 2.54 (1H, m), 2.90 (1H, m), 3.01 (1H, m), 3.20 (1H, m), 3.45 (1H, m) , 4.10 (2H, dd), 4.27 (1H, m), 4.60 (1H, m), 7.20 ~ 7.80 (13H, m, aromatic). m/z: 400 (MH+ ). HPLC method: column: Eclipse XDB-C18; 150 x 4.6 mm; 5 μm. Mobile phase A (0.1 % H3 PO4 ) contained in water; mobile phase B (acetonitrile). Gradient: 0 min (30% B); 8 min (95% B); 15 min (95% B). Flow rate: 1.0 ml min-1 . Wavelength: 210 nm. Temperature: 30 ° C. Residence time: 9.8 minInstance 16 : (S)-5- Biphenyl -4- base -4- Dibenzylamino group -1-((S)-2- Hydroxymethyl - Pyrrolidine -1- base )- E -1- ketone To (S)-5-biphenyl-4-yl-4-dibenzylamino-pentanoic acid hydrochloride (4.86 g, 10 mmol) in 100 mL CH2 Cl2 The suspension was added (S)-(+)-prolinol (1.11 g, 11 mmol), EDC·HCl (2.3 g, 12 mmol), HOBt (1.62 g, 12 mmol) and TEA (5 g). , 50 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was washed with water, dried and concentrated. The obtained residue was purified by column chromatography (ethyl acetate /Heptane = 1/2) to afford (S)-5-biphenyl-4-yl-4-dibenzylamino-1-((S) 2-hydroxymethyl-pyrrolidin-1-yl)-pentan-1-one.1 H NMR (CDCl3 ): 1.69 ( 1H, m, 3-CH H), 1.75 (1H, m, 3-CHH ), 1.94 (4H, m, CH2 CH2 ), 2.50 (1H, m, 2- CH H), 2.55 (2H, m, 5-CH2 ), 2.79 (1H, m, 2- CHH ), 3.17 (1H, dd, 4-CH), 3.31 (2H, m, CH2 ), 3.54 (2H, d, CH2 ), 3.58 (2H, m, CH2 ), 3.88 (2H, d, CH2 ), 4.09 (1H, m, CH), 5.14 (1H, s, OH), 7.10~7.50 (19H, m, aromatic). HPLC method: column: Eclipse XDB-C18; 150 x 4.6 mm; 5 μm. Mobile phase A (0.1 % H3 PO4 ) contained in water; mobile phase B (acetonitrile). Gradient: 0 min (30% B); 8 min (95% B); 15 min (95% B). Flow rate: 1.0 ml min-1 . Wavelength: 210 nm. Temperature: 30 ° C. Residence time: 9.6 min.Instance 17 : (S)-5- Biphenyl -4- base -4- Dibenzylamino group -1-((R)-2- Hydroxymethyl - Pyrrolidine -1- base )- E -1- ketone (S)-5-Biphenyl-4-yl-4-dibenzylamino-pentanoic acid hydrochloride (4.86 g, 10 mmol) in 100 mL CH2 Cl2 The suspension was added (R)-(-)-melamine (1.11 g, 11 mmol), EDC·HCl (2.3 g, 12 mmol), HOBt (1.62 g, 12 mmol) and TEA (5 g). , 50 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was washed with water, dried and concentrated. The obtained residue was purified by column chromatography (ethyl acetate / heptane = 1/2) to afford (S)-5-biphenyl-4-yl-4-dibenzylamino-1-((R) 2-hydroxymethyl-pyrrolidin-1-yl)-pentan-1-one.1 H NMR (CDCl3 ): 1.69 ( 1H, m, 3-CH H), 1.75 (1H, m, 3-CHH ), 1.94 (4H, m, CH2 CH2 ), 2.50 (1H, m, 2- CH H), 2.55 (2H, m, 5-CH2 ), 2.79 (1H, m, 2- CHH ), 3.18 (1H, dd, 4-CH), 3.31 (2H, m, CH2 ), 3.54 (2H, d, CH2 ), 3.57 (2H, m, CH2 ), 3.87 (2H, d, CH2 ), 4.12 (1H, m, CH), 5.12 (1H, d, OH), 7.10~7.50 (19H, m, aromatic). HPLC method: column: Eclipse XDB-C18; 150 x 4.6 mm; 5 μm. Mobile phase A (0.1 % H3 PO4 ) contained in water; mobile phase B (acetonitrile). Gradient: 0 min (30% B); 8 min (95% B); 15 min (95% B). Flow rate: 1.0 ml min-1 . Wavelength: 210 nm. Temperature: 30 ° C. Residence time: 9.5 min.Instance 18 : (S)-5- Biphenyl -4- base -4- Dibenzylamino group - Methyl valerate -((S)-1- Phenyl - Ethyl )- Guanamine To (S)-5-biphenyl-4-yl-4-dibenzylamino-pentanoic acid hydrochloride (4.86 g, 10 mmol) in 10 mL CH2 Cl2 (S)-Methyl-(1-phenyl-ethyl)-amine (0.19 g, 1.36 mmol), EDC·HCl (0.29 g, 1.5 mmol), HOBt (0.21 g, 1.5) Methyl) and TEA (0.63 g, 6.2 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was washed with water, dried and concentrated. The obtained residue was purified by column chromatography (ethyl acetate / heptane = 1/5) to afford (S)-5-biphenyl-4-yl-4-dibenzylamino-pentanoic acid methyl- ((S)-1-Phenyl-ethyl)-guanamine.1 H NMR (CDCl3 ): 1.40 (3H, d, CH3 ), 1.74 ( 1H, m, 3-CH H), 1.90 (1H, m, 3-CHH ), 2.50 (3H, s, CH3 ), 2.60 (2H, m, 2- CH2 ), 2.80 (2H, m, 5-CH)2 ), 3.20 (1H, dd, 4-CH), 3.57 (2H, d, CH2 ), 3.89 (2H, d, CH2 ), 6.02 (1H, q, CH), 7.10~7.50 (24H, m, aromatic). HPLC method: column: Eclipse XDB-C18; 150 x 4.6 mm; 5 μm. Mobile phase A (0.1 % H3 PO4 ) contained in water; mobile phase B (acetonitrile). Gradient: 0 min (30% B); 8 min (95% B); 15 min (95% B). Flow rate: 1.0 ml min-1 . Wavelength: 210 nm. Temperature: 30 ° C. Residence time: 11.1 minInstance 19 : (S)-5- Biphenyl -4- base -4- Dibenzylamino group - Methyl valerate -((R)-1- Phenyl - Ethyl )- Guanamine To (S)-5-biphenyl-4-yl-4-dibenzylamino-pentanoic acid hydrochloride (4.86 g, 10 mmol) in 10 mL CH2 Cl2 The suspension was added (R)-methyl-(1-phenyl-ethyl)-amine (0.19 g, 1.36 mmol), EDC·HCl (0.29 g, 1.5 mmol), HOBt (0.21 g, 1.5). Methyl) and TEA (0.63 g, 6.2 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was washed with water, dried and concentrated. The residue was purified by column chromatography (ethyl acetate /Heptane = 1/5) to afford (S)-5-biphenyl-4-yl-4-dibenzylamino-pentanoic acid methyl- ( (S)-1-Phenyl-ethyl)-guanamine.1 H NMR (CDCl3 ): 1.45 (3H, d, CH3 ), 1.73 ( 1H, m, 3-CH H), 1.90 (1H, m, 3-CHH ), 2.51 (3H, s, CH3 ), 2.63 (2H, m, 2- CH2 ), 2.79 (2H, m, 5-CH)2 ), 3.20 (1H, dd, 4-CH), 3.54 (2H, q, CH2 ), 3.87 (2H, q, CH2 ), 6.02 (1H, q, CH), 7.10~7.50 (24H, m, aromatic). HPLC method: column: Eclipse XDB-C18; 150 x 4.6 mm; 5 μm. Mobile phase A (0.1 % H3 PO4 ) contained in water; mobile phase B (acetonitrile). Gradient: 0 min (30% B); 8 min (95% B); 15 min (95% B). Flow rate: 1.0 ml min-1 . Wavelength: 210 nm. Temperature: 30 ° C. Residence time: 11.0 min.Instance 20 : 5- Biphenyl -4- base -(S)-4- Dibenzylamino group -1- Pyrrolidine -1- base - E -1- ketone To 5-biphenyl-4-yl-(S)-4-dibenzylamino-pentanoic acid hydrochloride (1.46 g, 3 mmol) in CH2 Cl2 The solution was added, followed by the addition of triethylamine (0.34 g, <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> CDI (0.73 g, 4.5 mmol). After stirring for 30 minutes, the reaction mixture was diluted with water, and the organic layer was dried and concentrated to give 5-biphenyl-4-yl-(S)-4-dibenzylamino-1-pyrrolidin-1-yl-pentane- 1-ketone.1 H NMR (CDCl3 ): 1.80 ( 2H, m, 3-CH2 ), 1.88 (2H, m, CH2 ), 1.98 (2H, m, CH2 ), 2.53 (2H, m, 2-CH)2 ), 2.81 (2H, m, 5-CH)2 ), 3.20 (1H, dd, 4-CH), 3.26(2H, m, CH2 ), 3.38 (2H, m, CH2 ), 3.54 (2H, d, CH2 ), 3.84 (2H, d, CH2 ), 7.10~7.4 (19H, m, aromatic). HPLC method: column: Waters Xbridge-Phenyl; 150 x 3.0 mm; 3.5 μm. Mobile phase A (0.1% DEA) is contained in water; mobile phase B (acetonitrile). Gradient: 0 min (90% B); 10 min (95% B); 15 min (95% B). Flow rate: 0.7 ml min-1. Wavelength: 210 nm. Temperature: 30 ° C. Residence time: 11.2 min.Instance twenty one : (S)-5- Biphenyl -4- base -4-(1,3- Dihydrogen - Different -2- base )- Methyl valerate -(R-1- Phenyl - Ethyl )- Guanamine To (S)-5-biphenyl-4-yl-4-(1,3-di-oxy-1,3-1,3-dihydro-isoindol-2-yl)-pentanoic acid (4.0 g, 10 mmol ) contained in 100 mL CH2 Cl2 N-methyl-(R-1-phenyl-ethyl)amine (1.48 g, 11 mmol), EDC·HCl (2.3 g, 12 mmol), HOBt (1.62 g, 12 mmol) and TEA (5 g, 50 mmol), and the mixture was stirred at room temperature for 12 hr. After washing the mixture with water, it was dried and concentrated. The residue was purified by column chromatography (ethyl acetate / hexanes / EtOAc) to afford (S)-5-biphenyl-4-yl-4-(1,3-dihydro-isoindole- 2-yl)-pentanoic acid methyl-(R-1-phenyl-ethyl)-guanamine.1 H NMR (CDCl3 ): 1.39 ( 3H, d), 2.34 (3H, m), 2.51 (3H, s), 2.60 (1H, m), 3.24 (1H, m), 3.46 (1H, m), 4.65 (1H, m) , 5.99 (1H, m), 7.20~7.80 (18H, m, aromatic). HPLC method: column: Eclipse XDB-C18; 150 x 4.6 mm; 5 μm. Mobile phase A (0.1% H3 PO4 ) contained in water; mobile phase B (acetonitrile). Gradient: 0 min (30% B); 8 min (95% B); 15 min (95% B). Flow rate: 1.0 ml/min. Wavelength: 210 nm. Temperature: 30 ° C. Residence time: 9.9 min.Instance twenty two : (S)-5- Biphenyl -4- base -4-(1,3- Dihydrogen - Different -2- base )- Methyl valerate -(S-1- Phenyl - Ethyl )- Guanamine To (S)-5-biphenyl-4-yl-4-(1,3-di-oxy-1,3-1,3-dihydro-isoindol-2-yl)-pentanoic acid (4.0 g, 10 mmol ) contained in 100 mL CH2 Cl2 N-methyl-(S-1-phenyl-ethyl)amine (1.48 g, 11 mmol), EDC·HCl (2.3 g, 12 mmol), HOBt (1.62 g, 12 mmol) and TEA (5 g, 50 mmol), and the mixture was stirred at room temperature for 12 hr. After washing the mixture with water, it was dried and concentrated. The residue was purified by column chromatography (ethyl acetate / hexanes / EtOAc) to afford (S)-5-biphenyl-4-yl-4-(1,3-dihydro-isoindole- 2-yl)-pentanoic acid methyl-(S-1-phenyl-ethyl)-guanamine.1 H NMR (CDCl3 ): 1.39 ( 3H, d), 2.34 (3H, m), 2.51 (3H, s), 2.60 (1H, m), 3.24 (1H, m), 3.46 (1H, m), 4.65 (1H, m) , 5.99 (1H, m), 7.20~7.80 (18H, m, aromatic). HPLC method: column: Eclipse XDB-C18; 150 x 4.6 mm; 5 μm. Mobile phase A (0.1 % H3 PO4 ) contained in water; mobile phase B (acetonitrile). Gradient: 0 min (30% B); 8 min (95% B); 15 min (95% B). Flow rate: 1.0 ml min-1 . Wavelength: 210 nm. Temperature: 30 ° C. Residence time: 9.9 min.Instance twenty three : 2-(S)-1- Biphenyl -4- Methyl -4(R)-2- Hydroxymethyl - Pyrrolidine -1- base )-4- Side oxy - Butyl )- Different -1,3- Diketone To (S)-5-biphenyl-4-yl-4-(1,3-di-oxy-1,3-1,3-dihydro-isoindol-2-yl)-pentanoic acid (4.0 g, 10 mmol ) contained in 100 mL CH2 Cl2 (R)-prolinol (1.12 g, 11 mmol), EDC·HCl (2.3 g, 12 mmol), HOBt (1.62 g, 12 mmol) and TEA (5 g, 50 mmol) were added. The mixture was stirred at room temperature for 12 hours. The reaction mixture was washed with water, dried and concentrated. The residue was purified by column chromatography to give 2-(S)-1-biphenyl-4-ylmethyl-4(R)-2-hydroxymethyl-pyrrolidin-1-yl)-4- side Oxy-butyl)-isoindole-1,3-dione.1 H NMR (CDCl3 ): 1.57 (1H, m), 1.78 (1H, m), 1.93 (2H, m), 2.24 (1H, m), 2.30 (2H, m), 2.57 (1H, m), 3.1-3.6 (5H, m), 3.72 (1H, m), 3.95 (1H, m), 4.60 (1H, m), 7.20~7.80 (13H, m, aromatic). HPLC method: column: Eclipse XDB-C18; 150 x 4.6 mm; 5 μm. Mobile phase A (0.1 % H3 PO4 ) contained in water; mobile phase B (acetonitrile). Gradient: 0 min (30% B); 8 min (95% B); 15 min (95% B). Flow rate: 1.0 ml min-1 . Wavelength: 210 nm. Temperature: 30 ° C. Residence time: 7.6 min.Instance twenty four : 2-(S)-1- Biphenyl -4- Methyl -4(S)-2- Hydroxymethyl - Pyrrolidine -1- base )-4- Side oxy - Butyl )- Different -1,3- Diketone To (S)-5-biphenyl-4-yl-4-(1,3-di-oxy-1,3-1,3-dihydro-isoindol-2-yl)-pentanoic acid (4.0 g, 10 mmol ) contained in 100 mL CH2 Cl2 (S)-prolinol (1.12 g, 11 mmol), EDC·HCl (2.3 g, 12 mmol), HOBt (1.62 g, 12 mmol) and TEA (5 g, 50 mmol) were added. The mixture was stirred at room temperature for 12 hours. The reaction mixture was then washed with water, dried and concentrated. The residue was purified by column chromatography to give 2-(S)-1-biphenyl-4-ylmethyl-4(S)-2-hydroxymethyl-pyrrolidin-1-yl)-4- side Oxy-butyl)-isoindole-1,3-dione.1 H NMR (CDCl3 ): 1.53 ( 1H, m), 1.83 (2H, m), 1.98 (1H, m), 2.22 (1H, m), 2.32 (2H, m), 2.59 (1H, m), 3.22 (1H, dd) , 3.30-3.50 (4H, m), 3.56 (1H, m), 4.13 (1H, m), 7.20~7.80 (13H, m, aromatic). HPLC method: column: Eclipse XDB-C18; 150 x 4.6 mm; 5 μm. Mobile phase A (0.1 % H3 PO4 ) contained in water; mobile phase B (acetonitrile). Gradient: 0 min (30% B); 8 min (95% B); 15 min (95% B). Flow rate: 1.0 ml min-1 . Wavelength: 210 nm. Temperature: 30 ° C. Residence time: 7.5 min.Instance 25 : (S)-5- Biphenyl -4- base -4- Dibenzylamino group - Benzyl valerate Add benzyl bromide (22.4 g, 130.8 mmol) to a suspension of (S)-4-amino-5-biphenyl-4-yl-pentanoic acid hydrochloride (10 g, 32.7 mmol) in 200 mL water. , K2 CO3 (18.1 g, 130.8 mmol) and NaOH (3.9 g, 98 mmol) and the mixture was heated to reflux for 4 h. Then, concentrated HCl was added, and the pH was adjusted to 4 to 5, extracted with ethyl acetate, and the organic layer was washed with water, dried and concentrated to give (S)-5-biphenyl-4-yl-4-dibenzylamine. Benzyl-valerate.1 H NMR (CDCl3 ): 1.70 ( 1H, m, 3-CH H), 1.9 0 (1H, m, 3-CHH ), 2.20 (1H, m, 2- CH H), 2.46 (1H, m, 5-CH H), 2.63 (1H, m, 2- CHH ), 2.83(1H, m, 5-CHH ), 3.18 (1H, dd, 4-CH), 3.52 (2H, d, CH2 ), 3.85 (2H, d, CH2 ), 4.98 (2H, s, CH2 ), 7.10~7.50 (24H, m, aromatic). HPLC method: column: Eclipse XDB-C18; 150 x 4.6 mm; 5 μm. Mobile phase A (0.1 % H3 PO4 ) contained in water; mobile phase B (acetonitrile). Gradient: 0 min (30% B); 8 min (95% B); 15 min (95% B). Flow rate: 1.0 ml min-1 . Wavelength: 210 nm. Temperature: 30 ° C. Residence time: 12.7 min.Instance 26 : (S)-5- Biphenyl -4- base -4- Dibenzylamino group - Palladium hydrochloride To a suspension of (S)-5-biphenyl-4-yl-4-dibenzylamino-pentanoic acid benzyl ester (14.5 g, 32.3 mmol) in water, 3.9 g of NaOH was added and the mixture was refluxed for 3 hours. After cooling to room temperature, the mixture was extracted with heptane and the aqueous layer was treated with concentrated HCl to adjust pH to 4 to 5, then the mixture was extracted with ethyl acetate, and the organic layer was washed with water, dried and concentrated. The obtained residue was treated with aq. EtOAc (EtOAc) EtOAc (EtOAc)EtOAc.1 H NMR (DMSO-d6 ): 1.75 ( 1H, m, 3-CH H), 1.92 (1H, m, 3-CHH ), 2.21 (1H, m, 2- CH H), 2.47 (1H, m, 5-CH H), 2.65 (1H, m, 2- CHH ), 2.84(1H, m, 5-CHH ), 3.20 (1H, dd, 4-CH), 3.54 (2H, d, CH2 ), 3.86 (2H, d, CH2 ), 7.10~7.50 (19H, m, aromatic), 10.8 (1H, s, COOH). HPLC method: column: Eclipse XDB-C18; 150 x 4.6 mm; 5 μm. Mobile phase A (0.1 % H3 PO4 ) contained in water; mobile phase B (acetonitrile). Gradient: 0 min (30% B); 8 min (95% B); 15 min (95% B). Flow rate: 1.0 ml min-1 . Wavelength: 210 nm. Temperature: 30 ° C. Residence time: 10.4 min.Instance 27 : 5- Biphenyl -4- base -(S)-4- Dibenzylamino group - Methyl valerate Add Concentrated H to a mixture of 4.9 g of 5-biphenyl-4-yl-(S)-4-dibenzylamino-pentanoic acid hydrochloride in 50 mL of MeOH2 SO4 (0.1 mL). The reaction mixture was heated to reflux for 12 hours. After removal of MeOH, the residue was dissolved in 50 mL ethyl acetate NaHCO3 Wash with water and dry. The solvent was removed and methyl 5-biphenyl-4-yl-(S)-4-dibenzylamino-pentanoate was obtained.1 H NMR (CDCl3 ): 1.65 ( 1H, m, 3-CH H), 1.87 (1H, m, 3-CHH ), 2.13 (1H, m, 2- CH2 ), 2.46 (1H, m, 2- CH2 ), 2.60 (1H, m, 5-CH)2 ), 2.81 (1H, m, 5-CH)2 ), 3.19 (1H, dd, 4-CH), 3.52 (2H, d, CH2 ), 3.55 (3H, s, OCH)3 ), 3.86 (2H, d, CH2 ), 7.10~7.50 (19H, m, aromatic). HPLC method: column: Eclipse XDB-C18; 150 x 4.6 mm; 5 μm. Mobile phase A (0.1 % H3 PO4 ) contained in water; mobile phase B (acetonitrile). Gradient: 0 min (90% B); 10 min (95% B); 15 min (95% B). Flow rate: 0.7 ml min-1 . Wavelength: 210 nm. Temperature: 30 ° C. Residence time: 13.9 min.Instance 28 : 5- Biphenyl -4- base -(S)-4- Dibenzylamino group - Valeric acid L- Menthyl ester At N2 n-BuLi (1.6 M, 0.9 mL, 1.44 mmol) was added to a solution of L-menthol in 10 mL of anhydrous THF. Then, 5-biphenyl-4-yl-(S)-4-dibenzylamino-pentanoic acid methyl ester contained in 5 mL of THF was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with a saturated aqueous The organic extracts were combined, and concentrated, and then purified, mjjjjjjjjjjjjj Amino-pentanoic acid L-menthyl ester.1 H NMR (CDCl3 ): 0.67 (3H, d, CH3 ), 0.79 (3H, d, CH3 ), 0.86 (3H, d, CH3 ), 1.26 (4H, m, CH2 -CH2 ), 1.56 (2H, m, CH2 ), 1.60 (1H, m, CH), 1.71 (1H, m, CH), 1.73 (1H, m, 3-CHH ), 1.87 (1H, m, 3-CH H), 2.14 (1H, m, 2-CHH ), 2.47 (1H, m, 2-CH H), 2.59 (1H, m, 5-CHH ), 2.78 (1H, m, 5-CH H), 3.17 (1H, dd, 4-CH), 3.54 (2H, d, CH2 ), 3.87 (2H, d, CH2 ), 4.56 (3H, m, OCH), 7.10~7.50 (19H, m, aromatic). HPLC method: column: Waters Xbridge-Phenyl; 150 × 3.0 mm; 3.5 μm. Mobile phase A (0.1% DEA) is contained in water; mobile phase B (acetonitrile). Gradient: 0 min (60 % B); 30 min (95 % B). Flow rate: 0.5 ml min-1 . Wavelength: 210 nm. Temperature: 35 ° C. Residence time: 27.3 min.Instance 29 : 5- Biphenyl -4- base -(S)-4- Dibenzylamino group - Valeric acid D- Menthyl ester At N2 n-BuLi (1.6 M, 0.9 mL, 1.44 mmol) was added to a mixture of D-menthol in 10 mL anhydrous THF. Then, 5-biphenyl-4-yl-(S)-4-dibenzylamino-pentanoic acid methyl ester contained in 5 mL of THF was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with a saturated aqueous The organic extracts were combined, and concentrated, and then purified, mjjjjjjjjjjjjj Amino-pentanoic acid L-menthyl ester.1 H NMR (CDCl3 ): 0.71 (3H, d, CH3 ), 0.87 (6H, d, CH3 ), 1.26 (4H, m, CH2 -CH2 ), 1.55 (2H, m, CH2 ), 1.64 (1H, m, CH), 1.78 (1H, m, CH), 1.88 (2H, m, 3-CH2 ), 2.04 (1H, m, 2-CHH ), 2.46 (1H, m, 2-CH H), 2.62 (1H, m, 5-CHH ), 2.80 (1H, m, 5-CH H), 3.16 (1H, dd, 4-CH), 3.55 (2H, d, CH2 ), 3.85 (2H, d, CH2 ), 4.60 (3H, m, OCH), 7.10~7.50 (19H, m, aromatic). HPLC method: column: Waters Xbridge-Phenyl; 150 × 3.0 mm; 3.5 μm. Mobile phase A (0.1% DEA) is contained in water; mobile phase B (acetonitrile). Gradient: 0 min (60 % B); 30 min (95 % B). Flow rate: 0.5 ml min-1 . Wavelength: 210 nm. Temperature: 35 ° C. Residence time: 22.9 min.Instance 30 : 5- Biphenyl -4- base -(S)-4- Dibenzylamino group - Valeric acid S- P-toluene ester To 5-biphenyl-4-yl-(S)-4-dibenzylamino-pentanoic acid hydrochloride (1.46 g, 3 mmol) in CH2 Cl2 The solution was added, followed by the addition of triethylamine (0.34 g, &lt;RTI ID=0.0&gt;&gt; The reaction mixture was stirred at room temperature for 15 min then 4-methyl-benzenethiol (0.74 g, 6 mmol). After 30 minutes, the reaction mixture was washed with EtOAcqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH - Dibenzylamino-pentanoic acid S-p-tolyl ester.1 H NMR (CDCl3 ): 1.72 ( 1H, m, 3-CH H), 1.95 (1H, m, 3-CHH ), 2.34 (3H, s, CH3 ), 2.43 (2H, m, 2- CH2 ), 2.79 (1H, m, 5-CH)2 ), 2.95 (1H, m, 5-CH)2 ), 3.17 (1H, dd, 4-CH), 3.52 (2H, d, CH2 ), 3.86 (2H, d, CH2 ), 7.10~7.40 (23H, m, aromatic). HPLC method: column: Eclipse XDB-C18; 150 x 4.6 mm; 5 μm. Mobile phase A (0.1 % H3 PO4 ) contained in water; mobile phase B (acetonitrile). Gradient: 0 min (90% B); 10 min (95% B); 15 min (95% B). Flow rate: 0.7 ml min-1 . Wavelength: 210 nm. Temperature: 30 ° C. Residence time: 14.8 min.Instance 31 : 2-[(1S,3R)-4-((R)-4- Benzyl -2- Side oxy - Oxazolidine -3- base )-1- Biphenyl -4- Methyl -3- methyl -4- Side oxy - Butyl ]- Different -1,3- Diketone method 1 Add 2-[(S)-4-((R)-4-benzyl-2-) to anhydrous THF to a solution of NaHMDS (6.5 mL, 6.5 mmol) in EtOAc (EtOAc) Oxyloxy-oxazolidin-3-yl)-1-biphenyl-4-ylmethyl-4-oxo-butyl]-isoindole-1,3-dione (3.00 g, 5.38 mmol) ). The reaction mixture was stirred for 1 hour then iodomethane (3.82 g, 26.90 mmol) was then added to the reaction mixture. After 12 hours, the reaction mixture was allowed to warm to room temperature and saturated NH was added.4 Cl (25 ml), the mixture was extracted with TBME. The combined organic extracts were washed with brine, dried and concentrated to give crystals crystals crystals crystalssssssssssssssss -oxazolidin-3-yl)-1-biphenyl-4-ylmethyl-3-methyl-4-oxo-butyl]-isoindole-1,3-dione, diastereomeric Isomer ratio (2R, 4S): (2S, 4S) = 97:3 as determined by HPLC. This material was recrystallized from TBME and heptane to give (2R, 4S): (2S, 4S) > 99:1 as determined by HPLC.1 H NMR (CDCl3 ): 1.35 ( 3H, d), 2.28 (1H, m), 2.25 (1H, m), 2.67 (1H, m), 2.95 (2H, m), 3.27 (2H, m), 3.50 (1H, m) , 4.15 (1H, m), 4.23 (1H, m), 7.15 ~ 7.80 (18H, m, aromatic). MS (ESI, m/e) 573 (MH+ ). 2-[(1S,3R)-4-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-1-biphenyl-4-ylmethyl-3-methyl The 4--4-oxo-butyl]-isoindole-1,3-dione is a crystalline solid and can be characterized by X-ray powder pattern. The strongest reflection in the X-ray diffraction pattern shows the following interplanar plane spacing (average 2θ to [o The meter is indicated by an error limit of ±0.2): 2θ to [o ]: 7.5, 9.5, 10.9, 16.9, 19.1, 21.4, 22.9, 24.9, 26.2, 27.6, 29.6, 30.9. Data were collected using Cu-Kα radiation using a Bruker D8 advanced diffractometer.method 2 Add 2-[(S)-4-((R)-4-benzyl-2-) to NaHMDS (2.1 mL, 2.1 mmol) in a solution of -60 ° C in anhydrous THF. Oxo-oxazolidin-3-yl)-1-biphenyl-4-ylmethyl-4-oxo-butyl]-isoindole-1,3-dione (1 g, 1.8 mmol ). The reaction mixture was stirred for 1 hour then iodomethane (1.2 g, 8.5 mmol) was then added to the mixture. After 12 hours, the reaction mixture was allowed to warm to room temperature and saturated NH was added.4 Cl (10 ml), the mixture was extracted with TBME. The combined organic extracts were washed with brine, dried and concentrated to give crystals crystals crystals crystalssssssssssssssss -oxazolidin-3-yl)-1-biphenyl-4-ylmethyl-3-methyl-4-oxo-butyl]-isoindole-1,3-dione, diastereomeric Isomer ratio (2R, 4S): (2S, 4S) = 95:5 as determined by HPLC.method 3 Add 2-[(S)-4-((R)-4-benzyl-2-) to NaHMDS (2.1 mL, 2.1 mmol) in a solution of -40 ° C in 5 mL anhydrous THF. Oxo-oxazolidin-3-yl)-1-biphenyl-4-ylmethyl-4-oxo-butyl]-isoindole-1,3-dione (1 g, 1.8 mmol ). The reaction mixture was stirred for 1 hour then iodomethane (1.2 g, 8.5 mmol) was then added to the mixture. After 12 hours, the reaction mixture was allowed to warm to room temperature and saturated NH was added.4 Cl (10 ml), the mixture was extracted with TBME. The combined organic extracts were washed with brine, dried and concentrated to give crystals crystals crystals crystalssssssssssssssss -oxazolidin-3-yl)-1-biphenyl-4-ylmethyl-3-methyl-4-oxo-butyl]-isoindole-1,3-dione, diastereomeric Isomer ratio (2R, 4S): (2S, 4S) = 94:6 as determined by HPLC.method 4 : Add 2-[(S)-4-((R)-4-benzyl-2- side to anhydrous THF to NaHMDS (2.1 mL, 2.1 mmol) in a solution of -10 ° C in 5 mL anhydrous THF Oxy-oxazolidine-3-yl)-1-biphenyl-4-ylmethyl-4-oxo-butyl]-isoindole-1,3-dione (1 g, 1.8 mmol) . The reaction mixture was stirred for 1 hour then iodomethane (1.2 g, 8.5 mmol) was then added to the mixture. After 12 hours, the reaction mixture was allowed to warm to room temperature and saturated NH was added.4 Cl (10 ml), the mixture was extracted with TBME. The combined organic extracts were washed with brine, dried and concentrated to give crystals crystals crystals crystalssssssssssssssss -oxazolidin-3-yl)-1-biphenyl-4-ylmethyl-3-methyl-4-oxo-butyl]-isoindole-1,3-dione, diastereomeric Isomer ratio (2R, 4S): (2S, 4S) = 90:10 as determined by HPLC.method 5 : To a solution of NaHMDS (2.1 mL, 2.1 mmol) in -78 ° C containing 5 mL of anhydrous toluene, 2-[(S)-4-((R)-4-benzyl-2-) Oxo-oxazolidin-3-yl)-1-biphenyl-4-ylmethyl-4-oxo-butyl]-isoindole-1,3-dione (1 g, 1.8 mmol ). The reaction mixture was stirred for 1 hour then iodomethane (1.2 g, 8.5 mmol) was then added to the mixture. After 12 hours, the reaction mixture was allowed to warm to room temperature and saturated NH was added.4 Cl (10 ml), the mixture was extracted with TBME. The combined organic extracts were washed with brine, dried and concentrated to give crystals crystals crystals crystalssssssssssssssss -oxazolidin-3-yl)-1-biphenyl-4-ylmethyl-3-methyl-4-oxo-butyl]-isoindole-1,3-dione, diastereomeric Isomer ratio (2R, 4S): (2S, 4S) = 77:23 as determined by HPLC.method 6 : To a solution of KHMDS (2.1 mL, 2.1 mmol) in -78 ° C containing 5 mL of dry THF, 2-[(S)-4-((R)-4-benzyl-2-) Oxo-oxazolidin-3-yl)-1-biphenyl-4-ylmethyl-4-oxo-butyl]-isoindole-1,3-dione (1 g, 1.8 mmol ). The reaction mixture was stirred for 1 hour then iodomethane (1.2 g, 8.5 mmol) was then added to the mixture. After 12 hours, the reaction mixture was allowed to warm to room temperature and saturated NH was added.4 Cl (10 ml), the mixture was extracted with TBME. The combined organic extracts were washed with brine, dried and concentrated to give crystals crystals crystals crystalssssssssssssssss -oxazolidin-3-yl)-1-biphenyl-4-ylmethyl-3-methyl-4-oxo-butyl]-isoindole-1,3-dione, diastereomeric Isomer ratio (2R, 4S): (2S, 4S) = 41:59 as determined by HPLC. HPLC method: column: Phenomenex Gemini C18; 150 × 3.0 mm; 3.0 μm. Mobile phase A (0.1 % H3 PO4 ) contained in water; mobile phase B (acetonitrile). Gradient: 0 min (30% B); 30 min (95% B); 35 min (95% B). Flow rate: 0.5 ml min-1 . Wavelength: 210 or 254 nm. Temperature: 30 ° C. Residence time: SM 25.0 min, (2S, 4S) 26.1 min, (2R, 4S) 26.9 min.Instance 32 : 2-[(S)-4-((R)-4- Isopropyl -2- Side oxy - Oxazolidine -3- base )-1- Biphenyl -4- Methyl -3- methyl -4- Side oxy - Butyl ]- Different -1,3- Diketone Add 2-[(S)-4-((R)-4-isopropyl-2-) in anhydrous THF to a solution of NaHMDS (6.5 mL, 6.5 mmol) in 20 mL anhydrous THF. Oxyloxy-oxazolidin-3-yl)-1-biphenyl-4-ylmethyl-4-oxo-butyl]-isoindole-1,3-dione (2.74 g, 5.38 mmol) ). The reaction mixture was stirred for 1 hour then iodomethane (3.82 g, 26.90 mmol) was then added to the reaction mixture. After 12 hours, the reaction mixture was allowed to warm to room temperature and saturated NH was added.4 Cl (25 ml), the mixture was extracted with TBME. The combined organic extracts were washed with brine, dried and concentrated to give &lt;RTIgt; 2-[(S)-4-((R)-4-isopropyl-2-oxooxy-oxazolidine-3-yl)-1 -biphenyl-4-ylmethyl-3-methyl-4-oxo-butyl]-isoindole-1,3-dione, diastereomeric ratio (2R, 4S): ( 2S, 4S) = 99.6: 0.4 was determined by HPLC.1 H NMR (CDCl3 ): 0.9 (6H, d), 1.2 ( 3H, d), 2.31 (3H, m), 3.12 (1H, m), 3.45 (1H, m), 3.75 (1H, m), 4.17 (1H, m) , 4.41 (1H, m), 4.47 (1H, m), 4.54 (1H, m), 7.15 ~ 7.70 (13H, m, aromatic). MS (ESI, m/e) 400 (MH+ ). HPLC method: column: Eclipse XDB-C18; 150 x 4.6 mm; 5 μm. Mobile phase A (0.1 % H3 PO4 ) contained in water; mobile phase B (acetonitrile). Gradient: 0 min (10% B); 10 min (95% B); 15 min (95% B). Flow rate: 1.0 ml min-1 . Wavelength: 210 nm. Temperature: 30 ° C. Residence time: 10.5 min.Instance 33 : 5- Biphenyl -4- base -(S)-4- Dibenzylamino group -1-((S)-2- Hydroxymethyl - Pyrrolidine -1- base )-(S)-2- methyl - E -1- ketone At N2 Add 2.5 mL LDA (1.0 M in THF) to 5-biphenyl-4-yl-(S)-4-dibenzylamino-1-((S) at -70 °C A mixture of 2-hydroxymethyl-pyrrolidin-1-yl)-pentan-1-one (0.53 g, 1 mmol) in 15 mL anhydrous THF. The mixture was stirred for an additional 1 hour then MeI (0.2 g, 1.4 mmol) was added. The resulting mixture was slowly warmed to room temperature and stirred for 3 hours, a saturated aqueous ammonium chloride solution was added, and the aqueous layer was extracted with ethyl acetate and concentrated to give 5-biphenyl-4-yl-(S)-4-dibenzylamine Keto-1-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-(S)-2-methyl-pentan-1-one. The ratio of diastereomers analyzed by HPLC: (2R, 4S): (2S, 4S) = 23:77.1 H NMR (CDCl3 ):1.04 (3H, d, CH3 ), 1.48 ( 1H, m, 3-CH H), 1.80 (4H, m, CH2 CH2 ), 1.90 (1H, m, 3-CH)H ), 2.45 (1H, m, 5-CH)H ), 2.60 (1H, m, 5-CH H), 2.96 (1H, m, 2- CHH ), 3.08 (1H, m, 4-CH), 3.20 (2H, m, CH2 ), 3.62 (2H, m, CH2 ), 3.57 (2H, m, CH2 ), 3.86 (2H, d, CH2 ), 4.05 (1H, m, CH), 5.07 (1H, d, OH), 7.10~7.50 (19H, m, aromatic). HPLC method: column: Waters Xbridge-Phenyl; 150 × 3.0 mm; 3.5 μm. Mobile phase A (0.1% DEA) is contained in water; mobile phase B (acetonitrile). Gradient: 0 min (55 % B); 30 min (55 % B); 30.1 min (95 % B); 35 min (95 % B). Flow rate: 0.5 ml min-1 . Wavelength: 210 nm. Temperature: 35 ° C. Residence time: (2R, 4S): 22.6 min; (2S, 4S): 20.0 min.Instance 34 : 5- Biphenyl -4- base -(S)-4- Dibenzylamino group -1-((R)-2- Hydroxymethyl - Pyrrolidine -1- base )-(R)-2- methyl - E -1- ketone At N2 2.5 mL LDA (1.0 M in THF) was added to 5-biphenyl-4-yl-(S)-4-dibenzylamino-1-((R) at -70 °C. A mixture of 2-hydroxymethyl-pyrrolidin-1-yl)-pentan-1-one (0.53 g, 1 mmol) in 15 mL anhydrous THF. The mixture was stirred for an additional 1 hour then MeI (0.2 g, 1.4 mmol) was added. The resulting mixture was slowly warmed to room temperature and stirred for 3 hours, a saturated aqueous ammonium chloride solution was added, and the aqueous layer was extracted with ethyl acetate and concentrated to give 5-biphenyl-4-yl-(S)-4-dibenzylamine 1-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-(R)-2-methyl-pentan-1-one. The ratio of diastereomers analyzed by HPLC: (2R, 4S): (2S, 4S) = 84:16.1 H NMR (CDCl3 ): 0.99 (3H, d, CH3 ), 1.42 ( 1H, m, 3-CH H), 1.70 (4H, m, CH2 CH2 ), 1.91 (2H, m, 3-CH)2 ), 2.50 (1H, m, 5-CH)H ), 2.60 (1H, m, 2- CHH ), 2.92 (1H, m, 4-CH), 3.00 (2H, m, CH2 ), 3.28 (2H, m, CH2 ), 3.60 (2H, m, CH2 ), 3.71 (2H, d, CH2 ), 4.11 (1H, m, CH), 5.12 (1H, d, OH), 7.10~7.50 (19H, m, aromatic). HPLC method: column: Waters Xbridge-Phenyl; 150 × 3.0 mm; 3.5 μm. Mobile phase A (0.1% DEA) is contained in water; mobile phase B (acetonitrile). Gradient: 0 min (50 % B); 20 min (50 % B); 30 min (60 % B). Flow rate: 0.5 ml min-1 . Wavelength: 210 nm. Temperature: 50 ° C. Residence time: (2R, 4S): 30.1 min; (2S, 4S): 30.8 minInstance 35 : 5- Biphenyl -4- base -(S)-4- Dibenzylamino group -(R)-2- methyl - Valeric acid (S)- methyl -(1- Phenyl - Ethyl )- Guanamine At N2 Add 2.5 mL LDA (1.0 M in THF) to 5-biphenyl-4-yl-(S)-4-dibenzylamino-1-((S) at -70 °C A mixture of 2-hydroxymethyl-pyrrolidin-1-yl)-pentan-1-one (0.53 g, 1 mmol) in 15 mL anhydrous THF. The mixture was stirred for an additional 1 hour then MeI (0.2 g, 1.4 mmol) was added. The resulting mixture was slowly warmed to room temperature and stirred for 3 hours, a saturated aqueous ammonium chloride solution was added, and the aqueous layer was extracted with ethyl acetate and concentrated to give 5-biphenyl-4-yl-(S)-4-dibenzylamine (-S)-methyl-(1-phenyl-ethyl)-decylamine. The ratio of diastereomers analyzed by HPLC: (2R, 4S): (2S, 4S) = 63:37.1 H NMR (CDCl3 ): 1.00 (3H, d, CH3 ), 1.38 (3H, d, CH3 ), 1.87 ( 2H, m, 3-CH2 ), 2.30 (3H, s, CH3 ), 2.60 (1H, m, 2-CH)2 ), 2.98 (2H, m, 5-CH)2 ), 3.55 (1H, dd, 4-CH), 3.58 (2H, d, CH2 ), 3.70 (2H, d, CH2 ), 6.00 (1H, m, CH), 7.10~7.50 (24H, m, aromatic). HPLC method: column: Waters Xbridge-Phenyl; 150 × 3.0 mm; 3.5 μm. Mobile phase A (0.1% DEA) is contained in water; mobile phase B (acetonitrile). Gradient: 0 min (65 % B); 30 min (65 % B); 30.1 min (95 % B); 35 min (95 % B). Flow rate: 0.5 ml min-1 . Wavelength: 210 nm. Temperature: 35 ° C. Residence time: (2R, 4S): 20.4 min; (2S, 4S): 19.3 min.Instance 36 : 5- Biphenyl -4- base -(S)-4- Dibenzylamino group -(R)-2- methyl - Valeric acid (R)- methyl -(1- Phenyl - Ethyl )- Guanamine At N2 2.5 mL LDA (1.0 M in THF) was added to 5-biphenyl-4-yl-(S)-4-dibenzylamino-1-((R) at -70 °C. A mixture of 2-hydroxymethyl-pyrrolidin-1-yl)-pentan-1-one (0.53 g, 1 mmol) in 15 mL anhydrous THF. The mixture was stirred for an additional 1 hour then MeI (0.2 g, 1.4 mmol) was added. The resulting mixture was slowly warmed to room temperature and stirred for 3 hours, a saturated aqueous ammonium chloride solution was added, and the aqueous layer was extracted with ethyl acetate and concentrated to give 5-biphenyl-4-yl-(S)-4-dibenzylamine (R)-2-methyl-pentanoic acid (R)-methyl-(1-phenyl-ethyl)-guanamine. The ratio of diastereomers analyzed by HPLC: (2R, 4S): (2S, 4S) = 75:25.1 H NMR (CDCl3 ):1.03 (3H, d, CH3 ), 1.37 (3H, d, CH3 ), 1.82 ( 1H, m, 3-CHH ), 1.92 ( 1H, m, 3-CH H), 2.41 (3H, s, CH3 ), 2.63 (1H, m, 2-CH2 ), 2.99 (2H, m, 5-CH)2 ), 3.57 (1H, m, 4-CH), 3.59 (2H, m, CH2 ), 3.70 (2H, d, CH2 ), 6.00 (1H, m, CH), 7.10~7.50 (24H, m, aromatic). HPLC method: column: Waters Xbridge-Phenyl; 150 × 3.0 mm; 3.5 μm. Mobile phase A (0.1% DEA) is contained in water; mobile phase B (acetonitrile). Gradient: 0 min (60% B); 40 min (60% B); 40.1 min (95% B); 45 min (95% B). Flow rate: 0.5 ml min-1 . Wavelength: 210 nm. Temperature: 35 ° C. Residence time: (2R, 4S): 33.4 min; (2S, 4S): 34.6 min.Instance 37 : 5- Biphenyl -4- base -(S)-4- Dibenzylamino group -(R)-2- Methylvaleric acid L- Menthyl ester At N2 Add LDA (1.0M in THF, 0.6 mL) to 5-biphenyl-4-yl-(S)-4-dibenzylamino-pentanoic acid L-menthol at -70 °C The ester (0.3 g, 0.5 mmol) was contained in 15 mL of dry THF. After 1 h, MeI (0.04 mL, 0.6 mmol) was evaporated. The mixture was diluted with a saturated aqueous solution of ammonium chloride and then extracted with ethyl acetate. The organic extracts were combined and concentrated to give 5-biphenyl-4-yl-(S)-4-dibenzylamino-(R)-2-methylpentanoic acid L-menthyl ester. According to HPLC analysis, the ratio of diastereomer (2R, 4S): (2S, 4S) was 57:43.1 H NMR (CDCl3 ): 0.68 (3H, d, CH3 ), 0.99 (3H, d, CH3 ), 0.80 (3H, d, CH3 ), 0.85 (3H, d, CH3 ), 1.27 (4H, m, CH2 -CH2 ), 1.55 (2H, m, CH2 ), 1.62 (1H, m, CH), 1.73 (1H, m, CH), 1.75 (1H, m, 3-CHH ), 1.86 (1H, m, 3-CH H), 2.15 (1H, m, 2-CH), 2.60 (1H, m, 5-CHH ), 2.79 (1H, m, 5-CH H), 3.18 (1H, dd, 4-CH), 3.56 (2H, d, CH2 ), 3.85 (2H, d, CH2 ), 4.57 (3H, m, OCH), 7.10~7.5 0 (19H, m, aromatic). HPLC method: column: Waters Xbridge-Phenyl; 150 × 3.0 mm; 3.5 μm. Mobile phase A (0.1% DEA) is contained in water; mobile phase B (acetonitrile). Gradient: 0 min (60 % B); 30 min (95 % B). Flow rate: 0.5 ml min-1 . Wavelength: 210 nm. Temperature: 35 ° C. Residence time: (2R, 4S): 32.1 min; (2S, 4S): 31.7 min.Instance 38 : 5- Biphenyl -4- base -(S)-4- Dibenzylamino group -(R)-2- Methylvaleric acid D- Menthyl ester At N2 Add LDA (1.0M in THF, 0.6 mL) to 5-biphenyl-4-yl-(S)-4-dibenzylamino-pentanoic acid D-menthol at -70 °C The ester (0.3 g, 0.5 mmol) was contained in 15 mL of dry THF. After 1 h, MeI (0.04 mL, 0.6 mmol) was evaporated. The mixture was diluted with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic extracts were combined and concentrated to give 5-biphenyl-4-yl-(S)-4-dibenzylamino-(R)-2-methylpentanoic acid D-menter. According to HPLC analysis, the ratio of diastereomer (2R, 4S): (2S, 4S) was 64:36.1 H NMR (CDCl3 ): 0.70 (3H, d, CH3 ), 0.85(6H, d, CH3 ), 0.98(3H, d, CH3 ), 1.25(4H, m, CH2 -CH2 ), 1.56(2H, m, CH2 ), 1.65(1H, m, CH), 1.79(1H, m, CH), 1.89(2H, m, 3-CH2 ), 2.08(1H, m, 2-CH), 2.63 (1H, m, 5-CHH ), 2.79(1H, m, 5-CH H), 3.17(1H, dd, 4-CH), 3.57(2H, d, CH2 ), 3.86 (2H, d, CH2 ), 4.62 (3H, m, OCH), 7.10~7.5 0 (19H, m, aromatic). HPLC method: column: Waters Xbridge-Phenyl; 150 × 3.0 mm; 3.5 μm. Mobile phase A (0.1% DEA) is contained in water; mobile phase B (acetonitrile). Gradient: 0 min (60 % B); 30 min (95 % B). Flow rate: 0.5 ml min-1 . Wavelength: 210 nm. Temperature: 35 ° C. Residence time: (2R, 4S): 23.4 min; (2S, 4S): 23.8 min.Instance 39 : 5- Biphenyl -4- base -(S)-4- Dibenzylamino group -(R)-2- Methylvaleric acid S- P-toluene ester At N2 Add LDA (1.0M in THF, 2.8 mL) to 5-biphenyl-4-yl-(S)-4-dibenzylamino-pentanoic acid S-pair at -70 °C Toluene ester (1.11 g, 2 mmol) was added to a mixture of 20 mL anhydrous THF. After 1 h, MeI (0.19 mL, 3 mmol) was added and the mixture was slowly warmed to room temperature and stirred for 3 hr. The mixture was diluted with a solution of ammonium chloride and extracted with ethyl acetate. The organic extracts were combined and concentrated to give 5-biphenyl-4-yl-(S)-4-dibenzylamino-(R)-2-methylpentanoic acid S-p-tolyl ester. According to HPLC analysis, the ratio of diastereomer (2R, 4S): (2S, 4S) was 66:34.1 H NMR (CDCl3 ): 1.13 (3H, d, CH3 ), 1.68 ( 1H, m, 3-CH H), 1.87 (1H, m, 3-CHH ), 2.34 (3H, s, CH3 ), 2.54 (1H, m, 2- CH2 ), 2.91 (1H, m, 5-CH)2 ), 3.07 (1H, m, 5-CH)2 ), 3.19 (1H, dd, 4-CH), 3.52 (2H, d, CH2 ), 3.86 (2H, d, CH2 ), 7.10~7.40 (23H, m, aromatic). HPLC method: column: Waters Xbridge-Phenyl; 150 × 3.0 mm; 3.5 μm. Mobile phase A (0.1% DEA) is contained in water; mobile phase B (acetonitrile). Gradient: 0 min (60 % B); 30 min (95 % B). Flow rate: 0.5 ml min-1 . Wavelength: 210 nm. Temperature: 35 ° C. Residence time: (2R, 4S): 20.1 min; (2S, 4S): 20.5 min.Instance 40 : (2S, 4S)-5- Biphenyl -4- base -4- Third butoxycarbonylamino group -2- methyl - Ethyl valerate (S)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-pentanoic acid ethyl ester (2 g) was added to tetrahydrofuran (18 ml). The resulting mixture was then cooled to -78 °C. Lithium bis(trimethylformamidine) guanamine (13.1 ml, 1 M solution in tetrahydrofuran) was added. The mixture was then stirred at -78 ° C for 45 minutes. Methyl iodide (1.56 ml) was then added and the mixture was stirred at -78 °C for 2 hours. 1N aqueous hydrochloric acid (20 ml) and ethyl acetate (10 ml) were added. The phases were separated and the organic layer was washed with 1N aqueous hydrochloric acid (10 ml) and then brine (20 ml). Then, the organic phase was dried over magnesium sulfate and concentrated under reduced pressure to give (2S,4S)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-methyl-pentanoic acid Ethyl ester. 1H NMR (CDCl3 ): 0.98 (3H), 1.09 (3H), 1.23 (9H), 1.38-1.43 (1H), 1.58-1.66 (1H), 2.31-2.36 (1H), 2.59-2.70 (2H), 3.76 (1H), 3.97 (2H), 4.19 (1H), 7.10 (2H), 7.17 (1H), 7.27 (2H), 7.37 (2H), 7.41 (2H).Instance 41 : 5- Biphenyl -4- base -(S)-4- Dibenzylamino group -(R)-2- Ethyl -1- Pyrrolidine -1- base - E -1- ketone At N2 LDA (1.0 M in THF, 2.8 mL) was added to 5-biphenyl-4-yl-(S)-4-dibenzylamino-1-pyrrolidine at -70 °C. A solution of 1-yl-pentan-1-one (1.0 g, 2 mmol) in 20 mL of dry THF. After 1 hour, iodoethane (0.45 g, 3 mmol) was added at -70 °C, and the reaction mixture was slowly warmed to room temperature. After 3 hours at room temperature, the mixture was diluted with a sodium chloride solution, extracted with ethyl acetate and concentrated to dryness to give 5-biphenyl-4-yl-(S)-4-dibenzylamino-- )-2-Ethyl-1-pyrrolidin-1-yl-pentan-1-one. According to HPLC analysis, the ratio of diastereomer (2R, 4S): (2S, 4S) was 79:21.1 H NMR (CDCl3 ): 0.77 (3H, m), 1.40-2.00 ( 8H, m), 2.39 (1H, m), 2.61 (1H, m), 3.04 (2H, m), 3.35 (4H, m), 3.7-3.9 ( 4H, m), 7.10~7.4 (19H, m, aromatic). HPLC method: column: Waters Xbridge-Phenyl; 150 x 3.0 mm; 3.5 μm. Mobile phase A (0.1% DEA) is contained in water; mobile phase B (acetonitrile). Gradient: 0 min (60% B); 30 min (95% B). Flow rate: 0.5 ml min-1. Wavelength: 210 nm. Temperature: 35 ° C. Residence time: (2R, 4S): 12.6 min; (2S, 4S): 12.2 min.Instance 42 : 5- Biphenyl -4- base -(S)-4- Dibenzylamino group -(R)-2- Isopropyl -1- Pyrrolidine -1- base - E -1- ketone At N2 LDA (1.0 M in THF, 2.8 mL) was added to 5-biphenyl-4-yl-(S)-4-dibenzylamino-1-pyrrolidine at -70 °C. a solution of 1-yl-pentan-1-one (1.0 g, 2 mmol) in 20 mL of dry THF, stirred at -70 ° C for one hour, then 2-iodopropane (0.51 g, 3 mmol) The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. A saturated ammonium chloride solution is added, the mixture is extracted with ethyl acetate and the combined organic extracts are concentrated to give 5-biphenyl-4-yl-(S)-4-dibenzylamino-(R)-2-iso Propyl-1-pyrrolidin-1-yl-pentan-1-one. According to HPLC analysis, the ratio of diastereomer (2R, 4S): (2S, 4S) was 72:28.1 H NMR (CDCl3 ): 0.68 (3H, d, CH3 ), 0.74(3H, d, CH3 ), 1.62 ( 2H, m, 3-CH2 ), 1.68 (2H, m, CH2 ), 1.78 (2H, m, CH2 ), 2.29(1H, m, CH), 2.44 (1H, m, 2- CH2 ), 2.81 (2H, m, 5-CH)2 ), 3.16 (1H, dd, 4-CH), 3.26(2H, m, CH2 ), 3.47(2H, m, CH2 ), 3.57 (2H, d, CH2 ), 3.77 (2H, d, CH2 ), 7.10~7.40 (19H, m, aromatic). HPLC method: column: Waters Xbridge-Phenyl; 150 x 3.0 mm; 3.5 μm. Mobile phase A (0.1% DEA) is contained in water; mobile phase B (acetonitrile). Gradient: 0 min (60 % B); 30 min (95 % B). Flow rate: 0.5 ml min-1 . Wavelength: 210 nm. Temperature: 35 ° C. Residence time: (2R, 4S): 13.8 min; (2S, 4S): 13.1 min.Instance 43 : 2-[(S)-4-((R)-4- Isopropyl -2- Side oxy - Oxazolidine -3- base )-1- Biphenyl -4- Methyl -3- Benzyl -4- Side oxy - Butyl ]- Different -1,3- Diketone Add 2-[(S)-4-((R)-4-isopropyl-2-) in anhydrous THF to a solution of NaHMDS (6.5 mL, 6.5 mmol) in 20 mL anhydrous THF. Oxyloxy-oxazolidin-3-yl)-1-biphenyl-4-ylmethyl-4-oxo-butyl]-isoindole-1,3-dione (2.74 g, 5.38 mmol) ). The reaction mixture was stirred for 1 hour then benzyl bromide (3.82 g, 22.30 mmol) was then added to the reaction mixture. After 12 hours, the reaction mixture was allowed to warm to room temperature and saturated NH was added.4 Cl (25 ml), the mixture was extracted with TBME. The combined organic extracts were washed with brine, dried and concentrated to give 2-[(1S,3R)-3-benzyl-1-(biphenyl-4-ylmethyl) 4-((4R)-4- Propyl-2-p-oxy-1,3-1,3-oxazolidin-3-yl)-1H-isoindole-1,3(2H)-dione. According to HPLC analysis, the ratio of diastereomer (2R, 4S): (2S, 4S) was >99:1. 1H NMR (CDCl3 ): 0.5-1.0 (6H, d), 2.11 (1H, m), 2.31 (1H, m), 2.61 (1H, m), 2.80 (3H, m), 2.91 (1H, m), 3.11 (1H, m), 3.43 (1H, m), 4.0-4.5 (5H, m), 7.05 ~ 7.70 (18H, m, aromatic). MS (ESI, m/e) 400 (MH+). HPLC method: column: Waters Xbridge-Phenyl; 150 × 3.0 mm; 3.5 μm. Mobile phase A (0.1% DEA) is contained in water; mobile phase B (acetonitrile). Gradient: 0 min (60 % B); 25 min (60 % B); 30 min (95 % B). Flow rate: 0.5 ml min-1 . Wavelength: 210 nm. Temperature: 35 ° C. Residence time: (2R, 4S): 16.7 min; (2S, 4S): 16.0 min.Instance 44 : (2R, 4S) -4- Amine -5- Biphenyl -4- base -2- methyl - Palladium hydrochloride To 2-[(1S,3R)-4-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-1-biphenyl-4-ylmethyl-3- Methyl-4-oxo-butyl]-isoindole-1,3-dione (100 mg, 0.175 mmol) in a solution of 10 mL of THF was added 2.5 mL of water at 0 ° C, then LiOH· H2 O (15 mg, 0.350 mmol). After stirring for 12 hours, 2 mL of concentrated HCl was added, then the mixture was refluxed for 2 hours and then cooled to room temperature. The resulting precipitate was filtered and dried under high vacuum to afford (2,,,,,,,,,,,,,,,,,,,, m/z: 283 (MH+ ). Spectrometer data is as described in Example 7 of WO 2008/083967.Instance 45 : 5- Biphenyl -4- base -(S)-4- Dibenzylamino group -(R)-2- methyl - Valeric acid 5-biphenyl-4-yl-(S)-4-dibenzylamino-1-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-pentane- A mixture of 1-ketone (0.5 g, 0.9 mmol) in 10 mL of 6N HCl was heated to reflux for 6 h. The water was then removed and the residue obtained was dissolved in 20 mL ethyl acetate to NaHCO3 Water cleaning. The organic phase was concentrated to give 5-biphenyl-4-yl-(S)-4-dibenzylamino-(R)-2-methyl-pentanoic acid.1 H NMR (CDCl3 ): 0.88 (3H, d, CH3 ), 1.65 (1H, m, 3-CH H), 1.82 (1H, m, 3-CHH ), 2.55 (1H, m, 2-CH), 2.65 (1H, m, 4-CH), 3.14 (2H, m, 5-CH)2 ), 3.59 (2H, d, CH2 ), 3.85 (2H, m, CH2 ), 7.10~7.50 (19H, m, aromatic). HPLC method: column: Eclipse XDB-C18; 150 x 4.6 mm; 5 μm. Mobile phase A (0.1 % H3 PO4 ) contained in water; mobile phase B (acetonitrile). Gradient: 0 min (90% B); 10 min (95% B); 15 min (95% B). Flow rate: 0.7 ml min-1 . Wavelength: 210 nm. Temperature: 30 ° C. Residence time: 11.2 min.Instance 46 : 5- Biphenyl -4- base -(S)-4- Dibenzylamino group -(R)-2- methyl - Valeric acid 5-biphenyl-4-yl-(S)-4-dibenzylamino-(R)-2-methyl-pentanoic acid-(S)-methyl-(1-phenyl-ethyl) - A mixture of guanamine (0.5 g, 0.9 mmol) in 10 mL of 6N HCl was heated to reflux for 6 h. The water was then removed and the residue obtained was dissolved in 20 mL ethyl acetate to NaHCO3 Water cleaning. The organic phase was concentrated to give 5-biphenyl-4-yl-(S)-4-dibenzylamino-(R)-2-methyl-pentanoic acid.1 H NMR (CDCl3 ): 0.88 (3H, d, CH3 ), 1.65 (1H, m, 3-CH H), 1.82 (1H, m, 3-CHH ), 2.55 (1H, m, 2-CH), 2.65 (1H, m, 4-CH), 3.14 (2H, m, 5-CH)2 ), 3.59 (2H, d, CH2 ), 3.85 (2H, m, CH2 ), 7.10~7.50 (19H, m, aromatic). HPLC method: column: Eclipse XDB-C18; 150 x 4.6 mm; 5 μm. Mobile phase A (0.1 % H3 PO4 ) contained in water; mobile phase B (acetonitrile). Gradient: 0 min (90% B); 10 min (95% B); 15 min (95% B). Flow rate: 0.7 ml min-1 . Wavelength: 210 nm. Temperature: 30 ° C. Residence time: 11.2 min.Instance 47 : 5- Biphenyl -4- base -(S)-4- Dibenzylamino group -(R)-2- methyl - Valeric acid 5-biphenyl-4-yl-(S)-4-dibenzylamino-(R)-2-methyl-pentanoic acid-(R)-methyl-(1-phenyl-ethyl) - A mixture of guanamine (0.5 g, 0.9 mmol) in 10 mL of 6N HCl was heated to reflux for 6 h. The water was then removed and the residue obtained was dissolved in 20 mL ethyl acetate to NaHCO3 Water cleaning. The organic phase was concentrated to give 0.3 g of 5-biphenyl-4-yl-(S)-4-dibenzylamino-(R)-2-methyl-pentanoic acid.1 H NMR (CDCl3 ): 0.88 (3H, d, CH3 ), 1.65 (1H, m, 3-CH H), 1.82 (1H, m, 3-CHH ), 2.55 (1H, m, 2-CH), 2.65 (1H, m, 4-CH), 3.14 (2H, m, 5-CH)2 ), 3.59 (2H, d, CH2 ), 3.85 (2H, m, CH2 ), 7.10~7.50 (19H, m, aromatic). HPLC method: column: Eclipse XDB-C18; 150 x 4.6 mm; 5 μm. Mobile phase A (0.1 % H3 PO4 ) contained in water; mobile phase B (acetonitrile). Gradient: 0 min (90% B); 10 min (95% B); 15 min (95% B). Flow rate: 0.7 ml min-1 . Wavelength: 210 nm. Temperature: 30 ° C. Residence time: 11.2 min.Instance 48 : 5- Biphenyl -4- base -(S)-4- Dibenzylamino group -(R)-2- methyl - Valeric acid Add 5-biphenyl-4-yl-(S)-4-dibenzylamino-(R)-2-methylpentanoic acid-S-pair to a mixture of tetrahydrofuran (2 ml) and water (5 ml) Toluene ester (200 mg, 0.35 mmol). Then, lithium hydroxide (20 mg) was added to the mixture. Then, the resulting mixture was stirred at room temperature for 12 hours. A 1 M hydrochloric acid solution was added to the mixture to become acidic. The tetrahydrofuran solvent is then removed from the mixture. Then ethyl acetate (5 ml) was added and the phases were separated. The organic phases were combined and dried to give 5-biphenyl-4-yl-(S)-4-dibenzylamino-(R)-2-methyl-pentanoic acid.1 H NMR (CDCl3 ): 0.88 (3H, d, CH3 ), 1.65 (1H, m, 3-CH H), 1.82 (1H, m, 3-CHH ), 2.55 (1H, m, 2-CH), 2.65 (1H, m, 4-CH), 3.14 (2H, m, 5-CH)2 ), 3.59 (2H, d, CH2 ), 3.85 (2H, m, CH2 ), 7.10~7.50 (19H, m, aromatic). HPLC method: column: Eclipse XDB-C18; 150 x 4.6 mm; 5 μm. Mobile phase A (0.1 % H3 PO4 ) contained in water; mobile phase B (acetonitrile). Gradient: 0 min (90% B); 10 min (95% B); 15 min (95% B). Flow rate: 0.7 ml min-1 . Wavelength: 210 nm. Temperature: 30 ° C. Residence time: 11.2 min.Instance 49 : 5- Biphenyl -(S)-4- Amine -4- base -(R)-2- Methyl valerate In H2 0.3 g of 5-biphenyl-4-yl-(S)-4-dibenzylamino-(R)-2-methyl-pentanoic acid and 0.1 g of palladium on carbon were contained in 10 mL of AcOH under an atmosphere. The mixture was heated to 50 ° C and stirred for 12 hours. The reaction mixture was filtered and concentrated. To the residue was added 3M HCl in ethyl acetate, filtered and dried to give 5-biphenyl-(S)-4-amino-4-yl-(R)-2-methylpentanoate Acid salt. Spectrometer data is as described in Example 7 of WO 2008/083967.Instance 50 : (2R, 4S) -4- Amine -5- Biphenyl -4- base -2- methyl - Palladium hydrochloride To 2-[(S)-4-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)-1-biphenyl-4-ylmethyl-3-methyl 4--4-oxo-butyl]-isoindole-1,3-dione (102 mg, 0.2 mmol) in a solution of 10 mL of THF was added 2.5 mL of water at 0 ° C, followed by the addition of LiOH·H2 O (15 mg, 0.350 mmol). After 12 hours, 2 mL of concentrated HCl was added and then the mixture was refluxed for 2 hr. The reaction mixture was allowed to cool to room temperature, filtered and dried to give (2,,,,,,,,,,,,,,,, Spectrometer data is as described in Example 7 of WO 2008/083967.Instance 51 : (2R, 4S) -4- Amine -5- Biphenyl -4- base -2- methyl - Ethyl valerate Stirring (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid hydrochloride (100 mg, 0.32 mmol) in 10 mL 3~4M at room temperature The suspension in HCl / EtOH was taken for 12 hours. The reaction mixture was concentrated under vacuum to give (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentic acid ethyl ester. Spectrometer data is as described in Example 9-1 of WO2008/083967.Instance 52 : 5- Biphenyl -4- base -(S)-4- Dibenzylamino group -(R)-2- methyl - Valeric acid ((R)-2- Hydroxyl -(R)-1- methyl -2- Phenyl - Ethyl )- methyl - Guanamine At N2 LiCl (500 mg, 0.84 mmol) was suspended in THF (3 mL) and cooled to -70 ° C. then diisopropylamine (0.53 mL, 3.8 mmol) was added to the suspension, followed by dropwise addition of n- BuLi (2.2 mL, 1.6 M in hexanes, 3.50 mmol). After 30 minutes, 5-biphenyl-4-yl-(S)-4-dibenzylamino-pentanoic acid ((R)-2-hydroxy-(R)-1-A at -70 °C Benzyl-2-phenyl-ethyl)-methyl-decylamine (0.99 g, 1.67 mmol) in THF (4 mL) was added to 5-biphenyl-4-yl-(S)-4- a solution of dibenzylamino-1-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-pentan-1-one (0.53 g, 1 mmol) in anhydrous THF (4 mL) . After 1 h, MeI (470 mg, 3.34 mmol) was added and the mixture was stirred 30 min. Then add NH4 Cl (3 mL, saturated aqueous). The resulting mixture was slowly warmed to room temperature and the aqueous layer was extracted with EtOAc (EtOAc). The organic layer was dried and concentrated to give 5-biphenyl-4-yl-(S)-4-dibenzylamino-(R)-2-methyl-pentanoic acid ((R)-2-hydroxy- ( R)-1-methyl-2-phenyl-ethyl)-methyl-decylamine. The ratio of diastereomers analyzed by HPLC: (2R, 4S): (2S, 4S) = 99:1.1 H NMR (DMSO-D6 ): 0.83-.89 (3H, m), 1.23-1.29 (3 H, m), 1.43-1.65 (2 H, m), 2.62-3.07 (8 H, m), 3.47-3.69 (4 H, m ), 4.38-4.58 (1 H, m), 5.39-5.42 (1 H, m) , 7.08~7.67 (24 H, m). HPLC method: column: Waters Xbridge-Phenyl; 150 × 3.0 mm; 3.5 μm. Mobile phase A (0.1% DEA) is contained in water; mobile phase B (acetonitrile). Gradient: 0 min (60% B); 20 min (95% B); 25 min (95% B); 35 min (95% B). Flow rate: 0.5 ml min-1. Wavelength: 254 nm. Temperature: 35 ° C. Residence time: (2R, 4S): 16.7 min; (2S, 4S): 17.2 min.

無no

Claims (11)

一種式(10)化合物或其鹽，(10)； 其較佳地具有根據式(10-a)之組態(10-a)； 其中R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R10係選自 X，其中X為鹵基，較佳氯； 基團–NR5”R6”，其中R5”及R6”彼此獨立地為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基、C3 -C7 -環烷基，或者R5”及R6”與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，較佳地R5”及R6”與其所連接之氮一起形成對掌性部分； 基團–O-Rx，其中Rx與其所連接之氧一起形成對掌性部分；及 基團–S-R5，其中R5為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基； R11為氫或基團R8，R8為C1 -C7 -烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基。a compound of the formula (10) or a salt thereof, (10); preferably having a configuration according to formula (10-a) (10-a); wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from the group consisting of hydroxyl groups, Substituted with a substituent of C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy, halo, carboxy and pendant oxy, and R 10 is selected from X, wherein X is halo, preferably chloro; group -NR5 "R6", wherein R5 "and R6" independently of one another C 1 -C 7 - alkyl, C 6 -C 10 - aryl, C 6 -C 10 - aryl, -C 1 -C 7 - An alkyl group, a C 3 -C 7 -cycloalkyl group, or R 5" and R 6" together with the nitrogen to which they are attached form a 3 to 10 member, preferably a 4 to 7 membered monocyclic or bicyclic ring which may be saturated or unsaturated and optionally containing one, two or three additional heteroatoms such as nitrogen, oxygen, or sulfur, and which may be unsubstituted or substituted by one, two or three substituents independently selected from hydroxyl, C 1 -C 7 - alkyl, C 1 -C 7 - alkoxy, halo, carboxyl group and the oxygen side Substituted by a substituent, preferably R5" and R6" together with the nitrogen to which they are attached form a palm-like moiety; the group -O-Rx, wherein Rx forms a palm-like moiety with the oxygen to which it is attached; and a group - S-R5, wherein R5 is C 1 -C 7 -alkyl, C 6 -C 10 -aryl or C 6 -C 10 -aryl-C 1 -C 7 -alkyl; R 11 is hydrogen or a group R 8 R8 is C 1 -C 7 -alkyl or C 6 -C 10 -aryl-C 1 -C 7 -alkyl, preferably methyl. 如請求項1之式(10)化合物，其中當R11為R8，R8為C1 -C7 -烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基時，則R10係選自 基團–NR5”R6”，其中R5”及R6”彼此獨立地為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基、C3 -C7 -環烷基，或者R5”及R6”與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，較佳地R5”及R6”與其所連接之氮一起形成對掌性部分； 基團–O-Rx，其中Rx與其所連接之氧一起形成對掌性部分；及 基團–S-R5，其中R5為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基。Paragraph 1 of formula (10) compound of the request, wherein when R11 is R8, R8 is a C 1 -C 7 - alkyl or C 6 -C 10 - aryl, -C 1 -C 7 - alkyl, preferably methyl When R10 is selected from the group -NR5"R6", wherein R5" and R6" are independently of each other C 1 -C 7 -alkyl, C 6 -C 10 -aryl, C 6 -C 10 -aryl a base-C 1 -C 7 -alkyl, C 3 -C 7 -cycloalkyl, or R 5" and R 6" together with the nitrogen to which they are attached form a 3 to 10 member, preferably a 4 to 7 membered ring or Bicyclic, which may be saturated or unsaturated and optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or independently selected by one, two or three Substituted from a substituent of a hydroxyl group, a C 1 -C 7 -alkyl group, a C 1 -C 7 -alkoxy group, a halogen group, a carboxyl group and a pendant oxy group, preferably R 5" and R 6" are formed together with the nitrogen to which they are attached chiral moiety; group -O-Rx, wherein Rx is formed to which they are attached together with the oxygen on the palm portion; and the group -S-R5, wherein R5 is C 1 -C 7 - alkyl, C 6 -C 10 -Aryl or C 6 -C 10 -aryl-C 1 -C 7 -alkyl. 如請求項1之式(10)化合物，其中該化合物具有式(4)，或其鹽，(4)； 其較佳地具有根據式(4-a)之組態，(4-a)； 其中R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 X為鹵基，較佳氯。A compound of the formula (10), wherein the compound has the formula (4), or a salt thereof, (4); preferably having a configuration according to formula (4-a), (4-a); wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably 4 to 7-membered monocyclic or bicyclic ring, The ring may be saturated or unsaturated and optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or one, two or three independently selected from the group consisting of hydroxyl groups, Substituted with a substituent of a C 1 -C 7 -alkyl group, a C 1 -C 7 -alkoxy group, a halogen group, a carboxyl group and a pendant oxy group, and X is a halogen group, preferably chlorine. 如請求項1之式(10)化合物，其中該化合物具有式(3-II-A)，或其鹽，(3-II-A)； 其較佳地具有根據式(3-II-A-a)之組態，(3-II-A-a)； 其中R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5”及R6”彼此獨立地為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基、C3 -C7 -環烷基，或者R5”及R6”與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，較佳地R5”及R6”與其所連接之氮一起形成對掌性部分。A compound of the formula (10), wherein the compound has the formula (3-II-A), or a salt thereof, (3-II-A); it preferably has a configuration according to formula (3-II-Aa), (3-II-Aa); wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered single or double ring The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or selected from one, two or three independently. hydroxy, C 1 -C 7 - alkyl, C 1 -C 7 - alkoxy, halo, carboxyl group and the oxo substituent, and R5 "and R6" independently of one another C 1 -C 7 - Alkyl, C 6 -C 10 -aryl, C 6 -C 10 -aryl-C 1 -C 7 -alkyl, C 3 -C 7 -cycloalkyl, or R 5" and R 6" The nitrogen together form from 3 to 10 members, preferably from 4 to 7 members, monocyclic or bicyclic, which may be saturated or unsaturated and optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur. And which may be unsubstituted or one, two or three independently selected from the group consisting of hydroxyl, C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy, halo, carboxy and pendant oxy Substituent substitution, preferably R5" and R6" together with the nitrogen to which they are attached Pair chiral section. 如請求項1之式(10)化合物，其中該化合物具有式(3-III-A)，或其鹽，(3-III-A)； 其較佳地具有根據式(3-III-A-a)之組態，(3-III-A-a)； 其中R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 Rx與其所連接之氧一起形成對掌性部分。The compound of the formula (10), wherein the compound has the formula (3-III-A), or a salt thereof, (3-III-A); it preferably has a configuration according to formula (3-III-Aa), (3-III-Aa); wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered single or double ring The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or selected from one, two or three independently. Substituents of a hydroxy group, a C 1 -C 7 -alkyl group, a C 1 -C 7 -alkoxy group, a halogen group, a carboxyl group, and a pendant oxy group are substituted, and Rx forms a palmitic moiety together with the oxygen to which it is attached. 如請求項1之式(10)化合物，其中該化合物具有式(3-IV)，或其鹽，(3-IV)； 其較佳地具有根據式(3-IV-a)之組態，(3-IV-a)； 其中R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基。The compound of the formula (10), wherein the compound has the formula (3-IV), or a salt thereof, (3-IV); it preferably has a configuration according to formula (3-IV-a), (3-IV-a); wherein R1 and R2 are independently of each other a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered single or double ring The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or selected from one, two or three independently. Substituted with a substituent of a hydroxyl group, a C 1 -C 7 -alkyl group, a C 1 -C 7 -alkoxy group, a halogen group, a carboxyl group and a pendant oxy group, and R 5 is a C 1 -C 7 -alkyl group, a C 6 -C group 10 -Aryl or C 6 -C 10 -aryl-C 1 -C 7 -alkyl. 如請求項1之式(10)化合物，其中該化合物具有式(5-II-A)，或其鹽，(5-II-A)； 其較佳地具有根據式(5-II-A-a)之組態，(5-II-A-a)； 其中R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代， R5”及R6”彼此獨立地為C1 -C7 -烷基、C6 -C10 -芳基、C6 -C10 -芳基-C1 -C7 -烷基、C3 -C7 -環烷基，或者R5”及R6”與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，較佳地R5”及R6”與其所連接之氮一起形成對掌性部分，且 R8為C1 -C7 -烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基。The compound of the formula (10), wherein the compound has the formula (5-II-A), or a salt thereof, (5-II-A); it preferably has a configuration according to formula (5-II-Aa), (5-II-Aa); wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered single or double ring The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or selected from one, two or three independently. Substituted by a substituent of a hydroxyl group, a C 1 -C 7 -alkyl group, a C 1 -C 7 -alkoxy group, a halogen group, a carboxyl group and a pendant oxy group, and R 5" and R6" are independently C 1 -C 7 -alkanes a C 6 -C 10 -aryl group, a C 6 -C 10 -aryl-C 1 -C 7 -alkyl group, a C 3 -C 7 -cycloalkyl group, or a nitrogen to which R 5" and R 6" are attached Forming together from 3 to 10 members, preferably from 4 to 7 members, monocyclic or bicyclic, which ring may be saturated or unsaturated and optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, And it may be unsubstituted or substituted by one, two or three independently selected from the group consisting of a hydroxyl group, a C 1 -C 7 -alkyl group, a C 1 -C 7 -alkoxy group, a halogen group, a carboxyl group and a pendant oxy group. Substituent substitution, preferably R5" and R6" together with the nitrogen to which they are attached Chiral moiety, and R8 is C 1 -C 7 - alkyl or C 6 -C 10 - aryl, -C 1 -C 7 - alkyl, preferably methyl. 如請求項1之式(10)化合物，其中該化合物具有式(5-III-A)，或其鹽，(5-III-A)； 其較佳地具有根據式(5-III-A-a)之組態，(5-III-A-a)； 其中R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 Rx與其所連接之氧一起形成對掌性部分。The compound of the formula (10), wherein the compound has the formula (5-III-A), or a salt thereof, (5-III-A); it preferably has a configuration according to formula (5-III-Aa), (5-III-Aa); wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered single or double ring The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or selected from one, two or three independently. Substituents of a hydroxy group, a C 1 -C 7 -alkyl group, a C 1 -C 7 -alkoxy group, a halogen group, a carboxyl group, and a pendant oxy group are substituted, and Rx forms a palmitic moiety together with the oxygen to which it is attached. 如請求項1之式(10)化合物，其中該化合物具有式(5-IV)，或其鹽，(5-IV)， 其較佳地具有根據式(5-IV-a)之組態，(5-IV-a)， 其中R1及R2彼此獨立地為氫或氮保護基，或者R1及R2與其所連接之氮一起形成3至10-員，較佳4至7-員單環或雙環，該環可為飽和或不飽和且可視情況含有一個、兩個或三個諸如氮、氧或硫之其他雜原子，且其可為未經取代或經一個、兩個或三個獨立選自羥基、C1 -C7 -烷基、C1 -C7 -烷氧基、鹵基、羧基及側氧基之取代基取代，且 R5為C1 -C7 -烷基、C6 -C10 -芳基或C6 -C10 -芳基-C1 -C7 -烷基，且 R8為C1-C7-烷基或C6 -C10 -芳基-C1 -C7 -烷基，較佳甲基。A compound of the formula (10), wherein the compound has the formula (5-IV), or a salt thereof, (5-IV), which preferably has a configuration according to formula (5-IV-a), (5-IV-a), wherein R1 and R2 are each independently a hydrogen or nitrogen protecting group, or R1 and R2 together with the nitrogen to which they are attached form a 3 to 10-member, preferably a 4 to 7-membered single or double ring The ring may be saturated or unsaturated and may optionally contain one, two or three other heteroatoms such as nitrogen, oxygen or sulfur, and which may be unsubstituted or selected from one, two or three independently. Substituted with a substituent of a hydroxyl group, a C 1 -C 7 -alkyl group, a C 1 -C 7 -alkoxy group, a halogen group, a carboxyl group and a pendant oxy group, and R 5 is a C 1 -C 7 -alkyl group, a C 6 -C group 10 -aryl or C 6 -C 10 -aryl-C 1 -C 7 -alkyl, and R 8 is C1-C7-alkyl or C 6 -C 10 -aryl-C 1 -C 7 -alkyl , preferably methyl. 一種如請求項1至9中任一項之化合物之用途，其係用於合成NEP-抑制劑N-(3-羧基-1-側氧基丙基)-(4S)-(對苯基苯基甲基)-4-胺基-(2R)-甲基丁酸或其鹽，或NEP抑制劑前藥N-(3-羧基-1-側氧基丙基)-(4S)-(對苯基苯基甲基)-4-胺基-(2R)-甲基丁酸乙酯或其鹽。Use of a compound according to any one of claims 1 to 9 for the synthesis of NEP-inhibitor N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylbenzene) Methyl)-4-amino-(2R)-methylbutyric acid or a salt thereof, or NEP inhibitor prodrug N-(3-carboxy-1-yloxypropyl)-(4S)-(pair Ethyl phenylphenylmethyl)-4-amino-(2R)-methylbutanoate or a salt thereof. 一種用於製備N-(3-羧基-1-側氧基丙基)-(4S)-(對苯基苯基甲基)-4-胺基-(2R)-甲基丁酸或其鹽，或N-(3-羧基-1-側氧基丙基)-(4S)-(對苯基苯基甲基)-4-胺基-(2R)-甲基丁酸乙酯或其鹽之方法，其包括製造如請求項1至7中任一項所定義之化合物或其鹽。A method for preparing N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutyric acid or a salt thereof Or N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutyric acid ethyl ester or a salt thereof A method of producing a compound or a salt thereof as defined in any one of claims 1 to 7.
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