TW200306292A - Production of chirally pure α -amino acids and N-sulfonyl α -amino acids - Google Patents

Abstract

Methods for production of chirally pure α -amino acids and N-sulfonyl α -amino acids are described. An aldehyde and a cyanide salt are reacted with an α -methylbenzylamine to afford a product. The product reacts with a strong acid, is neutralized, and is extracted. The resulting product is subsequently hydrogenated and hydrolyzed to provide a product which is dissolved in a strong acid to provide a salt of a chirally pure α -amino acid, which is reacted to provide the chirally pure α -amino acid. Another method involves mixing ephedrine hemihydrate and an N-sulfonyl α -ethylnorvaline in ethanol at a molar ratio of 1:1; heating the mixture to dissolve the solids; cooling to allow formation of a precipitate; washing with an organic solvent to give diastereomeric salt; recrystallizing the salt; dissolving the recryustallized salt in an organic solvent and strong aqueous acid, separating the layers; washing the organic extract; drying and concentrating to provide chirally pure N-sulfonyl α -amino acid.

Description

V. Description of the invention (〗) Main invention The present invention relates to a novel material --- a novel production method of amine grade and basic acid. The compounds of the present invention are useful in dimethyl diamines including in pharmaceutical compositions. In the evening, 5 have been used in various aspects. Effectively and completely deleted aspects, the present invention includes a system of mirror image isomers. Chiral chiral pure s-10 and two hands' to prepare: amine alcohol, succinyl hydrazone to prepare ν, "· 15 radical di-supply-a kind used to prepare chiral ^-hinder the hair == :: 看 后 物 _ When you can know that the present invention is about the method of preparing chiral ammonium acid. The method of dissociation of base acid This article 8 provides-a kind of chirality called amino amine :: == fanghe Compounds' which can be converted into amino alcohols, alcohols, and other deficient target compounds, such as alcohols or acid groups, 2- 20 200306292

As used herein, the term "chiral," refers to a compound that contains greater than about 95% s-mirror isomers when measured by chiral high performance liquid chromatography (HPLC), and is preferably greater than About 97%. Other methods for measuring chiral purity include customary analytical methods, including specific optical rotation, and customary methods.

The chemical method used. However, the technique used to measure chiral purity is not a limitation of the invention. X As used herein, "pharmaceutically useful," the term refers to a compound that has a desired biological effect, whether as a therapeutic agent, immunostimulant or compression agent, 'adjuvant, or vaccine agent. Similarly, There are various compounds, 10 which are suitable for non-pharmaceutical applications, for example, diagnostic agents, labeling agents, etc. can be prepared by the method of the present invention. However, other pharmaceutical useful compounds can be generated by this method. 9 15 Consumption by employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Cooperatives print compounds produced by this month and any target compounds that they convert into can be used from pharmaceutical or physiologically acceptable acids or laboratory-derived tread types. These salts include but are not limited to the following With organic acids 2 Inorganic acids ^ Listed as, cool acid, lactic acid, clavulanic acid, tartaric acid, No. cont., Trans-butenedioic acid, cis-butenedioic acid, malonic acid, tauric acid, ^ a 20 salts formed by hydrogen turbidity, hydrogen filling acid, phosphoric acid, sour acid, sulfuric acid, methyl toluene sulfonic acid and similar known acceptable acids, and mixtures thereof. Other salts include metals Soil testing metals, such as hydrogen and oxygen), (such as potassium hydroxide) feed or town, formed salts. W and other types of compound vinegar produced by the present invention, amines and other "prodrugs" ,, type, 2 these to the formula, · ,. Drug B, which can be converted into active groups in vivo. Yu—Shen • 4- 200306292 A7 B7 V. Description of the Invention (3) In the specific example required, the prodrug is an ester. See, e.g., B. Tita and Fanwei, Revisiting Peony · Ad Hoc "Approach as a Complement to Ligand Design", Drug Research Review, i6 (3) · 233_241, ed., John Wiley & Sons (1996 ). 5 Natural and unnatural 01-amino acids, natural and unnatural 2-amino alcohols, and intermediates thereof can be prepared according to the present invention. typical. The 0-amino acid is described by the formula (NH2) (CHR.) (C00H), where R · is an aliphatic group. The α-amino acid prepared according to the present invention can be converted into sulfofluorenyl α-amino acid and other desired compounds. These other desired compounds include, but are not limited to, related 2-amino alcohols, aldehydes, oximes, and their pharmaceutically acceptable salts, hydrates, and prodrugs. Similarly, natural and unnatural N-sulfofluorenyl α-amino acids, natural and unnatural sulfonyl 2-amino alcohols, and intermediates thereof can be prepared according to the present invention. Therefore, the techniques known to those skilled in this field can be used to easily reduce the N-acidamino acids described in this article to 2-amino alcohols, or convert them to related aldehydes, oximes , And its pharmaceutically acceptable salts, hydrates, and prodrugs. Printed by a member of the Intellectual Property Bureau of the Ministry of Economic Affairs and a consumer cooperative. 20 is converted to chiral pure 2-amino alcohol. In another example, a chiral pure N · sulfofluorenyl α-amino acid having the formula (R) 2CH (CH2) nCH (C02H) NH-S (0) 2R prepared according to the present invention may be Easily converted to a sulfonyl 2-amino alcohol having the formula (R) 2CH (CH2) nCH (CH2OH) NHS (0) 2R. Appropriately, in the above formula, η is 0 to about 10; R is a lower alkyl group, and the paper size is in accordance with the Chinese National Standard (CNS) A4 specification (210x297 publicly known 200306292 A7 B7) V. Description of the invention (4) Substituted Lower alkyl, lower alkenyl, substituted lower alkenyl, lower fast radical, substituted lower alkynyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, benzyl, Substituted benzyl, cycloalkyl, (¾ indio, CH (lower alkyl) -2-sweeten, CH (lower alkyl) _4-methyl-5oxybenzyl, CH (lower alkyl) benzene Or ch (〇H) -4-SCH3-phenyl; and R 'is selected from other suitable groups from H, lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower Alkenyl, lower alkynyl, substituted lower alkynyl, heterocyclyl, substituted heterocyclyl, phenyl, substituted benzyl, benzyl, substituted benzyl, cycloalkyl, and substituted A cycloalkanoyl group. In another example, the compound has the formula (R) 2CH (CH2) nCH (CH2OH) NH-S (0) 2-2-C4H2S-5-Cl Amino alcohols are prepared according to the method of the invention. The chiral pure compound prepared by the method according to the present invention is not limited to the above formula. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, the term "alkyl," as used herein, refers to straight chains and branches having one to 15 A saturated aliphatic hydrocarbon group of ten carbon atoms. It is preferably one to eight carbon atoms, and preferably one to six carbon atoms; "alkenyl," which is intended to include straight chains and branches with at least one carbon-carbon bicarbonate Bond and two to eight carbon atoms, preferably an alkyl group of two to six carbon atoms; "alkynyl," is intended to cover straight and branched chains with at least one carbon-carbon parameter bond and two to eight carbon atoms , Preferably an alkyl group of 20 to 6 carbon atoms. The term "lower," as used herein, refers to any group having the above definition of one to six carbon atoms. "Substituted alkyl", "Substituted alkenyl," "Substituted alkynyl '," "Substituted lower alkyl,", "Substituted lower alkenyl,", "Substituted lower alkynyl," Refers to the alkyl, alkenyl, alkyne-6- as just described

200306292 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (5) ---, lower alkyl, lower alkenyl, and lower alkynyl, which have one to three selected from the following groups Substituents: halogen, CN, OH, amine, aryl, heterocyclyl, substituted aryl, substituted heterocyclyl 2, alkoxy, substituted alkoxy, aryloxy , Substituted aryloxydioxane 5-ylcarbonyl, alkylcarboxy, alkylamino, and arylthio. These substituents may be attached to any carbon atom of the alkyl, alkenyl, or alkynyl group if the i is a stable chemical group. The term "aryl," as used herein, refers to a carbocyclic aromatic system, which may be a single ring, or an aromatic polycyclic ring, which is fused or linked together such that at least the 10-ring or linked ring -Partially formed a total aromatic system. The aryl group includes, but is not limited to, phenyl, naphthyl, biphenyl, anthryl, tetranaphthyl, benzonaphthyl, and hydroindenyl. "Substituted aryl" means an aryl group as defined immediately above, which has one to four substituents selected from the group consisting of: halogen, CN, OH, 15 N0, amine, alkyl, Cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkoxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio. Substituted benzyl "system Refers to benzyl (Bn) with one to five substituents selected from the group consisting of: dentin, CN, OH, 20N2, amine, alkyl, cycloalkyl, olefin , Alkynyl, alkoxy, aryloxy, substituted alkoxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio. As used herein, the term "heterocyclyl" refers to a stable 'to a member monocyclic or a stable polycyclic heterocyclic group, which is saturated, partially unsaturated, or unsaturated -7- This paper applies to the standard National Standard A (CNS) A4 g (21 ^ H97 issued

200306292 Α7 V. Description of the invention (6) 10 15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy 20 and it contains carbon atoms and consists of one to four heteroatoms selected from the group consisting of atoms. The S atom can be oxidized. The two dimers = = di Γ; fruit = any of the above heterocyclic ring groups = square group%. If the resulting structure is chemically connectable to any heteroatom or carbon atom. For example, tetrahydrofuran, hexahydropyridyl, hexahydropyridyl, 2 hydrazone, yaheptinyl, silk, M-based, yl-based, radio-based, talhuyl, decyl, Hexadecyl, molybdenyl, indoxy, 'material-based', phenanyl, creanyl, benzocreanyl, benzopyridinyl, hydrazone, quot; Shifeng, isoamyl, and tetrachlorothiopiperan. 'Compared to the "substituted heterocyclic group" used herein, the term is used to describe the heterocyclic group just defined, which has one to four Each is selected from the group consisting of the following substituents: halogen, CN, OH, NO2, amine, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl , Substituted alkynyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, alkoxy, substituted alkoxy, alkylamino, substituted alkyl A few bases, an alkyl group, a substituted alkyl group, an alkyl group, a substituted alkyl group, an arylthio group, or a substituted arylthio group. As used herein, the term "substituted cycloalkyl" refers to a carbon-based ring having more than three carbon atoms forming a stable ring and having from one to five substituents selected from the group consisting of: · Il, CN, OH, NO2, amine, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, oxo, aryloxy, substituted alkoxy, burn Base paper, base paper calculation standard This paper applies Chinese National Standard (CNS) A4 specification (210 X297 mm) 200306292 B7 A7

Group, alkylamino group, substituted alkylamino group, arylthio group, heterocyclic group, substituted heterocyclic group, aminoalkyl group, and substituted aminoalkyl group. When "substituted alkylcycloalkyl,", "substituted alkyl 0Bn,", "substituted alkylpyridyl", "substituted alkylfuryl", "substituted 5 Alkyl NHR / ', and "phenyl (substituted) alkyl," "substituted alkane is 0H" and "substituted alkyl SRs" are substituted in the following formula I and formulas mentioned below The action will take place on an alkyl group or related base compound. The definition of the I group in formulae I and la below is used to define a substituted hexahydropyridyl system as a substituted heterocyclic group. Particularly desirable Substituted 10 groups are N-alkyl-, N-aryl-, N-fluorenyl-, and N-sulfonylhexahydropyridinyl. Particularly suitable N-fluorenyl-hexahydropyridyl is N-th Tributoxycarbonyl (BOC) -hexahydropyridine. However, those skilled in this field can easily identify other suitable substituents. The Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs printed the "alkane" used in this article. The term "oxy" refers to a 0 (alkyl) group, wherein the 'connection point' in 15 is via an oxygen atom and the alkyl group can be optionally substituted. As used herein, the term "aryloxy" refers to a 0 (aryl) group, where the point of attachment is via an oxygen atom and the aryl group can be optionally substituted. As used herein, the term "alkynyl" refers to a C0 (alkyl) group, wherein the alkyl group can be optionally substituted and the point of attachment is through the carbon atom of the carbonyl group. As used herein, the term "alkynyl carboxy" refers to a oxo (alkynyl) group in which the alkyl group is optionally substituted and the point of attachment is through the carbon atom of the carboxyl group. As used herein, the term "aminoalkyl" refers to the second and third amines, wherein the alkyl or substituted alkyl group containing one to eight carbon atoms may be the same or different, and the point of attachment Tied to a gas atom. -9- Standard for timely home care (CNS) A4 hemp — (_ 21G χ297 public love) 200306292

The term _ prime 'refers to α, Br, F, or j. For example, when ^ additionally indicates the type of ring structure, the term "ring" structure refers to, for example, the structure,-Zhen 3 ^ R4 forms a ring structure in Formula 1, including a single ring structure and fusion.环 结构。 Ring structure. The term "non-nuclear nucleophilic test" refers to a non-nucleophilic test reagent that incorporates a nucleophile, nucleophile, or adheres to a reagent used in accordance with the present invention. Isopropyl is known to have a variety of Non-nucleophilic tests and include sodium hydride, hydrogen sulfoxide, di, and: human with amine lithium and hexafluorenyl diazide azide. The word water in 10 is known to mean one containing at least one test and water. Solution. Skills: There are many kinds of alkalis that can be easily dissolved in water and include alkali metal hydroxides, lithium hydroxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. The alkaline aqueous solution may contain other substances that will not interfere with the The reagents for the reaction of the invention include organic> cereals, for example, tetrahydrofuran, methanol, ethanol, or hydrocarbon solvents, salts, for example, sodium gasification, and buffers. 15 The term "hydrated acid" means A solution containing at least one acid and water. The acid produced by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs may contain other reagents that do not interfere with the reaction of the present invention. The term "strong acid" or "strong base" refers to an acid or ion that can be completely ionized in solution.-General strong acids include HQ, HBr, HI, HNO3, H2S04, and HC104.-General strong Includes argon oxide 20 compounds of alkali metals (Li, Na, K, Rb, Cs) and hydroxides of heavy alkaline earth metals (ca, Sr, Ba). Inorganic "acid" or "inorganic" tests include compounds that are not broken. The term "organic solvents" includes any known carbon-containing solvents that do not react with the reagents used in the reaction and include saturated hydrocarbon solvents. Unsaturated few cereals include aromatic smoke solvents, alcohols, halogenated dishes. 'Scales, and vinegar-10 ~ This paper scale is applicable to National Standard T (CNS) A4 regulations U10x297 mm) " --- 200306292 A7 B7 V. Description of the invention (9) Acid salts etc. Synthetic chiral pure compounds can be prepared by the methods described below. Those skilled in this field will be able to easily select appropriate synthetic methods and reagents, which are 5 organic compounds known to those skilled in this field Techniques or changes in these methods. Usually 'see, the all-encompassing organic synthesis method, "selectivity, strategy and efficacy in modern organic chemistry", ed., J. Fleming,

Pergamon Press, New York (1991); All-inclusive Organic Chemistry, "Synthetic Methods and Reactions of Organic Compounds", ed. J.F. S. Stewart, 10 Pergamon Press, New York (1979). One of the problems of chiral pure α-amino acids is to provide a method for preparing chiral pure α-amino acids from chiral impure α-amino acids. In the preparation of chiral pure α-amino acid XXXXVI, a new type of Strecker α-amino acid was used to synthesize a 15-symbol variant (Scheme 14; Journal of Organic Chemistry 54: 1055-1062 (1989)). In this way (in the figure ^, the aldehyde χχχχνιι and the cyanide salt and α-methylbenzylamine or its salt are used in a 1 :: 1 mole ratio in a suitable printing solvent for the clothing consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. The reaction is carried out to obtain the compound χχχχνιΙΙ. The desired cyanide salts included are sodium cyanide and potassium cyanide. However, other suitable cyanide 20 salts can be easily selected for use in the method of the present invention. The solvent is preferred : I: methanol to water. The reaction is preferably carried out for about 12 to about 24 hours, and preferably about 18 hours. However, longer or shorter reaction times can also be used. Optionally, according to this reaction, A suspension containing precipitates is formed, which is filtered and washed (for example, with water) to obtain a powder. Compound-11-This paper size applies the national standard (CNS) A4 ^ (21〇X 297 mm) ) __ 200306292 A7 -------_____ B7 V. Description of the invention (10) Printed by XXXXVIII, a strong inorganic acid used by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, which must be cooled when dissolved with the compound to dissolve (For example, about 〇〇c The compound XXXXIX is provided to about 10.0. Where possible, the strong inorganic acid is sulfuric acid. However, other strong inorganic acids can also be easily selected. The reaction mixture is neutralized with an inorganic base 5 and extracted with an organic solvent. Compound χχχχΐχ. Appropriately, extraction reaction can be performed with ethyl acetate or other suitable compounds, and also includes drying and concentration to obtain compound χχχχχχ. The hydrogenolysis reaction is in the presence of a suitable catalyst under, for example, 3 atm pd or RaNi pressure was used to filter to remove the catalyst, and then concentrated to remove the solvent to obtain compound XXXXX. Then, the compound χχχχχ was dissolved with an aqueous acid to obtain a derivative of formula XXXXVI. Meanwhile, χχχχχ was dried to form a powder form, It is dissolved in a strong inorganic acid at high temperature to obtain a chiral pure ... amino acid salt. For example, it can be used for 100 hydrochloric acid. Or, those skilled in this field can easily choose other acids And other suitable temperatures. 15 If possible, the hydrolysis step is performed for about 12 to 18 hours, or longer. In a suitable embodiment, this step is performed for 16 hours. Optionally, the resulting reaction mixture is concentrated to obtain a product comprising an amino acid salt and a low equivalent ammonium salt. In this example, the product is an amine Acid argon chloride and 1 equivalent of beryllium gaseous. Dissolve this product in water and add 20 'to the test, for example, sodium hydroxide or ammonium hydroxide to form a solution. -12- This paper size applies ΐ National Standard (CNS) A4 Specification (210 × 297 mm 200306292 A7 B7 V. Description of Invention (u)

Λ XXXXVII CN salt 〇 CN Human N, 〇 2 strong acid xxxxvm h2n, ^ 〇 0 h2n "

XXXXIX 3 H2 / catalyst

OH 10 JR h2n 4 strong inorganic acid xxxxvi h2n ^ o R eight h2n xxxxx 15 Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs 20 These chiral pure a-amino acids generated according to the method of the present invention can be easily used The resulting form is used or converted into the desired target compound. For example, '-chiral pure a-amino acid can be easily obtained by reducing ^ amino acid to 2-amino alcohol and recrystallizing the 2-amino alcohol to obtain chiral pure amine pure 2- Amino alcohol. The chiral pure a-amino acid of the present invention is easily shown by the beakers provided by the artisans skilled in this field and by the information known to the artisans skilled in this field. -Determining the Strike Preparation Techniques of Very Amino Acids 1 In another aspect, the present invention provides a kind of N • two-base α, which is impure and has β " blade-burning silk-based radicals, to provide _ hand Schematic representation of a pure N-sulfofluorenyl alpha-amino acid. ^ XT ^ 〇 N-fluorenyl CX-amino acid Green is sulfanyl β-ethyl orthanoline. In another-specific example, the original -13- this quotient is moderate F · NS) A4 specifications ⑵ 0 297 · 200306292 A7 The invention shows that the amino acid compound can be selected from N-gamma β · ethyl lysine, Substituted by N-pyridylchloroamine and N-continuous n-propyl-ortho-leucine. Alternatively, those skilled in the art can perform the method according to the present invention with another selected N-heteroα-amino acid having a β-branched silk substituent to prepare related chiral pure compounds. 10 15 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20, where appropriate, N_twoyl β · ethyllysine (or another selected compound) and chiral pure ephedrine hemihydrate can be used in & Alcohol towels are based on the Mohr ratio. The mixture was then heated to dissolve the solid. In a specific example, the mixture is heated to about 800c. However, other suitable temperatures can be easily selected. After that, the mixture was cooled to form a temple. This cooling step can be performed at room temperature or at a reduced temperature (about 5t) overnight (about 1/0), the temperature and duration of the step 4 of the day can be suspended upward or downward as required or desired. Any After cooling, the floating liquid can be filtered or washed, and then recrystallized and then transferred to — and strong aqueous acid. Appropriately, the recrystallization step is performed in Hai Yi's Wei Yi g purpose and The recrystallized salt is separated. This can be filtered by filtration or other conventional methods. Appropriately, the salt is dissolved in an organic solvent and a strong aqueous acid. The organic extract is washed, dried and concentrated to produce chirality. Pure brewing α-amino acid. In a specific example, the washing step is performed with a strong aqueous acid, such as hydrochloric acid, and the drying is performed with sodium sulfate, etc. As appropriate, these chiral pure α_ Amino acids and amino acids can be used for a variety of purposes. For example, this hydrazine and sulphosulfinoamino acid can be converted into related N-sulfofluorenyl 2-amino alcohols by the methods described herein. -14- This paper size applies to China ii ^ (CNS) A4 specification (210 X 297 male gy ---______________ _ I. 200306292 A7 ------ B7 V. Explanation of the invention (13) Therefore, 'In a specific example, the chiral pure α-amino acid generated according to the present invention can be used to synthesize chiral continyl amines. A suitable method for the preparation of these chiral N-leaf-fe-α-amino acids is provided herein. Amino alcohols 5 The method of the present invention provides the synthesis of α-amino acids and N-sulfonyl α-amines. An effective way for the chiral pure S mirror image isomers of amino acids, which can be used to prepare 2-amino alcohols or N-sulfonyl 2-amino alcohols, and their intermediates, which can be used for a variety of purposes. Printed by the Consumer Affairs Cooperative of the Property Bureau. For example, the example compounds provided herein, N-sulfofluorenyl 2-amino 10 alcohol and its related aldehydes, oximes, and salts can be used to regulate the formation of stone-amyloid hydrazone. Involved in amyloid iliac vascular disease, cerebral amyloid iliac vascular disease, systemic amyloidosis, Alzheimer's disease syndrome (AD), hereditary cerebral hemorrhage with German amyloid iliosis, including body muscles Inflammation, Down's syndrome, etc. Therefore, compounds of formula (I) can modulate the development of AD or other 15 stone-starch in the brain The disease caused by the increase in the concentration of 朊 protein or the formation of powdery 朊 in individuals who are at risk of these. These compounds and their uses are in US Patent Application No. 10 / 014,304, which was filed simultaneously on December 11, 2001 There is a more detailed explanation, which is incorporated herein as Cangkao. Compounds of formula (I) include pharmaceutically acceptable salts and / or hydrates or prodrugs thereof, wherein formula (I) is:

⑴ -15- ^ »Applicable national standard (CNS) A4 specification (21 ^ x297 ^ 53 · 200306292 A7 B7 V. Description of the invention (14) R3 is selected from the group consisting of hydrogen, alkyl, and substituted alkyl R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkylcycloalkyl, substituted alkylcycloalkyl, phenyl (substituted) alkyl, alkyl 0H, substituted Alkyl OH, alkyl OBn, substituted alkyl OBn, 5 alkylpyridyl, substituted alkylpyridyl, alkylfuranyl, substituted alkylfuranyl, CH (OH) phenyl, CH (OH) substituted phenyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, N-substituted-hexahydrocarbyl, hexahydro Hexahydrocarbyl, tetrahydrothiopiperanyl, substituted tetrahydrothiopiperanyl, 2-hydroindene, substituted 10 2-hydroindene, phenyl, substituted phenyl, alkyl NHr7 , And substituted alkyl NHR7; but R3 and R4 are not hydrogen at the same time; R7 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, benzyl, substituted benzyl, alkyl OH, substituted alkyl OH 15 alkyl SR8, or substituted alkyl sr8; R8 is alkyl, substituted alkyl, benzyl, or substituted benzyl; or R3 and R4 can form a ring together; consumption by employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Cooperative printed R5 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cH2 cycloalkyl, 20 substituted CH2 rings Alkyl, benzyl, substituted benzyl, and ch2ch2qr9; Q is 0, NH or S; R9 is lower alkyl, substituted lower alkyl, phenyl, or substituted phenyl; -16- 200306292 A7 B7 V. Description of the invention (15 R6 is selected from the group including hydrogen, halogen and CF3, T is selected from the group including

〇

An and

OH 10 15 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, R! And R2 are each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, CF3, alkenyl, substituted alkenyl, Alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl 'and (CH2) n (l, 3) di4alkane, where η is 2 to 5; w, y and ζ are each independently selected from the group consisting of: c, CRw and N ', but at least one of W, Y and z must be c;

Rio is selected from the group including hydrogen and halogen; X is selected from the group including 0, s' so2, and NRii;

Rll is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, phenyl, and substituted benzyl. The point of attachment of the W-X-Y-Z-C heterocyclic group to the S02 group is not a limitation of the present invention. However, in a preferred embodiment, the ring system is connected to the S02 group via a carbon atom. However, the ring may be connected via O, S, or N20 heteroatoms. The compound of formula (I) contains one or more asymmetric carbon atoms and this compound contains one or more asymmetric (chiral) centers and thus generates optical isomers and diastereoisomers. Although shown in formula (I) is not related to stereochemistry, when the compound of formula (I) contains one or more chiral centers, at least -17- this paper size applies to the national standard (CNS) A4] (210x297) Love] '~' ___________ 200306292 Α7 Β7 V. Description of the invention (16) The chiral center derived from α-amino acid must be S-stereochemistry. More preferably, the carbon atoms connected to NR, T, R3 and R4 are S-stereochemistry. In a specific example, the present invention relates to a method for preparing a chiral S image isomer of N-sulfofluorenyl 2-amino alcohol having the general formula la:

R

R 10

NH (CH2) n

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, where R is lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, naphthene , Substituted cycloalkyl, phenyl, substituted phenyl, benzyl, 15 substituted benzyl, CH2 cycloalkyl, CH2-3-1, indole, CH (lower alkyl) -2- Squeeze, CH (lower alkyl) -4-methoxyphenyl, CH (lower alkyl) phenyl, or CH (OH) -4-SCH3-phenyl and η is from 0 to about 10. If desired, the compound prepared according to the method of the present invention contains at least one chiral carbon center, wherein R is the same in the above structure. In certain specific examples, the R group is methyl, ethyl, and n-propyl, and more preferably R is ethyl. However, the present invention also includes the production of α-amino acids and 2-amino alcohols, but the R groups are different here. Among these compounds, one or more other chiral centers may appear; however, the other chiral centers must be optically pure and must not interfere with the chirality of the present invention. Standard (CNS) A4 specification (210 X 297 mm) 200306292 A7 B7 V. Description of the invention (17) Pure s mirror image of α-amino acid, 2-amino alcohol, and N-sulfonyl 2-amino alcohol Formation of isomers. In another preferred embodiment, the chiral carbon center is S-stereochemistry which produces a mirror-isomeric pure product. 5 In a specific example, the method of the present invention is used to produce chiral pure o-amino acid 'which can be easily converted into N-sulfoamidoamino acid. For example, a chiral pure amino acid prepared according to the method of the present invention can be used to prepare a compound of formula (1). Particularly desirable compounds of formula (I) include thienylsulfenium sulfonium, and the more desired is '5-_17 17 cephenamine hydrazone' and the most desired is 5-_. Sedphenamine 10 sulfofluorene, which is cold-branched on the first alcohol side chain. Therefore, regarding formula (I), the compound produced according to the present invention may have a structure in which X is s, W is C, γ is C (or CR1 ()) and Z is C (or CR1G), and the amine Sulfonium is attached to C2 of the thiophene ring. Preferably, X is S, W is C, Y is C (or CR10), ζ is C (or O110), and R6 is halogen. Most preferably, X is 15 8, ^^ is 0, y is 0, 2 is (:, 116 is halogen, and D is printed by C (〇H) RiR2, which is an employee consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. Among them, Ri and R2 is hydrogen, R3 is Η 'R4 is a lower alkyl group of S-stereochemistry, and R5 is Η. Other possible compounds of formula (I) are furansulfuron, wherein X is 0, W is C, and Y is C, and Z is C. In a particular specific example, the furansulfuronium of formula (I) can also be described by the / 3-branch of the side chain of the 20th alcohol. Therefore, regarding the compound of formula (I), In these compounds, T is CCOH)! ^^, wherein & and r2 are hydrogen, R3 is Η, R4 is a lower alkyl group of S-stereochemistry, R5 is Η, and R6 is halogen. In the preliminary screening analysis in vitro and in vivo, the selected compounds of these structures have unexpectedly good results. ^ -Powder-like 朊 inhibition-19-This paper is in accordance with China National Standard (CNS) A4 (210 X 297 mm) 200306292 A7

14 and, in many cases, has better activity than compounds of formula IX having other heterocycles (e.g., furan, where X is 0). However, other such compounds of formula (I) are also useful for the purposes described herein. In addition, other chiral pure amino acids and 5-amino-2-amino acids prepared by the present invention can be converted into the desired N-sulfofluorenyl 2-amino alcohols, which include compounds of formula (I). The compound of formula VII is described by sulfamonium, which has a branch on the side chain of the first alcohol group. Therefore, regarding the amidine compounds, among these compounds, T is 0: (011) 1¾, R1 and R2 are hydrogen, R3 is fluorene, FU is a lower alkyl group of S-stereochemistry, and Rs is η. These and chiral pure N-% fluorenyl alpha-amino acids can be prepared according to the methods described below. The first method in the production process involves reacting 2-amino alcohol Π with an appropriate sulfonium halide in the presence of a base such as triethylamine (TEA) and an appropriate solvent to obtain a compound of formula III. R2 and Ri in the compound are hydrogen 15 ^ 'N-sulfonic acid primary alcohol is oxidized with gas chromate bond (PCC) or printed under the clothing of the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, Ministry of Economy and Technology Then the related aldehyde IV is obtained, which can be reacted with Grignard reagent (RMgX, where r is an organic group and X is a halogen) to obtain a second alcohol V which is a mixture of diastereoisomers , Which can be separated by high performance liquid chromatography (HPLC) (Figure 2). 20 -20- This paper is used for National Standard (CNS) A4 specifications (21 × 297 mm) 200306292 A7 V. Description of the invention (19 Picture 2 OH h2n

Ri Π

PCC or Swem when in III, R ^ R ^ h 10

15 The first method in the printed clothing manufacturing method of the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs includes reacting ^ _amino acid or _ with an appropriate sulfonium in the presence of -_ such as triethylamine and _ appropriate solvents And pay for the compound of formula X (Figure 3). The intermediate Xanthate X (Rx = H) can be used standard methods, such as: Jin 4, E, or cyanuric acid / NaBH4 to feed into the related _ alcohol vm (Ri = R2 = H). Alternatively, the intermediate N-sulfonyl ester X (RX == alkyl, Bn) can be converted to aldehyde IV by DiBAL 〇20 -21- This paper applies Chinese National Standard (CNS) A4 specification (210x297 mm) 200306292 A7 B7 V. Description of invention (20) Picture 3

DiBAL alkyl, Bn

III VIII Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 15 Finally, the intermediate N-sulfonyl ester X (Rx = alkyl, Bn) can be reacted with 2 equivalents of Grignard reagent to obtain the third alcohol III, which r1 = R2 = base. Alternatively, at the third alcohol III where R! Is not equal to R2, the relevant Weinreb amide of N-sulfonic acid (see Figure 11) can be prepared and then reacted with 20 RiMgX and IMgX. In the case of a compound of formula X (RX = H) having an asymmetric center on CK-amino acid carbon, the pure mirror isomer can be analyzed by the standard recrystallization method of salts with various chiral bases Process. In the variation of the second method of preparing the first alcohol, the paper size α_-22- is firstly applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200306292 A7

200306292 A7 B7 V. Explanation of the invention (22 :) Then XV is obtained, followed by primogen 4 amino alcohol, and then the luteinization yields the target compound XVI. See diagrams 2 to 5, r5 is Η.

15 In the preparation of N-alkylated amines viii (r5 = carbonized, etc.), the amine confirmation ester XVII is tested by employees of the Intellectual Property Bureau of the Ministry of Economic Affairs by using an appropriate base such as potassium carbonate followed by alkylation. The consumer cooperative printed formulation RSX or N-alkylated was treated using Mitsunobu conditions (ioh / DEAD, TPP). This N-alkylated sulfamidine is reduced by UBI ^ to obtain N-alkylated amine sulfonium of the -th alcohol series VIII (Figure 6). These first-alcohol viii can be converted to the second alcohol v or aldehyde IV series by the chemical methods outlined above. Alternatively, the N-alkylated sulfasalamide, or related

Weinreb ammonium can be obtained by treatment with Zaliya reagent to obtain N-alkylated tertiary alcohol III. -twenty four-

200306292

V. Description of the Invention 23 Figure 6

ORx Rx = alkyl or Bn xvn or R5OH / DEAD / TPP 2 LiBH4

1 Base / R5X

vm When the heterocyclic ring of the sulfamidine connected to the above alcohol is thiophene, the related stone wind derivative XIX can be prepared by oxidizing the thiophene compound xvm with MCPBA (Figure 7). 10 Figure 7 15 r6 ·

r2 Ri MCPBA

XVIII

XIX

OH

Printed by the Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 20 The change method of amine sulfonium derived from unnatural 2-amino alcohols is the Bucherer correction method using Strecker α-amino acid synthesis (Figure 8). In this way, the ‘Take XX series’ reacts with the cyanide anion and ammonium carbonate to obtain the hydantoin XXI, which is hydrolyzed to the amino acid χχιι. This compound is then reduced to XIXII and sulfonated to give the desired compound of formula XXIV. -25- This paper size applies to China National Standard (CNS) A4 (210x297) 200306292 A7 B7 V. Description of the invention (24 Figure 8

Rb

Ra

1 NaCN / (NH4) 2C03 9 Rb 2 NaOH

Ra

XX

XXI h2n XXII 3 L1AIH4

Rb

Rb HO

HN—S—Hetar \ l II-〇 4 HetarylS〇2Cl

Ra —- HO ’h2n

XXIII

XXIV 10 In the case of sulfamonium derived from 2-amino alcohols containing N or O heteroatoms in the side chain, the reaction pathway is designed to start with D-serine (Figure 9). In this route, D-serine XXV is first sulfonated to XXVI and then converted to ketone XXVII, which is reductively aminated to the target compound of formula XXVIII. 15 Figure 9

〇Ή II co2h h2n

OH 〇

TEA Y-

co2h, II π x 0 11 LJ-HN II

Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20

XXV

0 〇H XXVI

BuLi

RcMgX

H κ ^ νη2 Na (OAc) 3BH R. HOAc 6 xx vm -26-

Rc 'II 〇

co-HN

OH xxvn This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) 200306292 Α7 Printing of clothing by employees ’cooperatives of the Intellectual Property Bureau of the Ministry of Economy -When the amino alcohol is mixed, = compound fine 0), designed as _IV «(as shown in Figure 2); as shown in Figure 10

XXIX 10 15 20 As mentioned in the section of V 2 rhyme ^ 2, due to the diastereoisomeric compounds produced in the preparation of the second alcohol series of isomeric mixtures, making 14 of these can cause pure non-pairing Another method for enantiomeric stereoisomers is outlined in Scheme 11 of σ ^ derived from L. isoleucine. This method uses the chemical method previously used by Roux 4 (tetrahedron 50: 5345d360 (1994)), including the addition of Grignard reagents to Weinreb amine XXX (derived from the essential α-amino acid ) Followed by the stereoselective reduction of YXXXI to give a single diastereoisomeric N-protected 2-amino alcohol XXXII. This compound is deprotected and then reacted with the sulfonium gas to give a pure diastereoisomeric aminesulfonium secondary alcohol of formula XXXIII. -27- This paper size applies to China National Standard (CNS) A4 (210x297 public love)

200306292 A7 B7 V. Description of the invention (26) Picture 11

B〇C

", 1 I RMgX

B〇C One

NOMe 5

XXX

XXXI

XXXIII

1 TFA

R 2 TEA

NaBH,

XXXII 15 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20

When the heterocycle attached to the sulfamidine of the above alcohol is thiophene, the related 5-iodine and 5-fluoro • thiophene derivatives can be obtained by adding 5-bromo-thiophene derivative XXXIV (as shown in Figure 2) ) To 5-trialkyltin · thiophene intermediate XXXV, which can be converted to 5-ammonium (XXXVII) by treatment with sodium iodide and chloramine τ or by using SELECTFLUORtm (Eric Chemical Co., Ltd. ) And converted to 5-fluoro-thiophene analog (XXXVI) (u). A -28- 1 Paper size Gu Xun (X 297 mm) 200306292 A7 B7 V. Description of the invention 27 Figure 12

OH

ci XXXV

(R3Sn) 2 R-i ^ Ηβδη r3 Pd (PPh3) 4 Nal / Chloramine T

XXXVII XXXVI 10 15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. 20 An amine derived from cyclohexyl glycinol (glycin〇1) substituted at the 4 position on the cyclohexane ring by an alkoxy group and an amine group. Sulfonium can be prepared according to the methods described herein (Figure 13). This pathway is designed to first hydrogenate 4-L · hydroxybenzylglycine XXXVIII, followed by sulfonation, reduce the carboxylic acid with diborane and generate N, 0-acetonide XXXIX. This 4-hydroxyacetonide XXXIX is then 0-alkylated with sodium hydride and a monoalkylating agent such as alkyl or benzyl bromide. It is then treated with an aqueous acid to remove the protecting group to give a 4-ether derivative of the formula XXXX. Alternatively, the .acetonide XXXIX can be oxidized to 4-ketone, which can be reductively aminated and deprotected to obtain the related 4-amine analogue of the formula XXXXI. -29- This paper size applies to China National Standard (CNS) A4 (210x297 mm) line 200306292 A7 B7 V. Description of invention (28 Figure 13

4 DMP / TsOH

10 r6

NHR XXXXI

OR 15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. If desired, the oxime XXXXXIV can be derived from the relevant aldehyde IV by the standard method described in Figure 14. 20 Figure 14

〇II-S〆, II X 〇 IV

'Z

nh2oh • 30-

pH Y-

xo N r3 XXXXXIV This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) 200306292 A7 B7 V. Description of the invention (29) " Examples The following K examples are used to illuminate the representativeness of the method according to the present invention Those skilled in the art of compound chemistry will understand that although specific reagents and conditions are outlined in the following examples, these reagents and conditions are not a limitation of the present invention. Example 1 Method 1 5-Chloro-N-[(lS) -2-ethyl + benzylbutyl] xanthenamine

15 A. 5- (1-ethyl-propyl) _imidazole bite-2,4_dione Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs Sodium cyanide (12.0 g, 244.8 mmol) and 2-Ethylbutylaldehyde (10.0 耄, 81.3 mmol) was added to ammonium carbonate (25.4 g, 325.3 mol) in Η20 (300 ml). Ethanol (300 ml) was added and the salt was precipitated. The reaction mixture was heated to 90 ° C. After 1 hour, the mixture became homogeneous and stirred at 90 ° C for U hours. Cool to 25. (After that, about 500 ml of solvent was removed in vacuo. Concentrated HC1 was added to acidify the mixture to pH 1-2 and form a precipitate. It was filtered and the precipitate was recrystallized from EtoAc to give 5- (1-ethyl-propyl) _imidazolidine_2,4_dione as a white solid (12.9 g, 93%). Mass spectrum (-ESI): 169 (MH), -31- This paper is applicable to China Standard (CNS) A4 specification (21 × 297 mm) 200306292 A7 B7 V. Description of the invention (30) Β · Ν · [(5-chloro-2-thienyl) continyl] -3-ethylprovaline Dissolve 5- (1-ethyl-propyl) -oral salivary-2,4-secondary j (12.3 g, 72.3 mmol) in 150 ml of an aqueous NaOH solution (π · 6 g, 289.2 mmol) Ear). The solution was heated by microwave in a sealed tank for i hours. (Microwave 5 conditions: 15 minutes @ 100% strength, 150 ° C, 50 psi, then 5 minutes 0 ° / 〇 intensity, then 15 minutes @ 100% strength, 150.50, 50 psi, then repeat the sequence). Water and ammonium hydroxide were removed from the reaction mixture in vacuum and the resulting crude amino acid and NaOH mixture was used without further purification In the next reaction. 1〇 The mixture of crude amino acid and NaOH was dissolved in 300 ml of water. The mixture was cooled to 0 ° C. in an ice bath. 5-chlorothiophene-2-sulfonyl chloride (17.3 g, 79.5 mmol) was dissolved in 100 ml of THF and added dropwise to the reaction mixture over a period of 0.5 hours. After 1 hour, the reaction mixture was gradually warmed to 25 ° C and stirred for 16 hours. The THF was removed in vacuo and the Ministry of Economic Affairs wisdom The property bureau employee consumer cooperative printed 15 and the mixture was acidified with IN HC1 to pH 1. After about 15 minutes, the precipitate began to scoop out from the milky white solution. After 1 hour, the mixture was cooled in the refrigerator for 1 hour and then filtered. The precipitate was washed with IN HC1 to obtain N-[(5-gas-2-thienyl) sulfonamido] -3-ethylorvaline (18.5 g, 78%) as a white solid. Mass spectrum (-ESI) · 325 (MH)-. 20 C. N-[(5-Gas-2-thienyl) sulfonamido] -3-ethyl-L_orvaline will be (+)-(lS, 2R) -Ephedrine hemihydrate (16.7 g, 95.6 mmol) added to a compound containing N-[(5-gas-2-thienyl) sulfonyl] -3-ethylorvaline (31.2 g, 95.6 mmol) in a suspension of 185 ml of EtOH. The compound is slowly heated to dissolve solids and form a precipitate. Cool at 5 ° C 18 -32- This paper size applies Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 200306292 A7 B7 V. Description of the invention (3i ) After hours, the resulting suspension was filtered off and Shen Dian was washed with cooled EtOH and EtOAc to give a diastereoisomeric salt in 27% yield. The salt was recrystallized from boiling EtOAc (420 mL) and filtered off. The resulting white solid was then dissolved in 300 ml of EtOAc and 300 5 ml of 1N HC1. The layers were separated and the organic extract was washed with IN HC1 (2 x 200 mL), dried (NaJCU), and concentrated to give N-[(5-Ga_2_fluorenyl) ¾fluorenyl] -3-ethyl -L-orthochloroamino acid as a white solid (5.6 g, 18%). Chiral HPLC [chiralpak AD (25x0.46 cm), 8: 2 hexane (0.1% TFA) · isopropanol, L-isomer was eluted in 9.6 minutes and D-isomer 10 was in 13.1 minutes Elution] indicated a chiral purity of 96%. [a] D25 = + 44.5 ° (c = 1% SOLUTION, MeOH). Mass spectrum (-ESI): 325 (M-H).

Analysis of CiiH16C1N04S2: Calculated value: C, 40.55; Η, 4.95; N, 4.30. 15 Found: C, 40.30; 30, 4.78; N, 4.16. Printed by D. 5-Chloro-N-[(lS) -2-ethyl-μ (hydroxymethyl) butyl] thiophene sulfonium at 0 ° C in a consumer cooperative of the Ministry of Economic Affairs ’Intellectual Property Bureau. -[(5-Chloro-2_thienyl) sulfoethylethyl-L-orvaline (5.6 g, ΐ7.2 mmol) in THF (150 ml) was added dropwise via an addition funnel- A solution containing 1M metcis tetrazolium complex in 20 THF (69 liters' 69 mol). After 15 minutes, the reaction mixture was warmed to 25C and stirred for 18 hours. It was then slowly quenched with 90 mL of AcOH in MeOH. The volatiles were removed in vacuo. The residue was then dissolved in EtOAc (300 ml), washed with saturated aqueous NaHcO3 (3 x 200 ml), dried (Na2S04), and concentrated to a white precipitate -33- 200306292 Α7 Β7 V. Description of the invention (32) g '96% yield, 96% chiral purity). The precipitate was recrystallized from heptane / EtOAc 4 ·· 1 to obtain optically pure 5-chloro-N-[(lS) -2-ethyl · 1- (transmethyl) butyl] -2-thiophene Amisulfin white needles (4.4 g, 81% yield). The melting point is 113-114X :. 5 [aL25 = +4.50 (c = 1% SOLUTION, DMSO). Mass spectrum (-ESI): 310 (M-VII)-. Analysis of ciiH18C1N03S2: Calculated value · C, 42.37; Η, 5.82; N, 4.49. Measured value · C, 42.37; Η, 5.79; N, 4.38. 10 E. 5-Chloro-N-[(lS) -2-ethyl-1-fluorenylbutyl] thiophene-2-aminesulfonium chloride Itb dichromate (2.4 g, 6.4 mmol) To a solution containing 5-chloro-N-[(lS) -2-ethyl-1- (hydroxymethyl) butyl] -2-thienylsulfonium (0.5 g, 1.6 mmol) in ch2C12 ( 20 ml). After 18 hours, the reaction mixture was filtered through a Yin plug. The filtrate was concentrated and the resulting residue was purified by silica gel column chromatography (eluent: 1: 4 EtOAC-hexane) to obtain 5-chloro-N-[(lS) -2-ethyl 1-Methylmethylbutyl] thiophene-2-aminesulfoniumsulfonate as a white solid (303 mg, 61%). [a] D25 = + 136.76 ° (c = 1% SOLUTION, CHC13). Mass Spectrum (-ESI): 308 (M-H)-printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. Analysis of 20 ChHkCINC ^ S]: Calculated: C5 42.64; H, 5.21; N, 4.52. Found: C, 42 · 57; H, 5.24; N, 4.52. Example 2 -34- This paper size applies Chinese National Standard (CNS) A4 (210x297 mm) A7 200306292 V. Description of the invention (33) Method 2 5-Chloro-N-[(lS) -2-ethyl-1 -Fluorenylbutyl] thiophene-2-aminosulfonium A. (2S) -3-ethyl-2-{[((lS) -1-phenylethyl] amino) valeronitrile containing (S) -(-)-a-methylbenzylamine hydrochloride (1.2 g '7.6 mmol) 5 of 80 ml 1: 1 Me0H / H20 potassium cyanide (0.5 g, 7.6 mmol Mol) and 2-methylbutyraldehyde (0.94 ml, 7.6 mmol). A precipitate formed after 30 minutes. After 20 hours, the suspension was filtered and washed with Η20 to give (2S) -3-ethyl-2-{[(lS) -1-phenylethyl] amino} valeronitrile as a white powder (1.29 g, 74%) Mass spectrum (+ ESI) 310 (M + H) +. Analysis and calculation of C15H22N2: C, 78 · 21; H, 9.63; N, 12.16. Found: C, 77.90; Η, 9.75; N, 12.32. Β. 3-Ethyl-N2-[(1S) -1-phenylethyl] -L-orthomelamine 15 at 0 ° C, (2S) -3-ethyl-2- { [(1S) + Phenylethyl] amine} Printed valeronitrile (2.7 g, 11.6 mmol) by the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperative, and added to 25 ml of sulfuric acid in portions. Warm the mixture to 25 ° C. After 2 days, the reaction mixture was poured into about 100 grams of crushed ice. Concentrated NEUOH was added to neutralize the acid. This mixture was extracted with EtOAcPx (100 ml), dried over NhSO4, filtered off and concentrated to give 3-ethylphenylethyl] heptavalinate (2.6 g, 90%), which Used in the next step without further purification. Mass spectrum (+ ESI): 249 (M + H) +. Analysis of C15H24N2O: Calculated: C, 72.54; Η, 9.74; Ν, 11.28. -35- Qian Zhang scale General Zhongguanjia Standard (CNS) A4 specification (2) 0X 297 mm 200306292 A7 B7 V. Description of the invention (34) Measured value · C, 72.24; H, 10.04; N, 11.01 C. 3-Ethyl ortholine amino acid amine will contain a 3-ethyl-N2-[(1S) -1-phenylethyl] orthovaline amidine (2 · 6 g, 10 · 5 The mixture of millimolar) and 5% Pd / C (800 mg) was shaken in a Parr apparatus at 35 atmospheres for 24 hours. The mixture was filtered through a Yin's salt plug and the solvent was removed in vacuo to obtain 3-ethyl small orthovalvaline ammonium amine as a white solid (1.4 g, 93%), which was used in the next reaction without further purification. Mass spectrum (+ ESI): 145 (M + H) +. 10 D · N-[(5-Chloro-1thienyl) pyridinyl] _3 · Ethylcardiogenovalinic acid Dissolve the ethyl 3-ethylorthochloroamine amide (ι · 2 g, 4.8 mmol) in concentrated HC1 (10 ml) and heated to 100 it for 16 hours. The reaction mixture was concentrated to a white solid including amino sulfonium chlorate and 1 equivalent of NH4C1 ', which was used without purification in the next step. 15 will Amino acid hydrochloride and 1 equivalent of NH4C1 (0.28 g, 1.19 mmol) The Ministry of Intellectual Property Bureau employee consumer cooperative printed Mohr) was dissolved in 6 ml of HbO and then NaOH (0.24 g, 6.0 mmol) was added. The solution was cooled to 0 ° C and then contained in 6 ml of THF. 5-Chlorophene 1 Sulfachloro (0.29 g, 1.32 mmol) was added dropwise. This substance was warmed to 25. After 19 hours, the THF was removed in vacuo. 20 The remaining solution was used with 10 ml of H20 was diluted and washed with EtOAc (2 x 10 ml). The solution was acidified with IN HC1 and a precipitate formed. It was filtered off to give N-[(5-chloro-2-thienyl) sulfonyl]- 3-ethyl-L-orthovaline acid as a white solid (0.17 g, 44%). Chiral HPLC indicated that only s-image isomers appeared. -36- 200306292 A7 B7 V. Description of the invention (35) Then According to the method of Example 1, rr 廿 # 1 is made from N-[(5-chloro · 2-thienyl) sulfonamido] -3-ethyl-L-lysine to produce "_chloro * __ 2_ethyl_ _Ylmethyl) butyl] I} phenamine and 5-chloro * [named 2-ethyl small methyl fluorenylbutyl] thiophen-2-aminesulfonium. Example 3 5IN- [⑽-2-ethyl light (Based on the base) Butyl amine was confirmed 10 15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 Fitted with a nitrogen inlet tube, mechanical stirrer, and - a 3 liter, 3-neck flask with addition funnel stopper of addition of hydrogen in the puncturing _M5 ml in 2M / TOF-prepared solution of 3.29 mole square). The solution was placed under nitrogen and cooled to 0c. Chlorodimethyl sulfite (73.8 ml, mole) was added dropwise between 30 minutes. The chop will be chopped and the raw material will be mixed for 30 / minute. The reaction mixture was cooled to rhenium and the 3 • ethylcardiogenic chlorogenic acid prepared according to US Provisional Patent Application No. 60 / 339,264 was solidified, and added in portions over a period of 15 minutes. The reaction mixture was slowly warmed to 25 ° C in an ice bath ' After 3 days at 25 ° C, the reaction mixture was cooled to zero. And methanol (217 mL) was added over a period of 80 minutes. The solution was stirred for an additional 40 minutes at 25 ° C and then concentrated in a water bath at 60 ° C under reduced pressure. The raw meal produced was tested with 20% sodium hydroxide (37.5 pen liters). Water (37.5 ml) was added, and the entire aqueous layer was washed with chloroform (3GG ml) and dried (Na2SO4). Concentrated under reduced pressure to give 3-ethyl-L-provaline alcohol (17.3 g, 91%) as an oil, which is used immediately or stored in the refrigerator overnight:

Opt. Rot. 25 [a] D t · 3 · 7 '!% Solution (DMSO); -37- Specifications (210x297 mm) 200306292 A7 B7 V. Description of the invention (36) 4 NMR (DMSO-d6, 500MHz) : δ = 4.38 (wide area s, 1H), 3.35 ((1 (1 overlaps with a wide area 8 at 5 3.32, == 4.5, 10.3 1 ^, 311), 3.14 (dd, J = 7 · 9,10 · 2Ηζ, 1H), 2.63 (m, 1H), 1.45 — 1.05 (m, 5Η), 0.82 and 0.81 (two overlapping three peaks, J = 7. · 4Ηζ, 6Η) 5 Mass spectrum (+ ESI): [Μ + Η] +, 132 (60%). One containing 3-ethyl-L-provaline alcohol (34.1 g, 0.26 mole) and dichloromethane (700 ml) of the mixture was placed under argon and cooled to 0 ° C. Triethylamine (36.2 ml, 0.26 mole) was added, followed by 5-chlorothiophene in methylene chloride (400 ml). 2-sulfohydrazone (56.4 g, 0.26 mole) was added dropwise 10. The reaction mixture was slowly warmed to 25 ° C when the ice bath melted. After 3 days at 25 ° C, the reaction mixture was divided into two A 0.6 liter portion. Dilute each portion with ethyl acetate (1 liter) and wash three times with saturated potassium phosphate monohydrate (200 ml) and once with brine (200 ml) And dried (Na2S04). Concentrated under reduced pressure to give a white solid (74.5 g, 92 15%). The product from several routes (87.98 g) was combined and heated with hot heptane: ethyl acetate (4: 1, (775 ml) was recrystallized to obtain the crystal of the target compound (74.9 g, 85%). Melting point was 115-117.6 ° C; Opt · Rot. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs [a] D25 = + 10.81o ( l% solution, MeOH); 20 lH NMR (DMSO-d6 ^ 500MHz): δ = 7.71 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 4.1 Hz, 1H), 7.22 (d, J = 4.1 Hz, 1H), 4.56 (t, J = 5.2 Hz, OH), 3.31-3.15 (m, 3H), 1.40-1.15 (m, 4H), 1.07 (m, lH), 0.79 and 0.76 (Three peaks of two overlaps, J = 7.3 Hz, 6H); -38- This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 200306292 A7 B7 V. Description of the invention (37) 13C NMR DMSO -d6, 100 MHz): δ 141.75, 133,73, 130.95, 127.60, 60.41, 56.89, 41 · 57, 21.31, 20.80, 11.79, 11.51; MS (-ESI): [Μ-Η]-, 1 Chlorine isotope type, 310 (100%), 312 (30%), 5 CUH18C1N03S2 Analysis: Calculated: C, 42 · 37; Η, 5.82; N, 4.49. Found: C, 42 · 34; Η, 5.65; N, 4.43. Chiral HPLC (Chiralpak AD, 25x0.46 cm, eluent 8 ·· 2, 0.1% THF in hexane / isopropanol, flow rate 0.5 ml / min, UV detection at 254 10 nm, The retention times of the S and R isomers were 10.95 minutes and 11.95 minutes, respectively), revealing that the S / R ratio was 100.0: 0.0. Example 4 5-Chloro-N-[(lS) -2-ethyl-1- (1-hydroxyethyl) butyl] thiophene

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, a solution containing fluorenyl magnesium bromide (1.4M, 7.0 ml, 9.7 mol) in toluene / THF (75: work) was added to a solution containing chloroethyl 1-fluorenylbutyl] thiophene-2-aminesulfonium (example! Or 2,10 g, 32 mmol) in THF (30 ml). The mixture was warmed to and within 2 hours After careful quenching with saturated aqueous ammonium chloride (25 ml). Mix -39- This paper size is timely standard (CNS) A4 size χ 297 public love γ 200306292 Α7 Β7 V. Description of the invention (38) The material was extracted with EtOAc (3 x 25 mL). The organic extract was dried over Na2Sc ^, transitioned and concentrated to give a colorless oil. The product was colored by a column; purified by Biotage, eluent: 1 : 4 EtOAc-Hexane, and paid 5-chloro-N-[(lS) -2-ethyl-1- (1-fatylethyl) butyl] pyrene_2-amine 5 white Solid (876 mg, 83%). The product was a diastereoisomeric mixture in a ratio of 3. · 7. The melting point was 95-98 ° C.

Analysis of Ci2H2GClN03S2: Calculated values: c, 44.23; H, 6.19; N, 4.30. Found: C, 44.25; Η, 6.35; N, 4.29. 10 Mass spectrum (-ESI): 324 (M-VII)-. fill-Analysis conditions A. Semi-preparative RP-HPLC conditions: Gilson Semi-Preparative HPLC System with Unipoint Software 15 Columns: Phenomenex C18 Luna 21.6 mm x 60 mm, 5 μ Solvent A: Water (0.02% TFA buffer) Solvent B: Acetonitrile (0.02% TFA buffer) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. Solvent gradient: Time 0: 10% B; 2.5 minutes: 10% B; 14 minutes: 90% B. 20 Flow rate: 22.5 ml / min. Product peaks were collected based on UV absorption and concentrated. Β. Analytical LCMS conditions: ChemStation Software's Hewlett Packard 1100 MSD column: YMC ODS-AM 2.0 mm x 50 mm, 5 μ column at 23 -40- This paper scale applies Chinese National Standard (CNS) A4 specifications (21 〇χ297mm) 200306292 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (39) ° C; 3μl injection; Solvent A: Water (0.02% TFA buffer solution) Solvent B · Ethiopia ( 0.02% TFA buffer) Gradient: Time 0: 95% A; 0.3 minutes: 95% A; 4.7 minutes: 10% 5 A; 4.9 minutes: 950 / 〇A. Flow rate: 1.5 ml / min; Detection: 254 nm DAD; API-ES Scanning Mode Positive 150-700; Fragmentor 70 mV o 10 C. Analytical LCMS conditions: ZMD (Waters) or Platform (Micromass) or LCZ (Micromass) ) Column: Zorbax SB-C8 Solvent: Acetonitrile + H20 (containing 0.1% TFA or 0.1% FA) Gradient: 2.5 minutes 15% acetonitrile-95% acetonitrile 15 Flow rate: 3 ml / min Detection: ELSD detection ( SEDEX55) UV 253 Determining (Schimadzu) Preferential Example 6-Pressure Release Analysis (RRA) 20 The compounds generated as described in Examples 1 to 4 will be subjected to RRA testing according to published techniques [Su Yi, DJ, Xu Fei, ρ ·, Jones ·, D ·, Keqi, M · I ·, and Kunner, E · M · (1999) ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,-,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 制剂, 制剂 1999, 1999, E.M. (1999), F., Phytosome release: monitoring amyloid precursor protein in mammalian cells (APP) A useful tool to resolve the problem ", Abstract Society of Neuroscience, Volume 25, Neuroscience-41- This paper is in accordance with the national standard (cns) a4 (210 X 297 mm)

200306292 A7 B7 V. Description of Invention (40) 29th Annual Meeting of the Society, Miami Beach, Florida, October 23-28, 1999]. In short, this analysis is performed as follows. A. Cell culture: CHO-K1 cells were completely DMEM 5 containing 37% C02 at 37 ° C (DMEM-containing 10% bovine fetal serum, 1% non-essential amino acids, and 1% penicillin-streptomycin) In high glucose. Two million cells were plated into 10-cm culture plates 24 hours before transfection. Transient transfection, as recommended by Gibco BRL, was performed using its Lipo-fectamine Plus system. First, 6 micrograms of pRSVO-luc 10 and 6 micrograms of APP-lacI construct DNA were added to 460 microliters of Opti_Mem transfection medium and incubated with 30 microliters of Plus reagent for 15 minutes. Then, a fat mixture containing 40 µl of Lipofectamine reagent and 460 µl of Opi-Mem transfection medium and a DNA-Plus reagent mixture were incubated for 15 minutes. During DNA-fat incubation, CHO-K1 cells were washed once 15 and covered with 5.0 ml of penicillin-streptomycin-free DMEM medium. A layer of the DNA-fat preparation was then applied to these cells and incubated overnight at 37 ° C. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, streaking 1 to 1.5 million transfected cells (100 microliters total volume) in each well to 20 bacteria free in clarified DMEM complete medium (DMEM-phenol free) , On an opaque Packard 96-well plate and incubate for 3-5 hours at 5% CO2. B. Compound Dilution Compounds are diluted in two different procedures; one procedure is used to supply a solvent-free compound (weigh the powder in a vial) and the other—the procedure uses -42-

200306292 A7

= Compound supplied from the mixture (20 ^ μ cultured in spores i) In two procedures, fresh 25mM Hepes and 25mM HePes / l / G DMS were prepared as diluents. The DMS was Used as a dilution control agent in all experimental plates. The following table describes the steps for compound dilution (please note that the last step is to add the compound to the cells / medium on the tissue culture plate): ~ -—_ -—-------- ZHKH] Dilution Stock Solution- --- 10 mg / ml X mg compound (vial) diluted with 100% DMSO 1 -----— 1 mg / ml 20 µl stock solution 180 µl 25mM Hepes diluted 2 200 µg / ml 60 μl dilution 1 240 μl 5 mM Heroes dilution 3 (on cell culture plates) 20 μg / ml 11.3 μl dilution 2 (at 100 μl cells / well) As some compounds get results in 96-well format at 20 mM, Bottom line] represents the procedure of dilution (please note that the average molecular weight of these compounds is 10 $ is used to calculate these dilutions and, as mentioned above, the last step is to add the compound to the cells / medium on the tissue culture plate) ·· Printed Concentration Dilution Stock Solution by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs-(Original > Chen Tang)-20 mM solution diluted 1 ~ ~ 200 μg / ml 6 μl health solution 194 μl 25 mM Hepes Dilute 2 (on cell culture plate) ~ 20 μg / milli 1L 3 microliters diluted 2 (at 100 microliters cells / well) -4 moderate ruler A4 S) N (C quasi-standard centimeter 97 200306292 A7 B7 V. Description of the invention (42)-Once the compound is diluted, The administration was repeated twice on the cells of the tissue culture plate (prepared as above). At 3rc containing 5% co2, the cells were incubated with the compound for another 36-48 hours. C. Analytical measurement 5 Performed luminase analysis (hcLite reagent, Packard)

TopCount instrument reads. Remove the medium from each well and use it in each well! 〇〇Ι of PBS instead of (containing Mg + 2) and added a volume (100 microliters) of LucLite solubilization / enzyme buffer to each well, and the culture plate was incubated at room temperature in the dark Middle 10 = —Mix on mixer. Luminase readings were then performed on a TopCount. Measurements are expressed and calculated in relative light units (rlu) and analyzed in MS Excel as follows. D. Analytical data The results of the analysis of the compounds exemplified herein are provided in Table 15 below. If a compound causes at least 1.5-fold increase in luminase activity and is non-toxic at 20 μW / ml, as determined by the disappearance of the signal (increased by ^ 0.75 ·), the compound is considered to have active. ΑΑΑ. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. SEM stands for the standard deviation of the multiple increase average (not shown). All test compounds were known to be non-toxic. 20 tables

Ex # concentration (μg / ml) APPI increase multiples 1-3 20 4.9 5-Chloro-N-[(lS) -2-ethyl-1-methylpentylbutyl] thiophene-2-aminesulfonium 4 20 7.2 5-Chloro-N-[(lS) -2-ethyl-1- (1-Ethylethyl9.7-yl) butyl] σsphen-2-amine Continued-44- This paper is applicable to China Standard (CNS) A4 Specification (210x297 mm) A7 200306292 B7 V. Description of Invention (43) All publications cited herein are incorporated herein by reference. Although the present invention has been described with a particularly good specific example, it should be understood that variations can be made without departing from the spirit of the present invention. These variations are covered by the scope of the attached patent application. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs -4 This paper size applies to China National Standard (CNS) A4 (210x297 mm)

Claims (1)

200306292 Scope of patent application A8 B8 C8 D8 5 10 2. 3. 15 4. Printing of clothing by employees' consumer cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. 20 6. 7. A method for preparing chiral pure amino acid or its salt, which Listing steps: ', (a) reacting aldehyde and cyanide salts with chiral ^ methylbenzylamine or its salt and filtering to obtain product (a); (b) subjecting a strong inorganic acid to product (a) Reaction; (c) neutralize the acid of reaction (b); (d) extract the product (b) from the neutralized acid; react with the catalyst in the presence of the catalyst; hydrogenate the product to obtain the product (C) And (f) hydrolyzing the product (C) in a strong aqueous acid to obtain a salt of a chiral pure acid. i The method according to item i of the patent application scope, further comprising neutralizing a chiral pure α-amino acid salt to obtain a chiral pure α-amino acid. For example, the method of applying for the first item of the patent scope, wherein the method is continued for 12 to 24 hours. The method is the method according to item 1 of the scope of patent application, wherein the reaction step generates a step of transitioning the liquid containing the remaining material and the material and washing it with water to obtain a powder. For example, the method of claim 1 in which the cyanide salt is selected from sodium cyanide and potassium cyanide. Such as the scope of patent application! The method of the item ', wherein the strong inorganic acid is sulfuric acid. For example, the method in the scope of patent application f6, wherein when t is added to the product ⑷, sulfuric acid is 0. (:. -46-This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X297 mm) 91529B Loading line 200306292 A8 B8 C8 D8 6. Application for patent scope 8 · If the method of the first scope of patent application is applied, Among them, the strong inorganic base is used in the neutralization step (c), which is really ammonium hydroxide. 9. The method of claim 1 in the scope of patent application, wherein the extraction step uses ethyl acetate as the extractant, and wherein, This step further comprises 5 steps of drying, filtering, and concentrating to obtain the product (b). 10. The method as claimed in the first item of the patent application, wherein the catalyst in the hydrogenation step (e) is palladium. Η · As applied The method according to item 1 of the patent, wherein the mixture is pressurized at 3 atmospheres in the hydrogenation step (e). 10 12. The method according to item 1 of the patent, wherein the hydrolysis step ⑺ is at 100 ° C. 13. The method according to the scope of the patent application, wherein the hydrogenation step (e) further includes the steps of filtering the mixture and removing the solvent. 14. The method according to the scope of the patent application, wherein , The water Step (f) 15 is performed for a period of 16 hours. 15. The method according to item 1 of the patent application scope, wherein the hydrolysis step ⑺ further comprises concentrating the reaction mixture generated to obtain amino hydrochloride and 1 The steps of equivalent ammonium chloride products. Printing of clothing by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 16. If the method of the scope of patent application is No. 15, it also includes the package 20 containing amino hydrochloride and 1 equivalent The step of dissolving the gasified ammonium product in water and adding sodium hydroxide to form a solution. Π. The method according to item i of the patent application, wherein the chiral amino acid has the formula (R) 2CH (CH2 ) nCH (C02H) NHR, where n is 0 to about 10; R is selected from the group consisting of: · lower-grade, -47-This paper size applies Chinese National Standard (CNS) A4 specifications (210 X 297 mm) '---- ~ 200306292 A8 B8 C8 VI. Application scope 10 15 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 Substituted lower alkyl, lower alkenyl, substituted lower alkenyl, Lower alkynyl Cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, CH2 cycloalkyl, CH2-3-indole, CH (lower alkyl) -2_ Furan, CH (lower alkyl) -4-methoxyphenyl, CH (lower alkyl) phenyl, or CH (OH) -4-SCH3-phenyl; and R 'is selected from the group consisting of : Fluorene, lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkyl, lower alkynyl, substituted lower alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl , Substituted heterocyclyl, phenyl, substituted phenyl, benzyl and substituted benzyl. 18. · A method for preparing a chiral 2-amino alcohol, the method comprising the following steps: preparing a chiral-amino acid according to item 1 of the scope of the patent application; reducing α-amino acid to 2-amino alcohol; and The 2-amino alcohol is recrystallized to obtain chiral pure 2-amino alcohol. 19. A method for resolving an N-sulfofluorenyl α-amino acid having a 10,000-branched alkyl substituent for preparing a chiral pure N-sulfonyl α-amino acid, comprising the following steps: ( a) A mixture of chiral pure ephedrine hemihydrate and N-sulfoamidoamino acid is formed in ethanol at a molar ratio of 1: 1: 1, wherein the N-sulfoamidoamino acid is selected from the group consisting of N-sulfofluorenyl / 5-ethylorthovaline acid, N-sulfofluorenyl valine acid, and N-sulfofluorenylyS-n-propylortholeucine; (b) heating the mixture (a) to About 80. 〇To dissolve solids; 48 This paper size applies the Chinese National Standard (CNS) A4 specification (21〇X 297 public love) 200306292 A8 B8 C8 D8 6. Application scope (C) The mixture is cooled to form a precipitate; (d) The precipitate is filtered to obtain a diastereoisomeric salt; (e) the diastereoisomeric salt is recrystallized; (f) the recrystallized salt is dissolved in an organic solvent and a strong aqueous acid and 5 The layers were separated to obtain an organic extract; (g) the organic extract was washed; and (h) the organic extract was dried and concentrated to obtain chiral pure N-sulfonyl α-amino acid. 20. The method of claim 19 in the scope of patent application, wherein the N-sulfonyl 10 ethyl orthochloroamino acid is a phenoyl group) continuation group] -3-ethyl orthovaline acid; and wherein In (d), the precipitate is washed with ethanol and ethyl acetate to obtain a diastereoisomeric salt. 21. The method of claim 19, wherein the cooling step is performed at 5 ° C for 18 hours. 15 22. The method of claim 19 in the scope of patent application, wherein the cooling step is performed at room temperature. 23. A method as claimed in claim 19, which further comprises a step of filtering the formed suspension after the cooling step. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 24. The method of item 19 in the scope of patent application, wherein the recrystallization step 20 is performed in boiling ethyl acetate. 25. The method according to item 19 of the patent application, further comprising the step of filtering out the recrystallized salt. 26. The method of claim 19, wherein the organic extract is washed with HC1. -49-This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200306292 Application for patent scope A8 B8 C8 D8 27. Method for applying for patent scope item 19, where the organic extract Dry over NaJCU. 28. A method for preparing a chiral team sulfonylfluorenylamino alcohol, comprising the following steps: preparing a chiral N • amino acid according to item 19 of the scope of patent application; reducing the fluorenylamino acid to N- Sulfofluorenyl 2-amino alcohol; and recrystallizing the N-fluorenyl 2-amino alcohol to obtain chiral pure sulfofluorenyl 2-amino alcohol. The method for declaring item 28 of the patent scope, wherein the sulfofluorenyl α__ amino alcohol is formula (I), or a pharmaceutically acceptable salt thereof, wherein formula 下列 has the following structural formula: ′, 15 Printed by the Ministry of Economic Affairs Intellectual Property Bureau's Consumer Cooperative (I) where: and R2 are each independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, CF3, alkenyl, substituted alkenyl Alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, and (CH2) n (1,3) dihenanedi-50- A8 B8 C8 D8 200306292 6. The scope of patent application where η is 2 to 5; R3 is selected from the group consisting of hydrogen, alkyl, and substituted alkyl; R4 is selected from the group consisting of hydrogen, alkyl, and substituted Alkyl, alkylcycloalkyl, substituted alkylcycloalkyl, phenyl (substituted) alkyl, 5 alkyl OH, substituted alkyl 0H, alkyl OBn, substituted alkyl 〇Bn, alkylpyridyl, substituted alkylpyridyl, alkylfuranyl, substituted alkylfuranyl, CH (OH) phenyl, CH (OH) substituted phenyl, alkenyl, Substituted alkenyl, cycloalkyl, substituted cycloalkyl, N_substituted-hexahydro10 pyridyl, hexahydropyridyl, substituted hexahydropyridyl, tetrahydrothiapiperanyl, substituted Tetrahydrothiopiperanyl, 2-hydroindene, substituted 2-hydroindene, phenyl, substituted phenyl, alkyl NHR7, and substituted alkyl NHR7; but R3 and R4 are not hydrogen at the same time 15 R? Is an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a + group, a substituted + group, an alkyl group OH, a substituted alkyl group OH, an alkyl group SR8, or Superseded Alkyl SR8; R8 is alkyl, substituted alkyl, amyl, or substituted octyl; 20 or R3 and R4 may form a ring together; Rs is selected from the group consisting of hydrogen, lower alkyl, and substituted lower Alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, ch2 cycloalkyl, substituted CH2 cycloalkyl, benzyl, substituted benzyl, and CH2CH2QR9; -51-This Paper size applies to China National Standard (CNS) A4 (210x297 mm) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 100306292 A8 B8 C8 D8 6. The scope of patent application 5 Q is 0, NH or S; R9 is lower alkyl, substituted lower alkyl, phenyl, or substituted benzene R6 is selected from the group including hydrogen, halogen and cf3; τ is selected from the group including 〇 and: N OH _ 10 15 Printed clothing by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 W 'Y and Z are each independently selected from the group consisting of: c, 〇110 and N; Rio is selected from the group consisting of 氲 and A halogen group, but at least one of W, Y and Z must be c; X is selected from the group consisting of 0, S, S02, and NRn; Rii is selected from the group consisting of: hydrogen, lower alkyl, Substituted lower alkyl, benzyl, substituted benzyl, phenyl, and substituted phenyl, but when the compound contains one or more chiral centers, at least the amino acid-derived chiral center Must be s-stereochemistry. 30. The method of claim 29, wherein ^ is halogen. 31. The method of claim 29, wherein r6 is chlorine or bromine. 32. The method of claim 29, wherein τ is C (0H) R1R2 and R1 and R2 are each hydrogen. 33. The method according to item 29 of the patent application, wherein w and z are both C. Brocade A B c D 200306292 6. Scope of patent application 34. For the method of scope 29 of the patent application, in which R4 is a low-grade base of S-stereochemistry. 35. The method according to item 29 of the scope of patent application, wherein X is S, W is C, Z is C, R6 is halogen, R4 is a lower-grade group of S-stereochemistry, R3 is nitrogen, and R5 is nitrogen, Ri and R2 are each nitrogen. 36. The method of claim 29, wherein R3CR4 is cyclohexyl. 37. The method of claim 29, wherein R3CR4 is a hexahydrogen σ specific bite or an N-substituted hexahydrorole bite. 10 38. The method of claim 29, wherein X is S, and W, Υ, and Z are independently C or CR10. t The paper size printed by the Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200306292. ) 、 A brief description of the component representative symbols of this representative map «+ Say ... * intended " / · Νί ', ·? / · * 、 / 〆 s ·· ―Trusted by j_gj :: This case shows' t…, f? ',; ΝΎ xi, 〆j 广, > < v, · ν λ yin' vs, 'jealous; · ◊ ί ·., / ·', '〆sv s Λ s. X… Ί ,,:' ::: 'Chemical formula Yi Yi, page 2-2