TW513394B - Process for converting propargylic amine-n-oxides to enaminones - Google Patents

Abstract

This invention concerns the use of a hydroxylic solvent in the preparation of enaminones from the corresponding amine N-oxides or propargylic amines via the general process outlined below.

Description

513394 A7 _—__ V. Description of the invention (f) (Please read the notes on the back before filling out this page) Clothing · Order This invention relates to a method for producing enamines from propargylamine gasification. Specifically, the present invention relates to a method for producing propargylamine-N-gases from propargylamine to K using conventional chlorine methods, and is utilized with or without the presence of a metal catalyst, and with or without heating The technique of exposure to a hydroxy solvent uses amine oxides to form enamine compounds. BACKGROUND OF THE INVENTION Enamones are multipurpose synthetic intermediates that can be easily converted into a wide variety of functional groups. Examples include (but are not limited to): monoamine ketones, iso-hydroxy ketones, alkyl substituted olefins. , And a variety of heterofluorene compounds, including isoxazole, pyrazole, pyrimidine, pyridine, and cyanine. Usually enamine pseudo is used to make very commercial compounds, such as pharmaceuticals, pesticides, dyes, etc. Enamines printed by the Consumer Cooperative of the Central Bureau of Standards of Didi can be synthesized by various methods, including amines and 1,3-diones, 3-round esters, pentenyl esters, pentenyl chloride, and S- The reaction of dioxanyl 1, 1, cyanoketene, ethylene, etc .; the condensation reaction with 11 dimethylformamide acetal; the halogenation reaction of enamines; the reaction of enol and enamines; The amine oxime sulfonate reacts with silane-based enol ethers instead of amine-assisted alkene amination; the amine-catalyzed dehydrogenation reaction of amine ketones; reaction). The preparation and application of enamines can be found in the following two review articles: Greenhill, J. V. C h em > Soc. R ft v. 1 9 7 7, 6, 2 7 7;

Kucklaender, U. &Quot; Ennaiinones as Synthons ", in C heaist ry αί_Enam i nes · Rappoport, Ed ·, V ο 1. 1, pp. 5 2 3-6 3 6, Chichester, UK: Wiley [1 9 9 4 ] 〇-3- This paper standard applies Chinese National Standard (CNS) Λ4 Regulation (210X29D >#)

A 513394 A7 __— I — B7 V. Description of the invention (2) Functionalized propargylamines can be easily prepared by using the terminal acetylenes and the lanthanum tritiated Marinich reaction of formaldehyde and amines. (Mannich, Chero. BeiT. 1 933, 66, 418), and in the case of 3-aryl or vinyl substituted prop-2-ynylamines, the use of 1-amine-prop-2-ynes and Aryl or vinyl halides or trifUtes are easily prepared by palladium-catalyzed coupling reactions. (Sanogashira, et. A 1. Terahedron Lett · 1 9 7 5 »4467; Unroe, et.aK Synthesis, 1987» 981; Stille, JK Ange w. Chew. Inti. E d. R n g1 > 1986, 25, 508 * Scott, et. A 1. A cc. C hem > Res > 1 988, 21, 47; Kalinin, VN Synthesis 1992, 413; Ritter, K. Synthpsir 1 993, 7 3 5). These amines can be processed using any standard gasification procedure (as discussed by Albini ·, A. in Synthesis, 1993, 263) or with dioxane reagents (see Murray, R. review article CLhem. Rev · 1 9 8 9, 1 1 8 7) easily converted to amine hydrazone-oxide. Although the detailed mechanism for the conversion of propargylamine-N-oxide to enamine hydrazone products has not been confirmed, it seems to be very similar to two known procedures; the heat of propargylamine-N-oxide [2,3] -σ shift Rearrangement of M and the reaction of some isoxazoles to enaminones. The following is suggested by a person: (Please read the notes on the back before filling this page)

This paper is inferior to the Chinese national standard bee (rNS) Λ4 specification (210X297 mm) 513394 A7 B7 V. Description of the invention (3) 0- Allene ether reaction is a known reaction (Reaction formula 1 below) 5 Cr a ί g, et. A 1. Tet ra dr on Le 11 * 1 979, 4025; Ha 11 st Γ 0 «Ι, et * a 1. Tet rad τ〇n L e 11 · 1 980, 667 Kh uthier 9 A-Η, et. A 1. J ♦ C he in * So c ♦ Che η. Co m] 〇u η * 1979 9 9) 〇K mentioned in each example [2, 3] ~ σ shift rearrangement 9 These reactions are carried out in pure or aprotic solvents (such as dimethylformamide ethyl i 眯, tetrahydrofuran Λ carbon tetrachloride), but not mentioned in it: earn amine Attst m product production method 〇 trans formula 1 (Please read the precautions on the back before filling this page)

Congratulations to Consumption Report by the Intermediate Bureau of the Ministry of Economic Affairs

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Mo2Nc / " As described by Liguori et al. In Tetrahedron 1988, 44, 125 (1), substituted enazolones can be obtained by the hydrolytic collapse reaction of certain substituted isoxazolines (the following reaction formula 2). The so-called isoxazolines are made by the 1,3-bipolar cycloaddition reaction of C-benzidine-N-phenylnitrone with alkynes (formed as a mixture of its local isomers (regioisomer) This shows that the substitution pattern of the isoxazoline ring will affect the results of this hydrolysis reaction. This method is an individual example of the formation of enamines from isoxazoline, not a general application, nor is it synthetic Effective transformation. Reverse tendon; 2 〇 ^ R.0 0 H3〇 '

〇 ^ N PhHN • Ph -5-This paper uses Chinese National Standards (CNS) M specifications (210X297 mm) 513394 A7 B7 V. Description of the invention (4) The present invention provides a method that uses exposure to hydroxyl-soluble solvents. A new synthetic method of M propargylamine-N-oxide to prepare enamine noodles. This new enamine-synthesis method is very convenient, can replace the existing method, and further expands the range of starting materials that can be converted into enaminone products. Summary of the Invention The present invention provides a novel method for synthesizing enamine hydrazones as shown in formula (I):

RX 1 1 χ ^ N ″ 2 (I) Rs where: X is selected from the group consisting of: Η, Ci-CU straight-chain alkyl, C 3 -C 6 branched alkyl C 3 -C 7 cycloalkyl , -CH: 1-phenyl 9 or -CH 2 -substituted phenyl; R 1 is selected from the group consisting of: Η 1, C 1 -C 6 straight alkyl, C 3 -C 6 branched alkane 9 C 3-C 7 TWI cycloalkyl, phenyl 9 substituted phenyl, -CH 2 -phenyl, or -CH 2 -substituted phenyl > or a group as shown below:

The size of this paper is applicable to Chinese National Standard (CNS) Λ4 specification (210X 297 mm) 513394 | 9i. 9 · 2 5 Like not: Α7 / almost a " 上 i __B7 Ls— m also "V. Description of the invention (5 ) R2 and R3 are each independently selected from the following groups: Ci-Ce straight alkyl, C3-C6 branched alkyl, C3-C7 cycloalkyl, or i-CH 2 -phenyl; R2 And R3 can also be combined with each other to form a ring containing 3-6 carbon atoms. Thus formed is a cyclic form of -NR2R3, which is, for example, the following (but not limited to these): -Nd-or-(33 R 4 and R 4 / are each independent and are selected from the group: Η, C 1 -C 6 straight-chain alkyl, C3-C6 branched alkyl, C3-C7 cycloalkyl, —OR 11, ~ NR 11 R 13 * NR 11 C ί 0) 0 R ίο, ~ NRn C (0) Ri 〇, -0 (:( 0)! {! ◦, -0C (0) 0Ri〇, or -0C (0) NHRi〇; substituted phenyl and -CH2-substituted phenyl, respectively as follows: (铕 先(Read the notes on the back and fill out this page)

IU-R9 are independent and selected from the following groups: Η, halogen, trifluoromethyl, C2-C 6 perfluoroalkyl, Ci -C 6 straight-chain alkyl group扃 货 二 消 贽 合 竹 社 印 ¾ C3 _C6 branched alkyl, C3-C7 cycloalkyl, -CN, -N〇2,-OR 11, ~ C 0 2 R 11 »~ BR 11 R is,- NR n C (0) 0 R n, -NRuC ^ Ru, -0C (0) Ru, -0C (0) 0Ru, or -0 C (0) Η HR ii; ^ R1〇 is selected from the following group : H, Ci-C6 linear alkyl, C3-C6 branched alkyl, C3-C7 cycloalkyl, phenyl, or -CH2-benz-7- Paper size ((, NS)) Λ4 gauge (2丨 0X297 mm) 513394 A7 B7 V. Description of the invention (6) group; R u and Ru are independent of each other, and are selected from the lower group: Η, C i -C 6 linear alkyl group, C 3- C 6 branched alkyl, C 3 -C 7 cycloalkyl, phenyl, or -CH 2 -phenyl;

Ru and RW are each independent and selected from the following groups: 逑, C 1_ _C 6 straight alkyl, C 3-(: 6 branched alkyl, C 3-C 7 cycloalkyl, phenyl, substituted Phenyl, -CΗ 2 -phenyl or -CΗ 2 _ substituted benzyl, C3 -C7 cycloalkyl can be optionally substituted from -R9 by 1-3 groups; R 12 specified in the following section And Ri / must not be phenyl or substituted phenyl at the same time; (Please read the notes on the back before filling this page)

R12 and M can also use their common carbon to join together to form a carbon ring with 3-6 carbon atoms;

Rn is an amine protecting group used to protect the NRu moiety. It can be used in any of the conditions listed in WB ft! Greened Protective Groups in Organic Synthesis, Voluae 2, Chapter 7, 1991 and its references. Those who can protect the amine group. Examples of suitable amine-protecting groups are as follows (but not limited to these): (a) fluorenyl-type protecting groups, such as formamyl, acetamidine, chloroacetamyl, dichloroacetamyl, trichloroacetamyl , Trifluoroethylfluorenyl, phenylethylfluorenyl, o-nitrophenoxyethylfluorenyl, second butylfluorenyl, trimethylethylvinyl (that is, 8- This paper applies to Chinese national standard (CNS) Λ4 Specifications (210X 297 mm) 513394 A7 B7 V. Description of the invention (7) Third butyl fluorenyl), cyclopropyl fluorenyl, anisole, o-nitrobenzyl fluorenyl, α-cyclobutanyl, etc., or (b) sulfonyl-type protecting groups, such as benzenesulfonyl, tosylsulfonyl, p-methoxybenzenesulfonyl, trifluoromethylsulfonyl, etc., or (c) sulfenyl-type protection Groups, such as phenylsulfinyl, o-nitrophenylsulfinyl, pentachlorobenzenesulfinyl, etc., or (d) urethane-type protecting groups, such as benzyloxycarbonyl, p-chlorobenzene Methyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-benzyloxycarbonyl, third butyloxycarbonyl, third pentyloxy carbonyl , Diisopropylmethoxycarbonyl, isopropyloxycarbonyl, allyloxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, 9-ylmethoxycarbonyl, 2-trimethyl Silylethoxycarbonyl, etc. "111 ~ 13 parts can also be linked together at will, or cyclic iminium forms exist as follows: (Please read the precautions on the back before filling this page) Order

This method includes the reaction of treating an amine N-oxide as shown in Chemical Formula U) with a hydroxy solvent and converting it into an enaminone.

X

R3 (II) This paper is suitable for Sichuan China National Standard (rNS) 8 size (210X 297 mm) 513394 A7 B7 91 9

> 1 Q V. Description of the invention (8 For the combination of materials, 12 R tt of X must be dealt with, 12 can be ηκ 'has / 11 R, including 11 packages, R shows 10, R' is 9 , R ', 8 son J, original 7 carbon R, said 6 pairs of R' but not 5 have R, containing 4-I of R 3 »1 · R 4 R or the conclusiveness of the spin is clear. Discuss the difference between the structure and the difference. The structure of the object is heterogeneous, and the light and the structure of the object include heteroinclusion, the salt of the substance. 2? Drugs, R2 is the difference between the structure R and X, You can learn about the state of matter I) Constructing the pure (I is different from the object must be able to synthesize and can be converted to S. In the technique, fttt. Au R away from the image. .Alternative and class 10 11 11 12

12 R and the physical structure of different departments, can 9 R may have 8 Qc: So, including R7 package 6 R, then 5 R set, 4 R13, R 4 or the use of pure can be refined to the structure of the difference The technical area is divided into different categories. The theory of bidding is that the family of the discussion club is based on the large in the field, and the mastery of acrobatic techniques is mixed with the benzene generation and the Wei Dynasty is replaced by the table system generation X: Μ, including the group, the group, the group, and the other. Among them. In the group election, the selection of 0 Yangjun's article A. This benzene product is used in the supply and extraction method when it is formed into a base and a chemical formula such as 12: The method of the best method is better than the inner class. Phenylaminobenzene Benzene _Institute 2) Η (Please read the precautions on the back before filling out this page) • Fill in the item and print it by the Diaobu Central Standards Bureau Bureau of Goods and Consumers Cooperatives ο

/ J

〆3 Ν 丨 R R2 from the group selected under the description of the group of alkane 鐽 straight paper ifc jishu chuanchuan national standard of China. (RNS) Λ4 specifications (210 × 297 public 蝥) 513394 A7 B7 V. Description of the invention (9 ) Branched alkyl, C3-C7 cycloalkyl, phenyl, -CH2-benzyl, or the following:

(Please read the notes on the back before filling this page)

, 1T ^ and ^ are independent of each other and are selected from the group of Ci: Ce-Ce linear alkyl, (: 3-(: 6-branched alkyl, C3-C7 cycloalkyl, or -C Η 2- Phenyl; R2 and R3 can also be combined with each other to form a ring containing 3-6 carbon atoms. This forms a cyclic form-NR2R3, such as the following (but not limited to these): -NO-N 〇-Ν0-(3, R5, R6, R8, R9 are independent of each other, and are selected from the following group: printed by Zhang Zhongzhong Standards Bureau member-T-Consumer Cooperatives? Muya, halogen, trifluoromethyl , C2-C6 perfluoroalkyl, Ci-Cs straight alkyl, C3-C6 branched alkyl, C3-C7 cycloalkyl, -CN, -N〇2, -OR η, -CO 2 Ru,- KR ii Ri3, -HR n C (0) ORu, -NR ii C i 0) R 11, -OCfOUu, -0C (0) 0Rii i or -0C (0) NHRu;

Ru and Ru > are independent and selected from the following groups: H, Ci-Cs This paper size is applicable to the Chinese National Standard (rNS) Λ4 specification (210X 297 mm) 513394 A7 B7 V. Description of the invention (10) Alkyl, c3-c6 branched alkyl, or -CH2-phenyl; C 7 cycloalkyl, phenyl,

Rn is selected from the following groups: H, Ci-C6 linear alkyl, C3-Ce branched alkyl, C3-C7 cycloalkyl, phenyl, or amine group used to temporarily protect the NRu moiety. An amidine group can be any known Greene capable of protecting an amine group under the conditions listed in Protective Groups in Organic Synthesis, Volume 2, Chapter 7, 1991 and its references. Examples of suitable amine-protecting groups are as follows (but not limited to those): This method includes a reaction in which an amine N-oxide of formula (I) is treated with a hydroxyl solvent to convert it to an enaminone: Ri-=- Ό

N, r3 (II) The present invention also provides another preferred method for synthesizing enamines as shown in formula (I): 0

r2 (Please read the notes on the back before filling in this page) The official bidder in the Ministry of Commerce_τ Consumption Hezhu and Yinlai N " I R3 (I) where 1 is the following: -12- This paper Scale Shizhou China National Standard Peak (CNS) Λ4 specification (210X 297 mm) V. Description of invention (11) A7 B7

The R 2 and R 3 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs are independent and selected from the following groups: C i -C 6 linear alkyl, C3-C6 branched alkyl, C3-C7 cycloalkane Group, or -CH 2 -phenyl; R 2 and R 3 may also be bonded to each other to form a ring containing 3-6 carbon atoms. Thus formed are cyclic forms of -NR2R3, which are, for example, the following (but not limited to these): —NC] —N ^) > — ^ services. —F / R5, R6, R8, R9 each Independent and selected from the group: Η, halogen, trifluoromethyl, C 2 -C 6 perfluoroalkyl, C i -C 6 straight alkyl, C3-C6 branched alkyl, C3_C7 ring Alkyl, -CN, -N〇2,-0 R 11, _ C 0 2 R u,-NR 11 R 13,-NR 11 C (0) 0 R 11,,-NR u C (0) R u, -0 C (0) R u, —0 C (0) 0 R u, or-0 C (0) NHR η; R u and RV are independent and selected from the following groups: H, C i-C 6 straight alkyl, C3-(: 6-branched alkyl, C3-C7 cycloalkyl, benzyl, or -CH 2 -phenyl; R is selected from the group: H, C i -C s Linear alkyl, C3-C6 branched alkyl, C3-C? Cycloalkyl, phenyl, or amine protecting group used to temporarily protect the NR u moiety, which may be any known 13- (Please read the precautions on the back before filling in this page) The size of the paper used for this edition is applicable to the Chinese National Standard (CNS) A4 (210X 297 mm) 5. Description of the invention (12) on 2 A7 B7 Π ♦ * 1 and listedThe texts mentioned in this article are related to the use of base protection amines. The protection of amines is enough to consider the following conditions-that is not limited to only / 1. In the chemical formula shown below, M can be stored in 11 states with R, and R can also be stored in the R state of R1. [Type N is the opposite of the ketolysin amine hydroxylene by encapsulation encapsulation method and other methods.

Oxygen I Ν amine display (please read the notes on the back before filling out this page) R1 Additional Note: The method is also better than the formula (R23 in the formula / R chemical, NR, such as 6 types of combination Ketolinene display, 11 ο £ If printed by employees of the Central Standards Bureau, Ministry of Economic Affairs, the consumer co-operatives, such as R2, the paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 513394 Α7 Β7 V. Description of the invention (13)

Ji 2 and 1 to 3 are independent and are selected from the following groups: Ci-Ce linear alkyl, C3-Cs branched alkyl, C3-C7 cycloalkyl, or -CH 2 -phenyl; R2 and R3 can also be combined with each other to form a pyrene containing 3-6 carbon atoms. Thus formed is a cyclic form of -HR 2R3, which is, for example, the following (but not limited to these): -Nd -◊ —nQ] —OR— R5, R6, R8, and Rs are independent of each other, and are from the chin group Selected: Η, halogen, trifluoromethyl, C2-C6 perfluoroalkyl, Ci-Cs linear alkyl, C3-C6 branched alkyl, Cs-C7 cycloalkyl, -CN,-H〇2, -OR 11, -CO 2 Rii, -NR 11 R is, ~ HRu C (0) ORii, -NR ii C i 0) R ii, -0C (0) Ru, -0C (0) 0Ru, or -0C (0) NHRu; Printed by the Consumers' Cooperatives of the Bureau of Difficulties and Standards Bureau (please read the precautions on the back before filling out this page). R u and RV are independent and are selected from the following groups: H, C i- C 6 straight-chain alkyl, C3-C6 branched alkyl, C3-C7 cycloalkyl, phenyl, or -CH 2 -phenyl; R 13 is selected from the lower group · H, C i -C 6 straight chain alkyl, (: 3-(: 6-branched alkyl, C3-C7 cycloalkyl, benzyl, or amine protecting group used to temporarily protect the NRu moiety, which may be any known -15- The size of this paper is applicable to Chinese National Standards (rNS) Λ4 specification (210 × 297 mm) 513394 A7 B7 91. y. Hu De V. Description of invention (14) G reene Listed and considered in Protective Groups in Organic Synthesis, Volume 2, Chapter 7, 1991 and its references: Those who can protect amine groups under the conditions of 1. Examples of suitable amine protecting groups are as follows (but not limited to (Those): NRuR13 can also exist in the form of cyclic fluoreneimine optionally as shown in the chemical formula below:

This method includes the reaction of treating an amine N-oxide as shown in chemical formula (Π) with hydroxyl-soluble I to convert it to enketone: Ri-^-〇 / 广 2 / r3 (II) (read (Please read the notes on the back before filling this page) The present invention also provides another better method: The standard rate of the enamine ketones as shown in formula (I) is Jr.

(丨) r3 where X is selected from the group consisting of: H, Ci-Cs straight alkyl, C3-C branched alkyl, C3-C7 cycloalkyl, phenyl, or -CH2-phenyl;-1 6 -The size of this paper is in accordance with the national standard of the state ((, NS) Λ4 specification (2 丨 〇X 297) 513394 A7 B7 V. Description of the invention (15) R i is selected from the following groups: H, C i -C 6 straight alkyl, C3-C6 branched alkyl, C3-C7 cycloalkyl, phenyl, substituted benzyl, -CH 2 ″ phenyl, or -CH 2 -substituted phenyl, these substitutions The bases are the same as above or as shown below: The members of the National Bureau of Standards and Decisions X Consumer Cooperatives printed f 0H " ^ and ^ are independent of each other and are selected from the following groups: Ci-C6 straight chain fluorenyl, (: 3-(: 6-branched alkyl, C3-C7 cycloalkyl, or -CH 2 -phenyl; R2 and R3 can also be combined with each other to form a pyrene containing 3-6 carbon atoms. What is formed is -HR 2 R3 in the form of a ring, which is as follows (but not limited to these): -nC]-^ or) 3 R12 and Rd are independent of each other and follow from the following group: Η, Ct-Ce Straight alkyl, C3-C6 branched alkyl, C3-C7 cycloalkyl, phenyl, or -ch2-phenyl, which C3-C7 cycloalkyl • phenyl and -CH 2 -phenyl can be substituted by the group selected from the above groups; R12 is required to be both phenyl or substituted phenyl; this method includes treatment with a hydroxyl solvent The reaction of the amine N-oxide shown in the chemical formula) to convert it into enone (I):-17- This paper size is applicable to China National Standard (CNS) Λ4 specification (210X 297 mm) (Please read first (Notes on the back, please fill out this page) 4

, 1T 513394 A7 B7 9L 3. 19 years n t ΓΗ

iLJ V. Invention Description (~

X

Rr 〇 · 〆

N, R3 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. (Ii) The amine N-oxide can be converted into enone by using the method within the scope of the present invention. The amine N-oxide is first added to an appropriate hydroxyl solvent, preferably under stirring, at a temperature of room temperature (or ambient temperature), or between room temperature and the reflux temperature of the solvent. In other cases, when an amine N-oxide is added to a hydroxyl solvent (preferably in a stirred state), it is in the presence of an acceptable catalyst (such as a palladium (Π) catalyst or a copper (I) catalyst). In this case, the temperature is at room temperature or between room temperature and the reflux temperature of the solvent. Two-phase solvent systems are quite good, in which amine N-oxides are converted to enamone in a two-phase mixture of water and water immiscible solvents (such as dichloromethane), which may or may not have a suitable catalyst ( For example, the presence of a palladium (Π) catalyst or a copper (I) catalyst, and a phase transition catalyst, such as a fourth amine salt, the addition temperature is at the ambient temperature, or between the ambient temperature and the reflux temperature of the organic solvent, And it is best to add while stirring. The amine N-oxide converted in this method can be oxidized to an amine as shown by the chemical formula (melon) using any standard oxidation procedure (Albini, A. Synthesis 1993, 263) or reacted with ethylene oxide reagent ( Murry, R. W. Chcm. Rev. 19 8 9,1 187); 18 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) (Please read the notes on the back before filling out this page ) 513394

V. Description of the invention (to)

Among them, X, R !, R2 and L are as defined above. In another embodiment, the present invention includes a method for converting an amine as shown in formula (III) into an enaminone as shown in formula (I). The steps of this method are as follows: (a) will be as shown in formula (III) The amine shown is converted into an amine N-oxide as shown in Chemical Formula (It). This step can be completed using conventional techniques; (b) treating the amine N-oxide with a hydroxy solvent according to the method described above. The amine N-oxide is converted into an enamine ketone as represented by formula (I). The hydroxy solvent suitable for the present invention may be any solvent or solvent mixture consisting of or containing the following ingredients: water, any C!.. G linear or branched alkyl alcohol, ethylene glycol, polyethylene glycol, 1,2-propanediol, polypropylene glycol, glycerol, 2-methoxyethanol, 2-ethoxyethanol, 2,2,2-trifluoroethanol, benzyl alcohol, benzene®, or any other materials Equivalent solvents are known for one or more free hydroxyl (-0H) substituents. Solvent systems containing one or more co-solvents plus one or more solvents are suitable for use in the present invention. The so-called co-solvent herein refers to the diluent of the main solvent and is selected from the following groups: hydroxyls, such as pentane, hexane or heptane; aromatic hydroxyls, such as benzene, toluene or xylene; ethers; for example Diethyl ether ^ tetrahydrofuran, dioxane or dimethoxyethane; chlorinated hydrocarbons, such as dichloromethane > chloroform > dichloroethane > or tetrachloroethane; or other common solvents such as ethyl acetate , N, N ~ dimethylformamide 5 N 5 N · -19- This paper size applies the Chinese National Standard (CNS) A4 Regulation (210 > < 297 mm) (Please read the precautions on the back first (Fill in this page again) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs

I I flnu flHH KHV ΊΊ3 nuB nHU 513394

A7 B7 V. Description of the invention (18) Dimethylacetamide, acetonitrile, dimethylsulfinium, acetone, etc. The definition of Ri in the compound represented by the formula (u) above is as follows: where R 2, R 3, R is easily prepared from the corresponding aryl bromide, iodide or triflate according to similar methods contained in the literature (eg Sanogashira, et · al · Tetrah ^ Hron Lett. 1975, 4467; 0 nroe, e t. a 1 ♦

Synthesis-Stuttgart 1987, 981), can also be processed using any standard oxidation method (Albini, A. Synthesis 1993, 263) or treated with a bicyclic gas ethane reagent (Murray, R.W. Chei, Rev, 1 989, 1 1 87) into the corresponding N-oxide, and then into a compound represented by formula (I) according to the method described above. The obtained compounds are suitable for preparing substances having vasopressin potency, such as compounds 10 and 11 shown in the following reaction scheme I. (Read the precautions on the back before you fill in this page) Printed by the National Bureau of Standards, τ. Printed by Consumer Cooperatives-20 A paper size is applicable to China! House bee (rNS) Λ4 size (210 × 297 mm) %) 513394 A7 B7 V. Description of the invention (I9

Reaction Scheme I co2h

Cl 1) S0CI2 Br 1 2) ΜθΟΗ

(Please read the precautions on the back before filling this page), \ u 口 _Dibu Zhongxing Standard Bureau member ΗConsumer Cooperative Co., Ltd. The paper size is applicable to the Chinese national standard (rNS) Λ4 size (210X 297 mm) 513394 A7 B7 V. Description of Invention (20 Reaction Scheme I (mine)

NaOH ΜθΟΗ o2h

〇CP

(Please read the precautions on the back before filling out this page.) It is printed by s-, τ Consumer Cooperatives of Didizhongzhong Standard Bureau in the range from the temperature of the garden to the reflux temperature of the solvent, or in aprotic solvents (such as Methylene chloride or tetrahydrofuran), and in the presence of a catalytic amount of dimethyl methylamine, in the temperature range of 0-40t, treat the carboxylic acid with thionyl chloride, and add formic acid after aging In this way, bromoformic acid 1 can be converted into the corresponding brewing 2. The methyl group as shown in compound 2 is preferably in the presence of a catalyst (such as bis (triphenylphosphine) palladium (I) chloride and europium (I) iodide), and the temperature in the garden to 801C Coupling reaction between organic alkali solvents (such as triethylamine) and dialkylaminopropyne (preferably 1-dimethylaminopropyne) within a range of 22 degrees-22-this paper applies China National Standard Binding (rNS) M specification (210 × 297 mm) The official member of the Ministry of Commerce _τ 消 贽 告 作 作 社 印 繁 513394 A7 B7 V. Description of the invention (21) Replacement of acetylene 3, the essence of this method The above is based on the method provided by Alani et. Al. Tetrah Adron Lett. 1993, 34, 6403¾ Sanogashira e t. A 1. Tetrahedron Lett. 1975, 4467. Intermediate 3 is then treated in an aprotic solvent (such as dichloromethane) at a temperature below room temperature according to some standard oxidation methods (Albini, A. Synthesis 1 993 · 2 6 3) with an oxidant, or with a bicyclic Oxygen reagent treatment (Murray, R.W. Chem. ReL 1989. 1187) converted to N-oxide. The intermediate N-oxide is not isolated, but can be rearranged in situ by heating in a hydroxy solvent (such as formazan) using any of the methods described herein to form the ene as shown in Chemical Formula 4. Compound 4 is treated with hydrazine in acetic acid at a temperature ranging from room temperature to the reflux temperature of the solvent to obtain compound 5. Treatment with a strong base (such as sodium trihalide or potassium argon and methyl iodide) in an aprotic solvent (such as dimethylformamide or tetrahydrofuran) at a temperature of 0-801 can make the heterocyclic nitrogen in compound 5 obtain an alkane And a mixture of local isomers 6 and 7 was prepared. Among the main isomers, compound 6 can be separated out by hydrolyzing sickle (such as sodium hydroxide solution or tetrahydrofuran solution of lithium hydroxide) using calendar analysis and / or crystallization procedures. A carboxylic acid represented by Chemical Formula 8. The intermediate carboxylic acid 8 is then converted into a compound by a method similar to that of sulfonium, preferably fluorenyl chloride. The saccharifying agent 9 was then used to convert the tricyclic benzohydro-5 H-pyrrole [2,1-c] [1,4] benzodiazepine (Albright et, al · US Patent 5536718, July 16, 1996) Or 6,11— 二 气 -23- This paper size is applicable to the Chinese National Standard (rNS) Λ4 specification (210X 297 mm (please read the precautions on the back before filling out this page) '1Τ 513394 A7 B7 V. Invention Note (22) -5H-BH; slightly [2,3_b] [1,5] benzodiazepine) salting to obtain compounds 10 and 11. The definition of Ri in the compound represented by Chemical Formula I is as follows:

Among them, R2, R3, R6, 1-8, R9, Rii and as defined above can be easily prepared from the corresponding aryl bromide, iodide or trMflate according to similar methods contained in the literature (eg Sanogashira, et al. Tetrahedron Lett. 1 9 7 5, 44675 Unroe, et al al Synthesis-Stuttgart 1987, 981), can also use any standard oxidation method (Albini, A · Synthesis 1 9 9 3, 2 6 3 > or bicyclic Oxygen reagent treatment (Murray, R · W · C he Zu, ·. Reh-1 989, 1 1 87) is converted into the corresponding N-oxide, and then the method described above is converted into a chemical formula such as (I) The compound shown. The obtained compound is suitable for the preparation of substances with vasopressin potency, such as compounds 10 and 11 shown in reaction scheme E under M. (Please read the precautions on the back before (Fill in this page) Secret clothes. * 11 Printed with 4'J Shui-Ji 24-24 by the member of the Intermediate Standards Bureau of the Ministry of Consumption and Consumption of Hezhu Society-This paper size is applicable to China National Standards (CNS) Λ4 specifications (210 × 297 mm) 513394 A7 B7 Printed by the Ministry of Justice, the Bureau of the Second Consumer Cooperative, India f. 5. Description of the invention (23

Reaction Process I

M HBoc NHBoc

21 (Please read the notes on the back before filling this page) • ^ 衣 ·

, 1T h2,

10% Pd / C EtOH

19

^ 1) NaN02, HCI 2) CuCN

N-chloroprene dicoimide

The size of this paper is suitable for the Chinese national cockroach (rNS) Λ4 specification (210X 297 mm) 513394 A7 B7. The Ministry of Standards and Technology Bureau of the People's Republic of China has been printed by the Consumer Cooperative F. 5. Description of the invention (24) 1 1 Enamine surface 15 ί W and compounds 10 and 11) can also be used. Using this new 1 1 chemical technology, chloro-4 -iodoaniline (12) is used as the starting material. In 2 reflux tetrahydrofuran, please treat with 1 I first 1 di-tert-butyl dicarbonate and diisopropylethylamine to obtain the compound. Read 1 1 13 〇The derivative of aryl iodide as shown in chemical formula 13 is immediately around Temperature 1 1 ° to 80 ° C in an organic solvent (such as triethylamine) ί 1 I and dialkylaminopropyne (preferably 1-dimethylaminopropyne) 1 reaction to make substituted acetylene 14, this method is essentially based on A1 am 1 This ant eta 1 ♦ Te t Γ ahedr 〇η. Lja 11. 1993, 34 ψ 6403 and page 1 I Sa no ga shi Γ aet • a 1 • trahadr ο η U tt 1975 9 4467 1 1 provided middle The product 14 is subsequently treated in an aprotic solvent (e.g. dichloromethane) at a temperature below room temperature according to some pseudo-oxidation methods. (1 A 1 bini > s Υ π thes is 1993, 263) treated with an oxidant $ 1 or treated with ethylene oxide reagent (Murray, R.W * Chedi—Re Y * 1 I 1989 1187) to N-oxide. Intermediate N-oxide is not isolated. I can be separated 9 but can be rearranged in situ by heating in hydroxyl solvent 1 in any of the methods described herein (e.g. formazan) to form enamine as shown in Chemical Formula 15 | Ketone 〇1 is treated with compound 1 in acetic acid in a Pandofan tent group ranging from room temperature to the temperature at which the solvent is refluxed to treat compound 15 to obtain compound 16. At a temperature of 0-εου in an aprotic solvent such as dimethylformamide or tetrahydrofuran) treatment with a strong base 1 1 1 f such as sodium argon or potassium hydride and methyl iodide) can make '16 16 The heterocyclic nitrogen is alkylated > and a mixture of the local isomers 17 and 18 is obtained as a 1 I product. Among them, the main isomer > Compound 17 can be firstly analyzed by dialysis and / 1 1 I -26-1 1 1 1 This paper size is applicable to Chinese national standard ((, NS) Λ4 specifications (210X 297 mm) Member of the Central Standards Bureau of the Ministry of Economics, printed by τ 消 贽 贽 社 社 f A7 _____B7___ V. Description of invention (25) or separation of crystallization procedures The substituted pyrazole derivative 17 can be dehydrogenated by the hydrogenation of the ribo-palladium catalyst in an alcohol solvent (We e ζ μ a η η, A · J. Am, Chent, Soc · Ϊ949, 7 1, 41 54) to obtain compound 19, followed by BOC-deprotection with trifluoroacetic acid to obtain pyrazole aniline 20. Aniline derivative 20 was then treated with N-chlorosuccinimide to give compound 21 ( Ne a 1 e, R · S · et a 1. J > 0rg > Chem > 1964, 29, 3390), and then carried out Sandroeyer ResctiorO to obtain nitrile 22 (Clark, Η · Τ · et al. Organic Synthesis, I. 1941, 514). Compound 22 was first treated with basic hydroperoxide (Katritzky, A.R. et a 1. Synthesis 1989, 949), and then prepared with dilute sulfuric acid and sodium nitrite. The amine 23 is hydrolyzed (Hales, N.J. et a K, Tetrahedron 1 995, 5 1, 7 4 0 3), and can be converted into carboxylic acid 8 after this series of treatments. The carboxylic acid 8 is converted into blood vessels. The process of vasopressin 10 and 11 is described in the above reaction scheme I. Compounds 10 and 11 are non-peptide mimetics of vasopressin (antidiuretic hormone, ADH), and vasopressin is a nonaminyl group Sour ife hormone and neurotransmitting substances. Vasopressin plays a very important role in the body's function of preserving water, because it can concentrate urine at the position of the ureter in the buttocks. In the absence of vasopressin in the recipient, the urine collecting duct of the kidney is almost impervious to water, so the hypoosmotic hip formed after filtering through the glomerulus, when passed through the proximal tubule in sequence, Heinz The circuit, and the distally curved tubule, become dilute urine excretion. However, because of the use of Chinese National Standard Squat (CNS) Λ4 specifications (210X297 mm) on the paper scale (please read the precautions on the back before filling this page)

513394 A7 \ 9 · 2 5 Correction __B7 j -Ψ B a ^ ^ 5 7 Description of the invention (26) —----- Identify the cause of volume reduction or blood loss during the filling process, vasopressin will be removed from the brain Released from the lower gland, the vasopressin V2 receptor in the renal ureter is activated, and the ureter becomes extremely permeable, so the water is absorbed again and excreted. In patients or animals with central or neurogenic diabetes insipidus, the synthesis of vasopressin in the subglandular is defective, so it is impossible or only to produce very little vasopressin. The hormone receptor is normal. If it still retains considerable sensitivity to the effects of vasopressin and vasopressin V2 agonists, then little or no vasopressin will be produced. In this way, they can no longer concentrate urine, so the volume of urine produced may be more than 10 times that of another healthy kidney in pairs. Angiotensin and desmopression are peptides very similar to natural vasopressin and can be used to treat patients with central diabetes insipidus if necessary. Vasopressin V2 agonists can also be used to treat patients with nocturnal enuresis, nocturia, urinary incontinence, and short delays in defecation. The vasopressin-like compound can be prepared by using the intermediate product of the present invention, and its effect is similar to that of vasopressin, and it is not limited whether it is shared with the vasopressin. Printed by the Ministry of Economic Affairs of the Ministry of Economic Affairs on the Industrial and Commercial Cooperatives ^. (Xu first read the precautions on the back before filling out this page) Compounds 10 (Example 22) and 11 (Example 23) of the present invention were performed according to the procedures under K Biological activity test. V / atGr-Loaded mice with unusually well-known compounds are known to have blood vessels plus E 促 V 2 for potency, fruit release, male or female blood pressure normal Spraque-Dawley mice weighing 350-500 grams (Charles River Laboratories, Inc. , A 28-This paper uses the national standard of the country ((: ^^) / \ 4 size (2 丨 0/297 mm) 513394 A7 B7 V. Description of the invention (27)

Kingston, NY) gg eat standard erosive diet (Purna Rodent Ub · Chow 5001) and arbitrary water. On the day of the test, rats were placed in metabolic cages, which had a device for separating urine and feces from the chicks, and a container for collecting urine. Test compounds or standard reagents were fed at a rate of 10 g / kg per 10 inl / kg. The vehicle solution used was 20 ¾ dimethyl acon (CDMS 0) dissolved in 2.5 S: pre-cooked corn starch. Thirty minutes after the test compound was fed, 30 l «l / kg of water was fed into the rat's pancreas with a feeding needle. During the test, rats were no longer fed water or food. Urine was collected within 4 hours after the test compound was fed, and then urine volume was measured. Use Fiske One-Ten 〇sffl0ffieter (Fiske Associates, Norwood, ΜΑ, 02062) or Advanced CRYOMATIC

Osmometer, Model 3C2 (Advanced Instruments, Norwood, MA) came to Australia (to determine the osmolality of urine. Na +, K + and Cl-heterozygotes were measured using specific electrodes in the Beckroan SYNCHR0H EL-ISE Electrode System analyzer The urine osmolarity concentration increases in a proportional manner. In the screening test, two mice are selected for each compound. If the difference in urine volume between the two mice exceeds 50! K, then a third mouse is selected. ----- ^ ----- (Please read the precautions on the back before filling this page), \-Printed by the Central Bureau of Standards of the Ministry of Oral Affairs, and printed by Consumer Hezhusha-29-This paper size Applicable to Chinese national standard ((, NS) Λ4 specification (210X 297 mm) 513394 A7 ________B7 V. Description of invention (28)

Compound # Example: urine volume reduction rate θ osmolality increase rate b Mouse type e 10 22 70¾ 325¾ CD 11 23 80¾ 272¾ CD a Percentage of urine volume reduction for those who control at an oral dose of 10 mg / kg b osmolality The increase rate of the degree is the percentage of the oral dose controlled at 10 mg / kg, indicating that the mouse species is Sprague-Dawley (CD). ----- ： --- Γ — 衣-(Please read the precautions on the back before filling this page)

Member of the Bureau of Standards of the Ministry of Justice and Economics of the People's Republic of China for the elimination of the standard 4 .. Water where R4 is hydrogen, 1? 2 and 83 are as defined above, which can use Dick in so n equal to the one described in US Patent No. 3,354,178. It is easily prepared by the method; wherein R4 is hydrogen, and R2 and R3 can also be combined to form a pyrrolidine ring easily available on the market, which is ox ^ ttremorine, and R4 is as defined above, but not Hydrogen, and R2 and 1 ^ 3 are also as defined above, and can be easily prepared according to the methods described in Trybubki et al. In U.S. Patent Nos. 5,550,257 and 4,937,235. -30- This paper uses the Chinese national standard (CNsT / W ^ (210X 297 ^ 1) 513394 A7 B7) V. Description of the invention (29 Transition gold tincture (such as palladium on carbon, platinum oxide), or In the presence of Raleigh nickel in a fermentation solvent (such as acetic acid), hydrogen is used for R3 and R4 as described above. Compound 24 performs a primogen reaction as follows R2 r3 Β4_Λ >^-ν;; 24 can also be borrowed By a certain rhenium reaction, such as the combination of ether and triethyl hydrazine Tetrahedron Letters at a comparative temperature or exposure to boron trifluoride and lithium dimethoxyaluminum hydride Coniffl insand LaHunyon, 30 (38), 5053 Method) 25-halide reagents of oxidized oxynidazole compounds were exposed to lithium boron trifluoride in tetrahydrofuran with the aid of Lewis acid (according to the method of Wasserman and Chi, 1 994, 35 (52), 9779) , Ether and copper hydride species obtained from the incorporation of sulfide bromide sulfide (according to Tetrahedron Letters 1989, to obtain compound 25. Compound 25 is a hydrolysis and possible metabolites (Lindeke ----- ; --- ^ 丨 — (Read first on the back Precautions to fill out this page) set by the Ministry drop in standard negative decision to the Indian consumer cooperatives J-

OH B * J. Pharro. Pharnic *, 1 972, 24, 25-31). In the above compound (M), the definition of Ri is as follows: R12 · c r12- where R12 and Rd are as defined above and can be easily prepared by adding lithium ions of propargylamine using methods well known to those skilled in the art; or X is as defined above, but it is not hydrogen, and it is the addition of the double cone 81 of propargylase to 1- (dialkylaminemethyl) benzotriazole Uatritzky, A · 31- Ί Paper scale is far from China Biaohuo ((VNS) Λ4 Regulation (210X 297mm) 513394 A7 B7 One by one ----------------------------___-. ________ V. Description of the invention (30)

Galllos, J. K. Yannakopoulu; K. Synthesis 1 9 8 9, 31), and can be used any standard oxidation method (Ai bin i, A · Synthesis 1993, 1263) or treated with ethylene oxide reagent (Murray, R.W.Chem, Rev. 1989, 1987) is easily converted to the corresponding N-oxide, and then converted to the compound according to the aforementioned method 1 ° These compounds are suitable for the preparation of certain 3 (2H) -furanone Intermediate products (_ exposed in acidic conditions, after Carpenter, B. f (·; Clemens, K · E .; Schmidt, E. Α * ί Hoffsann, Η · M · R. J. A at · Chem, Soc. 1 972, 94 (1 7), 62 1 3 (1 7), 62 1 3)), this intermediate product can be converted into a compound with anti-tenosterol and anti-diabetic functions according to the reaction scheme (Pelntan et al. (As of May 24, 1994 in U.S. Patent No. 5,314,9 13).

Reaction Process H ----- Γ-,--_each—— (诮 Please read the precautions on the back before filling this page) 26 0) H3

CuCI

/ CH3 1) n-BuLi, THF OAc Errolidine 27

, D 2) PhCOCKj Printed by Intermediate Standards Bureau of the Ministry of Economic Affairs -T Consumption Report f H3C-

OH 28

/ CH3 1) MCPBA O 2) MeOH, reflux 3) Amberlyst

Use _Pyridine to propargyl acetate 26 (can be easily prepared according to the method described by Clark and Pinder in J. Che®. Soc. 1958, 1967) into -32- This paper size is applicable to China National Standards (CNS) Λ4 specification (210X 297 mm) 513394

V. Description of the invention (31) (Read the precautions before filling in this page, and then fill in this page) The copper-catalyzed substitution reaction can be used to obtain the propargylamine 27. The use of n-butyl lithium in tetrahydrofuran in a slight excess Moore number at temperatures below room temperature (approximately -7 8 t! Is preferred) may cause monopropionization of the propargylamine at its terminal group position. Effect, and then add acetophenone to obtain propargyl alcohol 28. Intermediate 2 8 is followed by the use of an oxidant (A 1 b i n i, A · Synthesis, 199 3, 263) according to standard oxidation methods or with an ethylene oxide reagent (Murray, R. W. Chem ·

(Rev. 1989, 1187) The treatment of the intermediate product is carried out in an aprotic organic solvent at a temperature below room temperature, so that it can be converted into the corresponding N-oxide. The intermediate N-oxide is not separated, but can be obtained by heating in a hydroxy solvent (such as methanol) or by in-situ rearrangement using any of the procedures described above. This ketene is then treated in situ with an acidic catalyst (such as Amber 丨 yst @) to complete the cyclization reaction to remove pyrrolidine to obtain a substituted 3 (2Η) _furanone, which can be converted into an anti-cholesterol and anti-diabetic Functional compounds (Felman et al., U.S. Patent No. 5,314,913, May 24, 1994). The present invention will be described in more detail with the help of non-limiting examples. When the oil is exemplified in the Ministry of Economic Affairs, it is printed on the base of the Ministry of Consumers ’Cooperatives and printed on 1-Dimethyl Pickle-4-" 1-(3-(R)-0-octylamine formamidine-? Argon -Hydroyl il-2_ butyne N-argon hydrazine A solution of dimethyldioxirane in acetone (about 0.08M, 9ml) was dropped into (R) -octylaminocarboxylic acid-1- (4 -Dimethylamino) -2_but \ alkynyl) -2_oxo-3 -litoridine ester (250 mg) in dichloromethane (6 in 1) in ice-cold solution. Under 0 υ The reaction was stirred for 20 minutes, and then the solvent was removed in a krypton gas stream. -33- This paper ruler and Wenzhou China 丨 (rNS) Λ4 cypress (210 × 297 mm) 513394

V. Description of the invention (32) Printed by the Ministry of Economic Affairs Central Standard Jujube Bureau Ordnance Industry Consumer Cooperative, using ether to develop the residue to obtain the desired white powder N-oxide. M S (+ E S), m / z · 3 6 8 (M, Η) +. 1 Temporary example 2 1-Dimethyl, certain and certain 4- "1 1 (3- (R)-锊 一 2-气 一眼 给 某某))-2— 丁 @ Ν -Argide will be dimethyl diepoxy Ethane in acetone solution (about 0.08M, 17.8ml) (R)-1- (4 · {dimethylamino) -2-butyne) -3-hydroxy-2-Pttpyridine (250mg) ) In dichloromethane (8ml) in an ice-cold solution. The reaction was stirred at 0 ° C for 20 minutes, and then the solvent was removed in a gentle argon flow. This gave the desired yellow foamy N-oxide. MS (+ ES), m / ζ: 2 1 3 (Μ + Η) + 〇 Window Example 3 (R)-Caprylic acid formic acid-1- "4- (dimethylamino)-2-chloro-3-butane 1- 2-argon-3 -HH; 1-dimethylamino-4_ [1- (3- (R)-0-octylamine methylamidino-2-oxo -Pyrrolidinyl) -2 -butyne N-oxide (25mg) in methanol (1.5ml) was heated to 60 ° C. After the mixture was cooled, the solvent was evaporated to dryness in vacuo. The resulting residue was subjected to silicone gelling. (K 5J: methanol solution of dichloromethane as eluent), and then the solvent was evaporated in vacuo to give the title compound as a colorless oil. MS (FAB), Bi / z: 3 6 8 (Μ + Η) +. In the case of Example 4, (R)-1-U- (dimethyl prevent a certain)-? · -argon-3-butenyl 1 Ί 锊 _2-state , NK ni m one 34-(Please read the precautions on the back before filling in this page.

、 1T im This paper size Chengzhou China's home standard Cen ((, 吣) 8 4 specifications (2 丨 0 '/ 297 Gong) 513394

The Ministry of Economic Affairs ’s Standards for Industrial and Commercial Cooperatives, India, India, Japan, Japan, Japan, Japan, Japan, Japan, Japan, Japan, Japan, Japan, Japan, Japan, Japan, Japan, Japan Oxy-pyrrolidinyl) -2-butyrate N-oxide (2500 lg) in methanol (10 β 1) was heated to 601C. After the mixture was cooled, the solvent was evaporated to dryness in vacuo. The resulting residue was subjected to chromatography on silica gel (W5-20S: a solution of dichloromethane in methanol as the eluent), and then the solvent was evaporated under vacuum to obtain the title compound. MS (FAB), ηη / ζ: 213 (M + H) +. Example 5 1-f4 1-Crylyl) 2—Gas 3—Butyl 1—2—ITH; 1¾ PgSa was added to an ice-cold solution of 412ing in dichloromethane (4 * α1). The least amount of 3-chloroperoxybenzoic acid (362ieg). The reaction was stirred at 0C for 20 minutes. The resulting mixture was passed through 20 equivalents of basic aluminum oxide (Brock Biann Grade I, 150 mesh), and the N-oxide was diluted with 5 S: dichloromethane in methanol. After mixing all the parts containing the desired N-oxide, it was evaporated in vacuo to near dryness. Then the residue was treated with a small amount of methanol (approximately 25 ml) for three consecutive times, evaporated to dryness, and methanol was added to adjust the solution volume to 30 ml. The H-oxide formazan solution M was heated under reflux for about 5 hours and then cooled, and then the solvent was evaporated to dryness in a vacuum. The resulting residue was chromatographed on silica gel (M4X in dichloromethane in methanol as the eluent), the solvent was then evaporated off in vacuo, and the title compound was obtained as a colorless angular column after crystallization from ethyl acetate-hexane. Melting point: 99-101 t! OM (+ ES), m / z: 223 (M + H) +. Tube pus example 6, dimethyl anti-cage-2-propionic neodymium H-gMh was added to 1-dimethylamino-3-phenyl-2-propyne (1.0 g; using phenylacetylene and -3 5-This paper has passed the Chinese National Standard (CNS) Λ4 specification (210X 297 mm) ------------ (Please read the precautions before filling this page) Printed by Hezhu Co., Ltd., Central Bureau of Standards of the Ministry of Education ^ 513394 A7: B7 V. Description of the invention (34) Mannich reaction of methyl base and dimethylamine; Mannich Chem. Ber. 1 933, 66, 418 i Lattes, et a 1. Tetrahedron 1 982, 38, 2 3! 5 5) In an ice-cold solution of dichloromethane (15 ml), a small amount of 3-chlorophenylperoxybenzoic acid (1.13 g) was added over a period of 2 minutes. The reaction was stirred at Ot: for 20 minutes. The resulting mixture was passed through 20 equivalents of basic aluminum oxide (Brockeiann Gradel, 150 mesh), and then diluted with 5¾ dicarbamate in methanol. After mixing all the parts containing the desired N-oxide, it was evaporated in vacuo to a level close to dryness. Diethyl ether was added to precipitate the product as a colorless solid. MS (+ ES), ro / z: 176 (M + H) +. Example 7 3-Dimethylamino-1-phenyl-2-propene-1-proxyl-1-dimethylamino 3-phenyl-2-propyne N-oxide (250 mg) in methanol ( 20 ml) The solution was heated at reflux for 5 hours. After the mixture was cooled, the solvent was evaporated to dryness in vacuo, and the resulting residue was chromatographed on silica gel (using 2: 1 ethyl acetate-hexane as the eluent) to obtain a nearly colorless solid product. MS (+ ES), Di / z: 176 (M + H) +. The purified product W 1 H MMR and thin-layer chromatography identification results are the same as those obtained by the known reaction of 1-benzene-prop-2-yn-1-one dimethylamine; MeMulUn, et a 1. J. Chera Soc. (B) 1 9 6 6, 1217; Hirao, I. J.

Chem. Soc. Japan 1953, 56, 968 (Chem. Abs. 1955, 3185f). Tube_Example 8, 3-Dimethylamine, 1-cage-2-propane-1-gu, 7.5 mg of bis (acetonitrile) palladium (E) chloride and p-dimethylamino-3-benzene -36- The standard of this paper is Chuanchuan China S Standard (CNS) Λ4 specification (21〇 ×: 297mm) -------- Shi · ^ ______ 丁 ______ (Please read the note on the back first Please fill in this page again.) The Bureau of Standards and Decision of the Ministry of Economic Affairs g <Industrial and Consumer Cooperative Press f 513394 A7 B7 V. Description of the invention (35)-2-propyne H-oxide (50n »g) in formazan (ΙπιΠ solution The resulting mixture was stirred under an argon atmosphere and room temperature for 2 to 4 hours. The mixture was diluted with ethyl acetate and washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. The residue was analyzed by silica gel (using 2: 1 ethyl acetate-hexane as the eluent), and a nearly colorless solid product was obtained. MS (+ ES), ir / z: 176 (Μ + Η &gt; + 〇 Purified product M 1 H NMR and TLC analysis results are the same as those obtained by the known reaction of benzene-prop-2-yne-1-_ with dimethylamine; MeMullen, et al. J. Chein Soc. (B) 1966, 1217; Hir ao, I, J. Chein. Soc * Japan 1953, 56, 968 (Cheffi · Abs. 1 955, 3 1 85f) 〇 啻 _ Example 9 3-Dimethylamine -1 &quot; &quot; 笨 -2-propyl I-1-Hexyl iodide (5.5mg) was added to a 1-dimethylamino-3-benz-2-propyne N-oxide (50nig) formazan (1ml) solution, and the resulting mixture was Stir under argon atmosphere and room temperature for 4 days. The mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. The resulting residue was chromatographed with silica gel. (2: 1 ethyl acetate-hexane was used as the eluent), and a nearly colorless solid product was obtained. MS (+ ES), π / ζ: 176 (M + H) +. Purified product K 1 H NMR The results of identification by thin-film chromatography and the same as those obtained by the known reaction of 1-benzene-prop-2-yn-acetylene and dimethylamine were the same; M e M uI 1e η, eta 1. J. Chen Soc. (B) 1 966, 1 21 7; Hirao, I. J · C hem · Soc. Japan 1953, 56, 968 (Chero. 1 37-This paper uses Chinese national standard ((, NS) Λ4 specification (21 OX 297 mm) ----- ^ --- 10 ^-(Please read the Precautions to fill out this page), 11 full part in decisions by the Bureau of Standards negative X Bamboo Club Indian consumer report to 513394 A7 ___B7 V. invention is described in (36)

Abs · 1 955, 3185f Examination Example 1 0 3-Dimethylamino-1-cage-2-propen-1-side benzyldimethyltetradecylammonium chloride dihydrate (approximately lfflg) and bis (acetonitrile) palladium chloride (m (3.8mg)) were added to a dichloromethane-water two-phase solution of 1-dimethylamino-3-phenyl-2-propyne oxide (50®g) (1: 1, 2ml), and then stir the mixture for 24 hours. Then dilute the reaction mixture with ethyl acetate, then wash with saturated brine, dry the organic layer over anhydrous magnesium sulfate, and evaporate the solvent in vacuum. The resulting residue was decanted with silica gel (using 2: 1 ethyl acetate-hexane as the eluent) to obtain a nearly colorless solid product. MS (+ ES), ιβ / ζ: 176 (M + H ) +. The purified product K 1 H NMR and thin-film calendar identification results are the same as those obtained by the known reaction of 1-benzene-prop-2-yn-1-one with dimethylamine; MeMullen, et al · J · Che · Soc · (B) 1966, 1217; Hirao, I. J * Chew, Soc, Japan 1953, 56, 9 6 8 (C he in · A bs · 1 9 5 5, 3 1 8 5 f). Example 1 1 3-Dimethylamine-benzene-2-propane-1-Gujiangben methyldimethyldeca Tetrayl ammonium chloride dihydrate (about ling) and iodide subnet (2.8 mg) plus 1-dimethylamino-3 -benzyl-2-propane N-oxide (50 g) In a two-phase solution of methyl chloride-water (1: 1, 2®1), then the mixture was stirred vigorously for 24 hours. Then the reaction mixture was diluted with ethyl acetate and then washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent Then it is evaporated in a vacuum. The obtained residue is analyzed with silicone gel. The paper size is applicable to China National Standards (CNS) Λ4 specification (2ΚΓχ 297 mm) -----: ----- (Please read the back first Please pay attention to this page, please fill in this page),-Oral and Drip Department Central Standards Bureau, Shellfish Consumer Cooperative, India 513394 A7 B7 V. Description of the invention (37) (2: 1 ethyl acetate-hexane as eluent) The solid colorless product ◊ MS (+ ES), ιη / ζ: 176 (M + H) + is obtained, which is near colorless. The purified product M 1 H NMR and thin film analysis identification results are based on known 1-benzyl- The product obtained by the reaction of prop-2-ynylbenzene and dimethylamine is the same substance; MeMullen, et al. J. Chea Soc. (B) 1966, 1217;

Hi'rao, I · J · CheiB · Soc · Japan 1953, 56, 968 (Chem. Abs * 1 9 5 5, 3 1 85f) 〇 Example 1 2 4 -Dimethylamine-1 -Cage- 3-Butene-2-fluorene in 1-dimethylamino-4-benzene-2-butyne (0.5g; prepared by using Mannich reaction of 3-phenyl-1-propyne with formic acid and dimethylamine; Mornet, et. Al. Bull, Soc. Chero. Fr. 1974, 206) in dichloromethane (2) m) 1) ice-cold solution was added with a small amount of 3-chloroperoxybenzoic acid (0.52 g). The reaction was stirred at 0 T! For 20 minutes. The resulting mixture was passed through 20 equivalents of sickle aluminum oxide (Brockmann Gradel, 150 mesh), and then diluted with 10 ¾ methylene chloride in methanol. All parts containing the desired oxide are mixed and evaporated in a vacuum to near dryness. After brewing, the remaining residue was treated with the least amount of formazan (about 10 μηι) for three consecutive times, evaporated to dryness, and the volume of the solution was adjusted to 25ml by adding formazan. The N-oxide formazan solution was heated under reflux for about 4 hours, then cooled, and then the solvent was evaporated to dryness in a vacuum. The obtained residue was analyzed by silica gel (M 95: 5 ethyl acetate / hexane as eluent), and then the solvent was evaporated under vacuum to obtain the desired oily product OM (+ ES), Bi / z: 190 (Μ + Η) + 〇-39- This paper size reads Λ Chinese national standard 埤 ((, NS) Λ4 specifications (2) 〇 × 297 mm) ----- Γ-- · 衣 | 丨(Please read the precautions on the back before filling in this page) Printed by the Consumers' Cooperatives of the Bureau of Final Awards in the Ministry of Commerce; ^ 513394 A7 B7 V. Description of the Invention (38) 例 _Example 1 3 1-dimethylamino -1-Houpu-3-An ice-cold solution of 1-dimethylamino-2-pentyne (3.0 g) in dichloromethane (10 μm) was added with a small amount of 3-chloroperoxy stearic acid (4.66 g). The reaction was stirred for 20 minutes at 01. The resulting mixture was passed through 20 equivalents of basic aluminum oxide (Brockmann Gradel, 150 鼸 mesh), and then diluted with 5¾ dichloromethane solution. All 1-dimethylamine was contained. After mixing the various parts of N-2-pentyne N-oxide, it was evaporated under vacuum to a level close to dry solid. Then the residue was treated three times with a small amount of formazan (about 10 Offll), and evaporated to dry solid, then added The volume of the fermentation solution was adjusted to 901 »1. The formic fermentation solution (30ml) M of oxide (9βιιβο1) was heated under reflux for about 4 hours and then cooled, and then the solvent was evaporated to dryness in a vacuum. The obtained residue was used for Silica gel was analyzed (using 2! K dichloromethane solution as the eluent), and then the solvent was evaporated in vacuo to obtain the desired oily product. MS (+ ES), m / z: 1 2 8 (Μ + Η &gt; +. G _ Example 14 Methanase of 1-dimethylamino-1-pentene to 1-dimethylamino-2-pentyne N-oxide (lg) (30ml ) 117 mg (acetonitrile) of palladium chloride U) was added to the solution, and the mixture was stirred in an argon atmosphere and a chamber for 24 hours, and then evaporated to dryness under vacuum. The obtained residue was subjected to a silica gel analysis (M 2S; methylene chloride) The methanol solution is used as the eluent), and then the solvent is evaporated in a vacuum, that is, to the desired oily product. MS (+ ES), ιη / ζ: 128 (Μ + Η) +. 4 — — Paper The scale is applicable to China National Standard Floor (CNS) M specifications (210X297 mm) Γ --'---- (Please read the precautions on the back before filling in this page), 1T Standard Bureau Member X Consumer Cooperatives India 513394 A7 B7 V. Description of the invention (39) Fen _ Example 1 5 1-Dimethyl pickles a certain pinene-3-Guo N-oxidation of dimethylamino-2-pentyne To a solution of the formazan (30 ml) of the substance (lg) was added 8 6 ra g of iodide iodide, and the mixture was stirred under an argon atmosphere at room temperature for 24 hours, and then evaporated to dryness under vacuum. The resulting residue was decanted with silica gel (K 2¾ methylene chloride in methanol as the eluent), and then the solvent was evaporated in vacuo to obtain the desired oily product. MS (+ ES), ib / z: 128 (M + H) + 〇 Fen Example 16 4-Sea-2-hydrazone-clavonic acid. Shenyl ester in 4-bromo-2-chloro-benzoic acid (6.29 g) 1.64 ml of thionyl chloride was added to the methanol suspension, and then heated to 6 ο for 2 hours. The solvent was removed in vacuo, and the resulting residue was dissolved in ethyl acetate, and then washed sequentially with 0.5N sodium hydroxide (2x), water, and brine. The organic phase was dried over anhydrous sodium sulfate, the solvent was removed in vacuo, and the solvent was evaporated in vacuo to give 7.8 g of the title compound as an oil. 1 H NMR (300 MHz), d: 3.87 (s, 3H), 7.68-7.9 (ιη, 3H). Fen_Example 1 7 2 ， 氲 -4- (3-dimethylammonia-propane-1-1-a) ¾ Shen 酴. Shenmou_ In 4-bromo-2-chlorobenzoic acid methyl ester (18.69g ) Triethylamine (llOrnl) solution was added 1-dimethylamino-2-propyne (12.1ml), bis (triphenylphosphine) palladium chloride (S) (1.26g) and thallium iodide ( I) (0.t36g), the resulting mixture was slowly heated to 60 ° and then maintained at this temperature for 1 hour. Then cool to room temperature and filter with diatomaceous earth. The collected solids are acetic acid-41-This paper size is applicable to China National Standards (CNS) Λ4 specifications (210 × 297 mm) (Read the precautions on the back before filling This page) -rr fill in too 513394 A7 B7 V. Description of the invention (40 (please read the precautions on the back first and then fill in this page) yiku washing. The solvent was removed in vacuum, and the obtained residue was re-dissolved in ethyl acetate. , And then washed with three times the water. The mixed organic extracts were dried over anhydrous sodium sulfate, and the soluble surface was removed in vacuo to obtain the crude product. The crude product was purified by silica gel (225g) using column chromatography, and then Dilute with 40¾ ethyl acetate / hexane. Then remove the solvent in vacuo to obtain 17.7 g of the title compound as a viscous oil. MS (+ FAB), m / z: 252 (M + H) + 〇 啻Example 1 8 2 -Chloro- 4- (3-dimethyl I-amino-2-propanyl) benzoic acid, methyl ethyl 2-chloro-4-(3-dimethylamino-propyne 1-yl) benzoic acid, methyl ester (15,07g), and then slowly add the corresponding temperature to maintain the obtained N-oxidation (215g) agent. The product was stirred at the residual temperature and triturated with 70% ethyl acetate to obtain a dichloromethane (40ml) solution pre-cooled at -201, and then 3-chloroperoxybenzoic acid (10.76g) was added at -20t during the addition process. The mixture was then allowed to stir for 10-15 minutes. The material was purified by chromatography using KA cti ν ity G rade I, and then the solvent was evaporated under vacuum at 12-18¾ to dissolve the residue in 100 ml of methanol. It was heated at 65 ° C for 18 hours. After removing the solvent in vacuo, the resulting column chromatography was purified with silica gel (190 g), and then diluted with ester / hexane. Then, 5.68 g of the title compound was solid with diethyl ether containing some hexane. Melting point 92-96 ^. Official example 1 9 2-nitro-4- (1H-pyridine-3-yl) formamidine. Methyl ester in 2-amo-4-(3-dimethylamino- 2-propan-1-yl-1-yl) -benzoic acid, methyl ester (13.67g) in ethanol (53ml) suspension was added with 7.0g of hydrogen-42- (, NS) Λ4 is present (210X 297 mm) After losing the standard of the Ministry of Justice, printed by τ consumer cooperatives 513394 A7 B7 5. Description of the invention (41) Chlorination trap. The resulting mixture Heat at 75-8〇υ for 1 hour. The solvent is removed in vacuum. The remaining residue is dissolved in ethyl acetate, then washed with water and salt j water, then dried with anhydrous sodium sulfate, and the solvent is removed in vacuum, so This gave 12 g of the title compound as a rough solid. The melting point of the purified sample was 130-131 υ. Tube_Example 20 2- 氡 -4-Π- 甲 _1Η-ΒΗ; 崃 -3- 荜) caged acid. Methyl_ In a nitrogen atmosphere, 2_chloro-4-ΠΗ- Pyrazol-3-yl) -benzoic acid, dimethylformamide (30ml) in methyl alcohol (12.0g), dimethylformamide washed with hexane and sodium hydride (13.05g, 60¾ dispersion) Phenamine (6ml) in suspension. The resulting mixture was stirred at room temperature for 30 minutes. Then 9 · 5®1 methyl iodide was dripped in for a period of 15 minutes. This mixture was stirred for another 45 minutes at room temperature. An additional 5.16 ml of methyl iodide was then added, and the resulting mixture was stirred for another 75 minutes. The reaction mixture was then diluted with a small amount of water and concentrated in vacuo. The resulting residue was diluted with 500 ml of water and extracted five times with ethyl acetate. The mixed organic phase was evaporated in vacuo to obtain the crude product, which was then purified by glaze column chromatography M silica gel (15 5 ethyl acetate / hexane as eluent) to obtain the purified 1-methyl partial isomer (4.29 g) and a mixture of 1-methyl and 2-methyl local isomers (4.6 g). A mixture of these isomers was triturated three times with hexane to give an additional sample of 2,55 g of pure 1-methyl partial isomer. Melting point 66 * 5 -67t; MS (+ PAB), and / z: 25UM + H ". (Fen_Example 21 2-Gas 1- (1-methyl-1H — ITH; _ — some) ¾ Formic acid 43 -This paper size is applicable to Chinese national inscriptions ((, NS) Λ4 specifications (210X297 mm): ---: 丨-(read the precautions on the back before filling this page), 11 Quasi-station M, τ digestion Hezhusha f. A7 -B7. __________________________ V. Description of the invention (42) in 2-chloro-4- (1-methyl-1H-pyrazol-3-yl) -benzoic acid, a To the formic acid (32ml) solution of the base ester (6.85g) was added a 2.5N sodium hydroxide solution (15.3 mi). Then the reaction mixture was heated to 50 υ for 1 hour. The solvent was removed in vacuo The obtained residue was dissolved in 250 ml of water, and then cooled in an ice bath, and then acidified with 2N hydrochloric acid (24B1). The obtained precipitate was dried and dried to obtain 6.3 g of a colorless solid. Melting point 232-233¾; MSOFAB), Bi / z ： 236 (Μ + Η) + ° window _ Example 22 L2-qi-4-(1 one methyl one 1 H-hope · _-3-some)-cage one 1 (5 H · 11 Η-_ · slightly Radical one Γ ^ 1τ1M.4 ΐ cage and two &gt; yamine -10- something) a methyl group — Finely powdered 2-chloro-4- (1-methyl-1Η-pyrazol-3-yl) benzoic acid (6.3g) and dimethylformamide (2.16ml) were suspended in tetrahydrofluorene in a nitrogen atmosphere. _ (70®1) and dichloromethane (15ral &gt;). Then a solution of human grass brewed chlorine (2.43ml) in dichloromethane (5ml) was dropped, and the reaction was then stirred for 1 hour. The resulting 2-chloro- The 4- (1-methyl-1H-pyrazole-3 -yl) -benzidine chloride suspension was used without further purification. At 10,11-dihydro-511-pyrrole- [2 Diisopropylethylamine (7w) was added to a suspension of 1,1-(:] [1,4] benzobis || yahegine (4.93g) in dichloromethane (15®1). Then in normal In a flowing nitrogen atmosphere, the freshly prepared brewyl chloride was added over a period of 15 minutes. The obtained slightly warm reaction mixture 1 was stirred in nitrogen. After stirring for 1 hour, the residue obtained by reconverting the 18 substances was dissolved in a vacuum. Dichloromethane, followed by water, 5¾ sodium bicarbonate aqueous solution, and then washed with water. After the organic phase was washed with brine, dried over anhydrous sodium sulfate, the solvent was removed in vacuo to obtain the crude product Ran-44 paper Geometral bee with Chinese national standard (, NS) Λ4 specification (210X 297 mm) -----: --- 10 ^ II (Read the precautions on the back before filling in this page), 1T 513394 Member of the Intermediate Standards Bureau of the Ministry of Economic Affairs -T -Consumption cooperatives Yinfan A7 B7 V. Description of the invention (43) After purification by column chromatography M silica gel (using 30-40¾ ethyl acetate / hexane as the eluent), an oily product is obtained. Crystals were formed by stirring the oily product with hexane-containing ethyl ether for 24 hours. The precipitate was filtered to give the title compound as a crystalline solid. Melting point 148.5-1501C; MSiEIi, * »/ z ·· 4 0 2 ⑻ + · real_Li23 [2-chloro-4-(1-methyl-sleep-3 -yl) -phenyl]-(5,11 , Dihydro- 龀 certain Γ? ·· 3, b 1 Π · 5-m and diacridone- ^ Kibab some step A · 6,11-dihydro-5H-UH; pyryl [2, 3-b] [1,5] 1: 1 mixed salt of benzodiazepine-5-one and hydrochloric acid. 1,2-phenylenediamine (52g, 480mniol) and chloronicotinic acid (76g, 482 The mixture of cyclohexanol (480ml) solution was heated under reflux in nitrogen for 2.5 hours. Precipitation appeared after the heating started, and the lukewarm mixture was carefully poured into ice-cold dichloromethane (100 ®1) above. After the semi-solid mass was collected, washed with dichloromethane, and then dried in vacuo to give 98.9 g (83X) of the title compound, which was used in the next step without further purification. Step B.6,11 -Dihydro-pyryl [2,3-b] [l, 5] benzodiazepine In a nitrogen atmosphere, diborane sulfide dimethyl complex (35nl) was added to step A · 6, 11-Diargon-5H-pyrrolyl [2,3-b] [l, 5] Benzodiazepine-5-one and hydrochloric acid 1: 1 mixed salt (230 ml) solution f. The mixture was subjected to ultrasound at room temperature overnight, and then evaporated to dryness in vacuo. The resulting green residue was treated with 2N cold hydrochloric acid and ether. The cold aqueous layer was treated with 50 J: sodium hydroxide aqueous solution. Alkaliization to p Η 9, then -45- This paper is suitable for Sichuan National Standard (CNS) Λ4 specification (210 × 297 mm) -----; ---: 1 · yi II (please read the back first (Notes on this page, please fill in this page), 1T 513394 A7 B7 Ministry of Standards and Technology Bureau of the Ministry of Consumer Affairs β <τ Elimination Cooperative Shirt Impression V. Description of the Invention (44) 1 1 Extract the basic calendar with ethyl acetate. For organic extracts m water dried with potassium carbonate 1 1 and then evaporated to dryness 9 to obtain a solid 1 1 (24 · 35 g, 61 4¾) like a burgundy wine color [the crude product was purified by trituration with ether &lt; &gt; solid / -^ S Please 1 I first 1 The collected mixture (18. 5 g) is subjected to a quick calendar analysis (read 1 I He rck-60 f with silica as eluent of 20¾ ethyl acetate hexane). Back 1 1 TLC homogeneous extra product (yellow solid 11 g) C &gt; Note 1 1 group]-(5 step C. [2-chloro-4 4- (1-methyl-1Η-roan-3 -yl) -benzene , 11-binary 1 hydrogen m-pyridine [2,3 -b] [1, 5] Benzodiazepine-6-yl) -methyl ketone Refill this% Stir at room temperature under nitrogen atmosphere 2- Chloro-4 -Π-methyl-1 hydrazone-pyrazole-3- Page 1 I-based) -benzoic acid (1.9 g) and dichloromethane (20 ml) with straw chlorine (0.79 »1) 1 1 The mixture of the solution 1 hour 9 The mixture contains a catalytic amount of dimethylformamide 1 1 amine (0.01 »1) 〇 vacuum evaporation to remove the solvent &gt; the obtained rough solid brew 1 chloroform dissolved in 5 m 1 dimethyl Methylformamide, and then directly add 5, 1 1-di-1 hydrogen-monopyridine [2, 3-b] [1, 5] benzodiazepine (1.59 g) and potassium carbonate 1 I ( 1.25 g) of the mixture, &gt; After stirring the mixture at room temperature for 2 hours, 1 I 9 ethyl acetate and water were separated. The organic phase was washed with water and brine 10, dried over anhydrous sodium sulfate, and dried under vacuum, and then the solvent was removed by vacuum evaporation. The obtained product I was analyzed by column chromatography M silica gel (using ethyl acetate 1 with a linear gradient of 57-66¾). The hexane solution was used as the eluent.) Purification &gt; and recrystallization from ethanol-ether to obtain a colorless solid with a melting point of 202 ¾. I Fen_Example 24 I 1 1 (3 丨 -Nitrogen-.4-Hydroxy-¾)-amine tricarboxylic acid trimethyl ester 1 1 in 3-chloro-4 [-iodoaniline (20. 2! G) Tetrahydrofuran (2 0 0 ra 1) solution 1 I Add di-third butyl dicarbonate (3S 丨 g) and N, N- diisopropylethylamine 1 1 I -46- 1 1 1 1 Paper size is suitable for Sichuan National Standard Bee ((, NS) Λ4 size (210X 297 mm) 513394 A7 __ B7 — ·----5. Description of the invention (45) (30.9g). Roll the mixture back to heat for about 24 hours, then cooled, the solvent was removed by vacuum evaporation, and the resulting residue was dissolved in ethyl acetate (450 «1), then twice with 5» saline solution, once with saturated aqueous sodium bicarbonate solution, washed sequentially, and then with anhydrous sulfuric acid Dry with magnesium. Remove the solvent by vacuum evaporation. The obtained product is triturated with hexane to obtain a crystalline solid product. MS (-ES), m / z: 352 (^)-. Further purification can be accomplished by recrystallization with hot hexane. Fen _Example 25 1 ~ 3- 镫 -4- (3-Dimethyl amine amine-and-1-neodymium phenyl phenyl 1 diamine carbidine tributene is cooler than (3-chloro-4-iodo-phenyl Glutamic acid Triethylamine (120 ml) in triethylamine (120 ml) was deoxygenated with p-dimethylamino-2-propyne (2.82 g), and bis (triphenyltene) palladium chloride (E) (400mg), and iodine (54mg). The mixture was stirred under a nitrogen atmosphere at room temperature for about 6 hours, and then briefly heated (about 10 minutes) to 60t !. The resulting reaction mixture was cooled first, and then silicon After filtration through celite, the solvent was removed by vacuum evaporation. The obtained residue was washed with ethyl acetate three times, and then washed with saturated brine three times, and then dried over anhydrous magnesium sulfate. The solvent was removed by vacuum evaporation, and the obtained residue was purified by chromatography M silica gel. (Using 80¾ ethyl acetate in hexane as the eluent) Purified to obtain an amber oily product, which was allowed to stand and solidify. MS (+ ES), ιβ / ζ: 309 (Μ + Η) +. Example 26 'Γ3- 氲 Di Shen amine _ Propylene — I-clothing-Jiben amine I-amine third acid I-47-This paper size applies to China ^ specifications (210 × 297 mm) (Please read the precautions on the back before filling this page)

1T 513394 A7 ^ _ B7 — —- ---------------- — — _ V. Description of the invention (46) in [3 -Chloro-4- (3-dimethyl Amino-prop-1-ynyl) -phenyl] -carbamic acid tert-butyl ester (4.0 g) in dichloromethane 30 μπι 1) An ice-cold solution was added with a minimum of 3-chloro-oxybenzoic acid (2.34 g) . The reaction was stirred at 0¾ for 20 minutes, and the resulting mixture was passed through an equivalent amount of aluminum oxide (Brockmann Grade I, 150 mesh), and then diluted with a 5 L: dichloromethane solution. All the parts containing the desired amine N-oxide were mixed and evaporated in vacuo to a level close to dryness. Then treat the remaining three times with a small amount of formazan (approximately 50®1), evaporate to dryness, and add formazan to adjust the solution volume to 250ml. The N-oxide methanol solution M was heated under reflux for about 15 hours and then cooled, and then the solvent was evaporated to dryness under vacuum. The obtained residue was subjected to historical analysis with silica gel (using 80¾ ethyl acetate in hexane as eluent), and the desired pale yellow solid product was obtained after purification. MS ί + ES), ® / ζ: 325 (Μ + Η) + 〇 Tube MS Example 27 A 1-role-Ί-even)-rfe-醵 1-(pyrrolyl-1 &quot; · radical)-C-2 -Alkyne (prepared according to the method of Biel and DiPierro J. Am, Soc, 1958, 80, 4609) (0.545 g &gt; Dried Standard Division of the Ministry of Standards, τ 消 贽 贽 社 印 印 f -II n IIII-( Please read the precautions on the back before filling this page.) Tetrahydrofuran (15ml) solution was treated with n-butyllithium hexane solution (2.5M, 2.2 «« 1) at -781C, and the mixture was searched at -781 for 30 minutes. And then warmed to room temperature for a period of 1 hour. Then the mixture was treated with a solution of tetrahydrofuran (1811) in propyl ammonium (1 ml) to cool the temperature again to ~ 78 &lt; C. Then the temperature was increased for a further 2 hours. Warm to room temperature, this will leave the ethyl acetate and water. The water calendar is extracted with ethyl acetate, the mixed organic phase is washed with water and brine in order, and then dried over anhydrous sodium sulfate. Vacuum removed -48- Paper I Degree Shizhou China National Standard Binding ((, NS) Λ4 specification (210X 297 mm) is negative by the Ministry of Standards and Technology _τ Consumption printed by Hezhu Publishing Co., Ltd. 513394 A7 B7 5. Explanation of the invention (47) Solvent After that, the crude product was obtained. Then, using column chromatography M silica gel (using a 5¾ methylene chloride solution in methanol as the eluent), an oily product OM (+ ES) was obtained, π / ζ: 168 (M + Η ) + 〇 啻 妩 例 28 4 After a period of 4 4 A 1 1 1 (1 2 1 1 1 1) 1 1 1 1 1 3-brewing a small amount of 3-nitroperoxybenzoic acid in about 2 minutes (0.285 g) was added to an ice-cold solution of 2-methyl-5- (pyrrolidin-1-yl) -penta-3-yn-2-ol (0.25 g) in dichloromethane (6 ml). Stir under Ot: After 5 minutes of reaction, the resulting mixture was passed through 20 equivalents of alumina (Brocknann Grade I, 150 mesh), and then diluted with 5 «methylene chloride in methanol. All portions containing the desired amine N-oxide were After mixing, it was evaporated to near dryness under vacuum. The obtained residue was dissolved in methanol (20ml) and refluxed for 7 hours, and then the solvent was removed in vacuo. The obtained residue was chromatographed with silica gel (M 50¾ ethyl acetate in hexane solution as the eluent). ) After passivation, the desired amber solid product was obtained. MS (+ ES), ιη / ζ: 184 (Μ + Η) + 〇 Fen Example 29 2.2-dimethylformate 3 (21 1)-蛀 Sight_ 4-Hydroxy-4-methyl-1-(Bit pyridin-1-yl) -pent-1-ene-3-pyrene (0.075g) in p-toluenesulfonic acid (1ml) solution After treatment with acid (0.015 g), the resulting mixture was stirred at room temperature for about 15 hours. The solution was then diluted with ether, and then washed sequentially with water, 5¾ hydrochloric acid aqueous solution, sodium carbonate saturated aqueous solution, brine, and then dried over anhydrous magnesium sulfate. Careful removal of the solvent gives the desired oily product. It uses 1 Η N MR and thin calendar layer. One 49 one The paper size is applicable to the Chinese National Mark (rNS) Λ4 specification (210X 297 mm) (read the precautions on the back before filling this page) w Fill in too kl

The final result is similar to the commercial product of Aldrich Chemical Company. i Sinus_ M 3ft 1 a (34m · n &amp; tfe a 1 a) _ slash a photo gl 1 a (pyrrolidin-1-yl) -prop-2-yne (according to Biel and DiPUrro A® · Soc · 1958, 80, 4609 method) (0.545g) of dried 氡 furan (15ml) solution at -78t! With n-butyl chain in hexane solution ί 2 * 5M, 2.2 »1), the mixture was stirred at -78C 30 minutes and then warmed to room temperature for a period of 1 hour. The mixture was then treated with cyclohexane (0.69 g) in a solution of airfuran (lrnl) to cool the temperature to a spoon again. Then warm to room temperature for another 2 hours, so that ethyl acetate and water are removed. The water calendar was extracted with ethyl acetate, and the organic phase was washed sequentially with water and brine, and then dried over anhydrous sodium sulfate. The crude product was obtained after the solvent was removed in vacuo. Then use column chromatography M silica (using a methanol solution of 5¾ methylene chloride as the eluent) to obtain a white solid product. MS (+ ES), ιπ / ζ: 208 (Μ + Η) +. The example was printed by the Ministry of Standards of the Ministry of Defence, printed by τ Consumer Cooperative (please read the precautions on the back before filling out this page) 1-(卜 锊-琐 R 甚) Ί (畦 畦 -1-基) -propylene For a period of about 2 minutes, a small amount of 3-chloroperoxybenzoic acid (.285 g) was added to pyridin-1-yl) -prop-1-ynylcyclohexanase (0.31 g) in dichloromethane ( 6®1) in ice-cold solution. The reaction was stirred at 0 * 0 for 5 minutes. The resulting mixture was passed through 20 equivalents of basic aluminum oxide (Brock »ann Grade I, 150 mesh), and then diluted with 5 × dichloromethane in formic acid. After mixing all the parts containing the desired amine N-oxide, vacuum steam one 50 ~ This paper size is applicable to Chinese national standard ((, NS) Λ4 size (210X297 mm) A7

It has been cleared by the staff of the Bureau of Standards and Decisions of the Ministry of Standards that it was printed by Hezhusha. V. Invention Description (49) The degree of love is close to solidness. The resulting residue was dissolved in methanol (20 ml) for 7 hours, and then the solvent was removed in vacuo. The obtained residue was purified by silica gel (M503: acetic acid hexane solution as eluent) to obtain the desired amber solid product. MS (+ ES), 224 (M + H) +. Example 32: Oxygen-oxygenation: 4.51 dec-2-an-4--4-1- (1-hydroxy-cyclohexylbu 3- (pyrrolidin-1-yl) -propenone (0.11 g) After the formic acid Hml) solution was treated with p-toluenesulfonic acid (0.015g), the resulting mixture was stirred under a chamber for about 15 hours. Then the solution was diluted with ether, and then water, 5SJ hydrochloric acid aqueous solution, and sodium bicarbonate saturated aqueous solution were sequentially added. Wash with bright water, then dry with anhydrous magnesium sulfate. After removing the solvent in vacuum, the obtained residue was purified by silica gel (M15SK ethyl acetate in hexane solution as the eluent) to obtain the desired colorless oily product. 0 MS (CI), ro / z: 153 (M + H ”. G_ Example 3 3 1--1) -But-3-neodymium acetate 1-methyl-prop-2-ynyl ester (According to Clark and Pinder, J. Che ·· Soc · 1 958, 1 967 method) (7gm «t-pyridine (10.4 twist 1) of anhydrous tetrahydrofuran Π 25ιβ1) solution was treated with rhenium (I) chloride (0.3g) reflux Heat for 5 hours. It was then stirred at room temperature for about 15 hours, then the mixture was diluted with ether, and then taken three times with a 2N aqueous hydrochloric acid solution. These mixed organic extracts were washed with water and brine, and then dried over anhydrous magnesium sulfate. After removing the solvent in a vacuum, -51- This paper size is applicable to the Chinese national standard ((, NS) Λ4 size (210X 297 mm) (that is, read the precautions on the back before filling this page).

1T 91.513394 "A7 B7 V. Description of the invention ($) The residual distillation obtained will give the desired product as a colorless oil. Boiling point: 3 5 ° C (l.lrnroHg, MS (+ ES), ra / z: 124 (M + H) +. (Please read the precautions on the back before filling this page). Example 3 4. 2-Benzene -A solution of a solution of 1-yl) hex-3-; alkyn-2-yl-2- (pyrrolidin-1-yl) -but-3-yn (0.123g) in dry tetrahydrofuran (20ml) at -78 ° Treat with n-butyllithium in hexane solution (2.5M, 4.4ml) at C, stir the mixture at -78 ° C for 30 minutes, and then warm to room temperature over 1 hour. The mixture was then treated with tetrahydrofuran (lro) solution of acetophenone (1.2 g) to cool the temperature to -78 ° C again. Then warm to room temperature for another 2 hours, so that ethyl acetate and water are removed. The aqueous layer was extracted with ethyl acetate, and the organic phases were mixed, washed sequentially with water and brine, and then dried over anhydrous sodium sulfate. The crude product was obtained after removing the solvent in vacuo. Then use column chromatography with ‘silicone (using 5-10% dichloromethane in methanol as the eluent) to obtain an oily product that will solidify after standing. MS (+ ES), ni / z: 244 (M + H) +. Example 3 5 4 · Hydroxy-4 -fluorene-1-(pyrrolidine-1 -yl) -pentan-1-ene-3 -one _ Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs in about 2 minutes A small amount of 3-chloroperoxybenzoic acid (0.38 g) was added to 2-chloro-5- (pyrrolidin-1-yl) -hex-3-yn-2-ol (0.49 g) in dichloromethane (5 ml). In ice-cold solution. The reaction was stirred at 0 ° C for 5 minutes. The resulting mixture was passed through 20 equivalents of basic aluminum oxide (Brockraann Grade I, 150 mesh), and then diluted with 5% dichloromethane in methanol. All the parts containing the desired amine N_oxide were mixed and evaporated in vacuo to a level close to dryness. The remaining residue was dissolved in methanol (20rnl) -52- This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) 513394 A7 B7 DESCRIPTION OF THE INVENTION (51) 1 1 Heated under reflux for 13 hours, and then cooled and then removed the solvent under vacuum. The resulting residue 1 1 contains 4-hydroxy-4-benzene-1-(Iftpyridin-1 -yl) -pent-1 -ene-3 -one and 2, 1 1 5- __methyl-2 -benzene-furan -3-_, no need to go further--one step purification can be used in the next step 1 in 1 step (Example 36) 〇Read 1 Fen _ Example 36 on the back 1 I 2,5 -dimethyl-2--2-dioxin · Yi 1 1 will be 4-hydroxy-4 4-benzene-1-(_ pyrridine-1-yl) -penta matters 1 I-1-ene-3-_ and 2, 5- The dimethyl-2-benzene-furan-3 -one mixture was dissolved in this methanol (20 1), and then the mixture was stirred for 4 hours in the presence of Amber 1 y st ^ (0.5 g). The mixture was then filtered, and the solvent was removed under vacuum. The residue obtained was chromatographed on a silica gel (using 20¾ ethyl acetate in hexane solution 1 1 as the eluent). The desired oily product was obtained by chromatography. After the identification, it was prepared according to the method of Fel man 9 J i Γ k 〇vsky »He moli 1 Bo re 11 a, We 1 Is, Russel 1, and Ward J. Med ♦ Che» • 1 I 1992 &gt; 35 Confirmation for comparison 〇 1 1 Fen 豳 Example 37 1 2-(3-Dimethyl sucrose-prop-1-ynehua) -benzene 1 9k I in o-bromobenzene (10 · 0g) triethylamine ( To a 120m η deoxygenated solution was added 1 1 1 dimethylamino-2-propyne (2.82 g), bis (triphenylphosphine) palladium chloride 1 (I) (400 rag), and iodination Cuprous (54 in g) &lt; &gt; The mixture was stirred under nitrogen atmosphere I and room temperature for about 6 hours, and then briefly heated (about 10 minutes) to 1 1 601. The resulting reaction mixture was cooled first, and then diatomaceous earth was used. After 1 m The obtained residue was dissolved in ethyl acetate, and then washed with 1 I of water and saturated brine in order, and then dried over anhydrous magnesium sulfate. 〇1 1 I-5 3-1 1 1 1 Marker ((, NS) Λ4 specifications (2 丨 0X297 mm) 513394

The solvent was removed by vacuum evaporation, and the obtained residue was purified by chromatography M silica gel (using hexane solution of 50 ¾ ethyl acetate as eluent) to obtain the purified product i. Tube pus example 3 8 2-(Bu (3-Dishen very preventive-prop-2-ene-1- 腼))-clavol Add a small amount of 3-chloroperoxybenzoic acid (2.34g) to 2- (3 -Dimethylamino-prop-1-ynyl) -phenol (4.0 g) in dichloromethane (30 ml) in an ice-cold solution. The reaction was stirred at 0C for 20 minutes, and the resulting mixture was passed through 20 equivalents of experimental oxygen (Brockmann Gradel, 150 hoof mesh), and then diluted with 5¾ of dichloromethane in methanol. After mixing all the parts containing the desired amine N-oxide, it was evaporated under vacuum to a level close to dryness. Methanol was added to adjust the solution volume to 250 m 1. Immediately, the methanol solution of N-oxide was heated under reflux for 15 hours, and then cooled to obtain 2-(1- (3-dimethylamino-prop-2-en-1-one))-phenol and A mixture of chromone (1,4-benzylpiperazine) was used in the next step (Example 39) without further purification. Example 3 9 色 _ 戒 1.4. Cage and piperidone ^ 渋 部 屮 定 ^^-局 局 ^. 消 介 合 竹 社 印 5 ^ (¾Read the precautions before filling this page) The mixture of 2-Π- (3-dimethylamino-prop-2-ene-1- 嗣))-phenol and chromone obtained in Example 38 was dissolved in methanol (20 ml), and then Search the mixture for 4 hours in the presence of mber 1 yst ® (1 g). The solvent was then removed under vacuum, and the resulting residue was purified by silica gel chromatography (using 25¾ ethyl acetate in hexane as the eluent) to obtain the desired chromone product. Mon 5 4-Wooden and paper scales described in the Ten Kingdoms of Sichuan. ((, Milk) 8 4 platform (210/297 mm)

Claims (2)

513394 A8 B8 C8 D8 6. Scope of patent application 1. A method for preparing enaminones as shown in chemical formula (I) (I) where: X is selected from the group of lower glutamate: r2 r3, Cl -C 6 straight chain alkyl group, 3-Ce branched alkyl, C3-C? Cycloalkyl, -CH2-phenyl, or CH2-substituted phenyl; (Please read the notes on the back before filling this page) 1 From the following groups Selected:, Ci-C6 straight alkyl, C3-C6 branched alkyl, C3-C7 cycloalkyl, phenyl, substituted phenyl, -CH2-phenyl, or -CH2 -Substituted phenyl, or a group as shown below: Or R12-r12 · OH, printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs and replaced by t R2 and R3 are independent and selected from the following groups: Ci-Ce linear alkyl, C3-C6 branched alkyl, C3 -C7 cycloalkyl, or -CH 2 -phenyl; or R 2 and R 3 combine with each other to form a ring containing 3-6 carbon atoms | [? 4 and | ^ are independent of each other, and are from the lower group Selected: Η, 55- This paper size applies to Chinese National Standard (CNS) Α4 specification (210 × 297 mm 513394 A8 B8 C8 D8 6. Application scope of patent Ci-Ce straight-chain burned base, Cs-C6 branched-chain burned base , C3-C7 cycloalkyl, ~ 〇Rn »~ HRn R13, -NR 11 C (0) 0Ri〇, ~ * NRn C (0) Ri〇, -0C (0) Rlo, -0C (0) 0Rlo, Or -0C (0) NHRi〇; substituted phenyl and -CH 2 -substituted phenyl, respectively as follows: and Printed by Department 1 of the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs is selected from the following groups: Η, halogen, trifluoromethyl, C 2 -C 6 perfluoroalkyl, C i -C 6 linear alkyl, (: /-(: 6 branched alkyl, C3-C7 cycloalkyl, -CN, -N02, -0R 11, -C0 2 R 11 »-NR 11 R 13, ~ NRn C (0) 0Rn, -HRu C (0) Ru, -0C (0) Ru, -0C (0) 0Ru, or -0C (0) NHR 11; Rio is selected from the lower group: Η, C i -C 6 linear alkyl group, C 3 -C e branched fluorenyl, C 3 -C 7 cycloalkyl, phenyl, or -CH 2 -phenyl; Ru and RW are each independent, and are selected from the lower group: 逑, Ci- Cs straight-chain alkyl, C3-C6 branched alkyl, C3-C7 cycloalkyl, phenyl, or -CH2-phenyl; R and R / are independent of each other, and are selected from the lower group: Η, (: 1-(: 6 straight-chain alkyl group, (: 3-(: 6-branched alkyl group, (: 3-〇7 cycloalkyl group, phenyl group, substituted phenyl group, -CH 2 -phenyl group or -CH 2-Substituted benzyl, C3-C7 cycloalkyl can be selected from Rs-independently substituted by 1-3 groups; or with R / optionally using its common carbon junction-56----- ^ --- 1 -pack-(Please read the notes on the back before filling this page) • Breaking_ This paper size is in accordance with Chinese National Standard (CNS) A4 (210X 297 mm 513394 A8 B8 C8 D8) 6. The scope of the patent application is combined to form a carbon ring containing 3-7 carbon atoms; the provisions are as follows R12 and R / must not be phenyl or substituted phenyl at the same time; Rl2 'R12 OH R is an amine protecting group used to protect the NR u part; or NRuR13 parts are cyclically linked together, or M is as shown below Cyclopentimine forms exist: (Please read the notes on the back ¾ before filling in:: Write this page) Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. This method involves the reaction of treating the amine N-oxide as shown in Chemical Formula U) with a hydroxyl solvent and converting it to enaminone. 0 X Rl = (R -V / R2 r3 (II) The method according to item 1 of the scope of patent application, in which R 13 is an amine-protecting group selected from the lower group: (a) Alkyl-type protecting groups, such as methylamidino, ethylamido, and chloroacetamido Group, dichloroethenyl, trichloroethenyl, trifluoroethenyl, phenylethenyl, o-nitrophenoxyethenyl, second butylfluorenyl, trimethylethenyl (i.e. third Butyl), cypromidine, benzamidine, o-n-phenylene 57- This paper size applies to Chinese National Standard (CNS) A4 specifications (210X 297 mm 513394 A8 B8 C8 D8) Of-cyclobutylfluorenyl, etc. or (b) sulfonyl-type protecting groups, such as benzenesulfonyl, tosylsulfonyl, p-methoxybenzenesulfonyl, trifluoromethylsulfonyl, etc .; or (C &gt; sulfenyl type protecting groups, such as benzenesulfinyl, o-nifelensulfinate, pentafluorobenzenesulfinyl, etc., or (d) carbamoyl Ethyl acetate type protecting groups, such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzene Methyloxycarbonyl, third butyloxycarbonyl, third pentyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxymine, allyloxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl , Cyclohexyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2-trimethylsilylethoxy, and the like; (e) Aralkyl-type protecting groups such as benzyl, p-methoxybenzyl , P-nitrobenzyl, p-bromobenzyl, third butyloxycarbonyl, third pentyloxycarbonyl, diisopropylmethoxycarbonyl, or triphenylmethyl. 3. If the scope of patent application is the first Item method, wherein -NR 2 R 3 are combined with each other to form a ring selected from the group: _NC] -N ^ &gt; —- ^ or ~~ 1 ^ / ~ '? 〇4. If the scope of patent application The method according to item 1, wherein the hydroxy solvent is a solvent or a mixture of solvents selected from the group consisting of water, C i -C 8 linear or branched alkyl group, adipic acid, polyethylene glycol, 1 , 2-C Glycol, polypropylene glycol, glycerol, 2-methoxyacetic acid enzyme, 2-ethoxyacetic acid enzyme, 2,2,2-trifluoroethanol, benzyl alcohol or phenol. The paper size applies to Chinese National Standard (CNS) A4 size (210X 297mm) (Please read the notes on the back, and then fill in the items:: Write this page) Printed by the Employees 'Cooperatives of the Central Standards Bureau of the Ministry of Economics 513394 Printed by the Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economics A8 B8 C8 D8 VI. Application scope of patent 5. The method of the first scope of application for patent, wherein the enamine is (! -Octylaminocarboxylic acid-1- [4-(dimethylamino) -2-oxo-3 -Butenyl]-2-oxo + pyrrolidine_ 〇6. The method according to item 1 of the patent application, wherein the enamine_ is (R) -1-[4-(dimethylamino) -2- Oxy-3-butenyl] -3_hydroxy-2-pyrrolidinium. 7. As described in the method of the first item of the patent scope, wherein the enaminone is 1- [4-Π-pyrrole_yl) -2-oxo-3-butenyl] -pyridine surface. 8. The method according to item 1 of the application, wherein the enamine hydrazone is 3-dimethylamino-1-phenyl-2-propene-1-fluorene. 9. The method of claim 1 in the patent application, wherein the enamine fluorene is 1-dimethylamino-1-pentene-3-fluorene. 10. The method according to item 1 of the scope of patent application, wherein the enamine is 2-chloro-4- (3-dimethylamino-propyne, 1-yl) benzoic acid, methyl ester. 11. The method of claim 1 in the scope of patent application, wherein the enaminone is [3-chloro-4- (3-dimethylamino-prop-1-ynyl) -phenyl] -aminocarboxylic acid Butyl ester. 12. The method according to item 1 of the scope of patent application, wherein the enamine is 4-hydroxy-1,4-methyl-1 -succinyl-1-yl) -pentan-1-an-3-one. 13. The method of claim 1 in the patent application, wherein the enaminone is 1- (1-hydroxy-cyclohexyl) -3- (Bftpyridin-1-yl) -propenefluorene. 14. The method according to item 1 of the patent application, wherein the enamine_ is 4-hydroxy-4-4-pyrrolidin-1-yl) -pentene-3-fluorene. 15. The method according to item 1 of the scope of patent application, wherein the enamine hydrazone is 2- (1- -3-dimethylamino-prop-2-ene_1--phenol. -59-(Please read the back first Notes-JW ▼ Refilling and loading of items-: Write this page), 1T This paper size is applicable to China National Standard (CNS) A4 specifications (210 mm 297 mm) 513394 A8 B8 C8 D8 Patent scope 16.- A method for preparing an enamine hydrazone as shown in the chemical formula (I): Ο RiAH N &quot; I R3 (I), where R ί is selected from the lower group: C i _C e linear alkyl group, C 3 -C 6 branch Alkyl, C3-C7 cycloalkyl, benzyl, -CH2-phenyl, or the following: or ----.-- L0 ^ ------ 1T ------ 0 (Please read the notes on the back before filling out this page) Printed by R2 and Rs for the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Independent and selected from the following groups: Ci-Ce linear alkyl, C3-C6 branched alkyl, C3-C7 cycloalkyl, or -CH2-phenyl; or combined with each other to form a group containing 3- A ring of 6 carbon atoms; R 5, R 6, R 8, and R 9 are each independently selected from the group consisting of: Η, halogen, trifluoromethyl, (: 2-(: 6perfluoroalkyl) , (^-(^ Straight chain alkyl, Csi-Cs branched alkyl, C3-C7 cyclofluorenyl, -CN, ~ N0 2, -OR 11, -CO 2 R 11, -NR 11 R 13,- NR u C (0) 0R 11, one 60- This paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) 513394 A8 B8 C8 D8 Patent Application Range -NRu C (0) Ru, -0C ( 0) Ru, -OCfOmu, or -0C (0) NHRn; R u and R are independent of each other, and are selected from the lower group: Η, Ci-Ce linear alkyl, C3-C6 branched alkyl, C3- C7 cycloalkyl, phenyl, or -CH 2 -phenyl; R 13 is an amine protecting group used to temporarily protect the NR u moiety. This method involves the use of a hydroxyl solvent. The reaction is based on the amine N-oxide represented by the chemical formula (H), which converts it into enamine_P Ri-=-Ό N / bolt 2, r3 (II) WH ·· ΝΙΜΙΜ I «^ 1 (Please read first Note on the back, please fill out this page again) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 17. If the method of applying for the scope of the patent No. 16 is applied, -NR2R3 is combined with each other to form a ring selected from the lower group $- &lt;> or-18, as in the method of claim 16 in which the amine protecting group for temporarily protecting the NR11 part is selected from the following groups: (a) rattan-type protecting group, such as A Fluorenyl, ethenyl, chloroethenyl, dichloroethenyl, trichloroethenyl, trifluoroacetenyl, phenylethynyl, o-nitrophenoxyethenyl, second butylethenyl, triethyl Methylethenyl (also known as tert-butylfluorenyl), cyclopropenyl, benzamidine, o-nitrobenzyl, sigma-cyclobutanyl, etc. t or (b) sulfonyl-type protecting groups, such as Benzylsulfonyl, toluenesulfonyl, p-methoxybenzenesulfonyl, trifluoromethylsulfonyl, etc .; or 61-The size of the paper is subject to the Chinese National Standard (CNS) A 4 specifications (210 X 297 mm) 513394 A8 B8 C8 D8 patent application scope (C) sulfenic acid type protecting group, such as benzenesulfinyl group, o-n-phenylenesulfinyl group, pentachlorobenzenesulfinyl group , Etc., or (d) urethane-type ethoxy groups, such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-formyl Oxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, third butyloxycarbonyl, third pentyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, allyloxycarbonyl, ring Amyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, 9-pentylmethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, and the like. 1 9. A method for preparing enamine _ as shown by chemical formula (I): N〆I R3 r2 (Please read the notes on the back-then fill in,: write this page} Among them are the following: Central Standards of the Ministry of Economic Affairs Printed by Bureau Consumers Cooperative R 2 and R 3 are each independently selected from the group consisting of: ci-C e linear alkyl, (: 3- (: 6 branched alkyl, C3-C7 cycloalkyl, or -CH 2- Phenyl; or R 2 and R 3 are combined with each other to form a ring containing 3-6 carbon atoms; 62-This paper size applies to China National Standard (CNS) A4 specifications (210X 297 mm 513394 A8 B8 C8 D8 The scope of patent applications Rs, R6, Rs, and R9 are each independent, and are selected from the lower group. Η, halogen, trifluoromethyl, C2-C6 perfluoroalkyl, Ci-Cs straight alkyl, Ca- C6 branched alkyl, C3-C7 cycloalkyl, -CN, -NO 2, -OR 11, -CO 2 R 11, -NR n R 13,-HR n C (0) 0 R u • -NRuCiinRurOfMinRm- OCfOmu ,. ~ 0C (0) NH8u; R u is selected from the group: H, C t -C 6 linear alkyl, C 3 -C 6 branched alkyl, C 3 -C 7 cycloalkyl , Phenyl, or -CH 2 -phenyl, · R 13 is an amine protecting group used to protect the NR u moiety, or NR u R 13 is optionally a cyclic fluorene imine as shown in the chemical formula below Types exist: (Please read the notes on the back before filling this page) The method includes the reaction of treating an amine N-oxide as shown in the chemical formula (E) with a hydroxyl solvent and converting it into an enone. Ri3——N Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs / R2 R3 ( II) 20. The method according to item 19 of the scope of patent application, in which -NR2R3 is combined with each other to form a ring selected from the lower group 0-NC]-^ or--63- This paper size applies the Chinese National Standard (CNS ) A4 specification (210 X 297 mm 513394 A8 B8 C8 D8 patent application scope 21. If you apply for protection of NR u part (a) _ group, dichloroethenyl, o-nitrophenyl (also known as the third methyl phenyl group , Α (b) sulfonate, p-methoxybenzene (c) sulfenylsulfinic acid group, (d) aminomethylchlorobenzyloxycarbonyl group, p-methyltributyloxycarbonyl, isopropyloxyrigidyloxycarbonyl Methylsilyl 2 2 —Amine protecting groups such as those described in item 19 of the chemical range are secondary protecting groups, such as methyl, trichloroethenyl, oxyethenyl, and second butanyl ), Cypromidine-cyclobutylamyl, etc., and other protecting groups such as sulfonyl, trifluoromethyl acid-based protecting groups, such as pentasulfenic acid , Ethyl acetate-type protecting group, carbonyl group, p-nitrobenzyloxybenzyloxycarbonyl group, phenyl group, tertiary pentyloxycarbonylcarbonyl group, allyloxycarbonyl group, cyclohexyloxycarbonyl group, ethoxycarbonyl group, etc. The enamine method represented by the formula (I) is used to temporarily select from the following groups: phenyl, ethyl, chloroethyl, trifluoroethyl, phenyl, ethyl, butanyl, and trimethyl Ethyl ethyl, benzyl, o-nitrobenzene or benzenesulfonyl, toluenylsulfonyl, etc., or such as benzenesulfinyl, o-nitrobenzene, etc., or for example benzyl Oxycarbonyl, p-oxycarbonyl, p-bromobenzyloxy-o-n-benzyloxycarbonyl, thiyl, diisopropylmethoxycarbonyl, cyclopentyloxycarbonyl, gold 9-transylmethoxycarbonyl, 2- The three _ method: (Please read the notes on the back-• items and then fill in.: Write this page} Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economics Λ If Ra (I) R2 1 6 4-This paper size applies China National Standard (CNS) A4 specification (210 X 297 mm 513394 A8 B8 C8 D8 ^, patent application scope R i is as follows: R 2 and R 3 are each independently selected from the group consisting of: Ci-C6 straight alkyl, C3-C6 branched alkyl, C3-C7 cycloalkyl, or -CH2-phenyl; or R2 and R3 are combined with each other to form a ring containing 3-6 carbon atoms; R5, R6, R8, and R9 are each independent and selected from the following groups: Η, halogen, trifluoromethyl, C2-C6 perfluoro Alkyl, Ci-Cs linear alkyl, C3-C6 branched alkyl, C3-C7 cycloalkyl, -CH, -Η 0 2 &gt; -OR 11,-C 0 2 R 11 &gt; ~ NR n R 13 &gt; -NRn C (0) 0Ru, -NRuCiOUn, -0C (0) Ru,-0C (0) 0Rii, or -0 C f 0) Η HR ii; R and R〆 are independent of each other, from below Selected from the group: H, Ci-CU straight alkyl group, C3-C8 branched alkyl group, C3-C7 cycloalkyl group, phenyl group, or -CH2-phenyl group; Consumer Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs Printed (please read the precautions on the back before filling this page) R 13 is an amine protecting group used to protect the NR u part; or NR u R 13 is cyclic fluorene imine as shown in the chemical formula below K The type exists: 65- This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 513394 A8 B8 C8 D8 Patent application scope This method also includes treating amine N oxide as shown in chemical formula (E &gt; The reaction to convert it to enamone is 0 * »-| =-Ό N (Π) 23, as in the method of the scope of application for patent No. 22, in which -HR2R3 is combined with each other to form a ring selected from the lower group. -NC] —N ^) &gt; —N ^]-^ or-~ (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 24. If you apply for protection of HR u Department ia ) 醸, dichloroethyl, o-nitro (i.e., methyl group, fb) sulfo, p-methoxy (c) sulfenylsulfenylaminochlorobenzylcarbonyl, p-tributyloxy patent range 22 The method of the item, the amine protecting group is from the lower fluorenyl type protecting group, such as methyl fluorenyl, fluorenyl, trichloroethenyl, trifluorophenoxyethenyl, the second butyl tributenyl), Cyclopropyl group, α-cyclobutylfluorenyl, etc .; or a fluorenyl type protecting group, such as benzylsulfonyl, trifluoromethylsulfonylsulfonyl Protecting groups, such as benzene, pentafluorobenzenesulfinyl, etc. Ethyl formate-type protecting groups, such as oxycarbonyl, p-nitrobenzyloxycarbonylmethoxybenzyloxycarbonyl, o-nitrocarbonyl, third pentyl Oxycarbonyl, which is used to temporarily select from the group: ethynyl, chloroethenylethenyl, phenylethenyl, trimethylethenylbenzyl, o-n-phenylbenzyl, toluene Pickling group, etc., or sulfenyl group, o-n-phenylene, or benzyloxycarbonyl, p-yl, p-benzyloxybenzylcarbonyl, second isopropylmethoxycarbonyl-66 -The size of this paper applies to Chinese National Standard (CNS) A4 (210 X 297 mm) 513394 A8 B8 C8 D8 々 Application scope of patents, isopropyloxycarbonyl, allyloxycarbonyl, cyclopentyloxycarbonyl, diamond Oxycarbonyl, cyclohexyloxycarbonyl, 9-methylmethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, and the like. 25. A method for synthesizing enaminones as shown by chemical formula (I): (I) R3 wherein X is selected from the group consisting of: H, Ci-C6 straight chain alkyl, C3-C6 branched alkyl, 3-(: 7 cycloalkyl, phenyl, or -C Η 2 -phenyl; R 1 is selected from the lower group: H, C ± -C 6 linear alkyl, C3-C6 branched alkyl, C3-C7 cycloalkyl, phenyl, substituted phenyl, -CH2-phenyl, or -CH2- substituted phenyl, or the group shown below: T12 5… ten; OH s Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling out this Page) R 2 and R 3 are independent, and are selected from the following groups: C i -C 6 linear alkyl, C3-C6 branched alkyl, or C3-C7 cycloalkyl, or R2 R3 combines with each other to form a ring containing 3 to 6 carbon atoms; R and R / are independent of each other, and are selected from the lower group Η, Ci -C6 straight alkyl, C3-C6 branched alkyl, C3 -C7 cycloalkyl, phenyl, substituted benzyl, -CH2-phenyl or -CH2-substituted phenyl-67- This paper size applies to Chinese National Standard (CNS) A4 specification (210X29? Mm) 513394 A8 B8 C8 D8 VI. Application scope of patent, Ca-C7 cycloalkyl can be selected independently from Rs-R9 Substitute 1 to 3 radicals; R 12 and RV must not be phenyl or substituted phenyl at the same time; R5_R9 are independent and selected from the following groups: Η, halogen, trifluoromethyl, C2_C6 perfluoro Alkyl, Ci-Ce straight alkyl, {: 3-C6 branched alkyl, C3-C? Cycloalkyl, -CH, -N02, -ORn, -CO 2 Rn, -NR n Rib, -NRn C (O) ORu,-NRuUOVRu, -0C (0) Ru, -OC (0) ORu, or -OC (0) NHR u; The method also includes treating the amine N- as shown in chemical formula i H with a hydroxyl solvent. Oxide, reaction to convert it to enamine_ β X ml I 1.1 &gt; .mil ϋϋ I (please read the notes on the back before filling in this page) Order the R3 (II) printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 26. For the method of applying for the scope of patent No. 25, of which _NR2R3 combined with each other to form a ring selected from the following group 夂 -NC], —N) ——f / ^ or — | / This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm)