TW199161B - Improvements process for chemical reactions on camptothecin or analogs thereof - Google Patents

Abstract

A process for preparing a reduced camptothecin derivative in which a camptothecin substrate bearing a reducible substituent is hydrolyzed under alkaline conditions to open the lactone E ring and form a carboxylate salt. The carboxylate salt is reduced to form a reduced carboxylate salt which is then contacted with acid to reform the lactone E ring. This procedure results in substantially increased yields of camptothecin derivatives.

Description

199161 V. Description of the invention The background of the present invention Taifa tanxichengcheng The present invention is based on an improved procedure for carrying out a reaction on a compound with a tree-like structure. More specifically, the present invention is concerned with a procedure for easily performing a chemical reaction in a water medium while increasing the yield of camptothecin compounds. Back Jin: > On the hi tree is a five-ringed plant age, originally isolated by Wall et al CamDto theca acuminata wood and bark ('Μ. E. Wall, MC Wani, CE Cook, KH Palmer , AT McPhail and GA Sia, J. Am. Chem. Sot! .. 91: 388 (1 966)). The parent camptothecin is highly biologically active and shows strong inhibitory activity against nucleic acid biosynthesis. Camptothecin exhibits strong antitumor activity against experimentally transplanted cancers, such as leukemia L-12 10 in mice or Walker 256 tumors in mice. The potent anti-tumor activity of Camptotheca acuminata has stimulated considerable synthetic interest in the preparation of camptotheca analogs. Methods for preparing camptothecin analogues and various camptothecin analogues have been shown, for example, in U.S. Patent Nos. 4,894,456, 4,604,463, 4,545,880, 4,473,690 and 4,43 1,098 and references discussed in these U.S. patents. Camptotheca acuminata and many of its analogs have very limited solubility not only in water but also in most organic solvents. Therefore, when the five-membered ring is formed, it is difficult to perform the post-winding reaction on the camptothecin molecule. The low solubility of Camptotheca adriaticus and its analogues requires the use of large amounts of solvents. A lot of these are read first, and pay attention to it.% 堡 塡-% The Ministry of Wood Economy Ministry of Economic Affairs Central Standard C3: Industrial Consumers ’Cooperative Cooperative Printing Co., Ltd. Printed on this paper, the paper size is used in a. A B Jiayuban (CNS) T4 specification (210X297 public rescue ) 3 Λ (ί Π 6 99161 Fifth, the description of the invention () First read the contradictions and fill in%. Solvents on this page will cause problems, such as solvent treatment, solvent recovery, solvent cost, and compound loss during processing, resulting in a reduction in product yield Etc. Purification of the product camptothecin or camptothecin analogs and intermediates in the synthesis sequence by crystallization or chromatographic separation will be hindered and costly and / or infeasible due to the need for unusually large amounts of solvent. As mentioned above, there is a need to maintain a presence and seek a novel and improved method for preparing and purifying camptothecin and camptothecin analogues that can eliminate the use of large amounts of solvents in the prior art procedures. An object of the invention is to propose a procedure for preparing camptothecin and camptothecin analogues without the above-mentioned defects of the prior art procedures. A procedure for the preparation of camptothecin and its analogues can be used to produce the product camptothecin compound in high yields without the need for a large amount of expensive solvents. These and other purposes are produced by the KX Industrial and Consumer Cooperation Bureau of the Ministry of Economic Affairs It can be understood from the detailed description of the procedure of the present invention described below, in which the A, B, C or D ring of the camptothecin compound is added with a substituent that can be reduced under the neutral or neutral conditions, and then hydrolyzed The water-soluble substituent-containing carboxylic acid salt is formed. The reducible substituent on the salt is then reduced in a test or neutral medium to form a reduced camptothecin salt. Camptothecin derivatives can be deactivated by column chromatography followed by crystallization. Finally, contact with an acid to form the lactone E ring, thus forming a new, modified camptothecin compound. Note: The sharpness of this paper is based on the use of the 8-sleeper standard (CNS) 4 specifications (210X297: «:) 4 Λ (i Η 6 .. 五 工 ^ 明说 令 一 ^) as the program substrate of the present invention The camptothecin compound has a well-known framework structure of camptotheca age, containing Ring AE and additionally contain at least one substituent (R) that can be reduced under alkaline or neutral conditions on ring A, B, C, or D. The substrate can be the arborescent tree itself, where AD Chen Shang The substituent of is hydrogen atom. In addition, the matrix can also be a camptothecin compound with a non- 氲 substituted * that can be reduced under age or neutral conditions. The structure (formula) shown below and all of the diagram 1 The structure (formula) represents any and all of the camptothecin compound isomers having the structure shown. For example, it represents the possible different configuration of the camptothecin compound E ring at the 20-position to generate the camptothecin compound 20 (S ) And 20 (R) two enantiomers. The scope of the present invention also includes all isomers due to the structure and / or position of the R substituent. (Please read the notes to the back # ^ ¾ wood page)

Line-Printed by the Ministry of Economic Affairs, Central Federation of Employee Consumer Cooperatives 32. The term "reduction" is used in its broad chemical sense, meaning any reaction in which electrons are transferred from the reducing agent to the substrate. A substituent that can be reduced is one in which electrons can be transferred from the reducing agent or from other parts of the camptothecin skeleton structure to the substituent. The substituents (R) that can be reduced include nitro, cyano, nitro, alkenyl, alkynyl, formaldehyde, halogen, Ul, Br, I, Π, nitroso, etc. More suitable are alkenyl, alkynyl and aldehyde groups having 2 to 10 nitrile atoms. The above example is only for illustration. It must be understood that it can be used in the neutral or sample paper size. Η Η 家 榣 准 (CN5) > M specifications (210X297 public; Ϊ) 5 199161 Λ (i Π 6 Printed by the Employee Consumers ’Cooperative of the Central Bureau of Economic Affairs of the Ministry of Economic Affairs ^ V. Description of the invention () Any substituents that can be reduced by known reduction methods under the conditions of the invention can be the substituents on the substrate of the camphor tree of the invention program Of course, there can be more than one substituent (R) on the substrate of Hibiscus falcon. The number of substituents is more suitably one, but it can also be two, three or more bows, depending on the desire Availability of tree-age substrates. Camptothecin substrates may also contain other substituents that do not react during the reduction step. Examples of such non-reactive substituents include alkyl groups, hydroxyalkyl groups, alkylamino groups, and amine groups. Amino dialkyls, alkyl ethers, etc. A more suitable non-reactive group is one with up to 10 sulfonic atoms, and a more suitable one has 6 more sulfon atoms. A particularly suitable non-reactive group is methine digas Group (-0CH20-) and hypoethyldioxy (-0CHaCH20-), both occupying the camphor tree substrate The typical positions are two positions on the A-ring of camptothecin. In the case of methine dioxy or ethylidene dioxy, the reducible substituent R may exist in the camptothecin skeleton Above one or more positions of the remaining available substitution positions in the structure. For example, a typical substrate includes 9-amino-10, 11-methine diamino-yl camptothecin, 12-nitro-10, 11 -Methylenediaminoyl camptothecin, 7-Lu alkyl-9-nitro-10, 11-methylenedioxycamptothecin and the corresponding 1〇, 11-ethylidene diamino Camptothecin and other compounds. The 9-nitro and 12-nitro derivatives of methine diamino-camptothecin and hypoethyldioxycamptothecin can be used nitric acid / sulfuric acid in the traditional nitrification method It is prepared by nitration of chlorocamptothecin or hypoethyldioxycamptothecin. In the procedure of the present invention, the camptothecin containing substituents is first hydrolyzed under alkaline conditions to obtain Echen which is hydrolyzed to the corresponding Carboxylate and hydroxyl-containing carboxylates with substituents. The more appropriate hydrolysis reaction is to use appropriate hydrogen in aqueous solution (please read the back and forth precautions #filling the wooden shingle, this paper 5fc scale for use Zhongming Η family tree standard (CNS) T4 specification (210 father 297 male dragon) 6 199161 Λ (ί η 6 V. Description of the invention) Oxygen SI. The more suitable argon gas compound is gold tungsten hydrogen compound, of which The gold halide ions are those with 1-3 valences, and more suitable are hydroxides of metal and clay, such as sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydrochloride, magnesium hydroxide, etc. However, tfc can use trivalent metal hydroxide. Hydrogenated ammonium and organic hydroxides, for example, tetraalkylammonium hydroxide (H is NR4, where R is alkyl or H) is also suitable for the hydrolysis reaction The hydrolysis reaction is shown as "Reaction 1" in Scheme 1 below, where H is a metal ion or an ammonium ion. In Scheme 1, it should be understood that the reducing substituent R is on any one of the rings A-D, once it is on any available position of each ring. For example, a substituent on the A ring may appear at any one of positions 9, 10, 11, or 12. The substituent on the ring B is usually at the 7-position. The hydroxide is usually used in a stoichiometric ratio equal to the camptothecin matrix. However, a slightly higher or lower base usage than the stoichiometric tb case is obviously also effective in the hydrolysis reaction. .1 Read back attention items m% of the installed line

Ministry of Economic Affairs, Central Bureau of Standardization, Employee Consumers, #Cooperatives, Printed M, The paper standard is used in the middle of the paper (CNS) specifications (2) (ϊχ297 male dragon) 7 199161 A 6 η 6 V. Description of invention () Reaction 1

reduction

Printed by the Central Bureau of Economic Affairs of the Ministry of Economic Affairs, Mgongxiao Cooperative Society

The size of this paper is easy to use 8 8 楳 quasi 听 吣) 〒 4 specifications (2 father 0 father 297 ;;;) 8

5. Description of the invention () Then, the carboxylic acid salt having a reducible substituent is reduced to form a reduced carboxylic acid salt. The proton reaction must be carried out under neutral or basic (p Η > 7 · 〇) chopsticks so that the lactone that has been hydrolyzed will no longer form the lactone E ring. The reduction reaction can be carried out in a medium such as a neutral or aged water bar medium, or an organic solvent which does not interfere with the reduction reaction and the carboxylate can be substantially dissolved therein. Convenient organic solvents are protic solvents, such as C, -4 lower alcohols, mainly methanol, ethanol, propanol and butanol. Aprotic organic solvents, such as dimethylmethineamine (DMF) can also be used. The Ministry of Economic Affairs, Bureau of Standards, A Industrial Consumer Affairs Cooperative, printed 3i. The reduction reactions that can be carried out include hydrogenation, using 1 as the hydrogen source, for example, reducing nitro to amine, reducing fine to alkane, and reducing cyano to amine. The methyl group, reducing the halogen to hydrogen, etc., can be carried out in an alcohol solvent with an appropriate hydrogenation catalyst. Various hydrogenation catalysts for catalytic hydrogenation reactions are well-known and can be used in the reduction reaction of the present invention (see Η. 0. House, Modern Synthetic Reactions (modern synthesis reaction), 2nd ed., WA Benjamin, Inc., Menlo Park, (A, 1972)., Examples of which include bracelet metals, such as Pt, Pd, Ni, etc., can be suitably coated on supports such as charcoal, etc. Typically, the carboxylate is dissolved in absolute Hydrogenation in alcohol and under the action of a hydrogenation catalyst until the hydrogenation reaction (reduction reaction) is substantially complete. The reduction reaction can also be performed in an aqueous or alcohol / water medium. For example, nitrocamptothecin, such as 3-nitro Camptothecin can be successfully reduced to the corresponding aminocarboxylate in Fe / S04-NH * 0H in ethanol / water solvent (see I. Smith and JW Cpie, Org. Synth. Collect Vol. 3, ed . EC Horning, John Wiley and Sons, New York 9 This paper is used in the marginal standard a Η 家 橒 准 (CNS) regulation ί210210297 *) Λ ft η () 99l6i V. Description of the invention (, NY, 1955, p. 56 ) 〇Contrary precautions should be filled with% wood rw. Both traditional and traditional reduction reactions carried out in neutral or neutral media can be used as the reduction reaction of the present invention. Suitable reduction reactions include not only the above-mentioned Raization (Ha) and FeS04-NH40H methods, but also electrochemical reduction. Reaction, and the use of traps or hexene as a hydrogen source to cooperate with metal catalysts, such as Pd or Pt reduction reaction. The reduced carboxylic acid salt can be separated by traditional crystallization method or chromatographic separation method. Then the separation The reduced carboxylate is contacted with an acid, which is typically contacted with a water stripe acid solution to form the lactone Echen, which is a camptothecin compound, as shown in Figure 1. In addition, it may also contain a reduced carboxylate The acid is added directly to the reaction medium to acidify it to form the E ring. The reduced camptothecin compound with the E ring of the lactone is substantially less soluble in water than its carboxylate and can be filtered with simple and / or traditional Organic solvents, such as chloroform, methane, toluene, etc., can be easily separated by extraction. The central bureau of the Ministry of Economic Affairs, Mgong Consumer, cooperated to produce the acidification step. This acidification step can be performed with mineral or organic acids Suitable mineral acids include hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, etc. Suitable organic acids include acetic acid, p-toluenesulfonic acid, trifluoroacetic acid, oxalic acid, tartaric acid, etc. The acid is usually a dilute solution, which is more appropriate, 0.1-1.0 Molar / liter concentration, added, but the acid concentration is not a critical factor. The process of the present invention can be converted into water-soluble carboxylates by camptotheca cucurbita, the carboxylates are reduced and then lactonized. The formation of camptothecin age skeleton structure and other procedures enables high-yield reduction reactions on camptothecin and camptothecin analogs. The method of the present invention can lead to increased yields of camptothecin analogs and increased flexibility of the synthesis steps. The size of this paper is easy to use a Η 家 榣 毕 (CNS) Τ4 specifications (210X297 public; it) Λ () Η 6 199161 V. Description of invention () (please read the back-end considerations' item # code write a copy first The inventive program can be used to synthesize derivatives such as 20 (RS) -camptotheca 20 (S) _camptothecin or 2C (R) -camptotheca or mixtures of (R) and (S) enantiomers. When the mixture of enantiomers is reacted, the formation of carboxylate, the reduction reaction and the reformation of lactone ring can be carried out on the mixture. The resulting reduced (R) compound and (S) compound The mixture can be conveniently separated into other enantiomers using known separation procedures. For example, 20 (RS) -camptothecin derivatives can be passed through an appropriate optically active amine, for example, R- (+ ) -a-methylbenzylamine or S-(-)-a-methylbenzylamine, etc. are reacted according to the method shown in US Patent Application Serial No. 07 / 511,953 to form the corresponding diastereomeric aldamine It is removed from the category; here, the patent application is listed as a reference of the present invention. After separating the diastereoisomeric aldol, the aldol can be treated with acid A complete camptotheca pound ring structure is formed. Other features of the present invention can be more clearly understood through the description of the following examples, but these examples are for the purpose of explaining the present invention and are not intended to limit the present invention. In the following examples In the past, some practical examples were written in the past tense, and the presumably implementable examples were written in the present tense. Fen Lian Fen The Ministry of Economic Affairs, Central Bureau of Industry and Commerce A Co-operative Cooperative Society printed audio examples. 1——10-Amino-20 (RS) -Panthrene base FftSn, -ΝΗ, ΠΗ method mm 10-Nitro-20 (RS) -camptothecin (200 mg, 0.5 mg molecule) in 90% The suspension in MeOH (50 mK) and 0.1 N HaOH (5 mL) was heated under nitrogen at 50-60 ° C for one hour. Then, most of the MeOH was evaporated under reduced pressure, and the resulting brown solid was redissolved in Water (10ml) medium and small paper size 8 B home standard (CN5) TM specification (210x297 g)

V. Description of Invention ηη

A (i Η G Printed by the Central Ministry of Economic Affairs, A Gong Xiaoyao Cooperative and filtered with a G. 45 micron filter membrane to remove any insoluble materials. The water is removed under reduced pressure to obtain 10-nitro-2Q (RS)- Camptothecin sodium salt (213¾ g, yield 97%). Dissolve 10-nitro-20 (RS) -camptothecin sodium salt (200¾ g, (1.46¾ mol) in hot 50% ethanol aqueous solution ( 20 ml), then add to FeSCK · 7H2〇 (2.0 g, 7'2 mg) / boiling water (20 ml) solution. Slowly add camphor hydroxide (3 ml) to the boiling solution. The reaction mixture was filtered with Cel ite (diatomite trade name) pad while hot and washed with hot water (10 ml). After neutralizing the yellow fluorescent filtrate with dilute HC1, it was placed on a steam bath and heated for 15 minutes. The filtrate was cooled, and then extracted with CHC13 (5X100 mL). The gaseous extract was dehydrated (Na2S〇4) and evaporated under reduced pressure to obtain pure 10-amino-20 (RS) -camptothecin (184 mg, 100%) The spectral properties of this sample are the same as those of the standard sample. 10-Amino-20 < RS) -Lonely Tree Age. Prepared by the examples A mixture of 1Q-nitro-20 (RS) -camptothecin sodium salt (11.0 mg, 0.0 25 mg molecule) and 10% Pd / C (6.0 mg) in anhydrous EtOH (10 ml) was treated with 1 atm Ha 1 After that, the catalyst was removed by filtration with celite. The filter cake was washed thoroughly with anhydrous EtOH (50 mL) to obtain the remaining adsorbed product. After the filtrate was acidified with dilute HC1, it was warmed on a water bath for 1G minutes before reuse CHC13 extraction (5 × 25 mL). Then, the dehydrated (Na 2 SO 4) chloroform extract was evaporated under reduced pressure to obtain 10-amino-20 (RS) -camptothecin (7.0 mg, 76%). (讣 洗 读 1> || Backward note tragic Bian Xiangwai Sai writing π) installed. This paper is used in the standard scale of a Η family sample standard (CNS) ΤΊ specification (210x297 male dragon) 12 V. issued " / ] Description () The spectral properties are the same as those of the standard sample. J〇ttJ2UL · ——Amine even-camptothecin. Using Fαη, -ΝΗ, ΠΗ method. Preparation of 9_nitro-20 (RS)-喜The suspension of the tree age (2 0 0¾ g, 0.5 mg molecule) in 90% MeOH (50 ml) and 0.1 N NaOH (5 ml) was heated under nitrogen at 50-60 ° C for one hour. After that, Most The MeOH was distilled off under reduced pressure, and the resulting brown solid was redissolved in water (10 mL) and filtered through a 0.45 micron filter membrane to remove any insoluble materials. Then, the solvent was removed under reduced pressure to obtain 9-nitro-2Q ( RS) -Kizuki Ling Sodium Salt (215 mg, 98%) 0 Ministry of Economic Affairs, Yanyang 51 quasi-employee consumer cooperatives printed? 4 Dissolve 9-nitro-20 (RS) -camptothecin sodium salt (213 mg, 0.51 mg molecule) in hot 5G% ethanol aqueous solution (2Q ml) and add to FeS (K • 7H2 0 (2.0 g, 7.2 mg) / boiling water (20 mL) solution. Slowly add ammonium hydroxide (3 mL) to the boiling solution. The reaction mixture was then filtered with a celite filter pad while hot and washed with hot water (1Q mL) The filtrate was acidified with dilute HC1 and placed on a steam bath for 15 minutes. Next, the yellow precipitate was filtered off and dried (137 mg). The filtrate was extracted with CHC13 (5X50 mL). The dehydrated (NaaS04) radon was used The extract is evaporated under reduced pressure to obtain pure 9-amino-2Q (RS) -Camellia. The combined pure product weighs 146.0 mg (81%). The spectral properties of this sample are the same as those of the standard sample. G 旃Example 4-9-Amino-?. 0 (RD-lone pavilion. Use reminder. Kulu method description

The 9-nitro-20 (RS) -camptothecin sodium salt (20.0 mg, 0.4 S mg molecule) obtained in Example 3 and 10% Pd / C (1G.0 mg) on anhydrous EtOH paper scale While using CNS τ4 specifications (21〇x297 male dragon) 丨 in η 6 (5 ml) mixture received 1 atn. Ha treatment for 18 hours. After the water, use celite to filter out the catalyst. Wash the filter thoroughly with No'ItOH (50 mL) to obtain other adsorbed products. After the filtrate was acidified with dilute HC1, it was placed on a water bath and warmed for 10 minutes. The 9-nitro-2 0 (RS) -camptothecae precipitate (6.2 mg) was filtered out. The filtrate was extracted with CHC13 (5 × 20 ml). The dehydrated (HasS () «) acetone extract was evaporated under reduced pressure to obtain an additional amount of 9-amino-20 (1? 3) -camptotheca age (3.6 mg). The total yield of this product was 9.8 mg (58 %). The spectral properties of this sample are the same as those of the standard sample

Examining Example FS Using procedures similar to those described in Examples 1 and 2, 11-nitro-20 (RS)-, 9-nitro-20 (R)-, 9-nitro-20 (S)- , 10-nitro-20 (R)-, 10-nitro-20 (S)-, 11-nitro-20 (R)-, and 11-nitro-2 0 (S)- The alkali compound is reduced to the corresponding 11-amino-20 (RS)-, 9-amino-20 (R)-, 9-amino-20 (S)-, 10-amino by FeSChHOH method or catalytic reduction method Camptothecin derivatives such as -20 (R)-, 10-amino-20 (S)-, 11-nitro-20 (R) and 11-amino-20 (S)-. Example β β3i printed by the Cooperative Society of the Ministry of Economic Affairs, 揮 阳 楳 Bureau of Economic Affairs (please read the precautions before filling in the wooden page) Similar to the procedure of Example 1, the 9-nitro-10,11-times Methyldioxy-20 (S) -camptothecin suspension in NaOH-containing methanol is heated to obtain 9-nitro-10,11-methinediamino-20 (S) -camptothecin Sodium salt. Then dissolve the sodium salt in a hot 50% ethanol aqueous solution and add it to FeSO〆 7Ha 0 / boiling aqueous solution. Ammonium oxynitride was added to the boiling solution in the manner described in Example 1. After filtration, it is acidified by the same method as described in Example 1 in this paper. The paper is used in a standard (CNS) A4 specification (210x297 g *) 199161 Λ (i Β6 V. Description of the invention (and treatment will get 9 -Amino-10,11-methinediamino-20 (S) -Camellia age. Obviously, many modifications and changes can be made to the present invention according to the above description. Therefore, it is understood that Within the scope of the patent application, the present invention can also be operated in a way different from the above-mentioned to be explained separately.-Please read the note to the contrary. Benzene. Item pot.% 装 η Line Ministry of Economic Affairs Bureau A, Consumer, and Consumer Cooperation Co., Ltd. Printed paper with a standard BB BB standard (CNS) T4 specification (210x297 g *)

Claims (1)

A7 B7 C7 D7 VI. Application for Patent Scope No. δΟ 10925 No. 5 Patent Reexamination Case Application for Amendment of Patent Scope Amendment Date: 8 1 year 1 February 1-A method for preparing restoration of hiki tree insurance, which includes the following steps: (1) Hydrolyze a lactone E ring of a camptothecin compound with the structure shown below under alkaline conditions (please read the precautions on the back before writing this page) (Wherein at least one of rings A, B, C, and D contains at least one substituent R which can be reduced under basic or neutral conditions, the substituent R is selected from the group consisting of nitro, gas, C2M .Alkenyl, C * -1D alkynyl, halo, nitroso, and formyl group), in order to form a water-soluble substituted carboxylate with the chemical formula shown below • Installed. Ordered. 4. The Central Standard of the Ministry of Hydrocarbon Economics and Consumers ’Cooperatives prints neutrality or neutrality; the alkaline acid in the sexual salt is formed in the original source of the carboxyl ⑵ son from the sun, and the R group is replaced by the original source. The acid ester should be in contact with the acid monoester and the internal salt. The acid will make the carboxyl-enriched urethane regenerate the acid, and the order will be formed. The acid is re-circulated or the ore is formed. The paper is again suitable for China. National Standard (CNS) A4 specification (210 X 297 mm) 1 199161 Λ7 B7 Cl D7 'Application for patent scope in which the organic acid is essentially derived from acetic acid, p-toluenesulfonic acid, three gas vinegar Central Standards Bureau The consumer cooperatives are composed of printed acid, oxalic acid and tartaric acid. 2 _ The method as described in item 1 of the patent application, in which the valence of metal cations. 3. The method as claimed in item 1 of the patent scope, wherein the metal cation, tetra-Ci-, -alkylammonium ion or 4. The method as claimed in item 1 of the patent scope, where 5. As in the application of item 4 of the patent scope Method, where acid, sulfuric acid or phosphoric acid. 6. The method of item 丨 in the scope of the patent application, in which the nitro group at the 9, 10, 11 or 12 position of the A ring. 7. The method as in item 1 of the patent application scope. The chemical hydrogenation reaction. 8. The method as claimed in item 丨 of the patent application scope, wherein the reduction reaction using FeS〇4-NH4〇H is performed. 9. The method as claimed in item 7 of the patent application, in which the first step is to use H 2 as a hydrogen source. 10. A method as claimed in item 7 of the patent application, wherein the method is performed using hydrazine as a hydrogen source. 11. The method as claimed in item 7 of the patent application, which should be carried out using cyclohexene as a hydrogen source 12. The method as claimed in item 1 of the patent application, wherein the electrochemical reduction reaction. Η is monovalent or M is alkali metal or alkaline earth ammonium ion. The acid is mineral acid. The mineral acid is hydrochloric acid, the substituent of bromine is a single bit, the reduction reaction is urged, the reduction reaction is one, the catalytic hydrogenation is reversed, the catalytic hydrogenation is reversed, the catalytic hydrogenation is reversed, the reduction reaction system is 1. Please read the notes on the back before filling in this page. The paper size is in accordance with Chinese National Standard (CNS) Grade 4 (210 X 297 mm) 2