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CN108129357B - Preparation method of anamorelin intermediate - Google Patents

Preparation method of anamorelin intermediate Download PDF

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CN108129357B
CN108129357B CN201611091396.0A CN201611091396A CN108129357B CN 108129357 B CN108129357 B CN 108129357B CN 201611091396 A CN201611091396 A CN 201611091396A CN 108129357 B CN108129357 B CN 108129357B
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compound
formula
preparation
trimethylhydrazine
molar ratio
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CN108129357A (en
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王环玉
刘相奎
于净平
朱雪焱
程兴栋
张爱明
张喜全
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Shanghai Institute of Pharmaceutical Industry
Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Shanghai Institute of Pharmaceutical Industry
Chia Tai Tianqing Pharmaceutical Group Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/02—Compounds containing any of the groups, e.g. carbazates
    • C07C281/04—Compounds containing any of the groups, e.g. carbazates the other nitrogen atom being further doubly-bound to a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/02—Compounds containing any of the groups, e.g. carbazates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

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Abstract

本申请涉及药物合成领域，具体而言涉及阿拉莫林中间体的制备方法。一方面本申请以1‑boc‑1‑甲基肼为反应原料，利用甲醛类化合物与钯催化剂/氢源交替反应的方法一锅煮制备关键中间体N,N',N'‑三甲基肼羧酸叔丁酯，该方法操作简单，所用原料安全易得，与现有技术方法相比收率提高；另一方面，本申请的方法将N,N',N'‑三甲基肼羧酸叔丁酯与盐酸在有机溶剂中反应，可直接得到高收率高纯度的N,N,N'‑三甲基肼盐酸盐的结晶产品，该结晶产物无需进一步纯化，吸湿性小，便于保存，非常适合工业大生产。The present application relates to the field of pharmaceutical synthesis, in particular to a preparation method of an anamorelin intermediate. On the one hand, the present application uses 1-boc-1-methylhydrazine as a reaction raw material, and utilizes the method for the alternate reaction of formaldehyde compounds and palladium catalyst/hydrogen source to prepare the key intermediate N,N',N'-trimethylhydrazine carboxylate in one pot. Acid tert-butyl ester, the method is simple to operate, the raw materials used are safe and easy to obtain, and the yield is improved compared with the prior art method; on the other hand, the method of the present application uses N,N',N'-trimethylhydrazine carboxylic acid The reaction of tert-butyl ester and hydrochloric acid in an organic solvent can directly obtain a crystalline product of N,N,N'-trimethylhydrazine hydrochloride in high yield and high purity. The crystalline product does not require further purification, has low hygroscopicity, and is convenient for Preservation, very suitable for industrial mass production.

Description

Preparation method of anamorelin intermediate
Technical Field
The application relates to the field of drug synthesis, in particular to a preparation method of an anamorelin intermediate.
Background
Anamorelin (Anamorelin) is a ghrelin receptor agonist, developed by helsin medical services limited (Helsinn) and developed for the treatment of anorexia, cachexia or unexpected weight loss in non-small cell lung cancer patients.
The preparation method of anamorelin disclosed in WO01034593 at present mainly involves the following steps:
Figure BDA0001168565580000011
wherein, the raw material N, N, N' -trimethylhydrazine is an important intermediate for synthesizing the anamorelin and is also an important intermediate for synthesizing a plurality of new compound entities.
Figure BDA0001168565580000012
For the synthesis of N, N' -trimethylhydrazine or salts, the prior art discloses the following methods:
route one: silvina et al (Organic Process Research)&Development 2004,8,360-4Reduction to obtain N, N, N' -trimethylhydrazine:
Figure BDA0001168565580000013
and a second route: CLASS et al (J.Am.chem.Soc.,1953,75(12), 2937-H2939) use 1, 1-dimethyl hydrazine as raw material to produce imine and LiAlH4Reduction to obtain N, N, N' -trimethylhydrazine:
Figure BDA0001168565580000014
the raw material 1, 1-dimethylhydrazine used in the two routes has low boiling point, is extremely toxic, flammable and explosive, is difficult to store and transport, is expensive and is difficult to obtain; the prepared trimethyl hydrazine exists in an organic solution, cannot be stored for a long time and can only be prepared and used at present; after the salt formation by the acid, the obtained product is oily, and a crystalline compound cannot be obtained, so that the method is not suitable for industrial large-scale production.
And a third route: michael et al (Eur.J.Med.chem.35(2000)487-497) with Boc-NHNH2Using NaH and methyl iodide as raw material to obtain N, N ', N ' -trimethyl hydrazine carboxylic acid tert-butyl ester, and making said product react with trifluoroacetic acid to obtain N, N, N ' -trimethyl hydrazine trifluoro-butyl esterAcetate salt:
Figure BDA0001168565580000021
the NaH used in the step 1 of the method belongs to flammable dangerous goods, needs to react for a long time at a low temperature without water and oxygen, has harsh conditions, needs to be further purified by column chromatography, and has low yield; the N, N, N' -trimethylhydrazinium trifluoroacetate obtained in step 2 is an oil.
And a fourth route: WO01034593 discloses the preparation of N, N, N' -trimethylhydrazine dihydrochloride from 1, 1-dimethylhydrazine by formylation and LiAlH4Reducing to obtain N, N, N' -trimethylhydrazine, and then adding HCl/CH3Obtaining N, N, N' -trimethylhydrazine dihydrochloride under the condition of OH:
Figure BDA0001168565580000022
the method has the advantages that the reaction time in the step 1 is long, in the step 3, after the N, N, N '-trimethylhydrazine prepared in the step 2 is distilled, the N, N' -trimethylhydrazine and HCl form salt under the ultralow temperature condition, the conditions are harsh, the operation is complicated, the obtained product is oily at room temperature, the reaction yield in the last two steps is low, and the product is very hygroscopic and is not suitable for industrial large-scale production.
Disclosure of Invention
In one aspect, the present invention provides a process for the preparation of a compound of formula iv, comprising: reacting a compound shown in a formula III in the presence of a first formaldehyde compound, a first catalyst and a first hydrogen source to obtain a compound shown in a formula IV,
Figure BDA0001168565580000023
wherein the first formaldehyde compound is selected from formaldehyde or paraformaldehyde, and is preferably paraformaldehyde.
Wherein the first catalyst is a palladium catalyst or Raney nickel, preferably Pd (OH)2/C、Pd/C、PdCl2Pd or Pd (OH)2Most preferably Pd/C.
It is to be understood that the palladium catalyst of the present invention may also be a variety of palladium complex compounds prepared with a variety of palladium catalysts and ligands including, but not limited to, PCy3、AsPh3、n-Bu3P、(MeO)3P、Ph2P(CH2)2PPh2(dppe) or Ph2P(CH2)3PPh2(dppp)。
Wherein the first hydrogen source is selected from H2、HCOOH、HCOONH4、NH2NH2Or cyclohexenes, preferably H2。
Wherein the reaction is carried out in the presence of a solvent.
In some embodiments of the present application, H is used2The pressure of (A) is 0.1 to 100atm, preferably 1 to 20atm, most preferably 9.8 atm.
In some embodiments herein, in the step of reacting the compound of formula III to obtain the compound of formula IV, a suitable reaction solvent may be selected as needed, and the solvent is selected from one or more of water, methanol, ethanol, propanol, isopropanol, N-butanol, isobutanol, t-butanol, 1, 4-dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, N-dimethylformamide, N-dimethylacetamide, or dimethyl sulfoxide, preferably one or more of methanol, ethanol, propanol, isopropanol, N-butanol, isobutanol, or t-butanol, and most preferably ethanol.
In some embodiments of the present application, in the step of reacting the compound of formula iii to obtain the compound of formula iv, a suitable reaction temperature may be selected as required, the reaction temperature being from 0 ℃ to the boiling point of the reaction system, for example, the reaction temperature is from 25 ℃ to 120 ℃, preferably from 50 ℃ to 90 ℃; in some embodiments herein, the reaction temperature is 60 ℃.
It should be understood that the reaction temperature is not higher than the boiling point of the reaction system.
In some embodiments of the present application, in the step of reacting the compound of formula iii to obtain the compound of formula iv, the molar ratio of the compound of formula iii to the first formaldehydes may be selected as appropriate, and the molar ratio of the compound of formula iii to the first formaldehydes is expressed as the molar ratio of the compound of formula iii to formaldehyde, and may be 1: 0.01-1: 100, may be 1: 2-1: for example, in some embodiments herein, the molar ratio of the compound of formula iii to the first formaldehydes is 1: 3-1: 5.
in some embodiments of the present application, in the step of reacting the compound of formula iii to obtain the compound of formula iv, the compound of formula iii and the first catalyst may be in a suitable molar ratio selected according to the need, and the molar ratio of the compound of formula iii to the first catalyst may be 1: 0.001-1: 100, may be 1: 0.01-1: 0.1. for example, in some embodiments herein, the molar ratio of the compound of formula iii to the first catalyst is 1: 0.04-1: 0.08.
in some embodiments herein, in the step of reacting the compound of formula iii to obtain the compound of formula iv, a suitable reaction time may be selected as desired, for example, a reaction time of 0.1 to 24 hours. In some embodiments of the invention, the reaction time is 4 hours.
In some embodiments of the present application, the process for preparing a compound of formula iv further comprises the step of isolating the compound of formula iv from the reaction system; in some embodiments of the present application, the step of isolating the compound of formula iv is isolating the compound of formula iv by distillation.
In some embodiments of the present application, a step of concentrating the reaction system is included prior to isolating the compound of formula iv.
In some embodiments herein, the method further comprises the step of removing the catalyst from the reaction system prior to isolating the compound of formula iv; preferably, the step of removing the catalyst from the reaction system is preceded by concentration of the reaction system.
In another aspect, the present invention provides a process for the preparation of a compound of formula iii, comprising: reacting the compound of formula II in the presence of a second catalyst and a second hydrogen source to obtain a compound of formula III,
Figure BDA0001168565580000031
wherein the second catalyst is a palladium catalyst or Raney nickel, preferably Pd (OH)2/C、Pd/C、PdCl2Pd or Pd (OH)2Most preferably Pd/C.
It is to be understood that the palladium catalyst of the present invention may also be a variety of palladium complex compounds prepared with a variety of palladium catalysts and ligands including, but not limited to, PCy3、AsPh3、n-Bu3P、(MeO)3P、Ph2P(CH2)2PPh2(dppe) or Ph2P(CH2)3PPh2(dppp)。
Wherein the second hydrogen source is selected from H2、HCOOH、HCOONH4、NH2NH2Or cyclohexenes, preferably H2。
Wherein the reaction is carried out in the presence of a solvent.
In some embodiments of the present application, H is used2The pressure of (A) is 0.1 to 100atm, preferably 1 to 20atm, most preferably 9.8 atm.
In some embodiments herein, in the step of reacting the compound of formula II to obtain the compound of formula III, a suitable reaction solvent may be selected as needed, and the solvent is selected from one or more of water, methanol, ethanol, propanol, isopropanol, N-butanol, isobutanol, t-butanol, 1, 4-dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, N-dimethylformamide, N-dimethylacetamide, or dimethyl sulfoxide, preferably one or more of methanol, ethanol, propanol, isopropanol, N-butanol, isobutanol, or t-butanol, and most preferably ethanol.
In some embodiments of the present application, in the step of reacting the compound of formula II to obtain the compound of formula iii, the compound of formula II and the second catalyst may be selected according to the need to have a suitable molar ratio, and the molar ratio of the compound of formula II to the second catalyst may be 1: 0.001-1: 100, may be 1: 0.01-1: 0.1. for example, in some embodiments herein, the molar ratio of the compound of formula II to the second catalyst is 1: 0.04-1: 0.08.
in some embodiments of the present application, in the step of reacting the compound of formula II to obtain the compound of formula iii, a suitable reaction temperature may be selected as required, the reaction temperature being from 0 ℃ to the boiling point of the reaction system, for example, the reaction temperature being from 25 ℃ to 120 ℃, preferably from 50 ℃ to 90 ℃; in some embodiments herein, the reaction temperature is 60 ℃.
In some embodiments herein, in the step of reacting the compound of formula II to obtain the compound of formula iii, a suitable reaction time may be selected as desired, for example, a reaction time of 0.1 to 24 hours. In some embodiments of the invention, the reaction time is 4 hours.
In some embodiments herein, the compound of formula iii produced may be used without isolation to produce a compound of formula iv.
In yet another aspect, the present invention provides a process for preparing a compound of formula II, comprising: in the presence of a second aldehyde compound, reacting a compound of formula I to obtain a compound of formula II,
Figure BDA0001168565580000041
wherein the second aldehyde compound is selected from formaldehyde or paraformaldehyde, preferably paraformaldehyde.
Wherein the reaction is carried out in the presence of a solvent.
In some embodiments herein, in the step of reacting a compound of formula I to obtain a compound of formula II, a suitable reaction solvent may be selected as needed, and the solvent is selected from one or more of water, methanol, ethanol, propanol, isopropanol, N-butanol, isobutanol, t-butanol, 1, 4-dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, N-dimethylformamide, N-dimethylacetamide, or dimethyl sulfoxide, preferably one or more of methanol, ethanol, propanol, isopropanol, N-butanol, isobutanol, or t-butanol, and most preferably ethanol.
In some embodiments of the present application, in the step of reacting the compound of formula i to obtain the compound of formula II, a suitable reaction temperature may be selected as required, the reaction temperature being from 0 ℃ to the boiling point of the reaction system, for example, the reaction temperature being from 25 ℃ to 120 ℃, preferably from 50 ℃ to 90 ℃; in some embodiments herein, the reaction temperature is 80 ℃.
In some embodiments of the present application, in the step of reacting the compound of formula i to obtain the compound of formula II, the molar ratio of the compound of formula i to the second aldehyde compound can be selected as appropriate, and the molar ratio of the compound of formula i to the second aldehyde compound, expressed as the molar ratio of the compound of formula i to formaldehyde, can be 1: 0.01-1: 100, may be 1:1-1: 5. for example, in some embodiments herein, the molar ratio of the compound of formula i to the second aldehyde compound is 1:1.
in some embodiments of the present application, in the step of reacting the compound of formula i to obtain the compound of formula II, a suitable reaction time may be selected as desired, for example, a reaction time of 0.1 to 48 hours, preferably 12 to 24 hours. In some embodiments of the invention, the reaction time is 24 hours.
In some embodiments of the present application, the prepared compound of formula II may be used without isolation to prepare a compound of formula iii.
In a further aspect, the present invention provides a process for the preparation of a compound of formula iv, comprising steps (i), (ii) and (iii), or steps (a), (b) and (c):
(i) in the presence of a second aldehyde compound, reacting a compound shown in a formula I to obtain a compound shown in a formula II;
(ii) reacting the compound of the formula II in the presence of a second catalyst and a second hydrogen source to obtain a compound of the formula III;
(iii) reacting a compound shown in a formula III in the presence of a first formaldehyde compound, a first catalyst and a first hydrogen source to obtain a compound shown in a formula IV;
Figure BDA0001168565580000051
(a) reacting the compound of the formula I with a second aldehyde compound;
(b) adding a second catalyst and a second hydrogen source into the system in the step (a) to react;
(c) adding a first formaldehyde compound and a first hydrogen source into the system in the step (b) to react to obtain a compound in a formula IV;
Figure BDA0001168565580000052
wherein the first formaldehyde compound, the second formaldehyde compound, the first catalyst, the second catalyst, the first hydrogen source and the second hydrogen source are defined as above.
In some embodiments of the present application, H is used2The pressure of (A) is 0.1 to 100atm, preferably 1 to 20atm, most preferably 9.8 atm.
In some embodiments of the present application, the first formaldehyde-based compound and the second formaldehyde-based compound are the same.
In some embodiments herein, the first catalyst and the second catalyst are the same; in some embodiments of the invention, the second catalyst of step (ii) is further used as the first catalyst of step (iii).
In some embodiments of the present application, the first hydrogen source and the second hydrogen source are the same.
In some embodiments herein, step (i), step (ii), and step (iii) use the same reaction solvent; step (a), step (b) and step (c) use the same reaction solvent; the solvent is selected from one or more of water, methanol, ethanol, propanol, isopropanol, N-butanol, isobutanol, tert-butanol, 1, 4-dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide, preferably one or more of methanol, ethanol, propanol, isopropanol, N-butanol, isobutanol or tert-butanol, and most preferably ethanol.
In some embodiments of the present application, the process of steps (i) to (II) is not subjected to a step of isolating the compound of formula II.
In some embodiments of the present application, step (i) is not subjected to the steps of filtering, concentrating and isolating the compound of formula II.
In some embodiments of the present application, the process of steps (ii) to (iii) is not subjected to a step of isolating the compound of formula iii.
In some embodiments of the present application, step (ii) is not subjected to the steps of filtering, concentrating and isolating the compound of formula iii.
In some embodiments herein, step (i) or step (a) may be carried out at a temperature as desired, from 0 ℃ to the boiling point of the reaction system, for example at a temperature of from 25 ℃ to 120 ℃, preferably from 50 ℃ to 90 ℃; in some embodiments herein, the reaction temperature is 80 ℃.
In some embodiments of the present application, in step (i) or step (a), the molar ratio of the compound of formula i to the second formaldehyde compound, expressed as the molar ratio of the compound of formula i to formaldehyde, can be 1: 0.01-1: 100, may be 1:1-1: 5. for example, in some embodiments herein, the molar ratio of the compound of formula i to the second aldehyde compound is 1:1.
in some embodiments herein, in step (i) or step (a), a suitable reaction time may be selected as desired, for example a reaction time of from 0.1 to 48 hours, preferably from 12 to 24 hours. In some embodiments of the invention, the reaction time is 24 hours.
In some embodiments herein, the molar amount of the second catalyst in step (ii) or step (b), expressed as the molar ratio of the compound of formula i to the second catalyst, may be 1: 0.001-1: 100, may be 1: 0.01-1: 0.1. for example, in some embodiments herein, the molar amount of the second catalyst is 1, expressed as the molar ratio of the compound of formula i to the second catalyst: 0.03.
in some embodiments herein, in step (ii) or step (b), a suitable reaction temperature may be selected as desired, the reaction temperature being from 0 ℃ to the boiling point of the reaction system, for example, the reaction temperature being from 25 ℃ to 120 ℃, preferably from 50 ℃ to 90 ℃; in some embodiments herein, the reaction temperature is 60 ℃.
In some embodiments herein, in step (ii) or step (b), a suitable reaction time may be selected as desired, for example a reaction time of from 0.1 to 24 hours. In some embodiments herein, the reaction time is 4 hours.
In some embodiments herein, in step (iii) or step (c), a suitable reaction temperature may be selected as desired, the reaction temperature being from 0 ℃ to the boiling point of the reaction system, for example, the reaction temperature being from 25 ℃ to 120 ℃, preferably from 50 ℃ to 90 ℃; in some embodiments herein, the reaction temperature is 60 ℃.
In some embodiments herein, the molar amount of the first formaldehydic compound in step (iii) or step (c), expressed as the molar ratio of compound of formula i to formaldehyde, may be 1: 0.01-1: 100, may be 1: 2-1: for example, in some embodiments herein, the molar amount of the first formaldehydic compound is 1: 3.
in some embodiments herein, the molar amount of the first catalyst in step (iii) or step (c), expressed as the molar ratio of the compound of formula i to the first catalyst, may be 1: 0.001-1: 100, may be 1: 0.01-1: 0.1. for example, in some embodiments herein, the molar amount of the first catalyst, expressed as the molar ratio of the compound of formula i to the first catalyst, is about 1: 0.04.
in some embodiments herein, in step (iii) or step (c), a suitable reaction time may be selected as desired, for example a reaction time of from 0.1 to 24 hours. In some embodiments of the invention, the reaction time is 4 hours.
In yet another aspect, the present application provides a method for preparing N, N' -trimethylhydrazine hydrochloride, comprising: the compound shown in the formula IV reacts in the presence of HCl to obtain N, N, N' -trimethylhydrazine hydrochloride.
Wherein the molar ratio of N, N, N '-trimethylhydrazine to hydrochloric acid in the N, N, N' -trimethylhydrazine hydrochloride is about 1:1 to about 1: 2; in some embodiments of the invention, the molar ratio of N, N' -trimethylhydrazine to hydrochloric acid is about 1: 1.5.
Wherein the reaction is carried out in the presence of an organic solvent selected from one or more of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, 1, 4-dioxane, acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, benzene, toluene or xylene; in some embodiments of the invention, the organic solvent is selected from ethyl acetate.
In some embodiments herein, in the step of reacting the compound of formula iv to obtain N, N' -trimethylhydrazinehydrochloride, the molar ratio of the compound of formula iv to HCl is 1: 0.1-1: 100, preferably 1:1-1: 10; in some embodiments herein, the molar ratio of the compound of formula iv to HCl is 1: 6.2.
in some embodiments of the present application, in the step of reacting the compound of formula iv to obtain N, N' -trimethylhydrazine hydrochloride, a suitable reaction temperature may be selected as desired, the reaction temperature being-78 to 50 ℃, preferably-15 to 15 ℃; in some embodiments herein, the reaction temperature is 0 ℃.
In some embodiments of the present application, in the step of reacting the compound of formula iv to obtain N, N' -trimethylhydrazinehydrochloride, the reaction is carried out by mixing an organic solvent solution of HCl with an organic solvent solution of the compound of formula iv; preferably, the reaction is carried out by mixing a solution of HCl in ethyl acetate with a solution of the compound of formula IV in ethyl acetate. In some embodiments of the invention, the reaction is carried out by dropwise addition of a solution of HCl in ethyl acetate to a solution of the compound of formula IV in ethyl acetate.
In some embodiments of the present application, the N, N' -trimethylhydrazine hydrochloride is prepared as a solid compound.
In some embodiments of the present application, the N, N' -trimethylhydrazine hydrochloride is prepared as a solid crystalline compound.
In some embodiments of the present application, the step of preparing N, N' -trimethylhydrazine hydrochloride further comprises a step of filtration.
All solvents or reagents used in this application are commercially available and can be used without further purification.
In the present application, mass spectrometry is determined on a Q-tof mass spectrometer. The mass spectrometer was equipped with an electrospray ion source (ESI) operating in either positive or negative mode. The thin-layer chromatography silica gel plate is a (5 multiplied by 20cm) high-efficiency thin-layer chromatography silica gel precast plate manufactured by Tintangyou silica gel development Co.
In this application, Boc represents t-butyloxycarbonyl; NaH represents sodium hydride; LiAlH4Represents lithium aluminum hydride; HCl represents hydrogen chloride; Pd/C represents palladium carbon; atm is a unit of pressure, representing standard atmospheric pressure, e.g. 1atm represents 1 standard atmospheric pressure; TLC for thin layer chromatography.
The application provides a preparation method of N, N, N ' -trimethylhydrazine hydrochloride and an intermediate thereof, on one hand, the application takes 1-boc-1-methylhydrazine as a reaction raw material, and prepares a key intermediate N, N ', N ' -trimethylhydrazine carboxylic acid tert-butyl ester by one-pot boiling by utilizing a method of alternate reaction of formaldehyde compounds and palladium catalysts/hydrogen sources, the method is simple to operate, the used raw materials are safe and easy to obtain, and the yield is improved compared with the prior art; on the other hand, the method of the application enables the N, N ', N ' -trimethylhydrazinecarboxylic acid tert-butyl ester to react with hydrochloric acid in an organic solvent, can directly obtain the N, N, N ' -trimethylhydrazinehydrochloride crystallization product with high yield and high purity, does not need further purification, has small hygroscopicity, is convenient to store, and is very suitable for industrial mass production.
Drawings
FIG. 1 TLC chart of N, N, N' -trimethylhydrazine hydrochloride of example 2.
FIG. 2 TLC picture of N, N, N' -trimethylhydrazine of comparative example 1.
Detailed Description
The present invention is further illustrated by the following examples, but is not limited thereto. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers.
Reference example 11 preparation of boc-1-methylhydrazine (Compound of formula I)
Referring to the prior art synthesis method (e.g. as disclosed in WO 2007139346), the preparation method is as follows:
7.2g of hydrazine methyl sulfate (49.9mmol) are added to 144ml of water, cooled to 5 ℃ and 4.6g of NaHCO are added3Solid, adjusted to pH 10 with aqueous NaOH, to which 144ml of (Boc)2O (49.95mmol) in tetrahydrofuran was stirred for 12h and the reaction was monitored by TLC for completion (developing solvent: petroleum ether/ethyl acetate 2/1). Extraction with ethyl acetate (100 ml. times.3) and combination of the organic phases were carried out, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 6.0g (yield 82%) of the compound of the formula I as a colorless transparent liquid.
EXAMPLE 1 preparation of tert-butyl N, N ', N' -trimethylhydrazinecarboxylate (Compound of formula IV)
Mixing 1-boc-1-AHydrazyl (13g, 88.9mmol), paraformaldehyde (2.67g, 88.9mmol (in terms of formaldehyde)), 100ml of ethanol were added to a reaction flask, heated under reflux at 80 ℃ for 24 hours, and the completion of the reaction was monitored by TLC (developing agent: petroleum ether/ethyl acetate: 2/1), 10% palladium on carbon (4g) was added, hydrogen (9.8atm) was charged, and the mixture was stirred at 60 ℃ for 4 hours, and the completion of the reaction was monitored by TLC (developing agent: petroleum ether/ethyl acetate: 2/1). Paraformaldehyde (8.0g, 270mmol (as formaldehyde)) was added to the reaction solution containing palladium on carbon in the above step, hydrogen (9.8atm) was purged, reduction was carried out at 60 ℃ for 4 hours, and completion of the reaction was monitored by TLC (developing solvent: petroleum ether/ethyl acetate: 2/1). Suction filtration, removal of palladium carbon, filtrate reduced pressure concentration to obtain the compound crude product of formula IV, crude product reduced pressure distillation, obtain the compound pure product of formula IV (colorless transparent liquid 7.33g, total yield 47.3%). ESI-MS (M/z):197[ M + Na]+。
EXAMPLE 2 preparation of N, N, N' -trimethylhydrazino hydrochloride
A solution of HCl in ethyl acetate (2mol/L, 105ml) was added dropwise to a solution of compound of formula IV (6g, 34.45mmol) in ethyl acetate (20ml) under ice-cooling, 30min was completed and the reaction was filtered off with suction to afford N, N, N' -trimethylhydrazino hydrochloride as a solid crystal (4.4g, 99.2% yield). ESI-MS (M/z) 75[ M + H]+。
The N, N, N '-trimethylhydrazine hydrochloride is detected by a Thermo FisherICS-1100 ion chromatograph, the chlorine content in the product is 40.14 percent, and the molar ratio of the N, N, N' -trimethylhydrazine to the hydrochloric acid in the product is 1: 1.5.
EXAMPLE 3 preparation of the Compound of formula VII
Figure BDA0001168565580000091
Dissolving a compound (25g, 78.3mmol) of the formula V in 250ml of dichloromethane, reducing the temperature to-15 ℃ under the protection of nitrogen, and dropwise adding oxalyl chloride (14g, 110mmol) into the reaction system within 40min to obtain light yellow system; n, N-dimethylformamide (2.5ml) and triethylamine (14.1g, 139mmol) were added successively, and after 1.5h of dropwise addition and reaction at-15 to-20 ℃ for 3.5h, the reaction was checked by TLC for completion (developer: petroleum ether/ethyl acetate: 2/1). N, N, N' -trimethylhydrazine hydrochloride (17.3g) prepared in example 2 was added to the reaction solution at-20 ℃ over 1.5h, and a solution of triethylamine (39.6g, 391.5mmol) in dioxane was added dropwise to turn brown and gas was generated, the reaction was maintained at-20 ℃ for 20h, and the starting material was detected by TLC to be completely reacted. After warming to room temperature, 250ml of water was added, the layers were separated by stirring, the aqueous layer was extracted with dichloromethane (200ml), the organic phases were combined, washed successively with water (2X 250ml), saturated sodium bicarbonate (250ml) and saturated brine (250ml), dried over anhydrous sodium sulfate, filtered and the filtrate was rotary evaporated under reduced pressure to give 35.6g of the compound of formula VI.
Comparative example 1 preparation of N, N, N' -trimethylhydrazine
A solution of N, N, N' -trimethylhydrazine in 1, 4-dioxane was obtained by a synthesis method disclosed in the prior art (Silvina et al, Organic Process Research & Development 2004,8, 360-.
Product purity detection
The N, N, N' -trimethylhydrazine hydrochloride prepared in example 2 (addition to methanol followed by NH addition)3The methanolic solution of N, N ' -trimethylhydrazine to a methanolic solution of N, N ' -trimethylhydrazine) and the 1, 4-dioxane solution of N, N ' -trimethylhydrazine prepared in comparative example 1 were each detected by TLC (TLC detection conditions: developing agent: petroleum ether/ethyl acetate 2/1; color development conditions are as follows: iodine cylinder) as shown in fig. 1 and fig. 2 (fig. 1 is a TLC chart of N, N '-trimethylhydrazine hydrochloride of example 2, fig. 2 is a TLC chart of N, N' -trimethylhydrazine of comparative example 1, and the loading amount of the sample of fig. 1 is larger than that of the sample of fig. 2), wherein the dark spots are spots for developing color of the target compound.
The results show that figure 2 has other, in addition to the dark coloured spots of the target compound, also other, light coloured spots, indicating that the product prepared in example 2 is significantly more pure than comparative example 1.

Claims (48)

1.N,N,N'-三甲基肼盐酸盐的制备方法，包括：1. The preparation method of N,N,N'-trimethylhydrazine hydrochloride, comprising: (1)在第一甲醛类化合物、第一催化剂和第一氢源的存在下，式Ⅲ化合物进行反应得到式Ⅳ化合物，(1) in the presence of the first formaldehyde compound, the first catalyst and the first hydrogen source, the compound of formula III is reacted to obtain the compound of formula IV,
Figure FDA0003339412210000011
Figure FDA0003339412210000011
 (2)式Ⅳ化合物在HCl的存在下进行反应得到N,N,N'-三甲基肼盐酸盐；(2) The compound of formula IV is reacted in the presence of HCl to obtain N,N,N'-trimethylhydrazine hydrochloride; 其中所述第一甲醛类化合物选自多聚甲醛；Wherein the first formaldehyde compound is selected from paraformaldehyde; 其中所述第一催化剂选自Pd/C；wherein the first catalyst is selected from Pd/C; 其中所述第一氢源选自H2；wherein the first hydrogen source is selected from H 2 ; 所述N,N,N'-三甲基肼盐酸盐，其中N,N,N'-三甲基肼与盐酸的摩尔比为1:1.5，N,N,N'-三甲基肼盐酸盐为固体结晶化合物，The N,N,N'-trimethylhydrazine hydrochloride, wherein the molar ratio of N,N,N'-trimethylhydrazine and hydrochloric acid is 1:1.5, N,N,N'-trimethylhydrazine Hydrochloride is a solid crystalline compound, 还包括：在第二催化剂和第二氢源的存在下，式Ⅱ化合物进行反应得到式Ⅲ化合物，It also includes: in the presence of a second catalyst and a second hydrogen source, the compound of formula II is reacted to obtain the compound of formula III,
Figure FDA0003339412210000012
Figure FDA0003339412210000012
 其中所述第二催化剂选自Pd/C；wherein the second catalyst is selected from Pd/C; 其中所述第二氢源选自H2；wherein the second hydrogen source is selected from H 2 ; 还包括：在第二甲醛类化合物的存在下，式Ⅰ化合物进行反应得到式Ⅱ化合物，It also includes: in the presence of the second formaldehyde compound, the compound of formula I is reacted to obtain the compound of formula II,
Figure FDA0003339412210000013
Figure FDA0003339412210000013
 其中所述第二甲醛类化合物选自多聚甲醛。Wherein the second formaldehyde compound is selected from paraformaldehyde. 2.根据权利要求1的制备方法，其中所述式Ⅲ化合物进行反应得到式Ⅳ化合物的反应在溶剂的存在下进行。2. The preparation method according to claim 1, wherein the reaction of the compound of formula III to obtain the compound of formula IV is carried out in the presence of a solvent. 3.根据权利要求1的制备方法，其中式Ⅲ化合物进行反应得到式Ⅳ化合物步骤使用H2的压强为0.1-100atm。3. The preparation method according to claim 1, wherein the step of reacting the compound of formula III to obtain the compound of formula IV uses a pressure of H 2 of 0.1-100 atm. 4.根据权利要求2的制备方法，其中所述溶剂选自水、甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、1,4-二氧六环、甲酸、乙酸、丁酸、戊酸、丙酮、丁酮、戊酮、环戊酮、己酮、环己酮、乙醚、乙酸乙酯、乙酸丁酯、四氢呋喃、乙腈、苯、甲苯、二甲苯、二氯甲烷、三氯甲烷、四氯化碳、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或二甲基亚砜中的一种或一种以上。4. The preparation method according to claim 2, wherein the solvent is selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, 1,4-dioxane, Formic acid, acetic acid, butyric acid, valeric acid, acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, One or more of dichloromethane, trichloromethane, carbon tetrachloride, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide. 5.根据权利要求4的制备方法，其中所述溶剂选自甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇或叔丁醇中的一种或一种以上。5. The preparation method according to claim 4, wherein the solvent is selected from one or more of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol or tert-butanol. 6.根据权利要求5的制备方法，其中所述溶剂选自乙醇。6. The preparation method according to claim 5, wherein the solvent is selected from ethanol. 7.根据权利要求1的制备方法，其中式Ⅲ化合物进行反应得到式Ⅳ化合物的反应温度为0℃到反应体系的沸点。7 . The preparation method according to claim 1 , wherein the reaction temperature at which the compound of formula III is reacted to obtain the compound of formula IV is 0° C. to the boiling point of the reaction system. 8 . 8.根据权利要求7的制备方法，其中反应温度为50-90℃。8. The preparation method according to claim 7, wherein the reaction temperature is 50-90°C. 9.根据权利要求8的制备方法，其中反应温度为60℃。9. The preparation method according to claim 8, wherein the reaction temperature is 60°C. 10.根据权利要求1的制备方法，式Ⅲ化合物与第一甲醛类化合物的摩尔比以式Ⅲ化合物与甲醛的摩尔比表示为1：0.01-1：100。10. The preparation method according to claim 1, wherein the molar ratio of the compound of formula III to the first formaldehyde compound is expressed as the molar ratio of the compound of formula III to formaldehyde as 1:0.01-1:100. 11.根据权利要求10的制备方法，式Ⅲ化合物与第一甲醛类化合物的摩尔比以式Ⅲ化合物与甲醛的摩尔比表示为1：2-1：8。11. The preparation method according to claim 10, wherein the molar ratio of the compound of formula III to the first formaldehyde compound is represented by the molar ratio of the compound of formula III to formaldehyde as 1:2-1:8. 12.根据权利要求11的制备方法，式Ⅲ化合物与第一甲醛类化合物的摩尔比以式Ⅲ化合物与甲醛的摩尔比表示为1：3-1：5。12. The preparation method according to claim 11, wherein the molar ratio of the compound of formula III to the first formaldehyde compound is expressed as the molar ratio of the compound of formula III to formaldehyde in the range of 1:3-1:5. 13.根据权利要求1的制备方法，式Ⅲ化合物与第一催化剂的摩尔比为1：0.001-1：100。13. The preparation method according to claim 1, wherein the molar ratio of the compound of formula III to the first catalyst is 1:0.001-1:100. 14.根据权利要求13的制备方法，式Ⅲ化合物与第一催化剂的摩尔比为1：0.01-1：0.1。14. The preparation method according to claim 13, wherein the molar ratio of the compound of formula III to the first catalyst is 1:0.01-1:0.1. 15.根据权利要求14的制备方法，式Ⅲ化合物与第一催化剂的摩尔比为1：0.04-1：0.08。15. The preparation method according to claim 14, wherein the molar ratio of the compound of formula III to the first catalyst is 1:0.04-1:0.08. 16.根据权利要求1的制备方法，其中式Ⅱ化合物进行反应得到式Ⅲ化合物的步骤使用H2的压强为0.1-100atm。16. The preparation method according to claim 1, wherein the step of reacting the compound of the formula II to obtain the compound of the formula III uses H 2 at a pressure of 0.1-100 atm. 17.根据权利要求1的制备方法，其中所述式Ⅱ化合物进行反应得到式Ⅲ化合物的反应在溶剂的存在下进行。17. The preparation method according to claim 1, wherein the reaction of the compound of formula II to obtain the compound of formula III is carried out in the presence of a solvent. 18.根据权利要求17的制备方法，其中所述溶剂选自水、甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、1,4-二氧六环、甲酸、乙酸、丁酸、戊酸、丙酮、丁酮、戊酮、环戊酮、己酮、环己酮、乙醚、乙酸乙酯、乙酸丁酯、四氢呋喃、乙腈、苯、甲苯、二甲苯、二氯甲烷、三氯甲烷、四氯化碳、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或二甲基亚砜中的一种或一种以上。18. The preparation method according to claim 17, wherein the solvent is selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, 1,4-dioxane, Formic acid, acetic acid, butyric acid, valeric acid, acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, One or more of dichloromethane, trichloromethane, carbon tetrachloride, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide. 19.根据权利要求18的制备方法，其中所述溶剂选自甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇或叔丁醇中的一种或一种以上。19. The preparation method according to claim 18, wherein the solvent is selected from one or more of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol or tert-butanol. 20.根据权利要求19的制备方法，其中所述溶剂选自乙醇。20. The preparation method according to claim 19, wherein the solvent is selected from ethanol. 21.根据权利要求1的制备方法，其中式Ⅱ化合物与第二催化剂的摩尔比为1：0.001-1：100。21. The preparation method according to claim 1, wherein the molar ratio of the compound of formula II to the second catalyst is 1:0.001-1:100. 22.根据权利要求21的制备方法，其中式Ⅱ化合物与第二催化剂的摩尔比为1：0.01-1：0.1。22. The preparation method according to claim 21, wherein the molar ratio of the compound of formula II to the second catalyst is 1:0.01-1:0.1. 23.根据权利要求22的制备方法，其中式Ⅱ化合物与第二催化剂的摩尔比为1：0.04-1：0.08。23. The preparation method according to claim 22, wherein the molar ratio of the compound of formula II to the second catalyst is 1:0.04-1:0.08. 24.根据权利要求1的制备方法，在式Ⅱ化合物进行反应得到式Ⅲ化合物的步骤中，反应温度为0℃到反应体系的沸点。24. The preparation method according to claim 1, in the step of reacting the compound of formula II to obtain the compound of formula III, the reaction temperature is 0°C to the boiling point of the reaction system. 25.根据权利要求24的制备方法，在式Ⅱ化合物进行反应得到式Ⅲ化合物的步骤中，反应温度为25-120℃。25. The preparation method according to claim 24, in the step of reacting the compound of formula II to obtain the compound of formula III, the reaction temperature is 25-120°C. 26.根据权利要求25的制备方法，其中反应温度为60℃。26. The preparation method according to claim 25, wherein the reaction temperature is 60°C. 27.根据权利要求1的制备方法，其中所述式Ⅰ化合物进行反应得到式Ⅱ化合物的反应在溶剂的存在下进行。27. The preparation method according to claim 1, wherein the reaction of the compound of formula I to obtain the compound of formula II is carried out in the presence of a solvent. 28.根据权利要求27的制备方法，其中所述溶剂选自水、甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、1,4-二氧六环、甲酸、乙酸、丁酸、戊酸、丙酮、丁酮、戊酮、环戊酮、己酮、环己酮、乙醚、乙酸乙酯、乙酸丁酯、四氢呋喃、乙腈、苯、甲苯、二甲苯、二氯甲烷、三氯甲烷、四氯化碳、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或二甲基亚砜中的一种或一种以上。28. The preparation method according to claim 27, wherein the solvent is selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, 1,4-dioxane, Formic acid, acetic acid, butyric acid, valeric acid, acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, One or more of dichloromethane, trichloromethane, carbon tetrachloride, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide. 29.根据权利要求28的制备方法，其中所述溶剂选自甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇或叔丁醇中的一种或一种以上。29. The preparation method according to claim 28, wherein the solvent is selected from one or more of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol or tert-butanol. 30.根据权利要求29的制备方法，其中所述溶剂选自乙醇。30. The preparation method according to claim 29, wherein the solvent is selected from ethanol. 31.根据权利要求1的制备方法，在式Ⅰ化合物进行反应得到式Ⅱ化合物的步骤中，反应温度为0℃到反应体系的沸点。31. The preparation method according to claim 1, in the step of reacting the compound of formula I to obtain the compound of formula II, the reaction temperature is 0°C to the boiling point of the reaction system. 32.根据权利要求31的制备方法，在式Ⅰ化合物进行反应得到式Ⅱ化合物的步骤中，反应温度为50-90℃。32. The preparation method according to claim 31, in the step of reacting the compound of formula I to obtain the compound of formula II, the reaction temperature is 50-90°C. 33.根据权利要求32的制备方法，所述反应温度为80℃。33. The preparation method according to claim 32, wherein the reaction temperature is 80°C. 34.根据权利要求1的制备方法，式Ⅰ化合物与第二甲醛类化合物的摩尔比以式Ⅰ化合物与甲醛的摩尔比表示为1：0.01-1：100。34. The preparation method according to claim 1, wherein the molar ratio of the compound of formula I to the second formaldehyde compound is represented by the molar ratio of the compound of formula I to formaldehyde as 1:0.01-1:100. 35.根据权利要求34的制备方法，式Ⅰ化合物与第二甲醛类化合物的摩尔比以式Ⅰ化合物与甲醛的摩尔比表示为1：1-1：5。35. The preparation method according to claim 34, wherein the molar ratio of the compound of formula I to the second formaldehyde compound is represented by the molar ratio of the compound of formula I to formaldehyde in the range of 1:1-1:5. 36.根据权利要求35的制备方法，式Ⅰ化合物与第二甲醛类化合物的摩尔比以式Ⅰ化合物与甲醛的摩尔比表示为1：1。36. The preparation method according to claim 35, wherein the molar ratio of the compound of formula I to the second formaldehyde compound is represented by the molar ratio of the compound of formula I to formaldehyde as 1:1. 37.根据权利要求1的制备方法，其中式Ⅰ化合物进行反应得到式Ⅱ化合物的步骤，到式Ⅱ化合物进行反应得到式Ⅲ化合物的步骤的过程中，没有经历分离式Ⅱ化合物的步骤。37. The preparation method according to claim 1, wherein the step of reacting the compound of formula I to obtain the compound of formula II does not undergo the step of isolating the compound of formula II during the step of reacting the compound of formula II to obtain the compound of formula III. 38.根据权利要求1的制备方法，其中式Ⅱ化合物进行反应得到式Ⅲ化合物的步骤，到式Ⅲ化合物进行反应得到式Ⅳ化合物的步骤的过程中，没有经历分离式Ⅲ化合物的步骤。38. The preparation method according to claim 1, wherein the step of reacting the compound of formula II to obtain the compound of formula III does not undergo the step of isolating the compound of formula III during the step of reacting the compound of formula III to obtain the compound of formula IV. 39.N,N,N'-三甲基肼盐酸盐的制备方法，包括步骤(a)、(b)、(c)和(d)：39. A method for preparing N,N,N'-trimethylhydrazine hydrochloride, comprising steps (a), (b), (c) and (d): (a)式Ⅰ化合物与第二甲醛类化合物进行反应；(a) the compound of formula I reacts with the second formaldehyde compound; (b)向步骤(a)的体系中加入第二催化剂和第二氢源进行反应；(b) adding the second catalyst and the second hydrogen source to the system of step (a) for reaction; (c)向步骤(b)的体系中加入第一甲醛类化合物和第一氢源进行反应得到式Ⅳ化合物；(c) adding the first formaldehyde compound and the first hydrogen source to the system of step (b) and reacting to obtain the compound of formula IV;
Figure FDA0003339412210000031
Figure FDA0003339412210000031
 (d)式Ⅳ化合物在HCl的存在下进行反应得到N,N,N'-三甲基肼盐酸盐，(d) The compound of formula IV is reacted in the presence of HCl to obtain N,N,N'-trimethylhydrazine hydrochloride, 所述N,N,N'-三甲基肼盐酸盐，其中N,N,N'-三甲基肼与盐酸的摩尔比为1:1.5，N,N,N'-三甲基肼盐酸盐为固体结晶化合物，The N,N,N'-trimethylhydrazine hydrochloride, wherein the molar ratio of N,N,N'-trimethylhydrazine and hydrochloric acid is 1:1.5, N,N,N'-trimethylhydrazine Hydrochloride is a solid crystalline compound, 其中，第一甲醛类化合物和第一氢源的定义同权利要求1；Wherein, the definitions of the first formaldehyde compound and the first hydrogen source are the same as in claim 1; 其中，第二催化剂和第二氢源的定义同权利要求1；Wherein, the definitions of the second catalyst and the second hydrogen source are the same as in claim 1; 其中，第二甲醛类化合物的定义同权利要求1。Wherein, the definition of the second formaldehyde compound is the same as in claim 1. 40.根据权利要求1或39所述的制备方法，所述式Ⅳ化合物在HCl的存在下进行反应得到N,N,N'-三甲基肼盐酸盐的反应在有机溶剂的存在下进行，所述有机溶剂选自甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、1,4-二氧六环、丙酮、丁酮、戊酮、环戊酮、己酮、环己酮、乙醚、乙酸乙酯、乙酸丁酯、四氢呋喃、二氯甲烷、三氯甲烷、四氯化碳、乙腈、苯、甲苯或二甲苯的一种或一种以上。40. The preparation method according to claim 1 or 39, wherein the reaction of the compound of formula IV in the presence of HCl to obtain N,N,N'-trimethylhydrazine hydrochloride is carried out in the presence of an organic solvent , the organic solvent is selected from methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, 1,4-dioxane, acetone, butanone, pentanone, cyclopentanone , one or more of hexanone, cyclohexanone, ether, ethyl acetate, butyl acetate, tetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, benzene, toluene or xylene. 41.根据权利要求40的制备方法，所述有机溶剂为乙酸乙酯。41. The preparation method according to claim 40, wherein the organic solvent is ethyl acetate. 42.根据权利要求41的制备方法，在式Ⅳ化合物进行反应得到N,N,N'-三甲基肼盐酸盐的步骤中，所述反应是将HCl的有机溶剂溶液与式Ⅳ化合物的有机溶剂溶液混合进行的。42. According to the preparation method of claim 41, in the step that the compound of formula IV is reacted to obtain N,N,N'-trimethylhydrazine hydrochloride, the reaction is to combine the organic solvent solution of HCl with the compound of formula IV. The organic solvent solution is mixed. 43.根据权利要求42的制备方法，在式Ⅳ化合物进行反应得到N,N,N'-三甲基肼盐酸盐的步骤中，式Ⅳ化合物与HCl的摩尔比为1：0.1-1：100。43. According to the preparation method of claim 42, in the step that the compound of formula IV is reacted to obtain N,N,N'-trimethylhydrazine hydrochloride, the molar ratio of the compound of formula IV to HCl is 1:0.1-1: 100. 44.根据权利要求43的制备方法，在式Ⅳ化合物进行反应得到N,N,N'-三甲基肼盐酸盐的步骤中，式Ⅳ化合物与HCl的摩尔比为1：1-1：10。44. According to the preparation method of claim 43, in the step that the compound of formula IV is reacted to obtain N,N,N'-trimethylhydrazine hydrochloride, the mol ratio of the compound of formula IV to HCl is 1:1-1: 10. 45.根据权利要求44的制备方法，在式Ⅳ化合物进行反应得到N,N,N'-三甲基肼盐酸盐的步骤中，式Ⅳ化合物与HCl的摩尔比为1：6.2。45. The preparation method according to claim 44, in the step of reacting the compound of formula IV to obtain N,N,N'-trimethylhydrazine hydrochloride, the molar ratio of the compound of formula IV to HCl is 1:6.2. 46.根据权利要求1或39所述的制备方法，在式Ⅳ化合物进行反应得到N,N,N'-三甲基肼盐酸盐的步骤中，反应温度为-78-50℃。46. The preparation method according to claim 1 or 39, in the step of reacting the compound of formula IV to obtain N,N,N'-trimethylhydrazine hydrochloride, the reaction temperature is -78-50°C. 47.根据权利要求46的制备方法，在式Ⅳ化合物进行反应得到N,N,N'-三甲基肼盐酸盐的步骤中，反应温度为-15-15℃。47. The preparation method according to claim 46, in the step of reacting the compound of formula IV to obtain N,N,N'-trimethylhydrazine hydrochloride, the reaction temperature is -15-15°C. 48.根据权利要求47的制备方法，在式Ⅳ化合物进行反应得到N,N,N'-三甲基肼盐酸盐的步骤中，反应温度为0℃。48. The preparation method according to claim 47, in the step of reacting the compound of formula IV to obtain N,N,N'-trimethylhydrazine hydrochloride, the reaction temperature is 0°C.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1288467A (en) * 1998-01-16 2001-03-21 诺沃挪第克公司 Compounds with growth hormone releasing properties
CN1863763A (en) * 2003-08-08 2006-11-15 拉卓拉药物公司 Inhibitors of semicarbazide-sensitive amine oxidase (SSAO) and vap-1 mediated adhesion useful for treatment of diseases
CN102812037A (en) * 2009-10-30 2012-12-05 特兰齐姆制药公司 Macrocyclic Ghrelin Receptor Antagonists And Inverse Agonists And Methods Of Using The Same

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA73530C2 (en) * 1999-11-10 2005-08-15 Ново Нордіск А/С A compound having properties to release the growth hormone

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1288467A (en) * 1998-01-16 2001-03-21 诺沃挪第克公司 Compounds with growth hormone releasing properties
CN1863763A (en) * 2003-08-08 2006-11-15 拉卓拉药物公司 Inhibitors of semicarbazide-sensitive amine oxidase (SSAO) and vap-1 mediated adhesion useful for treatment of diseases
CN102812037A (en) * 2009-10-30 2012-12-05 特兰齐姆制药公司 Macrocyclic Ghrelin Receptor Antagonists And Inverse Agonists And Methods Of Using The Same

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
An Efficient Synthesis of Substituted Hydrazides;David J. Benstead等;《Synlett》;20051231(第10期);1571-1574 *
Novel Azapeptide Inhibitors of Hepatitis C Virus Serine Protease;Murray D. Bailey等;《J. Med. Chem.》;20041231;第47卷;3788-3799 *
Nβ-Fmoc-Nβ-Methyl-aza- β3-amino Acids;Ksenija Kisseljova等;《SYNLETT》;20111231(第3期);327-331 *
Use of Polyanions for Alkylation of Hydrazine Derivatives;Aleksei Bredih hin等;《Org. Lett.》;20071231;第9卷(第24期);4975-4977 *

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