CN108129357A - The preparation method of anamorelin intermediate - Google Patents
The preparation method of anamorelin intermediate Download PDFInfo
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- CN108129357A CN108129357A CN201611091396.0A CN201611091396A CN108129357A CN 108129357 A CN108129357 A CN 108129357A CN 201611091396 A CN201611091396 A CN 201611091396A CN 108129357 A CN108129357 A CN 108129357A
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- MDNZPLXDDBDLIY-UHFFFAOYSA-N CCC(C)CN(C(OC(C)(C)C)=O)N(C)C Chemical compound CCC(C)CN(C(OC(C)(C)C)=O)N(C)C MDNZPLXDDBDLIY-UHFFFAOYSA-N 0.000 description 1
- 0 CNN(C)*(C1(Cc2ccccc2)CN(*)CCC1)=O Chemical compound CNN(C)*(C1(Cc2ccccc2)CN(*)CCC1)=O 0.000 description 1
Classifications
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- 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
- C07C281/04—Compounds containing any of the groups, e.g. carbazates the other nitrogen atom being further doubly-bound to a carbon atom
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- 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
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- 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
Abstract
This application involves pharmaceutical synthesis field, in particular to the preparation method of anamorelin intermediate.One side the application is using 1 boc, 1 methyl hydrazines as reaction raw materials, it is treated different things alike using the method for benzaldehyde compound and palladium catalyst/hydrogen source alternation response and prepares key intermediate N, N', N' trimethyl hydrazine carboxylic acid's tert-butyl esters, this method is easy to operate, raw materials used safety is easy to get, and yield improves compared with art methods；On the other hand, the present processes are by N, N', N' the trimethyl hydrazine carboxylic acid tert-butyl ester react in organic solvent with hydrochloric acid, can directly obtain the N of high-purity in high yield, N, the crystalline product of N' trimethyl hydrazine hydrochlorides, the crystallized product need not be further purified, and hygroscopicity is small, convenient for preserving, it is very suitable for industrial big production.
Description
Technical field
This application involves pharmaceutical synthesis field, in particular to the preparation method of anamorelin intermediate.
Background technology
Anamorelin (Anamorelin) is a kind of ghrelin receptor agonist, limited by the pungent medical share in Hull
Company (Helsinn) researches and develops, and apositia, cachexia or unexpected weight are exploited in Patients with Non-small-cell Lung
The treatment of mitigation.
The preparation method of anamorelin disclosed in WO01034593 relates generally to following steps at present：
Raw material N therein, N, N'- trimethyl hydrazines are the important intermediate of anamorelin synthesis and many noval chemical compounds
Important intermediate needed for entity synthesis.
For N, N, the synthesis of N'- trimethyls hydrazine or salt, prior art discloses following methods：
Route one：Silvina etc. (Organic Process Research＆Development 2004,8,360-362)
With 1,1- dimethylhydrazines for raw material, through formylated, LiAlH4Reduction, obtains N, N, N'- trimethyl hydrazines：
Route two：CLASS etc. (J.Am.Chem.Soc., 1953,75 (12), 2937-2939) using 1,1- dimethylhydrazines as
Raw material, through generating imines, LiAlH4Reduction, obtains N, N, N'- trimethyl hydrazines：
Raw materials used 1, the 1- dimethylhydrazines low boiling point of both the above route, severe toxicity is inflammable and explosive, stores transport difficult, price
It is expensive, it is difficult to obtain；Obtained trimethyl hydrazine is stored in organic solution, can not be preserved for a long time, can only now-making-now-using；It utilizes
For acid into after salt, it is grease to obtain, and can not obtain crystalline compounds, is not suitable for industrialized production.
Route three：Michael etc. (Eur.J.Med.Chem.35 (2000) 487-497) is with Boc-NHNH2For raw material, profit
N is obtained with NaH and iodomethane, N', N'- trimethyl hydrazine carboxylic acid's tert-butyl esters, N, N, N'- tri- is obtained by the reaction in the product and trifluoroacetic acid
Methyl hydrazine trifluoroacetate：
The NaH that the method step 1 uses belongs to inflammable dangerous goods, and anhydrous and oxygen-free, low temperature is needed to react for a long time,
Condition is harsh, and need to be further purified by column chromatography, and yield is low；The N that step 2 obtains, N, N'- trimethyl hydrazine trifluoroacetates
For grease.
Route four：WO01034593 discloses N, N, and the preparation of N'- trimethyl hydrazine dihydrochlorides is with 1,1- dimethylhydrazines
Raw material, through formylated, LiAlH4Reduction, obtains N, N, N'- trimethyl hydrazines, then in HCl/CH3N, N, N'- are obtained under conditions of OH
Trimethyl hydrazine dihydrochloride：
This method step 1 reaction time is long, and step 3 needs the N for preparing step 2, N, after the distillation of N'- trimethyls hydrazine,
With HCl into salt under condition of ultralow temperature, condition is harsh, cumbersome, and obtained product is at room temperature grease, and rear two-step reaction is received
Rate is low, and the product very moisture absorption, is not suitable for industrialized production.
Invention content
On the one hand, the present invention provides a kind of preparation method of IV compound of formula, including：In the first benzaldehyde compound,
In the presence of one catalyst and the first hydrogen source, III compound of formula carries out that IV compound of formula is obtained by the reaction,
Wherein described first benzaldehyde compound is selected from formaldehyde or paraformaldehyde, preferably paraformaldehyde.
Wherein described first catalyst be palladium catalyst or Raney nickel, preferably Pd (OH)2/C、Pd/C、PdCl2, Pd or
Pd(OH)2, most preferably Pd/C.
It should be appreciated that the palladium catalyst of the present invention can also be the various palladium complexes that various palladium catalysts are prepared with ligand
Compound, the ligand include but not limited to PCy3、AsPh3、n-Bu3P、(MeO)3P、Ph2P(CH2)2PPh2(dppe) or Ph2P
(CH2)3PPh2(dppp)。
Wherein described first hydrogen source is selected from H2、HCOOH、HCOONH4、NH2NH2Or cyclohexene, preferably H2。
Wherein described reaction carries out in the presence of the solvent.
In some embodiments of the application, H is used2Pressure for 0.1-100atm, preferably 1-20atm, it is optimal
It is selected as 9.8atm.
In some embodiments of the application, in the step of III compound of formula carries out that IV compound of formula is obtained by the reaction,
It can select suitable reaction dissolvent as needed, the solvent is selected from water, methanol, ethyl alcohol, propyl alcohol, isopropanol, n-butanol, different
Butanol, the tert-butyl alcohol, 1,4- dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, butanone, pentanone, cyclopentanone, hexanone, hexamethylene
Ketone, ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene,toluene,xylene, dichloromethane, chloroform, tetrachloro
Change the one or more in carbon, n,N-Dimethylformamide, n,N-dimethylacetamide or dimethyl sulfoxide (DMSO), preferably first
One or more in alcohol, ethyl alcohol, propyl alcohol, isopropanol, n-butanol, isobutanol or the tert-butyl alcohol, most preferably ethyl alcohol.
In some embodiments of the application, in the step of III compound of formula carries out that IV compound of formula is obtained by the reaction,
It can select suitable reaction temperature as needed, the boiling point that reaction temperature arrives reaction system for 0 DEG C, such as reaction temperature is
25-120 DEG C, preferably 50-90 DEG C；In some specific embodiments of the application, the reaction temperature is 60 DEG C.
It should be appreciated that reaction temperature is not above the boiling point of reaction system.
In some embodiments of the application, in the step of III compound of formula carries out that IV compound of formula is obtained by the reaction,
III compound of formula can select suitable molar ratio, III compound of formula and the first formaldehyde as needed with the first benzaldehyde compound
The molar ratio of class compound is represented with the molar ratio of III compound of formula and formaldehyde, can be 1：0.01-1：100, or 1：
2-1：8, for example, in some specific embodiments of the application, III compound of formula and the molar ratio of the first benzaldehyde compound
1 is expressed as with the molar ratio of III compound of formula and formaldehyde：3-1：5.
In some embodiments of the application, in the step of III compound of formula carries out that IV compound of formula is obtained by the reaction,
III compound of formula can select suitable molar ratio as needed with the first catalyst, and III compound of formula is rubbed with the first catalyst
You are than that can be 1：0.001-1：100, or 1：0.01-1：0.1.For example, in some specific embodiments of the application
In, the molar ratio of III compound of formula and the first catalyst is 1：0.04-1：0.08.
In some embodiments of the application, in the step of III compound of formula carries out that IV compound of formula is obtained by the reaction,
The suitable reaction time can be selected as needed, such as the reaction time is 0.1-24 hours.In some specific implementations of the present invention
In mode, the reaction time is 4 hours.
In some embodiments of the application, the preparation method of IV compound of formula is still further comprised from reaction system
The step of IV compound of separate type；In some specific embodiments of the application, the step of IV compound of separate type, is
It is separated by distillation IV compound of formula.
In some embodiments of the application, further include what reaction system was concentrated before IV compound of separate type
Step.
In some embodiments of the application, further included before IV compound of separate type and remove catalyst in reaction system
The step of；Preferably, first reaction system is concentrated before the step of removing catalyst in reaction system.
On the other hand, the present invention provides a kind of preparation method of III compound of formula, including：In the second catalyst and the second hydrogen
In the presence of source, Formula II compound carries out that III compound of formula is obtained by the reaction,
Wherein described second catalyst be palladium catalyst or Raney nickel, preferably Pd (OH)2/C、Pd/C、PdCl2, Pd or
Pd(OH)2, most preferably Pd/C.
It should be appreciated that the palladium catalyst of the present invention can also be the various palladium complexes that various palladium catalysts are prepared with ligand
Compound, the ligand include but not limited to PCy3、AsPh3、n-Bu3P、(MeO)3P、Ph2P(CH2)2PPh2(dppe) or Ph2P
(CH2)3PPh2(dppp)。
Wherein described second hydrogen source is selected from H2、HCOOH、HCOONH4、NH2NH2Or cyclohexene, preferably H2。
Wherein described reaction carries out in the presence of the solvent.
In some embodiments of the application, H is used2Pressure for 0.1-100atm, preferably 1-20atm, it is optimal
It is selected as 9.8atm.
In some embodiments of the application, in the step of Formula II compound carries out that III compound of formula is obtained by the reaction,
It can select suitable reaction dissolvent as needed, the solvent is selected from water, methanol, ethyl alcohol, propyl alcohol, isopropanol, n-butanol, different
Butanol, the tert-butyl alcohol, 1,4- dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, butanone, pentanone, cyclopentanone, hexanone, hexamethylene
Ketone, ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene,toluene,xylene, dichloromethane, chloroform, tetrachloro
Change the one or more in carbon, n,N-Dimethylformamide, n,N-dimethylacetamide or dimethyl sulfoxide (DMSO), preferably first
One or more in alcohol, ethyl alcohol, propyl alcohol, isopropanol, n-butanol, isobutanol or the tert-butyl alcohol, most preferably ethyl alcohol.
In some embodiments of the application, in the step of Formula II compound carries out that III compound of formula is obtained by the reaction,
Formula II compound can select suitable molar ratio as needed with the second catalyst, and Formula II compound is rubbed with the second catalyst
You are than that can be 1：0.001-1：100, or 1：0.01-1：0.1.For example, in some specific embodiments of the application
In, the molar ratio of Formula II compound and the second catalyst is 1：0.04-1：0.08.
In some embodiments of the application, in the step of Formula II compound carries out that III compound of formula is obtained by the reaction,
It can select suitable reaction temperature as needed, the boiling point that reaction temperature arrives reaction system for 0 DEG C, such as reaction temperature is
25-120 DEG C, preferably 50-90 DEG C；In some specific embodiments of the application, the reaction temperature is 60 DEG C.
In some embodiments of the application, in the step of Formula II compound carries out that III compound of formula is obtained by the reaction,
The suitable reaction time can be selected as needed, such as the reaction time is 0.1-24 hours.In some specific implementations of the present invention
In mode, the reaction time is 4 hours.
In some embodiments of the application, III compound of formula being prepared can be used to prepare formula IV without isolation
Compound.
In another aspect, the present invention provides a kind of preparation method of Formula II compound, including：In the second benzaldehyde compound
In the presence of, type I compound carries out that Formula II compound is obtained by the reaction,
Wherein described second benzaldehyde compound is selected from formaldehyde or paraformaldehyde, preferably paraformaldehyde.
Wherein described reaction carries out in the presence of the solvent.
It, can in the step of type I compound carries out that Formula II compound is obtained by the reaction in some embodiments of the application
To select suitable reaction dissolvent as needed, the solvent is selected from water, methanol, ethyl alcohol, propyl alcohol, isopropanol, n-butanol, isobutyl
Alcohol, the tert-butyl alcohol, 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, dichloromethane, chloroform, four chlorinations
One or more in carbon, n,N-Dimethylformamide, n,N-dimethylacetamide or dimethyl sulfoxide (DMSO), preferably first
One or more in alcohol, ethyl alcohol, propyl alcohol, isopropanol, n-butanol, isobutanol or the tert-butyl alcohol, most preferably ethyl alcohol.
It, can in the step of type I compound carries out that Formula II compound is obtained by the reaction in some embodiments of the application
It is 25- to select suitable reaction temperature, the boiling point that reaction temperature arrives reaction system for 0 DEG C, such as reaction temperature as needed
120 DEG C, preferably 50-90 DEG C；In some specific embodiments of the application, the reaction temperature is 80 DEG C.
In some embodiments of the application, in the step of type I compound carries out that Formula II compound is obtained by the reaction, formula
I compound can select suitable molar ratio, type I compound and the second formaldehydes as needed with the second benzaldehyde compound
The molar ratio for closing object is represented with the molar ratio of type I compound and formaldehyde, can be 1：0.01-1：100, or 1：1-1：5.
For example, in some specific embodiments of the application, type I compound and the molar ratio of the second benzaldehyde compound are changed with formula I
The molar ratio for closing object and formaldehyde is expressed as 1：1.
It, can in the step of type I compound carries out that Formula II compound is obtained by the reaction in some embodiments of the application
To select the suitable reaction time as needed, such as the reaction time is 0.1-48 hours, preferably 12-24 hours.In this hair
In some bright specific embodiments, the reaction time is 24 hours.
In some embodiments of the application, the Formula II compound being prepared can be used to prepare formula III without isolation
Compound.
Further aspect, the present invention provide a kind of preparation method of IV compound of formula, including step (i), (ii) and (iii),
Or step (a), (b) and (c)：
(i) in the presence of the second benzaldehyde compound, type I compound carries out that Formula II compound is obtained by the reaction；
(ii) in the presence of the second catalyst and the second hydrogen source, Formula II compound carries out that III compound of formula is obtained by the reaction；
(iii) in the presence of the first benzaldehyde compound, the first catalyst and the first hydrogen source, III compound of formula carries out anti-
It should obtain IV compound of formula；
(a) type I compound is reacted with the second benzaldehyde compound；
(b) the second catalyst is added in into the system of step (a) and the second hydrogen source is reacted；
(c) it adds in the first benzaldehyde compound into the system of step (b) and the first hydrogen source is carried out formula IV is obtained by the reaction and be changed
Close object；
Wherein, the first benzaldehyde compound, the second benzaldehyde compound, the first catalyst, the second catalyst, the first hydrogen source
And second hydrogen source it is defined as described above.
In some embodiments of the application, H is used2Pressure for 0.1-100atm, preferably 1-20atm, it is optimal
It is selected as 9.8atm.
In some embodiments of the application, the first benzaldehyde compound and the second benzaldehyde compound are identical.
In some embodiments of the application, the first catalyst and the second catalyst are identical；In some tools of the present invention
In body embodiment, the second catalyst of step (ii) is further used as the first catalyst of step (iii).
In some embodiments of the application, the first hydrogen source and the second hydrogen source are identical.
In some embodiments of the application, step (i), step (ii) and step (iii) are molten using identical reaction
Agent；Step (a), step (b) and step (c) use identical reaction dissolvent；The solvent be selected from water, methanol, ethyl alcohol, propyl alcohol,
Isopropanol, n-butanol, isobutanol, the tert-butyl alcohol, 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, dichloromethane
One kind in alkane, chloroform, carbon tetrachloride, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or dimethyl sulfoxide (DMSO) or
More than one, preferably one or more in methanol, ethyl alcohol, propyl alcohol, isopropanol, n-butanol, isobutanol or the tert-butyl alcohol,
Most preferably ethyl alcohol.
In some embodiments of the application, the process of step (i) to step (ii) does not undergo separate type II chemical combination
The step of object.
In some embodiments of the application, step (i) is without the step of experience filtering, concentration and separate type II compounds
Suddenly.
In some embodiments of the application, the process of step (ii) to step (iii) does not undergo separate type III and changes
The step of closing object.
In some embodiments of the application, step (ii) is without experience filtering, concentration and III compound of separate type
Step.
In some embodiments of the application, step (i) or step (a) can select suitably to react temperature as needed
Degree, the boiling point that reaction temperature arrives reaction system for 0 DEG C, such as reaction temperature are 25-120 DEG C, preferably 50-90 DEG C；In this Shen
In some specific embodiments please, the reaction temperature is 80 DEG C.
In some embodiments of the application, in step (i) or step (a), type I compound and the second formaldehydes chemical combination
Object can select suitable molar ratio as needed, and the molar ratio of type I compound and the second benzaldehyde compound is with type I compound
It is represented with the molar ratio of formaldehyde, can be 1：0.01-1：100, or 1：1-1：5.For example, some in the application are specific
In embodiment, type I compound and the molar ratio of the second benzaldehyde compound are expressed as with the molar ratio of type I compound and formaldehyde
1：1.
In some embodiments of the application, in step (i) or step (a), it can select as needed suitable anti-
Between seasonable, such as the reaction time is 0.1-48 hours, preferably 12-24 hours.In some specific embodiments of the invention, instead
It is 24 hours between seasonable.
In some embodiments of the application, in step (ii) or step (b), the mole of the second catalyst is with formula I
Compound and the molar ratio of the second catalyst represent can be 1：0.001-1：100, or 1：0.01-1：0.1.For example,
In some specific embodiments of the application, the mole of the second catalyst is with type I compound and mole of the second catalyst
Than being expressed as 1：0.03.
In some embodiments of the application, in step (ii) or step (b), it can select as needed suitable anti-
It is 25-120 DEG C, preferably 50-90 DEG C to answer temperature, the boiling point that reaction temperature arrives reaction system for 0 DEG C, such as reaction temperature；
In some specific embodiments of the application, the reaction temperature is 60 DEG C.
In some embodiments of the application, in step (ii) or step (b), it can select as needed suitable anti-
Between seasonable, such as the reaction time is 0.1-24 hours.In some specific embodiments of the application, the reaction time is 4 hours.
In some embodiments of the application, in step (iii) or step (c), it is suitable to select as needed
Reaction temperature, the boiling point that reaction temperature arrives reaction system for 0 DEG C, such as reaction temperature are 25-120 DEG C, preferably 50-90 DEG C；
In some specific embodiments of the application, the reaction temperature is 60 DEG C.
In some embodiments of the application, in step (iii) or step (c), the first benzaldehyde compound mole
It is represented with the molar ratio of type I compound and formaldehyde, can be 1：0.01-1：100, or 1：2-1：8, for example, in this Shen
In some specific embodiments please, the first benzaldehyde compound mole is expressed as with the molar ratio of type I compound and formaldehyde
1：3.
In some embodiments of the application, in step (iii) or step (c), the mole of the first catalyst is with formula I
Compound and the molar ratio of the first catalyst represent, can be 1：0.001-1：100, or 1：0.01-1：0.1.For example,
In some specific embodiments of the application, the mole of the first catalyst is with type I compound and mole of the first catalyst
Than representing about 1：0.04.
In some embodiments of the application, in step (iii) or step (c), it is suitable to select as needed
Reaction time, such as reaction time are 0.1-24 hours.In some specific embodiments of the invention, the reaction time is 4 hours.
In another aspect, this application provides a kind of N, N, the preparation method of N'- trimethyl hydrazine hydrochlorides, including：Formula IV is changed
Object is closed to carry out that N, N, N'- trimethyl hydrazine hydrochlorides is obtained by the reaction in the presence of HCl.
Wherein described N, N, in N'- trimethyl hydrazine hydrochlorides, N, N, the molar ratio of N'- trimethyls hydrazine and hydrochloric acid is about 1:1-
1:2；In some specific embodiments of the present invention, N, N, the molar ratio of N'- trimethyls hydrazine and hydrochloric acid is about 1:1.5.
Wherein described reaction carries out in presence of organic solvent, and the organic solvent is selected from methanol, ethyl alcohol, propyl alcohol, different
Propyl alcohol, n-butanol, isobutanol, the tert-butyl alcohol, 1,4- dioxane, acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, second
Ether, ethyl acetate, butyl acetate, tetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, benzene, toluene or dimethylbenzene
One or more；In certain specific embodiments of the invention, organic solvent is selected from ethyl acetate.
In some embodiments of the application, carry out that N, N, N'- trimethyls hydrazonium salt acid is obtained by the reaction in IV compound of formula
In the step of salt, the molar ratio of IV compound of formula and HCl are 1：0.1-1：100, preferably 1：1-1：10；In some of the application
In specific embodiment, the molar ratio of IV compound of formula and HCl are 1：6.2.
In some embodiments of the application, carry out that N, N, N'- trimethyls hydrazonium salt acid is obtained by the reaction in IV compound of formula
In the step of salt, suitable reaction temperature can be selected as needed, and reaction temperature is -78-50 DEG C, preferably -15-15 DEG C；
In some specific embodiments of the application, the reaction temperature is 0 DEG C.
In some embodiments of the application, carry out that N, N, N'- trimethyls hydrazonium salt acid is obtained by the reaction in IV compound of formula
In the step of salt, the reaction is that the organic solvent solution of HCl is mixed to what is carried out with the organic solvent solution of IV compound of formula；
Preferably, the reaction is that the ethyl acetate solution of HCl is mixed to what is carried out with the ethyl acetate solution of IV compound of formula.At this
In some specific embodiments of invention, the reaction is the acetic acid that the ethyl acetate solution of HCl is added drop-wise to IV compound of formula
It is carried out in ethyl ester solution.
In some embodiments of the application, the N that is prepared, N, N'- trimethyls hydrazine hydrochloride are solid chemical compound.
In some embodiments of the application, the N that is prepared, N, N'- trimethyls hydrazine hydrochloride are solid crystal
Close object.
In some embodiments of the application, N is prepared, the step of N, N'- trimethyl hydrazine hydrochlorides still further comprises
The step of filtering.
All solvents used in this application or reagent are commercially available, and can be used without being further purified.
In this application, mass spectrum is measured in Q-tof mass spectrographs.It is operated under positive or negative pattern that there are one mass spectrograph outfits
Electric spray ion source (ESI).Tlc silica gel plate is efficient using (5 × 20cm) of Yantai Jiang You silica gel development corporation, Ltd.
Tlc silica gel prefabricated board.
In this application, Boc represents tertbutyloxycarbonyl；NaH represents sodium hydride；LiAlH4Represent Lithium Aluminium Hydride；HCl is represented
Hydrogen chloride；Pd/C represents palladium carbon；Atm is pressure unit, represents standard atmospheric pressure, such as 1atm represents 1 standard atmospheric pressure；
TLC represents thin-layer chromatography.
This application provides a kind of N, N, the preparation method of N'- trimethyls hydrazine hydrochloride and its intermediate, on the one hand this Shen
Please using 1-boc-1- methyl hydrazines as reaction raw materials, the method one of benzaldehyde compound and palladium catalyst/hydrogen source alternation response is utilized
Pot cooks standby key intermediate N, N', N'- trimethyl hydrazine carboxylic acid's tert-butyl ester, and this method is easy to operate, and raw materials used safety is easy to get,
Yield improves compared with art methods；On the other hand, the present processes are by N, N', N'- trimethyl hydrazine carboxylic acid's tert-butyl esters
Reacted in organic solvent with hydrochloric acid, can directly high-purity obtains N in high yield, N, the crystallization productions of N'- trimethyl hydrazine hydrochlorides
Product, the crystallized product need not be further purified, and hygroscopicity is small, convenient for preserving, be very suitable for industrial big production.
Description of the drawings
The N of Fig. 1 embodiments 2, N, the TLC figures of N'- trimethyl hydrazine hydrochlorides.
The N of Fig. 2 comparative examples 1, N, the TLC figures of N'- trimethyl hydrazines.
Specific embodiment
It is further illustrated the present invention below with embodiment, but the present invention is not intended to be limited thereto.It is not noted in the following example
The experimental method of bright actual conditions, usually according to normal condition or according to the normal condition proposed by manufacturer.
The preparation of 1 1-boc-1- methyl hydrazines (type I compound) of reference example
With reference to the synthetic method (such as method disclosed in WO2007139346) of the prior art, preparation method is as follows：
7.2g methylsulfuric acids hydrazine (49.9mmol) is added in 144ml water, is cooled to 5 DEG C, adds in 4.6g NaHCO3Gu
Body adjusts pH to 10 with NaOH aqueous solutions, 144ml (Boc) is added dropwise thereto2The tetrahydrofuran solution of O (49.95mmol), is stirred
Mix 12h, TLC monitorings the reaction was complete (solvent：Petrol ether/ethyl acetate=2/1).Ethyl acetate extracts (100ml × 3), closes
And organic phase, saturated common salt water washing, anhydrous sodium sulfate drying are concentrated under reduced pressure, obtain colourless transparent liquid type I compound 6.0g
(yield 82%).
The preparation of embodiment 1 N, N', N'- trimethyl the hydrazine carboxylic acid tert-butyl ester (formula IV compound)
By 1-boc-1- methyl hydrazines (13g, 88.9mmol), paraformaldehyde (2.67g, 88.9mmol (in terms of formaldehyde)),
100ml ethyl alcohol adds in reaction bulb, and 80 DEG C are heated to reflux (for 24 hours), and (solvent is completed in TLC monitoring reactions：Petrol ether/ethyl acetate
=2/1) 10% palladium carbon (4g), is added in, is filled with hydrogen (9.8atm), (solvent is completed in 60 DEG C of stirring 4h, TLC monitoring reactions：
Petrol ether/ethyl acetate=2/1).Into above-mentioned steps, the reaction solution containing palladium carbon adds in paraformaldehyde (8.0g, 270mmol
(in terms of formaldehyde)), it is filled with hydrogen (9.8atm), 4h is reacted in 60 DEG C of reduction, TLC monitorings the reaction was complete (solvent：Petroleum ether/second
Acetoacetic ester=2/1).It filters, removes palladium carbon, filtrate decompression is concentrated to give formula IV crude compound, and crude product vacuum distillation obtains formula
IV pure compounds (colourless transparent liquid 7.33g, total recovery 47.3%).ESI-MS(m/z):197[M+Na]+。
The preparation of embodiment 2 N, N, N'- trimethyl hydrazine hydrochloride
The ethyl acetate solution of HCl (2mol/L, 105ml) is added dropwise to formula IV compound (6g, 34.45mmol) under ice bath
Ethyl acetate (20ml) solution in, 30min drops finish, the reaction was complete, filter, obtain the N of solid crystallization way, N, N'- front threes
Base hydrazine hydrochloride (4.4g, yield 99.2%).ESI-MS(m/z):75[M+H]+。
By above-mentioned N, N, N'- trimethyls hydrazine hydrochloride is examined using Thermo FisherICS-1100 ion chromatographs
It surveys, chlorinity is 40.14% in product, N in expression product, N, and the molar ratio of N'- trimethyls hydrazine and hydrochloric acid is 1:1.5.
The preparation of 3 formula of embodiment, VII compound
V compound of formula (25g, 78.3mmol) is dissolved in 250ml dichloromethane, nitrogen protection is cooled to -15 DEG C,
In oxalyl chloride (14g, 110mmol) is added dropwise in reaction system in 40min, system is light yellow；Sequentially add N, N- dimethyl
1.5h is added dropwise in formamide (2.5ml) and triethylamine (14.1g, 139mmol), maintains to react 3.5h between temperature -15~-20 DEG C
Afterwards, TLC detections the reaction was complete (solvent：Petrol ether/ethyl acetate=2/1).At -20 DEG C, in 1.5h into reaction solution plus
Enter the N of the preparation of embodiment 2, N, N'- trimethyls hydrazine hydrochloride (17.3g), then be added dropwise the two of triethylamine (39.6g, 391.5mmol)
Six ring solution of oxygen, system become brown, there is gas generation, and keeping the temperature -20 DEG C of reaction 20h, TLC detection raw materials, the reaction was complete.It rises to
Room temperature, adds water 250ml, stirs liquid separation, and water layer is extracted with dichloromethane (200ml), merges organic phase, with water (2 × 250ml),
Saturated sodium bicarbonate (250ml) and saturated salt solution (250ml) wash successively, anhydrous sodium sulfate drying, filtering, filtrate decompression rotation
Steaming obtains VI compound of 35.6g formulas.
The preparation of comparative example 1 N, N, N'- trimethyl hydrazine
The reference prior art (Silvina etc., Organic Process Research＆Development 2004,8,
Synthetic method disclosed in 360-362) has obtained N, N, Isosorbide-5-Nitrae-dioxane solution of N'- trimethyl hydrazines.
Product purity detection
The N that embodiment 2 is prepared, N, N'- trimethyls hydrazine hydrochloride (are added in methanol, then add in NH3First
Alcoholic solution obtains N, N, the methanol solution of N'- trimethyl hydrazines) and comparative example 1 N, N, the 1,4- of N'- trimethyl hydrazines that are prepared
Dioxane solution detects (TLC testing conditions by TLC respectively：Solvent：Petrol ether/ethyl acetate=2/1；Color condition：
Iodine cylinder), as a result (Fig. 1 is the N of embodiment 2, and N, the TLC figures of N'- trimethyl hydrazine hydrochlorides, Fig. 2 is comparison as depicted in figs. 1 and 2
The N of example 1, N, the TLC figures of N'- trimethyl hydrazines, and the volume containing the sample of Fig. 1 samples is more than the volume containing the sample of Fig. 2 samples), wherein dark
Spot is the colour developing spot of target compound.
The results show that Fig. 2, other than having the colour developing spot of dark target compound, also apparent other light shows
Color spot point illustrates that the purity for the product that embodiment 2 is prepared is substantially better than comparative example 1.
Claims (10)
1. the preparation method of IV compound of formula, including：In the presence of the first benzaldehyde compound, the first catalyst and the first hydrogen source
Under,
III compound of formula carries out that IV compound of formula is obtained by the reaction,
Wherein described first benzaldehyde compound is selected from formaldehyde or paraformaldehyde；
Wherein described first catalyst is selected from palladium catalyst or Raney nickel；
Wherein described first hydrogen source is selected from H2、HCOOH、HCOONH4、NH2NH2Or cyclohexene.
2. the preparation method of claim 1, further includes：In the presence of the second catalyst and the second hydrogen source, Formula II compound into
III compound of formula is obtained by the reaction in row,
Wherein described second catalyst is selected from palladium catalyst or Raney nickel；
Wherein described second hydrogen source is selected from H2、HCOOH、HCOONH4、NH2NH2Or cyclohexene.
3. the preparation method of claim 2, further includes：In the presence of the second benzaldehyde compound, type I compound is reacted
Formula II compound is obtained,
Wherein described second benzaldehyde compound is selected from formaldehyde or paraformaldehyde.
4. the preparation method of IV compound of formula, including step (i), (ii) and (iii)：
(i) in the presence of the second benzaldehyde compound, type I compound carries out that Formula II compound is obtained by the reaction；
(ii) in the presence of the second catalyst and the second hydrogen source, Formula II compound carries out that III compound of formula is obtained by the reaction；
(iii) in the presence of the first benzaldehyde compound, the first catalyst and the first hydrogen source, III compound of formula react
To IV compound of formula；
Wherein, the definition of the first benzaldehyde compound, the first catalyst and the first hydrogen source is the same as claim 1；
Wherein, the definition of the second catalyst and the second hydrogen source is the same as claim 2；
Wherein, the definition of the second benzaldehyde compound is the same as claim 3.
5. the process of the preparation method of claim 4, wherein step (i) to step (ii) does not undergo separate type II compounds
Step.
6. the process of the preparation method of claim 4, wherein step (ii) to step (iii) does not undergo III compound of separate type
The step of.
7. the preparation method of IV compound of formula, including step (a), (b) and (c)：
(a) type I compound is reacted with the second benzaldehyde compound；
(b) the second catalyst is added in into the system of step (a) and the second hydrogen source is reacted；
(c) the first benzaldehyde compound is added in into the system of step (b) and the first hydrogen source carries out that IV compound of formula is obtained by the reaction；
Wherein, the definition of the first benzaldehyde compound and the first hydrogen source is the same as claim 1；
Wherein, the definition of the second catalyst and the second hydrogen source is the same as claim 2；
Wherein, the definition of the second benzaldehyde compound is the same as claim 3.
8. the preparation method of any one of claim 4 or 7, wherein the first benzaldehyde compound and the second benzaldehyde compound phase
Together；Wherein the first hydrogen source and the second hydrogen source are identical.
The preparation method of 9.N, N, N'- trimethyl hydrazine hydrochloride, including：IV compound of formula carries out reacting in the presence of HCl
To obtaining N, N, N'- trimethyl hydrazine hydrochlorides, wherein the N, N, in N'- trimethyl hydrazine hydrochlorides, N, N, N'- trimethyls hydrazine with
The molar ratio of hydrochloric acid is about 1:1-1:2.
10. the preparation method of claim 9, the preparation method system that wherein IV compound of formula passes through any one of claim 1-8
It is standby.
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