CN107056681B - A kind of support method replaces the preparation method of cloth intermediate - Google Patents
A kind of support method replaces the preparation method of cloth intermediate Download PDFInfo
- Publication number
- CN107056681B CN107056681B CN201710200984.1A CN201710200984A CN107056681B CN 107056681 B CN107056681 B CN 107056681B CN 201710200984 A CN201710200984 A CN 201710200984A CN 107056681 B CN107056681 B CN 107056681B
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- compound represented
- structural formula
- structure formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
- C07D211/56—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention discloses the preparation methods that a kind of support method replaces cloth midbody compound 1- benzyl -3- methylamino -4- methyl piperidine dihydrochloride comprising following steps: (1) being deprotected composite structure formula (VI) compound represented 1- benzyl -3- amino -4- methyl piperidine by the chosen property of structure formula (V) compound represented；(2) target compound 1- benzyl -3- methylamino -4- methyl piperidine dihydrochloride shown in structure formula (I) is generated through primary amine Monomethylation as structure formula (VI) compound represented.This method has the characteristics that raw material is easy to get, route is novel, by-product is few, easy to operate, high income.
Description
Technical field
The present invention relates to the preparation methods that a kind of support method replaces cloth intermediate, more particularly to support method to replace cloth intermediate 1- benzyl-
The preparation method of 3- methylamino -4- methyl piperidine dihydrochloride.
Background technique
Support method is for a kind of new oral non-receptor type tyrosine protein kinase (JAK) suppression that cloth is Pfizer Inc.'s research and development
Preparation, its chemical name is 3- ((3R, 4R) -4- methyl -3- (methyl-(7H- pyrrolo- [2,3-d] pyrimidine-4-yl) amino piperazines
Pyridine -1- base) -3- oxo propionitrile, clinically for treating or intolerable moderate insufficient to methotrexate (MTX) response to serious
Active rheumatoid arthritis adult patients.
According to related patents and document report, there is a plurality of alternative preparation support method to replace the route of cloth at present, but produce
The wider synthetic route of upper application is as shown below:
Starting material (3R, 4R)-(1- benzyl -4- methyl piperidine -3- base) methylamine of this route is with 1- benzyl -3- first
Base amino -4- methyl piperidine dihydrochloride is that raw material tears toluoyltartaric (L-DTTA) or tartaric acid chemistry open by L- bis-
It separately wins.Therefore 1- benzyl -3- methylamino -4- methyl piperidine dihydrochloride is in support method for very heavy in the synthesis process of cloth
It wants, the research of preparation method also has great importance and application value.
Currently, there are mainly two types of for the preparation method of 1- benzyl -3- methylamino -4- methyl piperidine dihydrochloride.The
A kind of synthetic route of method is as shown below:
The route selects Lithium Aluminium Hydride as reduction methylating reagent, and risk is big, and reaction condition is harsher, reacts
Journey is not easily controlled, and post-processing is cumbersome, and product isolates and purifies difficulty and the by-product of its catalytic hydrogenation is more, post-processing removal of impurities
It is difficult.
The synthetic route of second method is as shown below:
The route synthesizes 1- benzyl -4- methyl-1 by starting material, and the process yield of 2,5,6- tetrahydropyridines is low, by-product
It is more；Selectivity is low during ethylene linkage is oxidized to alcohol；Addition reaction is carried out with methylamine and is readily generated elimination by-product, is not easy point
From purifying.
It will be apparent to a skilled person that during preparation support method is for cloth intermediate, using different preparation sides
The obtained product purity of method, yield are also different.The registration of drug declare in drug production process, preparation method
Selection be it is vital, because it is related to, whether operating procedure easy, and whether intermediate is easy to purifies and separates, the shape of by-product
At the various aspects problem such as quality of final product, suitable preparation method can be better met industrialization with minimum cost and be needed
It asks.
According to route reported in the literature preparation support method for the double salt of cloth intermediate 1- benzyl -3- methylamino -4- methyl piperidine
Hydrochlorate can exist and isolate and purify the problems such as difficult, yield is low, and column chromatography is needed to carry out purified product in preparation process, be unfavorable for
Industrialized production.
Therefore, there is an urgent need to develop the new method of one kind to synthesize the double hydrochloric acid of 1- benzyl -3- methylamino -4- methyl piperidine
Salt is to meet production needs.
Summary of the invention
It is an object of the invention to provide a kind of synthesis 1- benzyl -3- methyl ammonia in place of overcome the deficiencies in the prior art
The method of base -4- methyl piperidine dihydrochloride.
To achieve the above object, the technical solution used in the present invention are as follows:
A kind of support method replaces the preparation method of cloth intermediate, comprising the following steps:
(1) composite structure Formula IV compound represented 1- benzyl-is deprotected by the chosen property of structural formula V compound represented
3- amino -4- methyl piperidine:
(2) target shown in composite structure Formulas I is generated through primary amine Monomethylation as structural formula VI compound represented
Compound 1- benzyl -3- methylamino -4- methyl piperidine dihydrochloride:
Pass through hydrazine hydrate and the structural formula in the step (1) as the preferred embodiment of the preparation method
V compound represented carries out selectivity in solvent A and is deprotected the generation structural formula VI compound represented.
Preferably, in the step (1), reaction temperature is 25~100 DEG C, and the reaction time is 1~12h, and solvent A is selected from
At least one of ethyl alcohol, methanol, isopropanol, DMF.
Preferably, structure formula (V) compound represented and the molar ratio of hydrazine hydrate are 1:1.0~5.0.
It is highly preferred that the solvent A is ethyl alcohol in the step (1), the reaction temperature is 50~90 DEG C, wherein
Structure formula (V) compound represented and the molar ratio of hydrazine hydrate are 1:1.0~3.0.Most preferably, in the step (1), knot
Structure formula (V) compound represented and the molar ratio of hydrazine hydrate are 1:1.2.Specific reaction equation is as follows:
As the preferred embodiment of the preparation method, in the step (2), existing for catalyst and reducing agent
Under the conditions of, the structural formula VI compound represented and methylating reagent carry out primary amine Monomethylation generation in solvent B
Target compound shown in structural formula I；Wherein, methylating reagent is selected from formaldehyde, paraformaldehyde, dimethyl suflfate, carbonic acid diformazan
At least one of ester；Solvent B is selected from least one of methanol, ethyl alcohol, isopropanol；Catalyst is selected from sodium methoxide, sodium ethoxide
At least one of；Reducing agent is NaBH4；Acid is hydrochloric acid.
Preferably, reaction temperature be 25~90 DEG C, the reaction time be 1~for 24 hours.
Preferably, structural formula VI compound represented and the mole dosage of methylating reagent ratio are 1:1.0~2.0；Structure
Formula IV compound represented and the mole dosage of reducing agent ratio are 1:1.0~3.0；Structural formula VI compound represented and catalyst
Mole dosage ratio be 1:1.0~2.0.
It is highly preferred that the methylating reagent is paraformaldehyde in the step (2), the catalyst is sodium methoxide,
The solvent B is methanol, and the reaction temperature is 40~70 DEG C, wherein the structural formula VI compound represented, poly first
Aldehyde, sodium formate, NaBH4Molar ratio be 1:1.0~1.2:1.0~1.4:1.4~1.6.Most preferably, in the step (2)
In, the structural formula VI compound represented, paraformaldehyde, sodium formate, NaBH4Molar ratio be 1:1.05:1.2:1.5；Institute
It states in the imidization step in amino Monomethylation, the solvent is methanol；Salt in the amino Monomethylation
Change in step, the solvent is isopropanol.Specific reaction equation is as follows:
As the preferred embodiment of the preparation method, the structural formula V compound represented passes through following steps system
:
(11) II compound represented of structural formula generates III compound represented of structural formula through catalytic hydrogenation；
(12) III compound represented of structural formula is reacted in solvent C with phthalic anhydride, obtains structural formula (IV) institute
The compound shown；
(13) benzyl protection is carried out to secondary amine on the basis of IV compound represented of structural formula, obtained shown in structural formula V
Compound.
As the preferred embodiment of the preparation method, in the step (11), the system pressure of catalytic hydrogenation is 4~
8Mpa, reaction temperature are 25~90 DEG C.
Preferably, the catalyst that catalytic hydrogenation uses is Pd/C, and auxiliary catalysis acid is in formic acid, acetic acid, hydrochloric acid
It is at least one；Solvent is selected from least one of methanol, ethyl alcohol.
It is highly preferred that the metallic catalyst is 10%Pd/C (wet) in the step (11), the acid is hydrochloric acid,
The solvent is methanol, and the reaction temperature is 45-55 DEG C, described, and system pressure is 4~8MPa, wherein for every 1mol's
Formula II compound represented, 10%Pd/C (wet) is 100~120g, and hydrochloric acid is 25~40mL.Most preferably, in the step
Suddenly in (11), for the formula II compound represented of every 1mol, it is 108g, hydrochloric acid 30mL that 10%Pd/C is (wet), described
Reaction temperature is 50 DEG C, system pressure 5MPa.Specific reaction equation is as follows:
As the preferred embodiment of the preparation method, in the step (12), reaction temperature is 60~150 DEG C,
Reaction time is 1h~12h；Solvent C is selected from least one of acetic acid, DMF, formic acid, methanol, ethyl alcohol.
Preferably, III compound represented of structural formula and the molar ratio of phthalic anhydride are 1:1.0~2.0.
It is highly preferred that in the step (12), the formula II I compound represented and phthalic anhydride rub
You are than being 1:1~1.2, and the solvent is acetic acid, and the temperature is 118~125 DEG C.Most preferably, in the step (12),
The formula II I compound represented and the molar ratio of phthalic anhydride are 1:1.05.Specific reaction equation is as follows:
As the preferred embodiment of the preparation method, in the step (13), in the presence of a base, structural formula
IV compound represented is reacted in solvent D with benzyl bromine generates structural formula V compound represented；Wherein, reaction temperature be 25~
90 DEG C, the reaction time is 2h~for 24 hours；Solvent D is selected from acetonitrile, tetrahydrofuran, methylene chloride, chloroform etc., and alkali used is selected from
Sodium hydride, sodium methoxide, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, potassium carbonate, at least one in cesium carbonate
Kind；
Preferably, the mole dosage ratio of structural formula IV compound represented and benzyl bromine is 1:1.0~2.0；IV institute of structural formula
The mole dosage ratio of the compound and alkali that show is 1:1.0~3.0.
It is highly preferred that the alkali is triethylamine in the step (13), the solvent is acetonitrile, the reaction temperature
It is 25~40 DEG C, wherein the molar ratio of structural formula IV compound represented, benzyl bromine and triethylamine is 1:1~1.2:1~2.It is optimal
Selection of land, in the step (13), structural formula IV compound represented, the molar ratio of benzyl bromine and triethylamine are as follows: 1:1.01:1.5.
Specific reaction equation is as follows:
As the preferred embodiment of the preparation method, the support method is for cloth intermediate using step system shown in the following figure
:
On the other hand, the present invention also provides one kind, and the support method as shown in structural formula V replaces cloth intermediate:
Compared with prior art, technical solution of the present invention has the advantages that
1, synthesis support method of the present invention replaces cloth intermediate 1- benzyl -3- methylamino -4- methyl piperidine dihydrochloride
Method have the characteristics that raw material is easy to get, route is novel, by-product is few, easy to operate, high income.
2, synthesis support method of the present invention replaces cloth intermediate 1- benzyl -3- methylamino -4- methyl piperidine dihydrochloride
Method, using 3- amino-4-methylpyridine as starting material, directly progress catalytic hydrogenation, can avoid the life of other by-products
At high income；Using phthalic anhydride as amino protecting group, and the mode of hydrazine hydrate Deprotection, selectivity height are secondary
Product is few, is convenient for purifies and separates.On the whole, route high income of the present invention, by-product be few, product is easy to purify, and is
Support method provides new thinking for the preparation of cloth key intermediate (as shown in structural formula I).
Detailed description of the invention:
Fig. 1 is support method of the present invention for cloth intermediate 1- benzyl -3- methylamino -4- methyl piperidine dihydrochloride
The schematic diagram of representative synthetic method.
Specific embodiment
To better illustrate the object, technical solutions and advantages of the present invention, the present invention is made combined with specific embodiments below
It further illustrates.
Prepare embodiment 1: the preparation of compound III
Be arranged experimental group 1~5 distinguish prepare compound III, the method are as follows: by compound II, acid, 100mL solvent,
10%Pd/C (wet) is placed in hydriding reactor, in 4~8MPa hydrogen depress 45~55 DEG C reaction 16~for 24 hours, until not inhaling hydrogen, TLC
Examine raw material fully reacting.It is cooled to room temperature, filters, after filtrate decompression concentration, add ethyl acetate (50mL) to dissolve, with 5% hydrogen
Aqueous solution of sodium oxide tune PH to 12, layering, aqueous layer with ethyl acetate extract 2 times (30mL × 2), merge organic phase, anhydrous slufuric acid
Sodium dries 6h, and compound III is concentrated under reduced pressure to obtain in filtering.The difference of experimental group 1~5 and experimental result are as shown in table 1 below:
Table 1
The characterize data of compound III:1H-NMR (DMSO, 300MHz) δ: 0.89 (d, J=6.3Hz, 3H, CH 3CH)；
1.23~1.26 (m, 2H, CHCH 2CH2)；1.66~1.72 (m, 1H, CH3CH)；2.42~2.44 (m, 1H, CHCH2NH)；2.52
~2.60 (m, 2H, CH2CH 2NH)；2.68~2.72 (m, 1H, CHCH aHbNH)；2.92~2.96 (m, 1H, CHCHa H bNH)；
3.45~3.49 (m, 1H, CHCH2NH)；3.53~3.58 (m, 1H, CHNH2)；6.98 (d, J=8.4Hz, 2H, NH2)。MS(m/
z):115([M+H]+)。
Prepare embodiment 2: the preparation of compound IV
Experimental group 1~6 is set and distinguishes prepare compound III, the method are as follows: compound III, neighbour are added into reaction flask
Phthalate anhydride, 40mL solvent under stirring condition, react 1~12h at 60~150 DEG C, are down to room temperature, it is full that hydrogen chloride is added
The ethanol solution 40mL of sum, stirring 1h to solid are precipitated, and continue to stir 5h, and 0 DEG C stands overnight to solid precipitation filtering completely,
Filter cake is added in the mixed solution of methylene chloride (50mL) and water (20mL), with saturated aqueous sodium carbonate tune pH to 9-10,
Organic phase is collected in extraction, and water phase extracts 2 times (50mL × 2) with methylene chloride, and the dry 6h of anhydrous sodium sulfate is filtered, is concentrated under reduced pressure
Obtain compound IV.The difference of experimental group 1~6 and experimental result are as shown in table 2 below:
Table 2
The characterize data of compound IV:1H-NMR (DMSO, 300MHz) δ: 0.92~0.94 (m, 2H, CH 2aHbCH)；0.99
~1.02 (m, 1H, CH2a H bCH)；1.21~1.24 (m, 2H, CHCH 2CH2)；1.64~1.70 (m, 1H, CH3CH)；2.41~
2.44(m,1H,CHCH2NH)；2.53~2.58 (m, 2H, CH2CH 2NH)；2.68~2.70 (m, 1H, CHCH aHbNH)；2.71~
2.75(m,1H,CHCHa H bNH)；3.41~3.46 (m, 1H, CHCH2NH)；3.59~3.62 (m, 1H, CHN)；7.23~7.32
(m,2H,Ar-H)；7.62~7.70 (m, 2H, Ar-H).MS(m/z):245([M+H]+)。
Prepare embodiment 3: the preparation of compound V
Experimental group 1~6 is set and distinguishes prepare compound V, the method are as follows: compound IV, 60mL are added into reaction flask
The solution (25mL) of the aforementioned solvents of bromobenzyl is added dropwise under ice bath for solvent, alkali, and drop, which finishes, is warmed to room temperature~80 DEG C of reaction 2h, and decompression is dense
Solvent is evaporated off in contracting, and water (50mL), methylene chloride (100mL) is added, and stirs 10min, layering, dichloromethane layer saturated salt solution
2 times (50mL × 2), the organic phase dry 6h of anhydrous sodium sulfate are washed, compound V is concentrated under reduced pressure to obtain in filtering.Experimental group 1~6
Difference and experimental result are as shown in table 3 below:
Table 3
The characterize data of compound V:1H-NMR(DMSO,300MHz)δ:1.02(m,3H,CH 3CH)；1.25~1.29 (m,
2H,CHCH 2CH2)；1.66~1.71 (m, 1H, CH3CH)；2.43~2.46 (m, 1H, CHCH2NH)；2.55~2.59 (m, 2H,
CH2CH 2NH)；2.69~2.71 (m, 1H, CHCH aHbNH)；2.73~2.76 (m, 1H, CHCHa H bNH)；3.42~3.48 (m,
1H,CHCH2NH)；3.50~3.53 (m, 1H, CHN)；3.58~3.60 (s, 2H, Ar-CH2)；7.21~7.34 (m, 7H, Ar-
H)；7.65~7.71 (m, 2H, Ar-H).MS(m/z):386([M+H]+)。
Prepare embodiment 4: the preparation of compound VI
Experimental group 1~6 is set and distinguishes prepare compound VI, the method are as follows: compound V is dissolved in solvent (60mL) and water
In the mixed solution for closing hydrazine, 1~12h is reacted under counterflow condition, is down to room temperature, water 50mL is added, and stirring 1h has solid appearance, mistake
Filter, filtrate decompression concentration, is added the mixed solution of methylene chloride (100mL) and water (50mL), stirs 30min, layering, dichloromethane
For alkane layer with saturated common salt water washing 2 times (50mL × 2), compound VI is concentrated under reduced pressure to obtain in the dry 6h of anhydrous sodium sulfate, filtering.It is real
Difference and the experimental result for testing group 1~6 are as shown in table 4 below:
Table 4
The characterize data of compound VI:1H-NMR (DMSO, 300MHz) δ: 0.93~0.95 (m, 2H, CH 2aHbCH)；1.01
~1.03 (m, 1H, CH2a H bCH)；1.24~1.29 (m, 2H, CHCH 2CH2)；1.63~1.70 (m, 1H, CH3CH)；2.44~
2.48(m,1H,CHCH2NH)；2.53~2.58 (m, 2H, CH2CH 2NH)；2.65~2.68 (m, 1H, CHCH aHbNH)；2.89~
2.93(m,1H,CHCHa H bNH)；3.41~3.47 (m, 1H, CHCH2NH)；3.52~3.55 (m, 1H, CHN)；3.60~3.62
(s,2H,Ar-CH2)；7.21~7.34 (m, 5H, Ar-H).MS(m/z):205([M+H]+)。
Embodiment 1: the preparation of compound I
Experimental group 1~6 is set and distinguishes prepare compound I, the method are as follows: compound VI is dissolved in solvent 20mL, is added
Enter methylating reagent, alkali, 25~90 DEG C of 4~15h of stirring are cooled to 0 DEG C, and sodium borohydride is added, continue at room temperature stirring 1~
3h under condition of ice bath, adds water quenching to go out, and filters, filtrate decompression concentration.Remaining light yellow oil is dissolved in isopropanol, is persistently led to
Enter hydrogen chloride gas, 50 DEG C of reaction 2h are cooled to 0 DEG C of stirring 2h, and solid is precipitated, and filter cake is washed with isopropanol, are dried in vacuo, obtain
Compound I.The difference of experimental group 1~6 and experimental result are as shown in table 5 below:
Table 5
The characterize data of compound I:1H-NMR (DMSO, 300MHz) δ: 0.92 (d, J=6.0Hz, 3H, CH 3CH)；1.10
~1.28 (m, 2H, CHCH 2CH2)；1.54~1.58 (m, 1H, CH3CH)；1.59~1.77 (m, 2H, CH2CH 2N)；1.98~
2.04(m,2H,CHCHa H bN)；2.22~2.24 (s, 3H, CH 3NH)；2.50~2.52 (s, 1H, NH)；2.64~2.69 (m,
2H,CHCH aHbN)；3.02~3.06 (m, 1H, NHCH)；3.35~3.60 (m, 2H, PhCH 2)；7.25~7.36 (m, 5H, Ar-
H)。MS(m/z):219([M+H]+)。
Embodiment 2: the preparation of compound I
(1) preparation of compound III: by 0.1mol compound II, 3.0mL hydrochloric acid, 100mL methanol, 10.8g 10%Pd/
C (wet) is placed in hydriding reactor, depresses 50 DEG C of reaction 20h in 5MPa hydrogen, and until not inhaling hydrogen, TLC examines raw material fully reacting.It is cold
But to room temperature, filtering adds ethyl acetate (50mL) to dissolve, extremely with 5% sodium hydrate aqueous solution tune PH after filtrate decompression concentration
12, layering, aqueous layer with ethyl acetate extracts 2 times (30mL × 2), merges organic phase, and the dry 6h of anhydrous sodium sulfate is filtered, decompression
It is concentrated to give compound III.The yield of compound III is 95.6%
(2) 87.6mmol compound III, 92.0mmol phthalic acid the preparation of compound IV: is added into reaction flask
Acid anhydride, 40mL acetic acid under stirring condition, react 2h at 118 DEG C, are down to room temperature, and the ethanol solution 40mL of hydrogen chloride saturation is added,
It stirs 1h to be precipitated to solid, continues to stir 5h, 0 DEG C stands overnight to solid precipitation completely, and filtering, filter cake is added to methylene chloride
In the mixed solution of (50mL) and water (20mL), with saturated aqueous sodium carbonate tune pH to 9-10, organic phase, water phase are collected in extraction
2 times (50mL × 2), the dry 6h of anhydrous sodium sulfate are extracted with methylene chloride, compound IV is concentrated under reduced pressure to obtain in filtering.Compound IV
Yield be 81.8%.
(3) 61.4mmol compound IV, 60mL acetonitrile, tri- second of 92.1mmol the preparation of compound V: are added into reaction flask
The acetonitrile solution (25mL) of 62.0mmol bromobenzyl is added dropwise under ice bath for amine, and drop, which finishes, is warmed to room temperature reaction 2h, and reduced pressure is evaporated off molten
Water (50mL), methylene chloride (100mL) is added in agent, stirs 10min, layering, dichloromethane layer is with saturated common salt water washing 2 times
Compound V is concentrated under reduced pressure to obtain in (50mL × 2), the organic phase dry 6h of anhydrous sodium sulfate, filtering.The yield of compound V is
90.9%.
(4) 38.9mmol compound V the preparation of compound VI: is dissolved in the mixed of ethyl alcohol (60mL) and 46.7mmol hydrazine hydrate
It closes in solution, reacts 5h under counterflow condition, be down to room temperature, water 50mL is added, stirring 1h has solid appearance, filters, filtrate decompression
The mixed solution of methylene chloride (100mL) and water (50mL) is added in concentration, stirs 30min, layering, dichloromethane layer saturation
Brine It 2 times (50mL × 2), compound VI is concentrated under reduced pressure to obtain in the dry 6h of anhydrous sodium sulfate, filtering.The production of compound VI
Rate is 84.3%.
(5) preparation of compound I: 24.5mmol compound VI is dissolved in methanol 20mL, and 25.7mmol poly first is added
Aldehyde, 29.4mmol sodium methoxide, 60 DEG C of stirring 6h are cooled to 0 DEG C, and 36.7mmol sodium borohydride is added, and continue to stir 2h at room temperature,
Under condition of ice bath, water quenching is added to go out, filtered, filtrate decompression concentration.Remaining light yellow oil is dissolved in isopropanol, is continually fed into chlorine
Change hydrogen, 50 DEG C of reaction 2h are cooled to 0 DEG C of stirring 2h, and solid is precipitated, and filter cake is washed with isopropanol, are dried in vacuo, obtain chemical combination
Object I.The yield of compound I is 85.5%.
Embodiment 3: the preparation of compound I
(1) preparation of compound III: by 0.1mol compound II, 4.0mL hydrochloric acid, 100mL methanol, 12.0g 10%Pd/
C (wet) is placed in hydriding reactor, depresses 55 DEG C of reaction 16h in 8MPa hydrogen, and until not inhaling hydrogen, TLC examines raw material fully reacting.It is cold
But to room temperature, filtering adds ethyl acetate (50mL) to dissolve, extremely with 5% sodium hydrate aqueous solution tune PH after filtrate decompression concentration
12, layering, aqueous layer with ethyl acetate extracts 2 times (30mL × 2), merges organic phase, and the dry 6h of anhydrous sodium sulfate is filtered, decompression
It is concentrated to give compound III.The yield of compound III is 96.2%
(2) 87.6mmol compound III, 96.4mmol phthalic acid the preparation of compound IV: is added into reaction flask
Acid anhydride, 40mL formic acid under stirring condition, react 3h at 101 DEG C, are down to room temperature, and the ethanol solution 40mL of hydrogen chloride saturation is added,
It stirs 1h to be precipitated to solid, continues to stir 5h, 0 DEG C stands overnight to solid precipitation completely, and filtering, filter cake is added to methylene chloride
In the mixed solution of (50mL) and water (20mL), with saturated aqueous sodium carbonate tune pH to 9-10, organic phase, water phase are collected in extraction
2 times (50mL × 2), the dry 6h of anhydrous sodium sulfate are extracted with methylene chloride, compound IV is concentrated under reduced pressure to obtain in filtering.Compound IV
Yield be 81.5%.
(3) 61.4mmol compound IV, 60mL chloroform, 70mmol hydrogen the preparation of compound V: are added into reaction flask
The acetonitrile solution (25mL) of 62.0mmol bromobenzyl is added dropwise under ice bath for sodium oxide molybdena, drips 60 DEG C of reaction 2h of Bi Shengzhi, and reduced pressure is evaporated off
Water (50mL), methylene chloride (100mL) is added in solvent, stirs 10min, layering, dichloromethane layer saturated common salt water washing 2
Compound V is concentrated under reduced pressure to obtain in secondary (50mL × 2), the organic phase dry 6h of anhydrous sodium sulfate, filtering.The yield of compound V is
90.1%.
(4) 38.9mmol compound V the preparation of compound VI: is dissolved in the mixed of methanol (60mL) and 42.8mmol hydrazine hydrate
It closing in solution, reacts 6h at 65 DEG C, be down to room temperature, water 50mL is added, stirring 1h has solid appearance, filters, filtrate decompression concentration,
The mixed solution of methylene chloride (100mL) and water (50mL) is added, stirs 30min, layering, dichloromethane layer saturated salt solution
2 times (50mL × 2), the dry 6h of anhydrous sodium sulfate are washed, compound VI is concentrated under reduced pressure to obtain in filtering.The yield of compound VI is
83.6%.
(5) preparation of compound I: 24.5mmol compound VI is dissolved in methanol 20mL, and 29.4mmol poly first is added
Aldehyde, 34.3mmol sodium methoxide, 40 DEG C of stirring 9h are cooled to 0 DEG C, and 39.2mmol sodium borohydride is added, and continue to stir 2h at room temperature,
Under condition of ice bath, water quenching is added to go out, filtered, filtrate decompression concentration.Remaining light yellow oil is dissolved in isopropanol, is continually fed into chlorine
Change hydrogen, 50 DEG C of reaction 2h are cooled to 0 DEG C of stirring 2h, and solid is precipitated, and filter cake is washed with isopropanol, are dried in vacuo, obtain chemical combination
Object I.The yield of compound I is 82.9%.
Embodiment 4: the preparation of compound I
(1) preparation of compound III: by 0.1mol compound II, 3.0mL acetic acid, 100mL ethyl alcohol, 11.0g 10%Pd/
C (wet) is placed in hydriding reactor, depresses 50 DEG C of reaction 20h in 6MPa hydrogen, and until not inhaling hydrogen, TLC examines raw material fully reacting.It is cold
But to room temperature, filtering adds ethyl acetate (50mL) to dissolve, extremely with 5% sodium hydrate aqueous solution tune PH after filtrate decompression concentration
12, layering, aqueous layer with ethyl acetate extracts 2 times (30mL × 2), merges organic phase, and the dry 6h of anhydrous sodium sulfate is filtered, decompression
It is concentrated to give compound III.The yield of compound III is 89.1%
(2) 87.6mmol compound III, 87.6mmol phthalic acid the preparation of compound IV: is added into reaction flask
Acid anhydride, 40mL acetic acid under stirring condition, react 2h at 125 DEG C, are down to room temperature, and the ethanol solution 40mL of hydrogen chloride saturation is added,
It stirs 1h to be precipitated to solid, continues to stir 5h, 0 DEG C stands overnight to solid precipitation completely, and filtering, filter cake is added to methylene chloride
In the mixed solution of (50mL) and water (20mL), with saturated aqueous sodium carbonate tune pH to 9-10, organic phase, water phase are collected in extraction
2 times (50mL × 2), the dry 6h of anhydrous sodium sulfate are extracted with methylene chloride, compound IV is concentrated under reduced pressure to obtain in filtering.Compound IV
Yield be 79.5%.
(3) 61.4mmol compound IV, 60mL acetonitrile, tri- second of 67.5mmol the preparation of compound V: are added into reaction flask
The acetonitrile solution (25mL) of 73.7mmol bromobenzyl is added dropwise under ice bath for amine, drips 80 DEG C of reaction 1h of Bi Shengzhi, be concentrated under reduced pressure be evaporated off it is molten
Water (50mL), methylene chloride (100mL) is added in agent, stirs 10min, layering, dichloromethane layer is with saturated common salt water washing 2 times
Compound V is concentrated under reduced pressure to obtain in (50mL × 2), the organic phase dry 6h of anhydrous sodium sulfate, filtering.The yield of compound V is
87.5%.
(4) 38.9mmol compound V the preparation of compound VI: is dissolved in the mixed of ethyl alcohol (60mL) and 77.8mmol hydrazine hydrate
It closing in solution, reacts 7h at 50 DEG C, be down to room temperature, water 50mL is added, stirring 1h has solid appearance, filters, filtrate decompression concentration,
The mixed solution of methylene chloride (100mL) and water (50mL) is added, stirs 30min, layering, dichloromethane layer saturated salt solution
2 times (50mL × 2), the dry 6h of anhydrous sodium sulfate are washed, compound VI is concentrated under reduced pressure to obtain in filtering.The yield of compound VI is
81.7%.
(5) preparation of compound I: 24.5mmol compound VI is dissolved in isopropanol 20mL, and 16mmol sulfuric acid two is added
Methyl esters, 29.4mmol sodium methoxide, 83 DEG C of stirring 6h are cooled to 0 DEG C, and 36.7mmol sodium borohydride is added, continues to stir at room temperature
2h under condition of ice bath, adds water quenching to go out, and filters, filtrate decompression concentration.Remaining light yellow oil is dissolved in isopropanol, is persistently led to
Enter hydrogen chloride gas, 50 DEG C of reaction 2h are cooled to 0 DEG C of stirring 2h, and solid is precipitated, and filter cake is washed with isopropanol, are dried in vacuo, obtain
Compound I.The yield of compound I is 83.4%.
Finally, it should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention rather than protects to the present invention
The limitation of range is protected, although the invention is described in detail with reference to the preferred embodiments, those skilled in the art should
Understand, it can be with modification or equivalent replacement of the technical solution of the present invention are made, without departing from the essence of technical solution of the present invention
And range.
Claims (13)
1. the preparation method that a kind of support method replaces cloth intermediate, which comprises the following steps:
(1) composite structure formula (VI) compound represented 1- benzyl-is deprotected by the chosen property of structure formula (V) compound represented
3- amino -4- methyl piperidine:
(2) target chemical combination shown in structure formula (I) is generated through primary amine Monomethylation as structure formula (VI) compound represented
Object 1- benzyl -3- methylamino -4- methyl piperidine dihydrochloride:
Wherein, the structure formula (V) compound represented is made by following steps:
(11) structural formula (II) compound represented generates structural formula (III) compound represented through catalytic hydrogenation:
(12) structural formula (III) compound represented is reacted in solvent C with phthalic anhydride, is obtained shown in structural formula (IV)
Compound:
Solvent C is at least one of acetic acid, DMF, formic acid, methanol, ethyl alcohol；
(13) benzyl protection is carried out to secondary amine on the basis of structural formula (IV) compound represented, obtained shown in structural formula (V)
Compound:
2. preparation method according to claim 1, which is characterized in that in the step (1), by hydrazine hydrate with it is described
Structure formula (V) compound represented carries out selectivity in solvent A and is deprotected the generation structure formula (VI) compound represented,
Solvent A is selected from least one of ethyl alcohol, methanol, isopropanol, DMF.
3. preparation method according to claim 2, which is characterized in that in the step (1), reaction temperature be 25~
100 DEG C, the reaction time is 1~12h.
4. preparation method according to claim 2, which is characterized in that in the step (1), shown in structure formula (V)
The molar ratio of compound and hydrazine hydrate is 1:1.0~5.0.
5. preparation method according to claim 1, which is characterized in that in the step (2), in catalyst and reducing agent
Under the conditions of existing, the structure formula (VI) compound represented and methylating reagent carry out primary amine monomethylation in solvent B
Reaction generates target compound shown in structure formula (I)；
Wherein, methylating reagent is selected from least one of formaldehyde, paraformaldehyde, dimethyl suflfate, dimethyl carbonate；Solvent B
Selected from least one of methanol, ethyl alcohol, isopropanol；Catalyst is selected from least one of sodium methoxide, sodium ethoxide；Reducing agent is
NaBH4。
6. preparation method according to claim 1, which is characterized in that in the step (2), reaction temperature is 25~90
DEG C, the reaction time be 1~for 24 hours.
7. preparation method according to claim 5, which is characterized in that in the step (2), shown in structure formula (VI)
The mole dosage of compound and methylating reagent ratio is 1:1.0~2.0；
Structure formula (VI) compound represented and the mole dosage of reducing agent ratio are 1:1.0~3.0；
Structure formula (VI) compound represented and the mole dosage of catalyst ratio are 1:1.0~2.0.
8. preparation method according to claim 1, which is characterized in that in the step (11), the system pressure of catalytic hydrogenation
Power is 4~8Mpa, and reaction temperature is 25~90 DEG C.
9. preparation method according to claim 1, which is characterized in that in the step (11), what catalytic hydrogenation used is urged
Agent is Pd/C, and auxiliary catalysis is at least one of formic acid, acetic acid, hydrochloric acid with acid.
10. preparation method according to claim 1, which is characterized in that in the step (12), reaction temperature be 60~
150 DEG C, the reaction time is 1h~12h.
11. preparation method according to claim 1, which is characterized in that in the step (12), shown in structural formula (III)
The mole dosage of compound and phthalic anhydride ratio is 1:1.0~2.0.
12. preparation method according to claim 1, which is characterized in that in the step (13), the condition existing for alkali
Under, structural formula (IV) compound represented is reacted in solvent D with benzyl bromine generates structural formula (V) compound represented；
Wherein, reaction temperature is 25~90 DEG C, and the reaction time is 2h~for 24 hours；Solvent D be acetonitrile, tetrahydrofuran, methylene chloride,
Chloroform, alkali used be sodium hydride, sodium methoxide, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, potassium carbonate,
At least one of cesium carbonate.
13. preparation method according to claim 12, which is characterized in that in the step (13), shown in structural formula (IV)
Compound and benzyl bromine mole dosage ratio be 1:1.0~2.0；
The mole dosage ratio of structural formula (IV) compound represented and alkali is 1:1.0~3.0.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710200984.1A CN107056681B (en) | 2017-03-30 | 2017-03-30 | A kind of support method replaces the preparation method of cloth intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710200984.1A CN107056681B (en) | 2017-03-30 | 2017-03-30 | A kind of support method replaces the preparation method of cloth intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107056681A CN107056681A (en) | 2017-08-18 |
| CN107056681B true CN107056681B (en) | 2019-10-01 |
Family
ID=59603023
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710200984.1A Active CN107056681B (en) | 2017-03-30 | 2017-03-30 | A kind of support method replaces the preparation method of cloth intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107056681B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108640923A (en) * | 2018-07-09 | 2018-10-12 | 湖南天地恒制药有限公司 | A kind of support method replaces the preparation method of cloth key intermediate |
| CN111848496B (en) * | 2020-07-28 | 2021-10-08 | 湖南华纳大药厂手性药物有限公司 | Preparation method of tofacitinib intermediate amine and double hydrochloride thereof |
| CN111808017B (en) * | 2020-08-05 | 2023-11-28 | 国家纳米科学中心 | Nitrogen-containing heterocyclic compound, and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010016005A1 (en) * | 2008-08-06 | 2010-02-11 | Pfizer Inc. | 6 substituted 2-heterocyclylamino pyrazine compounds as chk-1 inhibitors |
| CN103896826A (en) * | 2012-12-26 | 2014-07-02 | 上海朴颐化学科技有限公司 | Asymmetric synthesis method of nitrogen protected (3R,4R)-3-methylamino-4-methylpiperidine, and relevant intermediate and raw material preparation method |
| WO2015087201A1 (en) * | 2013-12-09 | 2015-06-18 | Unichem Laboratories Limited | An improved process for the preparation of (3r,4r)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine |
-
2017
- 2017-03-30 CN CN201710200984.1A patent/CN107056681B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010016005A1 (en) * | 2008-08-06 | 2010-02-11 | Pfizer Inc. | 6 substituted 2-heterocyclylamino pyrazine compounds as chk-1 inhibitors |
| CN103896826A (en) * | 2012-12-26 | 2014-07-02 | 上海朴颐化学科技有限公司 | Asymmetric synthesis method of nitrogen protected (3R,4R)-3-methylamino-4-methylpiperidine, and relevant intermediate and raw material preparation method |
| WO2015087201A1 (en) * | 2013-12-09 | 2015-06-18 | Unichem Laboratories Limited | An improved process for the preparation of (3r,4r)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107056681A (en) | 2017-08-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107056681B (en) | A kind of support method replaces the preparation method of cloth intermediate | |
| CN112062767A (en) | Preparation method and intermediate of rumepilone | |
| WO2005044805A1 (en) | A novel process for preparing donepezil and its derivatives | |
| CN109608468B (en) | Tofacitinib citrate impurity, and synthesis method and application thereof | |
| CN103360374A (en) | Synthesis method of vilazodone and salt thereof | |
| CN113292569A (en) | Preparation method of JAK inhibitor | |
| CN107935866B (en) | Preparation method of dapoxetine hydrochloride impurity | |
| CN112430208A (en) | Preparation method of PF-06651600 intermediate | |
| CN105461640A (en) | Preparation method of tyrosine kinase inhibitor | |
| CN109810059A (en) | A kind of preparation method of left-handed hydrochloric acid demethyl benzene ring pelargonate | |
| CN113336761B (en) | Preparation method of JAK inhibitor key intermediate | |
| CN116143599A (en) | Preparation method of high-purity pentoxifylline intermediate | |
| CN108623602A (en) | A method of prepare and purify and replaces Buddhist nun according to Shandong | |
| CN101298448B (en) | Synthetic method of 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-[(tetrahydro-2H-pyrrole-2-oxyl)methyl ] phenol | |
| CN102807516A (en) | Intermediate in amisulpride and method for preparing amisulpride by using intermediate | |
| CN102336676A (en) | New preparation method of dopexamine hydrochloride by ArCHR protection strategy | |
| CN108299466B (en) | Improved dolutegravir synthesis method | |
| MX2011003529A (en) | Thiazolyl-pyrazolopyrimidine compounds as synthetic intermediates and related synthetic processes. | |
| CN112094219A (en) | Method for preparing intermediate of potassium ion competitive retarder | |
| CN112778189A (en) | (3R,4S) -N-substituent-3-carboxylic acid-4-ethyl pyrrolidine, intermediate and lapatinib | |
| CN107628968B (en) | A kind of easy synthesis 1- amino -1- itrile group-cyclopropane method | |
| CN109574860A (en) | A method of preparing Vilantro | |
| CN113717178B (en) | Intermediate of SHP2 inhibitor and preparation method thereof | |
| CN115043845B (en) | Synthesis method of sildenafil | |
| CN108299236B (en) | Synthetic method of alpha-cyanoacrylate compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |