CN107163023A - A kind of preparation method of 5 Bromopyrimidine compound - Google Patents
A kind of preparation method of 5 Bromopyrimidine compound Download PDFInfo
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- CN107163023A CN107163023A CN201710405676.2A CN201710405676A CN107163023A CN 107163023 A CN107163023 A CN 107163023A CN 201710405676 A CN201710405676 A CN 201710405676A CN 107163023 A CN107163023 A CN 107163023A
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- AJQJGSRYCHQHQF-UHFFFAOYSA-N NCC(CCC1)CN1c(nc1)ncc1Br Chemical compound NCC(CCC1)CN1c(nc1)ncc1Br AJQJGSRYCHQHQF-UHFFFAOYSA-N 0.000 description 2
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- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a kind of preparation method of 5 Bromopyrimidine compound (base of 1 (base of 5 Bromopyrimidine 2) piperidines 3) methylamine; using the piperidine carboxylic acids of N Boc 3 as initiation material; target product is obtained through over-churning, reduction, condensation, substitution, de- tertbutyloxycarbonyl protection, condensation, reduction, the compound is important medicine intermediate.
Description
Technical field
The present invention relates to a kind of novel processing step of medicine intermediate, more particularly to a kind of 5- Bromopyrimidines compound (1-
(5- Bromopyrimidine -2- bases) piperidines -3- bases) methylamine preparation method a kind of preparation method.
Technical background
Compound (1- (5- Bromopyrimidine -2- bases) piperidines -3- bases) methylamine, structural formula is：
The derivative of this compound 5- Bromopyrimidines compound (1- (5- Bromopyrimidine -2- bases) piperidines -3- bases) methylamine and correlation
There is extensive use in pharmaceutical chemistry and organic synthesis.The synthesis of (1- (5- Bromopyrimidine -2- bases) piperidines -3- bases) methylamine at present
It is more difficult.It is easy to get accordingly, it would be desirable to develop a raw material, it is easy to operate, react easily controllable, the overall yield suitably side of synthesis
Method.
The content of the invention
The invention discloses the method that one kind prepares pyrimidine derivatives (1- (5- Bromopyrimidine -2- bases) piperidines -3- bases) methylamine,
Target product 8 is obtained through over-churning, reduction, condensation, substitution, de- tertbutyloxycarbonyl protection, condensation, reduction, synthesis step is as follows：
(1) using N-Boc-3- piperidine carboxylic acids as initiation material, 2 are obtained by esterification；
(2) reduction reaction is carried out 2, obtains 3；
(3) 3 progress condensation reactions are obtained 4；
(4) 4 progress substitution reactions are obtained 5,
(5) carry out de- tertbutyloxycarbonyl protection reaction 5 and obtain 6,
(6) 6 progress condensation reactions are obtained 7,
(7) 7 progress reduction reactions are obtained 8,
In a preferred embodiment, the methylating reagent used in described esterification prepare compound 2 is selected from original
Trimethyl orthoformate；Reducing agent used in described reduction reaction prepare compound 3 is selected from sodium borohydride；Described condensation reaction system
Alkali used in standby compound 4 is selected from potassium carbonate；Reagent used in described substitution reaction prepare compound 5 is selected from sodium azide；
Deprotection agent used in described de- tertbutyloxycarbonyl protection reaction prepare compound 6 is selected from hydrogen chloride；Described condensation reaction
Alkali used in prepare compound 7 is selected from potassium carbonate；Reducing agent used in described reduction reaction prepare compound 8 is selected from borine.
In a preferred embodiment, the solvent used in described esterification prepare compound 2 is selected from methanol；It is described
Reduction reaction prepare compound 3 used in solvent be selected from ethanol；Solvent choosing used in described condensation reaction prepare compound 4
From tetrahydrofuran；Solvent used in described substitution reaction prepare compound 5 is selected from N,N-dimethylformamide；Described de- uncle
Solvent used in butoxy carbonyl protection reaction prepare compound 6 is selected from dichloromethane；Described condensation protection reaction prepares chemical combination
Solvent used in thing 7 is selected from N,N-dimethylformamide.
In a preferred embodiment, the reaction temperature used in described esterification prepare compound 2 is room temperature；Institute
The temperature used in reduction reaction prepare compound 3 stated is room temperature；Temperature used in described condensation reaction prepare compound 4 is
The reflux temperature of solvent；Temperature used in described substitution reaction prepare compound 5 is the reflux temperature of solvent；Described de- uncle
Temperature used in butoxy carbonyl protection reaction prepare compound 6 is room temperature；Used in described condensation protection reaction prepare compound 7
Temperature be solvent reflux temperature；Temperature used in described reduction reaction prepare compound 8 is room temperature.
The present invention relates to a kind of preparation method of pyrimidine derivatives (1- (5- Bromopyrimidine -2- bases) piperidines -3- bases) methylamine, mesh
It is preceding to be reported without other Patents documents.
The present invention is further described by the following embodiment, and these descriptions are not present invention to be made into one
The restriction of step.It should be understood by those skilled in the art that the equivalent substitution made to the technical characteristic of the present invention, or change accordingly
Enter, still fall within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) synthesis of N- t-butoxycarbonylpiperidins -3- Ethyl formates
30g N-Boc-3- piperidine carboxylic acids are added in 220ml methanol, 25g trimethyl orthoformates is added, is stirred at room temperature
24 hours, concentrate, silica gel post separation obtains 32g N- t-butoxycarbonylpiperidin -3- Ethyl formates on residue.
(2) synthesis of N- tertbutyloxycarbonyls -3- hydroxymethyl piperidines
30g N- t-butoxycarbonylpiperidin -3- Ethyl formates are added in 400ml absolute ethyl alcohols, 16g boron is slowly added to
Sodium hydride, is stirred overnight at room temperature, and is slowly added to saturated ammonium chloride, and concentration removes ethanol, adds dichloromethane, and extraction point liquid is received
Collect organic phase, divide silica gel post separation on liquid, drying, concentration, residue to obtain 21g N- tertbutyloxycarbonyl -3- hydroxymethyl piperidines.
(3) synthesis of N- tertbutyloxycarbonyls -3- ((mesyloxy) methyl) piperidines
20g N- tertbutyloxycarbonyl -3- hydroxymethyl piperidines are added in 190ml tetrahydrofurans, the anhydrous carbon of 13g is added
Sour potassium, adds 16g methylsufonyl chlorides, is heated to reflux, and stirs 2 hours, adds water and ethyl acetate, and extraction point liquid, collection has
Machine phase, is concentrated to give 23g N- tertbutyloxycarbonyls -3- ((mesyloxy) methyl) piperidines.
(4) synthesis of N- tertbutyloxycarbonyls -3- (azido methyl) piperidines
20g N- tertbutyloxycarbonyls -3- ((mesyloxy) methyl) piperidines is added to 200ml N, N- dimethyl formyls
In amine, 19g sodium azide is added, stirring 4 hours is heated to reflux, room temperature is cooled to, water and ethyl acetate is added, extraction divides liquid,
Organic phase is collected, divides silica gel post separation on liquid, drying, concentration, residue to obtain 12g N- tertbutyloxycarbonyls -3- (azido methyl)
Piperidines.
(5) synthesis of 3- (azido methyl) piperidines
10g N- tertbutyloxycarbonyls -3- (azido methyl) piperidines is added in 160ml dichloromethane, hydrogen chloride is passed through
Gas, is stirred at room temperature 5 hours, adds saturated sodium bicarbonate aqueous solution, and extraction point liquid collects organic phase, point liquid, drying, concentration
Obtain 5.1g 3- (azido methyl) piperidines.
(6) synthesis of 2- (3- (azido methyl) piperidin-1-yl) pyrimidine
5g 3- (azido methyl) piperidines is added in 110mlN, dinethylformamide, the chloro- 5- of 8.2g 2- are added
Bromopyrimidine, adds 9g Anhydrous potassium carbonates, and return stirring 6 hours is cooled to room temperature, added water and ethyl acetate, extraction point liquid, receives
Collect silica gel post separation on organic phase, point liquid, drying, concentration, residue obtain 7.2g 2- (3- (azido methyl) piperidin-1-yl)-
5- Bromopyrimidines.
(7) synthesis of (1- (5- Bromopyrimidine -2- bases) piperidines -3- bases) methylamine
7g 2- (3- (azido methyl) piperidin-1-yl) -5- Bromopyrimidines are added in 100ml tetrahydrofurans, added
35ml10M borines-tetrahydrofuran solution, are stirred at room temperature 16 hours, add water and ethyl acetate, and extraction point liquid collects organic phase,
Silica gel post separation on liquid, drying, concentration, residue is divided to obtain 5.4g (1- (5- Bromopyrimidine -2- bases) piperidines -3- bases) methylamine.
Claims (6)
1. the method that one kind prepares (1- (5- Bromopyrimidine -2- bases) piperidines -3- bases) methylamine, using N-Boc-3- piperidine carboxylic acids as starting
Raw material, target product 8, synthetic route are obtained through over-churning, reduction, condensation, substitution, de- tertbutyloxycarbonyl protection, condensation, reduction
It is as follows,
2. method according to claim 1, it is characterized in that described 7 steps reaction is,
(1) using N-Boc-3- piperidine carboxylic acids as initiation material, 2 are obtained by esterification；
(2) reduction reaction is carried out 2, obtains 3；
(3) 3 progress condensation reactions are obtained 4；
(4) 4 progress substitution reactions are obtained 5,
(5) carry out de- tertbutyloxycarbonyl protection reaction 5 and obtain 6,
(6) 6 progress condensation reactions are obtained 7,
(7) 7 progress reduction reactions are obtained 8,
3. method according to claim 1, it is characterised in that the examination that methylates used in described esterification prepare compound 2
One or more of mixtures of the agent in trimethyl orthoformate, dimethyl suflfate, iodomethane；It is prepared by described reduction reaction
Reducing agent used in compound 3 is selected from sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride, lithium aluminium hydride, borine
In one or more of mixtures；Alkali used in described condensation reaction prepare compound 4 is selected from sodium hydroxide, hydroxide
One kind in potassium, lithium hydroxide, sodium carbonate, potassium carbonate, triethylamine, sodium acid carbonate, pyridine, triisopropylamine, saleratus or
Several mixtures；Reagent used in described substitution reaction prepare compound 5 is selected from sodium azide；Described de- tertiary butyloxycarbonyl
Base protection reaction prepare compound 6 used in deprotection agent in hydrogen chloride, sulfuric acid, p-methyl benzenesulfonic acid, trifluoroacetic acid one
Plant or several mixtures；Alkali used in described condensation reaction prepare compound 7 is selected from sodium hydroxide, potassium hydroxide, hydrogen-oxygen
Change lithium, it is sodium carbonate, potassium carbonate, triethylamine, sodium acid carbonate, pyridine, triisopropylamine, one or more of mixed in saleratus
Compound；Reducing agent used in described reduction reaction prepare compound 8 is selected from sodium borohydride, potassium borohydride, lithium borohydride, cyano group
One or more of mixtures in sodium borohydride, lithium aluminium hydride, borine.
4. method according to claim 1, it is characterised in that the solvent used in described esterification prepare compound 2 is selected from
Methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, meta-xylene, N,
One or more of mixtures in dinethylformamide, DMAC N,N' dimethyl acetamide；Described reduction reaction prepares chemical combination
Solvent used in thing 3 be selected from methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, to two
One or more of mixtures in toluene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, water；It is described
Condensation reaction prepare compound 4 used in solvent be selected from tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene,
Meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, in one or more of mixtures；Described substitution
React the solvent used in prepare compound 5 and be selected from tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, toluene, adjacent diformazan
One or more of mixtures in benzene, paraxylene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide；
Solvent used in described de- tertbutyloxycarbonyl protection reaction prepare compound 6 is selected from tetrahydrofuran, dichloromethane, three chloromethanes
Alkane, ethyl acetate, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide
In one or more of mixtures；Solvent used in described condensation protection reaction prepare compound 7 is selected from tetrahydrofuran, two
Chloromethanes, chloroform, ethyl acetate, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, N,
One or more of mixtures in N- dimethyl acetamides；Solvent used in described reduction reaction prepare compound 8 is selected from
Methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, meta-xylene, N,
One or more of mixtures in dinethylformamide, DMAC N,N' dimethyl acetamide.
5. method according to claim 1, it is characterised in that the reaction temperature used in described esterification prepare compound 2
It is the reflux temperature of 0 DEG C~solvent；Temperature used in described reduction reaction prepare compound 3 is 0 DEG C~room temperature；Described contracting
Close the reflux temperature that the temperature used in reaction prepare compound 4 is 0 DEG C~solvent；The described institute of substitution reaction prepare compound 5
Temperature is the reflux temperature of 0 DEG C~solvent；Temperature used in described de- tertbutyloxycarbonyl protection reaction prepare compound 6
It is 0 DEG C~room temperature；Temperature used in described condensation protection reaction prepare compound 7 is the reflux temperature of 0 DEG C~solvent；It is described
Reduction reaction prepare compound 8 used in temperature be 0 DEG C~solvent reflux temperature.
6. method according to claim 1, it is characterised in that the reaction temperature used in described esterification prepare compound 2
It is room temperature；Temperature used in described reduction reaction prepare compound 3 is room temperature；The described institute of condensation reaction prepare compound 4
Temperature is the reflux temperature of solvent；Temperature used in described substitution reaction prepare compound 5 is the reflux temperature of solvent；
Temperature used in described de- tertbutyloxycarbonyl protection reaction prepare compound 6 is room temperature；It is prepared by described condensation protection reaction
Temperature used in compound 7 is the reflux temperature of solvent；Temperature used in described reduction reaction prepare compound 8 is room temperature.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104292213A (en) * | 2014-09-08 | 2015-01-21 | 湖南华腾制药有限公司 | Preparation method of pyrimidine derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104292213A (en) * | 2014-09-08 | 2015-01-21 | 湖南华腾制药有限公司 | Preparation method of pyrimidine derivative |
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