CN110305067A - A kind of optimum synthesis technique of anticancer drug Dacarbazine - Google Patents
A kind of optimum synthesis technique of anticancer drug Dacarbazine Download PDFInfo
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Abstract
The present invention provides a kind of optimum synthesis techniques of anticancer drug Dacarbazine, comprising: the synthesis of glycine methyl ester, the synthesis of N- formylglycine methyl esters, the synthesis of α-Methyl isocyanoacetate, the synthesis of α-isocyanide yl acetamide, the synthesis of 5- amino -4- Imidazole carboxamide, the synthesis of Dacarbazine；The synthesis of glycine methyl ester: weighing glycine 7.5g in 500mL round-bottomed flask, makees solvent with the steamed methanol of 200mL weight, cooling 15min is stirred in ice bath.22mL thionyl chloride is measured with syringe, is slowly added dropwise in reaction flask reaction at room temperature overnight.Extra thionyl chloride and methanol is evaporated off in rotation at room temperature, and residue is dissolved with hot methanol few as far as possible, is then quickly added into a large amount of cold ethers and reaction flask is put into ice bath cooling；The present invention has synthetic line reasonable by the improvement of the synthesis technology to anticancer drug Dacarbazine, raw material is cheap, and reaction condition is mild, the high advantage of total recovery, so that effective solution goes wrong and insufficient in the prior art.
Description
Technical field
The present invention relates to technical field of medicine synthesis, more specifically, more particularly to a kind of anticancer drug Dacarbazine
Optimum synthesis technique.
Background technique
Dacarbazine has the anticancer activity of wide spectrum as cell nonspecific drug, is able to suppress euphorbia egg decoctum, white blood
Sick L1210 and gland cancer 755 are clinically for treating the choice drug of malignant mela noma all the time, and Dacarbazine is in body
It is interior to be converted into a kind of compound similar with the biosynthesis intermediate product of purine, may have to the biosynthesis of purine
There is interference effect.The medicine enters after human body under the action of hepatomicrosome, and demethylation becomes monomethyl compounds, shows straight
The cytotoxicity connect mainly acts on the G2 phase of cell cycle, inhibits the conjunction of DNA, RNA and protein by alkylating
At performance antitumor action.Since the medicine has indispensable status to the treatment of certain cancers, more answered in recent years
The report that combined immunization for tumour is treated.Therefore, all the time, people are dedicated to the research of the compound synthesis technology,
It is expected that obtaining a simplicity, green, the synthetic route of economy.
According to literature survey, the synthetic route of Dacarbazine has three at present, and first route is directly with 5- amino -4- miaow
Azoles formamide is raw material, amino diazotising is obtained diazonium salt first, then obtain Dacarbazine with diformazan amine coupling.Two other is closed
All it is the improvement to first route in fact at route, that is, solves the problems, such as how to synthesize 5- amino -4- Imidazole carboxamide,
Its step and route 1 are same.
But using 4- imidazole formic acid as the route route 2 of Material synthesis 5- amino -4- Imidazole carboxamide, there are raw material valences
The disadvantages of lattice height, technical process security risk big (needing catalytic hydrogenation).And the synthetic route route based on diaminomaleonitrile
3, although route is succinct, the hydrogen cyanide for needing to use severe toxicity is raw material, and security risk is bigger.In addition, diaminomaleonitrile
Cost is also fairly expensive.
In view of this, being studied improvement for existing problem, the optimization for providing a kind of anticancer drug Dacarbazine is closed
At technique, it is intended to by the technology, achieve the purpose that solve the problems, such as and improve practical value.
Summary of the invention
The purpose of the present invention is to provide a kind of optimum synthesis techniques of anticancer drug Dacarbazine, to solve above-mentioned background
Itd is proposed in technology using 4- imidazole formic acid as the route route 2 of Material synthesis 5- amino -4- Imidazole carboxamide, there are cost of material
The disadvantages of height, technical process security risk big (needing catalytic hydrogenation).And the synthetic route route 3 based on diaminomaleonitrile,
Although route is succinct, the hydrogen cyanide for needing to use severe toxicity is raw material, and security risk is bigger.In addition, diaminomaleonitrile at
This also fairly expensive problem and deficiency.
To achieve the above object, the present invention provides a kind of optimum synthesis techniques of anticancer drug Dacarbazine, by following
Particular technique means are reached:
A kind of optimum synthesis technique of anticancer drug Dacarbazine, comprising: the synthesis of glycine methyl ester, N- formylglycine
The synthesis of methyl esters, the synthesis of α-Methyl isocyanoacetate, the synthesis of α-isocyanide yl acetamide, 5- amino -4- Imidazole carboxamide
Synthesis, the synthesis of Dacarbazine；The synthesis step of the glycine methyl ester are as follows: weigh glycine 7.5g (100mmol) in 500mL
In round-bottomed flask, solvent is made with the steamed methanol of 200mL weight, cooling 15min is stirred in ice bath.22mL is measured (about with syringe
300mmol) thionyl chloride is slowly added dropwise in reaction flask, and reaction is stayed overnight at room temperature.Extra two are evaporated off in rotation at room temperature
Chlorine sulfoxide and methanol, residue are dissolved with hot methanol few as far as possible, a large amount of cold ethers are rapidly then added and put reaction flask
Enter in ice bath and be quickly cooled down, the solid of a large amount of whites is precipitated at this time, filtering and washing obtains white solid 11.6g, yield 93.0%.
M.p.174~175 DEG C；1H-NMR(300MHz,D2O)δ:3.90(s,2H),3.78(s,3H)；13C-NMR
(75MHz,D2O)δ:168.7,53.4,40.2；MS-ESI m/z:179.2[2M+H]+.
The synthesis step of the N- formylglycine methyl esters are as follows: weigh glycine methyl ester 3.56g (0.4mol), methyl formate
10mL, triethylamine 5mL are placed in a reaction flask, and after 3d is stirred at room temperature, reaction flask are placed at 0 DEG C and stands 30min, are made solid
Body is precipitated, and is filtered to remove solid impurity；Liquid pressure-reducing is spin-dried for obtain colourless oily mater, TLC detection shows purity qualification, no
It need to further isolate and purify；Grease is placed in a vacuum drying oven drying, obtains colourless liquid 2.95g, yield 78.0%.
1H-NMR(300MHz,D2O)δ:8.25(s,1H),4.15(s,2H),3.83(s,3H)；13C-NMR (75MHz,
D2O)δ:171.7,164.6,52.8,39.8；MS-ESI m/z:118.2[M+H]+.
The synthesis step of the α-Methyl isocyanoacetate are as follows: N- formylglycine methyl esters 2.75g (23.5mmol) is molten
Solution is washed at the anhydrous dichloromethane that 100mL steams again in (DCM), and triethylamine 8.1mL (58.7mmol) is subsequently added into, and reaction is mixed
Object, which is placed in ice bath, stirs cooling 15min.It is to be cooled completely after, slowly be added dropwise phosphorus oxychloride 2.2mL (23.5mmol) Yu Fanli
In system, then continue to be stirred to react 1h in ice bath.Then solution is warmed to room temperature, and is slowly added to saturation Na2CO3Solution
Until pH is shown as alkalinity, continues stirring and be sufficiently layered to water phase and organic phase, separatory funnel separates organic layer, water layer DCM
It extracts (30mLx3).Merge organic layer, with saturated common salt water washing 3 times, the anhydrous MgSO of organic phase4Washing is dried, filtered,
Merging filtrate is simultaneously spin-dried for, and obtains crude product α-Methyl isocyanoacetate, which is isolated and purified with RP-HPLC, must be had after vacuum drying
The burgundy liquid 1.51g of extraordinary strong stimulus smell, yield 65.0%.
1H-NMR(300MHz,CDCl3)δ:4.21(s,2H),3.72(s,3H)；13C-NMR(75MHz,CDCl3) δ:
164.5,160.5,53.1,43.2；MS-ESI m/z:98.2[M-H]-.
The α-isocyanide yl acetamide synthesis step are as follows: take α-Methyl isocyanoacetate 1.0g (5.0mmol) in 25mL
In round-bottomed flask, 5.0mL methanol is added, rubber plug with overlapped mouth is closed.It will be dissolved with the methanol solution of 7mol/L ammonia with syringe
1.5mL (10.5mmol) is added in reaction system, is stirred overnight at room temperature.Revolving removes excess of ammonia and first after reaction
Residue (yellow solid) is redissolved in 10.0mL methanol, 5% active carbon is added, stirs 2h at 50 DEG C by alcohol.It is mixed
It closes object to filter by diatomite, filtrate is concentrated to get pale solid.RP-HPLC is not necessarily to analysis shows purity 95% into one
Step isolates and purifies, and product vacuum is dry, obtains pale solid 765mg, yield 91.0%.
M.p.113~114 DEG C；1H-NMR(300MHz,D2O)δ:4.71(s,2H),4.37(s,2H)；13C-NMR
(75MHz,D2O)δ:168.4,156.2,44.6；MS-ESI m/z:85.1[M+H]+.
The synthesis step of 5- amino -4- Imidazole carboxamide are as follows: take NaH (60%) 280mg (about 7.0mmol) in nitrogen protection
It is lower that tetrahydrofuran (THF) 10mL steamed again, the cooling 15min of ice bath is added；Take 420mg (5.0mmol) α-isocyanide yl acetamide molten
Solution is added dropwise in above-mentioned system in the THF that 5mL steams again, is stirred to react 0.5h；Separately take cyanamide 210mg
(5.0mmol) is dissolved in THF, is slowly added into reaction system by syringe.Charging finishes, and removes ice bath, keeps system slow
Slowly it is warmed to room temperature, continues overtime work reaction 3h, fraction solids are precipitated in the process.Reaction terminates, and 5.0mL water quenching reaction is added, and
PH to 9 or so is adjusted with dilute hydrochloric acid, methanol dissolution residual substance is used after being spin-dried for solvent, with short solid-phase extraction column and 0.25 μm of filter membrane
After filtered sample, sample RP-HPLC is purified [eluent is V (methanol): V (water)=15:85], merges fraction, revolving removes
Pale solid powder 430mg, yield 68.2% is lyophilized to obtain in methanol, Liquid Residue.
M.p.169~171 DEG C；1H-NMR(300MHz,DMSO-d6)δ:11.45(br,1H),7.14(s, 1H),6.80
(s,2H),5.56(s,2H)；13C-NMR(75MHz,DMSO-d6) δ:167.2,146.1,129.8,109.2；MS-ESI m/z:
127.1[M+H]+.
The synthesis step of the Dacarbazine are as follows: 5- amino -4- Imidazole carboxamide 378mg (3.0mmol) is taken to be placed in 50mL
In round-bottomed flask, 1.0mL distilled water ice bath stirring is added；It is slow after taking 1.2mL (about 12.0mmol) concentrated hydrochloric acid 2.0mL water to dilute
Slow to be added in reaction flask, reaction, which remains under ice bath, to be carried out；Take sodium nitrite (NaNO2) 207mg (3.0mmol) is dissolved in
It is slowly added in reaction system in 1.0mL distilled water, detects confirmatory reaction process sodium nitrite mistake with starch potassium iodide paper
Amount.Reaction solution becomes peony at this time, and reaction, which remains under ice bath, to be carried out.After stirring 0.5h, it is added dropwise into reaction system
Aqueous solution 0.5mL (4.5mmol) containing 40% dimethylamine continues low-temp reaction 2h.Reaction terminates, and reaction solution is lyophilized.It will
The residue of freeze-drying crosses solid phase chromatography column and 0.25 μm of filter membrane after being dissolved with water, sample RP-HPLC purify that [eluent is V (first
Alcohol): V (water)=15:85], merging fraction, low temperature revolving removes methanol, and light red solid powder 415mg is lyophilized to obtain in Liquid Residue,
Yield 76.2%.
M.p.203~205 DEG C；1H-NMR(300MHz,D2O) δ: 15.14 (br, 1H), 9.03 (br, 2H), 8.52 (s,
1H),2.51(s,6H)；13C-NMR(75MHz,D2O) δ:152.8,152.6,143.9,119.8,34.4；MS-ESI m/z:
181.3[M-H]-.
Due to the application of the above technical scheme, compared with the prior art, the invention has the following advantages:
The present invention has synthetic line reasonable, raw material is honest and clean by the improvement of the synthesis technology to anticancer drug Dacarbazine
Valence, reaction condition is mild, the high advantage of total recovery, so that effective solution goes wrong and insufficient in the prior art.
Specific embodiment
The following is a clear and complete description of the technical scheme in the embodiments of the invention, it is clear that described embodiment
Only a part of the embodiment of the present invention, instead of all the embodiments.
The present invention provides a kind of particular technique embodiment of the optimum synthesis technique of anticancer drug Dacarbazine:
A kind of optimum synthesis technique of anticancer drug Dacarbazine, comprising: the synthesis of glycine methyl ester, N- formylglycine
The synthesis of methyl esters, the synthesis of α-Methyl isocyanoacetate, the synthesis of α-isocyanide yl acetamide, 5- amino -4- Imidazole carboxamide
Synthesis, the synthesis of Dacarbazine；The synthesis step of glycine methyl ester are as follows: weigh glycine 7.5g (100mmol) in 500mL round bottom
In flask, solvent is made with the steamed methanol of 200mL weight, cooling 15min is stirred in ice bath.22mL is measured (about with syringe
300mmol) thionyl chloride is slowly added dropwise in reaction flask, and reaction is stayed overnight at room temperature.Extra two are evaporated off in rotation at room temperature
Chlorine sulfoxide and methanol, residue are dissolved with hot methanol few as far as possible, a large amount of cold ethers are rapidly then added and put reaction flask
Enter in ice bath and be quickly cooled down, the solid of a large amount of whites is precipitated at this time, filtering and washing obtains white solid 11.6g, yield 93.0%.
M.p.174~175 DEG C；1H-NMR(300MHz,D2O)δ:3.90(s,2H),3.78(s,3H)；13C-NMR
(75MHz,D2O)δ:168.7,53.4,40.2；MS-ESI m/z:179.2[2M+H]+.
The synthesis step of N- formylglycine methyl esters are as follows: weigh glycine methyl ester 3.56g (0.4mol), methyl formate
10mL, triethylamine 5mL are placed in a reaction flask, and after 3d is stirred at room temperature, reaction flask are placed at 0 DEG C and stands 30min, makes solid
It is precipitated, is filtered to remove solid impurity；Liquid pressure-reducing is spin-dried for obtain colourless oily mater, TLC detection shows purity qualification, is not required to
Further isolate and purify；Grease is placed in a vacuum drying oven drying, obtains colourless liquid 2.95g, yield 78.0%.
1H-NMR(300MHz,D2O)δ:8.25(s,1H),4.15(s,2H),3.83(s,3H)；13C-NMR (75MHz,
D2O)δ:171.7,164.6,52.8,39.8；MS-ESI m/z:118.2[M+H]+.
α-Methyl isocyanoacetate synthesis step are as follows: be dissolved in N- formylglycine methyl esters 2.75g (23.5mmol)
The anhydrous dichloromethane that 100mL steams again is washed in (DCM), is subsequently added into triethylamine 8.1mL (58.7mmol), reaction mixture is placed in
Cooling 15min is stirred in ice bath.It is to be cooled completely after, slowly be added dropwise phosphorus oxychloride 2.2mL (23.5mmol) in inverted stereo system
In, then continue to be stirred to react 1h in ice bath.Then solution is warmed to room temperature, and is slowly added to saturation Na2CO3Solution until
PH is shown as alkalinity, continues stirring and is sufficiently layered to water phase and organic phase, separatory funnel separates organic layer, and water layer is extracted with DCM
(30mLx3).Merge organic layer, with saturated common salt water washing 3 times, the anhydrous MgSO of organic phase4Washing is dried, filtered, filter is merged
Liquid is simultaneously spin-dried for, and obtains crude product α-Methyl isocyanoacetate, which is isolated and purified with RP-HPLC, must have extremely strong thorn after vacuum drying
Swash the burgundy liquid 1.51g of property smell, yield 65.0%.
1H-NMR(300MHz,CDCl3)δ:4.21(s,2H),3.72(s,3H)；13C-NMR(75MHz,CDCl3) δ:
164.5,160.5,53.1,43.2；MS-ESI m/z:98.2[M-H]-.
α-isocyanide yl acetamide synthesis step are as follows: take α-Methyl isocyanoacetate 1.0g (5.0mmol) in 25mL round bottom
In flask, 5.0mL methanol is added, rubber plug with overlapped mouth is closed.It will be dissolved with the methanol solution 1.5mL of 7mol/L ammonia with syringe
(10.5mmol) is added in reaction system, is stirred overnight at room temperature.Revolving removes excess of ammonia and methanol after reaction, will
Residue (yellow solid) is redissolved in 10.0mL methanol, and 5% active carbon is added, and stirs 2h at 50 DEG C.Mixture
It is filtered by diatomite, filtrate is concentrated to get pale solid.RP-HPLC is analysis shows purity 95%, without further dividing
It is from purifying, product vacuum is dry, obtain pale solid 765mg, yield 91.0%.
M.p.113~114 DEG C；1H-NMR(300MHz,D2O)δ:4.71(s,2H),4.37(s,2H)；13C-NMR
(75MHz,D2O)δ:168.4,156.2,44.6；MS-ESI m/z:85.1[M+H]+.
The synthesis step of 5- amino -4- Imidazole carboxamide are as follows: take NaH (60%) 280mg (about 7.0mmol) in nitrogen protection
It is lower that tetrahydrofuran (THF) 10mL steamed again, the cooling 15min of ice bath is added；Take 420mg (5.0mmol) α-isocyanide yl acetamide molten
Solution is added dropwise in above-mentioned system in the THF that 5mL steams again, is stirred to react 0.5h；Separately take cyanamide 210mg
(5.0mmol) is dissolved in THF, is slowly added into reaction system by syringe.Charging finishes, and removes ice bath, keeps system slow
Slowly it is warmed to room temperature, continues overtime work reaction 3h, fraction solids are precipitated in the process.Reaction terminates, and 5.0mL water quenching reaction is added, and
PH to 9 or so is adjusted with dilute hydrochloric acid, methanol dissolution residual substance is used after being spin-dried for solvent, with short solid-phase extraction column and 0.25 μm of filter membrane
After filtered sample, sample RP-HPLC is purified [eluent is V (methanol): V (water)=15:85], merges fraction, revolving removes
Pale solid powder 430mg, yield 68.2% is lyophilized to obtain in methanol, Liquid Residue.
M.p.169~171 DEG C；1H-NMR(300MHz,DMSO-d6)δ:11.45(br,1H),7.14(s, 1H),6.80
(s,2H),5.56(s,2H)；13C-NMR(75MHz,DMSO-d6) δ:167.2,146.1,129.8,109.2；MS-ESI m/z:
127.1[M+H]+.
The synthesis step of Dacarbazine are as follows: 5- amino -4- Imidazole carboxamide 378mg (3.0mmol) is taken to be placed in 50mL round bottom
In flask, 1.0mL distilled water ice bath stirring is added；After taking 1.2mL (about 12.0mmol) concentrated hydrochloric acid 2.0mL water to dilute slowly
It is added in reaction flask, reaction, which remains under ice bath, to be carried out；Take sodium nitrite (NaNO2) 207mg (3.0mmol) is dissolved in
It is slowly added in reaction system in 1.0mL distilled water, detects confirmatory reaction process sodium nitrite mistake with starch potassium iodide paper
Amount.Reaction solution becomes peony at this time, and reaction, which remains under ice bath, to be carried out.After stirring 0.5h, it is added dropwise into reaction system
Aqueous solution 0.5mL (4.5mmol) containing 40% dimethylamine continues low-temp reaction 2h.Reaction terminates, and reaction solution is lyophilized.It will
The residue of freeze-drying crosses solid phase chromatography column and 0.25 μm of filter membrane after being dissolved with water, sample purifies [eluent V with RP-HPLC
(methanol): V (water)=15:85], merge fraction, low temperature revolving removes methanol, and light red solid powder is lyophilized to obtain in Liquid Residue
415mg, yield 76.2%.
M.p.203~205 DEG C；1H-NMR(300MHz,D2O) δ: 15.14 (br, 1H), 9.03 (br, 2H), 8.52 (s,
1H),2.51(s,6H)；13C-NMR(75MHz,D2O) δ:152.8,152.6,143.9,119.8,34.4；MS-ESI m/z:
181.3[M-H]-.
In summary: a kind of optimum synthesis technique of anticancer drug Dacarbazine, by anticancer drug Dacarbazine
Synthesis technology improvement, have synthetic line it is reasonable, raw material is cheap, and reaction condition is mild, the high advantage of total recovery, to have
The solving of effect goes wrong and insufficient in the prior art.
It although an embodiment of the present invention has been shown and described, for the ordinary skill in the art, can be with
A variety of variations, modification, replacement can be carried out to these embodiments without departing from the principles and spirit of the present invention by understanding
And modification, the scope of the present invention is defined by the appended.
Claims (1)
1. a kind of optimum synthesis technique of anticancer drug Dacarbazine, comprising: the synthesis of glycine methyl ester, N- formylglycine first
Synthesis, the synthesis of α-Methyl isocyanoacetate, the synthesis of α-isocyanide yl acetamide, the conjunction of 5- amino -4- Imidazole carboxamide of ester
At the synthesis of, Dacarbazine；It is characterized by: the synthesis step of the glycine methyl ester are as follows: weigh glycine 7.5g
(100mmol) makees solvent in 500mL round-bottomed flask, with the steamed methanol of 200mL weight, and cooling 15min is stirred in ice bath；With note
Emitter measures 22mL (about 300mmol) thionyl chloride, is slowly added dropwise in reaction flask, and reaction is stayed overnight at room temperature；Room temperature backspin
Turn that extra thionyl chloride and methanol is evaporated off, residue is dissolved with hot methanol few as far as possible, is then rapidly added a large amount of cold
Ether and reaction flask is put into ice bath is quickly cooled down, and the solids of a large amount of whites are precipitated at this time, and filtering and washing obtains white solid
11.6g, yield 93.0%；m.p.174~175℃；1H-NMR(300MHz,D2O)δ:3.90(s,2H),3.78 (s,3H);13C-
NMR (75MHz,D2O)δ:168.7,53.4,40.2;MS-ESI m/z:179.2 [2M+H]+The N- formylglycine methyl esters
Synthesis step are as follows: weigh 3.56 g of glycine methyl ester (0.4mol), methyl formate 10mL, triethylamine 5mL and be placed in reaction flask
In, after 3d is stirred at room temperature, reaction flask is placed at 0 DEG C and stands 30 min, solid is precipitated, is filtered to remove solid impurity；
Liquid pressure-reducing is spin-dried for obtain colourless oily mater, TLC detection shows purity qualification, is not required to further isolate and purify；By oily
Object is placed in a vacuum drying oven drying, obtains 2.95 g of colourless liquid, yield 78.0%；1H-NMR(300MHz,D2O)δ:8.25
(s,1H),4.15(s,2H),3.83(s,3H);13C-NMR (75MHz,D2O)δ:171.7,164.6,52.8,39.8;MS-ESI
m/z:118.2[M+H]+The synthesis step of the α-Methyl isocyanoacetate are as follows: by N- formylglycine methyl esters 2.75g
(23.5mmol) is dissolved in the anhydrous dichloromethane that 100mL steams again and washes in (DCM), is subsequently added into triethylamine 8.1mL (58.7mmol),
Reaction mixture is placed in ice bath and stirs cooling 15min；
It is to be cooled completely after, slowly be added dropwise phosphorus oxychloride 2.2mL (23.5mmol) in inverted stereo system, then continue in ice bath
It is stirred to react 1h；Then solution is warmed to room temperature, and is slowly added to saturation Na2CO3Solution is shown as alkalinity up to pH, continues to stir
It mixes to water phase and organic phase and is sufficiently layered, separatory funnel separates organic layer, and water layer extracts (30mLx3) with DCM；
Merge organic layer, with saturated common salt water washing 3 times, the anhydrous MgSO of organic phase4Washing is dried, filtered, merging filtrate simultaneously revolves
It is dry, crude product α-Methyl isocyanoacetate is obtained, which is isolated and purified with RP-HPLC, must have extraordinary strong stimulus gas after vacuum drying
The burgundy liquid 1.51g of taste, yield 65.0%；1H-NMR(300MHz,CDCl3)δ:4.21(s,2H),3.72(s,3H);13C-
NMR(75MHz,CDCl3)δ:164.5,160.5,53.1,43.2;MS-ESI m/z:98.2[M-H]-The α-isocyano group acetyl
The synthesis step of amine are as follows: it takes α-Methyl isocyanoacetate 1.0g (5.0mmol) in 25mL round-bottomed flask, 5.0mL methanol is added,
Rubber plug with overlapped mouth is closed；
It will be added in reaction system dissolved with the methanol solution 1.5mL (10.5mmol) of 7mol/L ammonia with syringe, at room temperature
It is stirred overnight；Revolving removes excess of ammonia and methanol after reaction, and residue (yellow solid) is redissolved in 10.0mL
In methanol, 5% active carbon is added, stirs 2h at 50 DEG C；
Mixture is filtered by diatomite, and filtrate is concentrated to get pale solid；
RP-HPLC is dry by product vacuum without further isolating and purifying analysis shows purity 95%, obtains pale solid
765mg, yield 91.0%；m.p.113~114℃;1H-NMR(300MHz,D2O)δ:4.71(s,2H),4.37(s,2H);13C-
NMR (75MHz,D2O)δ:168.4,156.2,44.6;MS-ESI m/z:85.1[M+H]+.5- amino -4- Imidazole carboxamide
Synthesis step are as follows: take NaH (60%) 280mg (about 7.0mmol) that tetrahydrofuran (THF) 10mL steamed again is added under nitrogen protection,
Ice bath cools down 15min；It takes 420mg (5.0mmol) α-isocyanide yl acetamide to be dissolved in the THF that 5mL steams again, is added dropwise to
It states in system, is stirred to react 0.5h；Separately cyanamide 210mg (5.0mmol) is taken to be dissolved in THF, is slowly added by syringe
In reaction system；Charging finishes, and removes ice bath, is warmed to room temperature system slowly, continues overtime work reaction 3h, part is precipitated in the process
Solid；Reaction terminates, and 5.0mL water quenching reaction is added, and adjust pH to 9 or so with dilute hydrochloric acid, uses methanol molten after being spin-dried for solvent
Residue is solved, after short solid-phase extraction column and 0.25 μm of membrane filtration sample, sample purifies [eluent V with RP-HPLC
(methanol): V (water)=15:85], merge fraction, revolving removes methanol, and pale solid powder 430mg is lyophilized to obtain in Liquid Residue, receives
Rate 68.2%；m.p.169~171℃;1H-NMR(300MHz,DMSO-d6)δ:11.45(br,1H),7.14 (s, 1H),6.80
(s,2H),5.56(s,2H);13C-NMR(75MHz,DMSO-d6)δ:167.2,146.1,129.8,109.2;MS-ESI m/z:
127.1[M+H]+The synthesis step of the Dacarbazine are as follows: 5- amino -4- Imidazole carboxamide 378mg (3.0mmol) is taken to be placed in
In 50mL round-bottomed flask, 1.0mL distilled water ice bath stirring is added；1.2mL (about 12.0mmol) concentrated hydrochloric acid 2.0mL water is taken to dilute
After be slowly added into reaction flask, reaction is remained under ice bath and is carried out；Take sodium nitrite (NaNO2) 207mg (3.0mmol) is molten
Solution is slowly added in reaction system in 1.0mL distilled water, detects confirmatory reaction process nitrous acid with starch potassium iodide paper
Sodium is excessive；Reaction solution becomes peony at this time, and reaction, which remains under ice bath, to be carried out；
After stirring 0.5h, the aqueous solution 0.5mL (4.5mmol) containing 40% dimethylamine is added dropwise into reaction system, it is anti-to continue low temperature
Answer 2h；Reaction terminates, and reaction solution is lyophilized；Solid phase chromatography column and 0.25 μm of filter membrane are crossed after the residue of freeze-drying is dissolved with water,
Sample RP-HPLC is purified [eluent is V (methanol): V (water)=15:85], and fraction is merged, and low temperature revolving removes methanol, residual
Light red solid powder 415mg, yield 76.2% is lyophilized to obtain in liquid；
m.p.203~205℃;1H-NMR(300MHz,D2O) δ: 15.14 (br, 1H), 9.03 (br, 2H), 8.52 (s, 1H), 2.51
(s,6H);13C-NMR(75MHz,D2O)δ:152.8,152.6,143.9,119.8,34.4;MS-ESI m/z:181.3[M-
H]-。
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| CN112462047A (en) * | 2020-11-13 | 2021-03-09 | 北京元恩生物技术有限公司 | Nicarbazin detection kit and application thereof |
| WO2022126947A1 (en) * | 2020-12-18 | 2022-06-23 | 新发药业有限公司 | Environmentally friendly preparation method for substituted isonitrile compound |
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| 肖胜伟等: "抗癌药物达卡巴嗪的合成工艺优化", 《有机化学》 * |
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| CN112462047A (en) * | 2020-11-13 | 2021-03-09 | 北京元恩生物技术有限公司 | Nicarbazin detection kit and application thereof |
| WO2022126947A1 (en) * | 2020-12-18 | 2022-06-23 | 新发药业有限公司 | Environmentally friendly preparation method for substituted isonitrile compound |
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