CN113735740A - Preparation method of demethyl itopride nitrosamine - Google Patents
Preparation method of demethyl itopride nitrosamine Download PDFInfo
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- CN113735740A CN113735740A CN202111000137.3A CN202111000137A CN113735740A CN 113735740 A CN113735740 A CN 113735740A CN 202111000137 A CN202111000137 A CN 202111000137A CN 113735740 A CN113735740 A CN 113735740A
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- itopride
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- dichloromethane
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- demethyl
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- 229960005302 itopride Drugs 0.000 title claims abstract description 29
- XKLJHFLUAHKGGU-UHFFFAOYSA-N nitrous amide Chemical compound ON=N XKLJHFLUAHKGGU-UHFFFAOYSA-N 0.000 title claims abstract description 27
- QQQIECGTIMUVDS-UHFFFAOYSA-N N-[[4-[2-(dimethylamino)ethoxy]phenyl]methyl]-3,4-dimethoxybenzamide Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)NCC1=CC=C(OCCN(C)C)C=C1 QQQIECGTIMUVDS-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims description 9
- SWWQQSDRUYSMAR-UHFFFAOYSA-N 1-[(4-hydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol;hydrochloride Chemical group Cl.C1=CC(O)=CC=C1CC1C2=CC(O)=C(O)C=C2CCN1 SWWQQSDRUYSMAR-UHFFFAOYSA-N 0.000 title claims description 7
- 238000000034 method Methods 0.000 claims abstract description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 239000012043 crude product Substances 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 10
- 238000010511 deprotection reaction Methods 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- 235000010288 sodium nitrite Nutrition 0.000 claims description 8
- -1 methyl itopride Chemical compound 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 4
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 239000000047 product Substances 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 10
- 150000004005 nitrosamines Chemical class 0.000 abstract description 3
- 231100000024 genotoxic Toxicity 0.000 abstract description 2
- 230000001738 genotoxic effect Effects 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract 3
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 3
- 238000013517 stratification Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- GSYSFVSGPABNNL-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-(phenylmethoxycarbonylamino)acetate Chemical group COC(=O)C(P(=O)(OC)OC)NC(=O)OCC1=CC=CC=C1 GSYSFVSGPABNNL-UHFFFAOYSA-N 0.000 description 2
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SVDDJQGVOFZBNX-UHFFFAOYSA-N 2-chloroethyl carbonochloridate Chemical compound ClCCOC(Cl)=O SVDDJQGVOFZBNX-UHFFFAOYSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- WBNQDOYYEUMPFS-UHFFFAOYSA-N N-nitrosodiethylamine Chemical compound CCN(CC)N=O WBNQDOYYEUMPFS-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000005176 gastrointestinal motility Effects 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- UMFJAHHVKNCGLG-UHFFFAOYSA-N n-Nitrosodimethylamine Chemical compound CN(C)N=O UMFJAHHVKNCGLG-UHFFFAOYSA-N 0.000 description 1
- ZTOUXLLIPWWHSR-UHFFFAOYSA-N n-[[4-[2-(dimethylamino)ethoxy]phenyl]methyl]-3,4-dimethoxybenzamide;hydron;chloride Chemical compound Cl.C1=C(OC)C(OC)=CC=C1C(=O)NCC1=CC=C(OCCN(C)C)C=C1 ZTOUXLLIPWWHSR-UHFFFAOYSA-N 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C243/04—N-nitroso compounds
- C07C243/06—N-nitroso-amines
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Demethylitopride nitrosamine is an impurity that is easily found in the process of itopride production and is currently reported only rarely. Demethylitopride nitrosamines are genotoxic impurities that need to be controlled during the pharmaceutical manufacturing process. The invention reports a method for synthesizing demethylitopride nitrosamine for the first time, and provides guarantee for impurity control in itopride production.
Description
Technical Field
The invention relates to the field of synthesis of medical chemicals, in particular to a method for preparing demethylitopride nitrosamine.
Background
Itopride is a gastrointestinal motility promoting drug, first developed by north-land pharmaceutical corporation. Its standard designation is N- [4- [2- (N, N-dimethylamino) ethoxy]Benzyl radical]-3, 4-dimethoxybenzamide (CAS number: 122892-31-3) having the following chemical formula:
. In the process of research, the inventor finds an impurity with a brand new structure, namely demethylitopridine nitrosamine. Its standard name is N- [4- [2- (N-nitroso, N-methylamino) ethoxy]Benzyl radical]-3, 4-dimethoxybenzamide, the chemical structure of which is shown below
. The impurity is generated because demethylitopride generated in the process reacts with nitrite remained in the system under an acidic condition to generate the impurity with a nitrosamine structure. At present, no relevant report is found on demethylitopridine nitrosamine, and the demethylitopridine nitrosamine is an impurity with a novel structure. It has the structure of N-nitroso group. It is known that nitrosamines are mostly genotoxic, such as N, N-dimethylnitrosamine, N-diethylnitrosamine, etc. The presence of such impurities therefore poses a great risk to the safety of the drug, whose content must be monitored and controlled. However, the literature is irrelevant to the report of the impurity, and the preparation method of demethylitopridine nitrosamine is not available in the published technology.
Disclosure of Invention
In order to solve the problems, the scheme provides a preparation method of demethylitopride nitrosamine, which specifically comprises the following steps: a preparation method of demethylitopride nitrosamine comprises the following steps:
(1) the method comprises the following steps of (1) taking itopride hydrochloride as a starting material, and reacting the starting material with chloroformate under the condition of alkali to obtain N-alkoxycarbonyl demethylitopride;
(2) removing a protecting group of the methyl itopride to obtain the methyl itopride;
Further, the base in the step 1 is a weak base selected from one of triethylamine, N-diisopropylethylamine, potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate, and the molar ratio of the consumption of the weak base to the raw material itopride hydrochloride is 1:1-5: 1.
Further, the mole ratio of the chloroformate used in step 1 to the raw material itopride hydrochloride is 1.05:1-2: 1.
Further, in the deprotection process of step 2, when R is phenyl, the deprotection condition is 2-3M concentration NaOH or KOH solution, when R is benzyl, the deprotection condition is Pd/C and hydrogen, and when R is 2-chloroethyl, the deprotection condition is reflux heating.
Further, the solvent used in the step 3 is a mixed solvent of dichloromethane and water, and the volume ratio of dichloromethane to water is 1: 1.
Further, in the step 3, the acid is selected from one of hydrochloric acid or sulfuric acid, the concentration is 1-2M, and the molar ratio of the amount of the sodium nitrite to the initial raw material itopride hydrochloride is 1.2:1-3: 1.
Further, the refining method of the product in the step 3 is recrystallization, the used solvent is one or more selected from chloroform, ethyl acetate, dichloromethane and tetrahydrofuran, and the ratio of the volume milliliter number of the solvent to the gram number of the crude product is 5:1-20: 1.
has the advantages that: the method for preparing demethylitopride nitrosamine provided by the invention has the advantages of easily available raw materials, simplicity, convenience and high efficiency, provides an efficient standard preparation method for the first report of a substance synthesis route and the detection of demethylitopride nitrosamine impurities.
Drawings
FIG. 1 shows the preparation of demethylitopridine nitrosamine1H NMR；
FIG. 2 shows the preparation of demethylitopridine nitrosamine13C NMR；
FIG. 3 is ESI-MS of demethylitopridine nitrosamine.
Detailed Description
Example 1
100ml of dichloromethane, 10g of itopride hydrochloride and 6.1g of triethylamine are added into a 250ml flask, the temperature of a reaction system is reduced to 10 ℃ after the materials are fully dissolved, 4.7g of phenyl chloroformate is slowly added, then the temperature is increased to 40 ℃ for reflux reaction for 2 hours, a proper amount of water and hydrochloric acid are added after the reaction is finished, and the pH is adjusted to be = 3. After extraction and stratification, the organic layer is taken and evaporated to dryness, and about 12g of crude N-phenoxycarbonyldemethylitopride is obtained.
Dissolving the obtained crude product N-phenoxycarbonyl demethylitopride in a mixed solvent of 50ml DMSO and 50ml water, adding 10g of potassium hydroxide, heating to 90 ℃, refluxing for 2h, cooling to room temperature, adding 100ml of water, extracting with dichloromethane, washing the obtained dichloromethane layer by using 100ml of 1M hydrochloric acid aqueous solution, combining water phases, adding 4g of sodium nitrite, reacting for 2h at room temperature, extracting with dichloromethane after the reaction is finished, obtaining 2.9g of crude product demethylitopride nitrosamine, adding 20ml of ethyl acetate, and recrystallizing to obtain 1.4g of refined demethylitopride nitrosamine.
1H NMR (400MHz, DMSO-d6)δ 8.85 (t, J = 5.9 Hz, 1H ), 7.52 (dd, J = 8.4 Hz, J = 2.1 Hz 1H ), 7.48 (d, J = 2.1 Hz, 1H ), 7.24(m, 2H ), 7.01 (d, J = 8.4 Hz, 1H ), 6.90 (m, 2H ), 4.50 (m, 2H ), 4.40 (d, J = 5.9 Hz, 2H ), 4.29 (m, 2H), 3.80 (d, J = 1.7, 6H), 3.05 (s, 2H)。
13C NMR(100MHz, DMSO-d6) δ165.6, 156.84, 156.78, 151.2, 148.2, 132.48, 132.47, 128.7, 126.6, 120.5, 114.5, 114.3, 110.9, 110.6, 65.0, 63.5, 55.6, 55.5, 52.3, 44.0, 42.0, 40.1, 40.0, 39.8, 39.7, 39.5, 39.3, 39.1, 39.0, 31.7。
ESI-MS : C19H23N3O5 Cacl.(M+H)+:374.1716 found 374.1715。
Example 2
100ml of dichloromethane, 10g of itopride hydrochloride and 6.1g of triethylamine are added into a 250ml flask, the temperature of a reaction system is reduced to 10 ℃ after the materials are fully dissolved, 4.7g of phenyl chloroformate is slowly added, then the temperature is increased to 40 ℃ for reflux reaction for 2 hours, a proper amount of water and hydrochloric acid are added after the reaction is finished, and the pH is adjusted to be = 3. After extraction and stratification, the organic layer is taken and evaporated to dryness, and about 12g of crude N-phenoxycarbonyldemethylitopride is obtained.
Dissolving the obtained crude product N-phenoxycarbonyl demethylitopride in a mixed solvent of 50ml DMSO and 50ml water, adding 10g of potassium hydroxide, heating to 90 ℃, refluxing for 2h, cooling to room temperature, adding 100ml of water, extracting with dichloromethane, washing the obtained dichloromethane layer by using 100ml of 1M hydrochloric acid aqueous solution, combining water phases, adding 4g of sodium nitrite, reacting for 2h at room temperature, extracting with dichloromethane after the reaction is finished, obtaining 2.9g of crude product demethylitopride nitrosamine, adding 35ml of tetrahydrofuran, and recrystallizing to obtain 1.6g of refined demethylitopride nitrosamine.
Example 3
50ml of water and 50ml of dioxane, 10g of itopride hydrochloride and 5.1g of sodium bicarbonate are added into a 250ml flask, the temperature of a reaction system is reduced to 10 ℃ after the materials are fully dissolved, 5.2g of Cbz-Cl is slowly added, then the temperature is increased to 90 ℃ for reflux reaction for 2 hours, a proper amount of water is added after the reaction is finished, and the pH is adjusted to be = 3. Chloroform extraction and layering are carried out, then the organic layer is taken and evaporated to dryness, and about 10g of N-benzyloxycarbonyl demethylitopride crude product is obtained.
Dissolving the obtained crude product N-benzyloxycarbonyl demethylitopride in 100ml of methanol, adding 0.2g of 5% Pd/C catalyst, performing hydrogen replacement, reacting at room temperature for 24 hours, filtering after the reaction is finished, evaporating the filtrate to dryness, dissolving the obtained oily substance in 100ml of 1M hydrochloric acid solution, adding 4g of sodium nitrite, reacting at room temperature for 2 hours, extracting with dichloromethane after the reaction is finished to obtain 2.4g of crude product demethylitopride nitrosamine, adding 20ml of ethyl acetate, and recrystallizing to obtain 1.3g of refined demethylitopride nitrosamine.
Example 4
100ml of dichloromethane, 10g of itopride hydrochloride and 6.1g of triethylamine are added into a 250ml flask, the temperature of a reaction system is reduced to 0 ℃ after the materials are fully dissolved, 4.4g of chloroethyl chloroformate is slowly added, then the temperature is kept for reaction for 6 hours, a proper amount of water and hydrochloric acid are added after the reaction is finished, and the pH is adjusted to be = 3. After extraction and stratification, the organic layer is taken and evaporated to dryness, and about 11g of N-chloroethoxy carbonyl demethyl itopride crude product is obtained.
Dissolving the obtained crude product N-chloroethoxycarbonyl demethyl itopride in 100ml of methanol, heating to reflux for 12h, evaporating the solution to dryness after cooling to room temperature to obtain oily matter, dissolving the oily matter in 100ml of 1M hydrochloric acid solution, adding 4g of sodium nitrite, reacting for 2h at room temperature, extracting with dichloromethane after the reaction is finished to obtain 2.2g of crude product demethyl itopride nitrosamine, adding 20ml of ethyl acetate, and recrystallizing to obtain 1.2g of refined demethyl itopride nitrosamine.
Claims (7)
1. A preparation method of demethylitopridine nitrosamine is characterized by comprising the following steps:
the method comprises the following steps of (1) taking itopride hydrochloride as a starting material, and reacting the starting material with chloroformate under the condition of alkali to obtain N-alkoxycarbonyl demethylitopride;
removing a protecting group of the methyl itopride to obtain the methyl itopride;
under the condition of acid and sodium nitrite, demethyl itopride generates demethyl itopride nitrosamine;
2. The method according to claim 1, wherein the base in step (a) is a weak base selected from one of triethylamine, N-diisopropylethylamine, potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate, and the molar ratio of the weak base to the raw material itopride hydrochloride is 1:1-5: 1.
3. The method of claim 1, wherein the mole ratio of chloroformate used in step (a) to starting itopride hydrochloride is in the range of 1.05:1 to 2: 1.
4. The method of claim 1, wherein in the deprotection process of step (b), when R is phenyl, the deprotection conditions are 2-3M NaOH or KOH solution, when R is benzyl, the deprotection conditions are Pd/C and hydrogen, and when R is chloroethyl, the deprotection conditions are reflux heating.
5. The method according to claim 1, wherein the solvent used in step (c) is a mixed solvent of dichloromethane and water, and the volume ratio of dichloromethane to water is 1: 1.
6. The method according to claim 1, wherein the acid in step (c) is selected from one of hydrochloric acid or sulfuric acid, the concentration is 1-2M, and the molar ratio of the amount of the sodium nitrite to the initial raw material itopride hydrochloride is 1.2:1-3: 1.
7. The method of claim 1, wherein the purification method of the product in step (c) is recrystallization, the solvent is one or more selected from chloroform, ethyl acetate, dichloromethane and tetrahydrofuran, and the ratio of the volume of the solvent in milliliters to the weight of the crude product is 5:1-20: 1.
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