CN111100132A - Method for synthesizing procarbazine hydrochloride intermediate - Google Patents
Method for synthesizing procarbazine hydrochloride intermediate Download PDFInfo
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- CN111100132A CN111100132A CN201911420673.1A CN201911420673A CN111100132A CN 111100132 A CN111100132 A CN 111100132A CN 201911420673 A CN201911420673 A CN 201911420673A CN 111100132 A CN111100132 A CN 111100132A
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- 238000000034 method Methods 0.000 title claims abstract description 20
- MMIMIFULGMZVPO-UHFFFAOYSA-N benzyl 3-bromo-2,6-dinitro-5-phenylmethoxybenzoate Chemical compound [O-][N+](=O)C1=C(C(=O)OCC=2C=CC=CC=2)C([N+](=O)[O-])=C(Br)C=C1OCC1=CC=CC=C1 MMIMIFULGMZVPO-UHFFFAOYSA-N 0.000 title abstract description 6
- 229960001586 procarbazine hydrochloride Drugs 0.000 title abstract description 6
- 230000002194 synthesizing effect Effects 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 59
- 239000002904 solvent Substances 0.000 claims abstract description 18
- 238000002360 preparation method Methods 0.000 claims abstract description 17
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 14
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 11
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 11
- 230000008569 process Effects 0.000 claims abstract description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- 238000006243 chemical reaction Methods 0.000 claims description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 8
- 238000005917 acylation reaction Methods 0.000 claims description 8
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 claims description 8
- 239000011230 binding agent Substances 0.000 claims description 6
- 150000008280 chlorinated hydrocarbons Chemical group 0.000 claims description 6
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 6
- 238000006482 condensation reaction Methods 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 230000010933 acylation Effects 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 150000003512 tertiary amines Chemical group 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- RPFIHLIZZKXZAY-UHFFFAOYSA-N 4-(chloromethyl)-n-propan-2-ylbenzamide Chemical compound CC(C)NC(=O)C1=CC=C(CCl)C=C1 RPFIHLIZZKXZAY-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 3
- 125000000950 dibromo group Chemical group Br* 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 3
- 235000010299 hexamethylene tetramine Nutrition 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- OITNBJHJJGMFBN-UHFFFAOYSA-N 4-(chloromethyl)benzoic acid Chemical compound OC(=O)C1=CC=C(CCl)C=C1 OITNBJHJJGMFBN-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- XHFGWHUWQXTGAT-UHFFFAOYSA-N n-methylpropan-2-amine Chemical compound CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluic acid Chemical compound CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 229910001961 silver nitrate Inorganic materials 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 239000000150 Sympathomimetic Substances 0.000 description 1
- 229930186949 TCA Natural products 0.000 description 1
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 1
- DZGWFCGJZKJUFP-UHFFFAOYSA-N Tyramine Natural products NCCC1=CC=C(O)C=C1 DZGWFCGJZKJUFP-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 239000003317 industrial substance Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 229940064707 sympathomimetics Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229960003732 tyramine Drugs 0.000 description 1
- DZGWFCGJZKJUFP-UHFFFAOYSA-O tyraminium Chemical compound [NH3+]CCC1=CC=C(O)C=C1 DZGWFCGJZKJUFP-UHFFFAOYSA-O 0.000 description 1
Classifications
-
- 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
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/58—Preparation of carboxylic acid halides
- C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/18—Bridged systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing a procarbazine hydrochloride intermediate. The preparation method comprises the following steps: in a solvent, in the presence of a hydrolyzing agent, carrying out hydrolysis reaction on a compound shown as a formula II as shown in the specification to obtain a compound shown as a formula I. The preparation method has the advantages of high yield, high purity and stable process, and is suitable forAnd (4) industrial production.
Description
Technical Field
The invention relates to a synthesis method of a procarbazine hydrochloride intermediate.
Background
Procarbazine hydrochloride (structural formula is
) Is an anti-tumor chemotherapeutic agent, and can be used for treating Hodgkin lymphoma and specific brain cancer such as glioblastoma multiforme. It is a drug called alkylating agent. The drug is metabolized and activated in the liver. It also inhibits MAO, thereby increasing the effects of sympathomimetics, TCAs, and tyramine. FDA approval was obtained 7 months in 1969. It is listed in the world health organization's basic drug list, which is the most important drug list required by the basic health system.
p-aldehyde-N-isopropyl benzamide (structural formula is shown in the specification)
) Is an important intermediate of procarbazine hydrochloride. At present, the synthesis of the aldehyde-N-isopropylbenzamide mainly adopts p-methylbenzoic acid as a raw material, p-methyl isopropylamide is firstly synthesized, then, dibromo is carried out on methyl, and then, the methyl is hydrolyzed into aldehyde under the action of silver nitrate (Chinese patent CN 110156629A); or the methyl group on the methyl isopropylamide is directly oxidized to the aldehyde by nitric acid and cerium ammonium nitrate (bioorganic chemistry; vol.83; 2019; p.461-467).
In the bromination reaction, the dibromo of methyl in methyl isopropylamide is a free radical reaction, the reaction is difficult to complete, products substituted by monobromo are not few, and a silver nitrate reagent with a high price is needed for the dibromo reaction to obtain aldehyde, so that the bromination reaction is not environment-friendly. The method of directly oxidizing methyl into formaldehyde by nitric acid and ceric ammonium nitrate needs high-temperature reaction, has high danger and is not suitable for industrial production.
In view of this, it is urgently needed to develop a synthetic method of p-aldehyde-N-isopropylbenzamide, which has high yield, simple operation and environmental friendliness and is suitable for industrial chemical compound production.
Disclosure of Invention
The invention provides a synthesis method of a nilapanib intermediate, which is different from the prior art. The synthesis method has the advantages of high yield, high purity, stable process, simple operation, low cost and environmental friendliness, and is suitable for industrial production.
The invention provides a preparation method of a compound shown as a formula II, which comprises the following steps: in an organic solvent, carrying out the following reaction on the compound shown in the formula III and urotropine to obtain a compound shown in the formula II;
wherein X is halogen.
The halogen can be Cl, Br or I, and is preferably Cl.
The compound shown in the formula III is preferably
Among them, the organic solvent may be a solvent conventional in the art, and preferably a chlorinated hydrocarbon solvent (e.g., dichloromethane, chloroform, 1, 2-dichloroethane), and more preferably dichloromethane. The amount of the organic solvent may not be particularly limited. Preferably, the mass-to-volume ratio of the compound represented by formula III to the organic solvent is 0.1-2g/mL, such as 0.211 g/mL.
Wherein, the mol ratio of the urotropin to the compound shown in the formula III can be 1:1-1.5:1, such as 1: 1.
Wherein, the raw materials used in the reaction are preferably the organic solvent, the compound shown in the formula III and the urotropine.
The temperature of the reaction may be 25 to 50 deg.C, preferably 35 to 40 deg.C.
The progress of the reaction can be monitored by monitoring methods conventional in the art (e.g., TLC). The invention takes the disappearance of the compound shown as the formula III as the end point of the reaction. The reaction time may be 2 to 12 hours.
The reaction also comprises a post-treatment step, wherein the post-treatment step can adopt a post-treatment step which is conventional in the organic field, and the following steps are preferably adopted: and cooling, filtering, washing and drying the reaction liquid after the reaction is finished.
The preparation method of the compound shown in the formula II can also comprise the preparation of the compound shown in the formula III, and the preparation method of the compound shown in the formula III comprises the following steps:
in an organic solvent, in the presence of an acid-binding agent, carrying out a condensation reaction shown as the following on a compound shown as a formula IV and isopropylamine to obtain a compound shown as a formula III;
wherein X is as defined above.
The conditions and operations of the condensation reaction can be those conventional in the art, and the following are particularly preferred in the present invention:
among them, the solvent may be a solvent conventional in the art, and a chlorinated hydrocarbon solvent (e.g., dichloromethane, chloroform, 1, 2-dichloroethane) is preferable, and dichloromethane is more preferable.
Wherein, the acid-binding agent can be organic weak base, further can be tertiary amine organic weak base, and further can be triethylamine.
Wherein the molar ratio of the acid-binding agent to the compound shown in the formula IV can be 1:1-2:1, such as 1: 1.
Wherein, the molar ratio of the isopropylamine to the compound shown in the formula IV can be 1:1-1.2:1, such as 1: 1.
The condensation reaction may be carried out at a temperature of from 0 to 10 ℃.
The progress of the condensation reaction can be monitored by monitoring methods conventional in the art (e.g., TLC). In the invention, the disappearance of the compound shown as the formula III is taken as the end point of the reaction. The reaction time may be 1 to 12 hours.
The compound shown in the formula IV is preferably
The preparation method of the compound shown in the formula II can also comprise the preparation of the compound shown in the formula IV, and the preparation method of the compound shown in the formula IV comprises the following steps:
in an organic solvent, carrying out an acylation reaction on an acylation reagent and a compound shown as a formula V to obtain the compound shown as a formula IV;
wherein X is as defined above.
The conditions and operations of the acylation reaction can be those conventional in the art, and the following conditions are particularly preferred in the present invention:
among them, the solvent may be a solvent conventional in the art, and a chlorinated hydrocarbon solvent (e.g., dichloromethane, chloroform, 1, 2-dichloroethane) is preferable, and dichloromethane is more preferable.
Wherein, the acylating agent can be thionyl chloride. The molar ratio of the acylating agent to the compound represented by formula IV is not particularly limited as long as the reaction is not affected.
The temperature of the acylation reaction may be 50-80 ℃.
The progress of the acylation reaction can be monitored by monitoring methods conventional in the art (e.g., TLC, detection of hydrogen chloride gas production). The acylation reaction is used as the end point of the reaction without generating hydrogen chloride gas.
The compound shown as the formula V is preferablyIs composed of
The invention also provides a preparation method of the compound shown in the formula I, which comprises the following steps: in a solvent, in the presence of a hydrolyzing agent, carrying out hydrolysis reaction on a compound shown as a formula II as shown in the specification to obtain a compound shown as a formula I;
wherein X is as defined above.
Wherein, the operation and the condition of the preparation method of the compound shown in the formula II are as described above.
The above-mentioned hydrolyzing agent may be a conventional hydrolyzing agent in the art, preferably an organic weak acid, and more preferably acetic acid.
Wherein, the mol ratio of the hydrolytic agent to the compound shown in the formula II can be 1:1-3:1, such as 1.75: 1.
Wherein, the temperature of the hydrolysis reaction can be 50-100 ℃, and preferably 60-70 ℃.
The progress of the hydrolysis reaction can be monitored by monitoring methods conventional in the art (e.g., TLC). In the invention, the disappearance of the compound shown as the formula II is taken as the end point of the reaction. The time of the hydrolysis reaction may be 2 to 24 hours.
Wherein, the raw materials used in the hydrolysis reaction are preferably the solvent, the hydrolyzing agent and the compound shown in the formula II.
Wherein, the post-treatment step of the hydrolysis reaction can also be a post-treatment step which is conventionally adopted in the organic field, and the following steps are preferably selected: the reaction solution after the completion of the reaction was cooled, filtered and dried.
Wherein, the compound shown in the formula II is preferably
The invention also provides a compound shown as the formula II:
wherein X is as defined above.
The compound shown in the formula II is preferably
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the synthesis method has the advantages of high yield, stable process, simple operation, low cost and environmental friendliness, and is suitable for industrial production
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
170.6 g of p-chloromethylbenzoic acid are added to 500ml of thionyl chloride and heated slowly under reflux, whereupon the hydrogen chloride is taken up with water. When almost no hydrogen chloride is discharged, excessive thionyl chloride is distilled out at normal pressure, 190g of the residue is dissolved in 500ml of dichloromethane, 202g of triethylamine is added, 60g of isopropylamine is slowly dropped in an ice-water bath, the dropping speed is controlled so that the reaction temperature does not exceed 10 ℃, the addition is completed, the mixture is stirred until TLC shows that the reaction is finished, water is added for washing, and the organic phase is concentrated and dried to obtain 211g of p-chloromethyl-N-isopropylbenzamide.
1HNMR(CDCl3,400M)δ:7.90(d,J＝6.5Hz,2H),7.50(d,J＝6.5Hz,2H),6.09(brs,1H),4.63(s,2H),4.33-4.27(m,1H),1.25(d,J＝6.5Hz,6H).
211g of p-chloromethyl-N-isopropylbenzamide and 140g of urotropin were dissolved in 1000ml of methylene chloride and heated under reflux, and a large amount of solid was produced. After TLC reaction is finished, cooling and filtering are carried out, solid is washed by a small amount of dichloromethane and dried, and 340g of product with the purity of 98 percent is obtained. Adding 100ml of acetic acid and 900ml of water, heating to 60-70 ℃ for reaction, generating a large amount of solid, cooling, filtering and drying after the reaction is completed to obtain 160g of p-aldehyde-N-isopropyl benzamide, wherein the yield is 83.8 percent and the purity is 97.2 percent.
1HNMR(CDCl3,400M)δ:10.08(s,1H),7.96-7.89(m,4H),6.09(brs,1H),4.33-4.27(m,1H),1.29(d,J＝6.5Hz,6H)
Example 2
170.6kg of p-chloromethylbenzoic acid was added to 500 l of thionyl chloride, and the mixture was slowly heated under reflux to produce hydrogen chloride which was absorbed with water. When no hydrogen chloride is basically discharged, excessive thionyl chloride is distilled out at normal pressure, the residue is dissolved in 500L of dichloromethane, 202kg of triethylamine is added, 60kg of isopropylamine is slowly added dropwise in an ice-water bath, the dropping speed is controlled, the reaction temperature does not exceed 10 ℃, the addition is completed, the mixture is stirred until TLC shows that the reaction is finished, water is added for washing, and the organic phase is concentrated and dried to obtain 211kg of p-chloromethyl-N-isopropylbenzamide (the nuclear magnetic data are the same as above).
211kg of p-chloromethyl-N-isopropylbenzamide and 140kg of urotropin were dissolved in 1000 liters of methylene chloride and heated under reflux, and a large amount of solid was produced. TLC reaction was complete, cooled, filtered, and the solid was washed with a small amount of dichloromethane, dried, 342kg, 98.2% pure. Adding 100 liters of acetic acid and 900 liters of water, heating to 60-70 ℃ for reaction, generating a large amount of solid, cooling, filtering and drying after the reaction is completed to obtain 160kg of the p-aldehyde-N-isopropyl benzamide (the nuclear magnetic data are the same as above), wherein the yield is 83.8 percent and the purity is 97.1 percent.
Claims (10)
1. A preparation method of a compound shown as a formula II is characterized by comprising the following steps: in an organic solvent, carrying out the following reaction on the compound shown in the formula III and urotropine to obtain a compound shown in the formula II;
wherein X is halogen.
2. The process according to claim 1, wherein the halogen is F, Cl, Br or I, preferably Cl;
and/or the organic solvent is a chlorinated hydrocarbon solvent, and dichloromethane is further preferable;
and/or the mass-volume ratio of the compound shown in the formula III to the organic solvent is 0.1-2 g/mL;
and/or the molar ratio of the urotropine to the compound shown in the formula III is 1:1-1.5: 1;
and/or the raw materials used in the reaction are the organic solvent, the compound shown as the formula III and the urotropine;
and/or the temperature of the reaction is 25-0 ℃, preferably 35-40 ℃.
3. The process according to claim 1 or 2, further comprising the preparation of the compound of formula III, wherein the process for the preparation of the compound of formula III comprises the steps of:
in an organic solvent, in the presence of an acid-binding agent, carrying out a condensation reaction shown as the following on a compound shown as a formula IV and isopropylamine to obtain a compound shown as a formula III;
wherein X is as defined in claim 1 or 2.
4. A process according to claim 3, wherein the solvent is a chlorinated hydrocarbon solvent, more preferably dichloromethane;
and/or the acid-binding agent is organic weak base, further can be tertiary amine organic weak base, further can be triethylamine;
and/or the molar ratio of the acid-binding agent to the compound shown in the formula IV is 1:1-2: 1;
and/or the molar ratio of the isopropylamine to the compound shown in the formula IV is 1:1-1.2: 1;
and/or the temperature of the reaction is 0-10 ℃.
5. The method of claim 4, further comprising the step of preparing the compound of formula IV, wherein the method comprises the steps of:
in an organic solvent, carrying out an acylation reaction on an acylation reagent and a compound shown as a formula V to obtain the compound shown as a formula IV;
wherein X is as defined in claim 1 or 2.
6. The process according to claim 5, wherein the solvent is a chlorinated hydrocarbon solvent, more preferably dichloromethane;
and/or, the acylating agent is thionyl chloride;
and/or the temperature of the reaction is 50-80 ℃.
7. A process for the preparation of a compound of formula I, comprising the steps of: in a solvent, in the presence of a hydrolyzing agent, carrying out hydrolysis reaction on a compound shown as a formula II as shown in the specification to obtain a compound shown as a formula I;
wherein X is as defined in claim 1 or 2.
8. The preparation method according to claim 7, wherein the compound shown in formula II is prepared by the preparation method of the compound shown in formula II according to any one of claims 1 to 6;
and/or the hydrolytic agent is an organic weak acid, and further preferably acetic acid;
and/or the molar ratio of the hydrolytic agent to the compound shown in the formula II is 1:1-3: 1;
and/or the raw materials used in the hydrolysis reaction are the solvent, the hydrolyzing agent and the compound shown in the formula II;
and/or the temperature of the hydrolysis reaction is 50-100 ℃, preferably 60-70 ℃.
9. The method of claim 8, wherein the hydrolyzing agent is acetic acid;
and/or the temperature of the hydrolysis reaction is 60-70 ℃.
10. A compound of formula II:
wherein X is as defined in claim 1 or 2.
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| CN201911420673.1A CN111100132A (en) | 2019-12-31 | 2019-12-31 | Method for synthesizing procarbazine hydrochloride intermediate |
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