CN112028843A - Preparation method of 7-chloro-5- (2-fluorophenyl) -3H-1, 4-benzodiazepine-2-methylamine - Google Patents
Preparation method of 7-chloro-5- (2-fluorophenyl) -3H-1, 4-benzodiazepine-2-methylamine Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- PYOLGMAWZPLCMY-UHFFFAOYSA-N [7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-yl]methanamine Chemical compound NCC1=Nc2ccc(Cl)cc2C(=NC1)c1ccccc1F PYOLGMAWZPLCMY-UHFFFAOYSA-N 0.000 title claims abstract description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 48
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims abstract description 43
- UAFWJQYZZIJGPD-UHFFFAOYSA-N 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione Chemical compound FC1=CC=CC=C1C1=NCC(=S)NC2=CC=C(Cl)C=C12 UAFWJQYZZIJGPD-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000004519 manufacturing process Methods 0.000 claims abstract description 14
- UVCOILFBWYKHHB-UHFFFAOYSA-N desalkylflurazepam Chemical compound FC1=CC=CC=C1C1=NCC(=O)NC2=CC=C(Cl)C=C12 UVCOILFBWYKHHB-UHFFFAOYSA-N 0.000 claims abstract description 12
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000004537 pulping Methods 0.000 claims description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 238000000746 purification Methods 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 230000001476 alcoholic effect Effects 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 4
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 claims description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 3
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 abstract description 4
- 238000001035 drying Methods 0.000 description 6
- 229960003793 midazolam Drugs 0.000 description 6
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- UESSEMPSSAXQJC-UHFFFAOYSA-N ethanol;methanamine Chemical compound NC.CCO UESSEMPSSAXQJC-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- LSQOUBKWMBDIPL-UHFFFAOYSA-N [7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1h-1,4-benzodiazepin-2-yl]methanamine Chemical compound C12=CC(Cl)=CC=C2NC(CN)CN=C1C1=CC=CC=C1F LSQOUBKWMBDIPL-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 230000004799 sedative–hypnotic effect Effects 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 230000036640 muscle relaxation Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- -1 sedative hypnotic Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003556 thioamides Chemical class 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/20—Nitrogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of 7-chloro-5- (2-fluorophenyl) -3H-1, 4-benzodiazepine-2-methylamine, which comprises the following steps: (1) reacting 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one with phosphorus pentasulfide to prepare 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-thione; and (2) reacting 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-thione with methylamine alcohol solution to obtain 7-chloro-5- (2-fluorophenyl) -3H-1, 4-benzodiazepine-2-methylamine. The preparation method provided by the invention has the advantages of low cost, mild conditions, safe production, high yield, stable and reliable product quality, simple and convenient operation and suitability for industrial production.
Description
Technical Field
The invention relates to the field of medicine and chemical industry, in particular to a preparation method of 7-chloro-5- (2-fluorophenyl) -3H-1, 4-benzodiazepine-2-methylamine.
Background
Midazolam is a 2 nd generation benzodiazepine drug, has pharmacological properties such as anxiolytic, sedative hypnotic, anticonvulsant, central muscle relaxation and the like, and is widely used for administration before anesthesia operation. Midazolam was successfully developed by roche switzerland and was approved by FDA for marketing in 12 months of 1985 under the trade name Versed. With the expiration of patent protection and the introduction of 3 rd generation sedative hypnotic drugs, midazolam has turned to the common name drug and is marketed by imitation in many countries.
7-chloro-5- (2-fluorophenyl) -3H-1, 4-benzodiazepine-2-methylamine is a key intermediate for preparing midazolam. The structure is shown in formula III.
The reported preparation method of 7-chloro-5- (2-fluorophenyl) -3H-1, 4-benzodiazepine-2-methylamine mainly comprises the following 2 methods:
(1) 7-chloro-5- (2-fluorophenyl) -3H-1, 4-benzodiazepine-2-methanamine (J.Org.Chem.1978,43(5): 936-. However, the titanium tetrachloride reagent used in this method is expensive and the post-treatment is cumbersome; methylamine gas is adopted, so that the safety is poor and the operation requirement is strict.
(2) 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepin-2-one analogues are converted by Lawson's reagent into thioamides which are then reacted with tetrahydrofuran or dioxane solutions of amines (bioorg. Med. chem. Lett.2002,12: 3219-. However, the lawson reagent used in this method is expensive and the production cost is high.
Disclosure of Invention
Therefore, the invention aims to provide a preparation method of 7-chloro-5- (2-fluorophenyl) -3H-1, 4-benzodiazepine-2-methylamine aiming at the defects in the prior art, and the preparation method is low in cost, simple and convenient to operate and more suitable for industrial production.
The purpose of the invention is realized by the following technical scheme.
The invention provides a preparation method of 7-chloro-5- (2-fluorophenyl) -3H-1, 4-benzodiazepine-2-methylamine, which comprises the following steps:
(1) reacting 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-ketone shown in a formula I with phosphorus pentasulfide to prepare 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-thione shown in a formula II; and
(2) reacting 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-thione shown as a formula II with an alcoholic solution of methylamine to prepare 7-chloro-5- (2-fluorophenyl) -3H-1, 4-benzodiazepine-2-methylamine shown as a formula III;
the invention effectively prepares the 7-chloro-5- (2-fluorophenyl) -3H-1, 4-benzodiazepine-2-methylamine by creatively designing a reaction route. Specifically, 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-methanamine is prepared by first converting 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one into 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-thione, and then reacting with methylamine in an alcoholic solution (protic solution) state. The preparation method avoids using methylamine gas, has safe production, simple and convenient operation and low cost, and is suitable for industrial production.
According to the preparation method provided by the invention, the reaction in the step (1) is carried out in pyridine. In some embodiments, the weight ratio of 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepin-2-one to pyridine in step (1) is 1:4 to 20, such as 1:6 to 10.
The preparation method provided by the invention is characterized in that the molar ratio of 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one to phosphorus pentasulfide in the step (1) is 1: 0.5-1, and preferably 1: 0.6-0.8.
The preparation method provided by the invention is characterized in that the reaction in the step (1) is carried out at the temperature of 60-116 ℃, preferably 70-75 ℃.
According to the preparation method provided by the invention, the reaction in the step (1) is carried out for 8-10 hours.
The preparation method provided by the invention, wherein the step (1) further comprises the following steps: pulping and purifying the reaction product obtained after the reaction.
According to the preparation method provided by the invention, the solvent adopted by the pulping purification in the step (1) is a mixed solvent containing water and monohydric alcohol.
The preparation method provided by the invention is characterized in that the monohydric alcohol is C1-7A monohydric alcohol. Examples of monohydric alcohols suitable for use in the preparation process of the present invention include, but are not limited to: methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol and n-hexanol. In some embodiments, the monohydric alcohol is methanol, ethanol, or isopropanol. In some embodiments, the mixed solvent consists of water and ethanol.
According to the preparation method provided by the invention, the volume ratio of the monohydric alcohol to the water in the mixed solvent is 1: 0.5-1.5, preferably 1: 0.8-1.2, and more preferably 1: 0.8-1.
According to the preparation method provided by the invention, the pulping purification in the step (1) is carried out at the temperature of 0-30 ℃, preferably 10-20 ℃.
According to the preparation method provided by the invention, the time for pulping and purifying in the step (1) is not particularly required. In some embodiments, the time for the refining in step (1) is from 1 to 5 hours, and in some embodiments from 2 to 3 hours.
According to the preparation method provided by the invention, the alcohol solution of methylamine in the step (2) is a methanol solution of methylamine or an ethanol solution of methylamine, and preferably the ethanol solution of methylamine.
According to the preparation method provided by the invention, the concentration of the methylamine alcohol solution is 30-33 wt%.
According to the preparation method provided by the invention, the reaction in the step (2) is carried out in the presence of dimethyl sulfoxide. In some embodiments, the mass to volume ratio of 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-thione to dimethyl sulfoxide in step (2) is from 1:1 to 6g: ml, in some embodiments from 1:2 to 4g: ml, and in some embodiments, from 1:3 to 4g: ml.
According to the preparation method provided by the invention, in the step (2), the mass-to-volume ratio of the 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-thione to the alcoholic solution of methylamine is 1: 3-20 g: ml, preferably 1: 5-15 g: ml, and further preferably 1: 10-13 g: ml.
The preparation method provided by the invention is characterized in that the reaction in the step (2) is carried out at the temperature of 0-30 ℃, preferably 10-20 ℃.
According to the preparation method provided by the invention, the reaction in the step (2) is carried out for 20-60 minutes, preferably 30-40 minutes.
The preparation method provided by the invention, wherein the step (2) further comprises the following steps: pulping and purifying the reaction product obtained after the reaction.
According to the preparation method provided by the invention, the solvent used for pulping and purifying in the step (2) is water or toluene, and water is preferred.
According to the preparation method provided by the invention, the volume ratio of the solvent and the dimethyl sulfoxide adopted in the pulping and purifying in the step (2) is 0.5-1.5: 1, and preferably 0.8-1.2: 1.
According to the preparation method provided by the invention, the pulping purification in the step (2) is carried out at the temperature of 0-30 ℃, preferably 10-20 ℃.
According to the preparation method provided by the invention, the time for pulping and purifying in the step (2) is not particularly required. In some embodiments, the time for the refining by beating in step (2) is from 1 to 5 hours, and in some embodiments from 2 to 3 hours.
The invention has the following advantages:
(1) in the present invention, 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-methanamine is prepared by first converting 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one into 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-thione, and then reacting with methylamine in an alcoholic solution (protic solution). The method is simple and easy to operate, the used reagents are cheap and easy to obtain, and the production cost can be effectively reduced.
(2) The preparation method provided by the invention has mild conditions, the adopted methylamine reagent is methylamine alcohol solution (protonic solution) instead of methylamine gas, the production is safe, the yield is high, and the product quality is stable and reliable (the purity is usually more than 99 percent); and the operation steps are simplified, the amplification is easy, and the method is suitable for industrial production.
(3) The invention provides a preparation method of a novel midazolam key intermediate, namely 7-chloro-5- (2-fluorophenyl) -3H-1, 4-benzodiazepine-2-methylamine, which is beneficial to the production of midazolam and has wide industrial application prospect.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. The following description of at least one exemplary embodiment is merely illustrative in nature and is in no way intended to limit the invention, its application, or uses. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. Furthermore, it will be further understood that the terms "comprises" and/or "comprising," when used in this specification, specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof. The relative arrangement of the components and steps, the numerical expressions and numerical values set forth in these embodiments do not limit the scope of the present invention unless specifically stated otherwise.
Example 1
100g of 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepin-2-one was dissolved in 600ml of pyridine, 57.7g of phosphorus pentasulfide was added, the temperature was raised to 75 ℃ and the reaction was stirred for 8 hours. Concentrating, adding 200ml of ethanol and 160ml of water, and pulping for 2 hours at 10-15 ℃. After suction filtration and drying, 97g of 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-thione was obtained with a yield of 92%.
Dissolving 90g of 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-thione in 900ml of 30-33 wt% methylamine ethanol solution, slowly adding 360ml of dimethyl sulfoxide, controlling the temperature to be 12 +/-2 ℃, and stirring for 30 minutes. Concentrating until the volume is not reduced, slowly adding 360ml water, and pulping for 2 hr. Suction filtration and drying are carried out to obtain 95.7g of 7-chloro-5- (2-fluorophenyl) -3H-1, 4-benzodiazepine-2-methylamine with the yield of 85 percent.
Example 2
100g of 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepin-2-one was dissolved in 600ml of pyridine, 77g of phosphorus pentasulfide was added, the temperature was raised to 70 ℃ and the reaction was stirred for 8 hours. Concentrating, adding 200ml ethanol and 160ml water, and pulping for 2 hours at 15-20 ℃. After suction filtration and drying, 89.4g of 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-thione was obtained with a yield of 84.7%.
80g of 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-thione is dissolved in 800ml of 30-33 wt% methylamine ethanol solution, 240ml of dimethyl sulfoxide is slowly added, the temperature is controlled at 18 +/-2 ℃, and stirring is carried out for 30 minutes. Concentrating until the volume is not reduced, slowly adding 240ml of water, and pulping for 2 hours. Suction filtration and drying are carried out to obtain 72.6g of 7-chloro-5- (2-fluorophenyl) -3H-1, 4-benzodiazepine-2-methylamine with the yield of 91.7 percent.
Example 3
100g of 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepin-2-one was dissolved in 600ml of pyridine, 57.7g of phosphorus pentasulfide was added, the temperature was raised to 80 ℃ and the reaction was stirred for 8 hours. Concentrating, adding 200ml of isopropanol and 200ml of water, and pulping for 2 hours at 15-20 ℃. Suction filtration and drying are carried out, thus obtaining 93.2g of 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-thioketone with the yield of 88.3 percent.
90g of 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-thione is dissolved in 1170ml of a 30-33 wt% methylamine ethanol solution, 360ml of dimethyl sulfoxide is slowly added, the temperature is controlled at 15 +/-2 ℃, and the mixture is stirred for 30 minutes. Concentrating until the volume is not reduced, slowly adding 300ml water, and pulping for 2 hr. The mixture was filtered by suction and dried to obtain 79.8g of 7-chloro-5- (2-fluorophenyl) -3H-1, 4-benzodiazepine-2-methylamine with a yield of 89.6%.
Example 4
100g of 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepin-2-one was dissolved in 600ml of pyridine, 77g of phosphorus pentasulfide was added, the temperature was raised to 73 ℃ and the reaction was stirred for 8 hours. Concentrating, adding 200ml of isopropanol and 200ml of water, and pulping for 2 hours at 10-15 ℃. Suction filtration and drying were carried out to obtain 95.4g of 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-thione with a yield of 90.4%.
Dissolving 90g of 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-thione in 1100ml of 30-33 wt% methylamine ethanol solution, slowly adding 270ml of dimethyl sulfoxide, controlling the temperature to be 12 +/-2 ℃, and stirring for 30 minutes. Concentrating until the volume is not reduced, slowly adding 300ml water, and pulping for 2 hr. Vacuum filtration and drying are carried out, thus obtaining 80.5g of 7-chloro-5- (2-fluorophenyl) -3H-1, 4-benzodiazepine-2-methylamine with the yield of 90.3%.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (9)
1. A process for the preparation of 7-chloro-5- (2-fluorophenyl) -3H-1, 4-benzodiazepine-2-methanamine comprising the steps of:
(1) reacting 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-ketone shown in a formula I with phosphorus pentasulfide to prepare 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-thione shown in a formula II; and
(2) reacting 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-thione shown as a formula II with an alcoholic solution of methylamine to prepare 7-chloro-5- (2-fluorophenyl) -3H-1, 4-benzodiazepine-2-methylamine shown as a formula III;
2. the production process according to claim 1, wherein the reaction in the step (1) is carried out in pyridine;
preferably, the weight ratio of 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one to pyridine in step (1) is 1: 4-20, for example 1: 6-10.
3. The production method according to claim 1 or 2, wherein the molar ratio of 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepin-2-one to phosphorus pentasulfide in the step (1) is 1:0.5 to 1, preferably 1:0.6 to 0.8.
4. The production method according to any one of claims 1 to 3, wherein the reaction in the step (1) is carried out at a temperature of 60 to 116 ℃, preferably 70 to 75 ℃;
preferably, the reaction in the step (1) is carried out for 8-10 hours.
5. The production method according to any one of claims 1 to 4, wherein the step (1) further comprises the steps of: pulping and purifying a reaction product obtained after the reaction;
preferably, the solvent used for pulping purification in step (1) is a mixed solvent comprising water and monohydric alcohol;
more preferably, the monohydric alcohol is C1-7A monohydric alcohol; further preferably, the monohydric alcohol is one or more selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol and n-hexanol, preferably methanol, ethanol or isopropanol;
more preferably, the mixed solvent consists of water and ethanol;
more preferably, the volume ratio of the monohydric alcohol to the water in the mixed solvent is 1: 0.5-1.5, preferably 1: 0.8-1.2, and more preferably 1: 0.8-1;
preferably, the pulping purification in the step (1) is carried out at the temperature of 0-30 ℃, preferably 10-20 ℃;
preferably, the time of pulping and purifying in the step (1) is 1-5 hours, and preferably 2-3 hours.
6. The production method according to any one of claims 1 to 5, wherein the alcohol solution of methylamine in the step (2) is a methanol solution of methylamine or an ethanol solution of methylamine, preferably an ethanol solution of methylamine;
preferably, the concentration of the methylamine alcohol solution is 30-33 wt%;
preferably, the mass-to-volume ratio of the 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-thione to the methylamine alcohol solution in the step (2) is 1: 3-20 g/ml, preferably 1: 5-15 g/ml, and more preferably 1: 10-13 g/ml.
7. The production method according to any one of claims 1 to 6, wherein the reaction in step (2) is carried out in the presence of dimethyl sulfoxide;
preferably, the mass-to-volume ratio of the 7-chloro-5- (2-fluorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-thione to the dimethyl sulfoxide in the step (2) is 1: 1-6 g/ml, preferably 1: 2-4 g/ml, and more preferably 1: 3-4 g/ml.
8. The production method according to any one of claims 1 to 7, wherein the reaction in the step (2) is carried out at a temperature of 0 to 30 ℃, preferably 10 to 20 ℃;
preferably, the reaction in the step (2) is carried out for 20 to 60 minutes, preferably 30 to 40 minutes.
9. The production method according to any one of claims 1 to 8, wherein the step (2) further comprises the steps of: pulping and purifying a reaction product obtained after the reaction;
preferably, the solvent used for pulping and purifying in the step (2) is water or toluene, preferably water;
preferably, the volume ratio of the solvent and the dimethyl sulfoxide adopted in the pulping purification in the step (2) is 0.5-1.5: 1, preferably 0.8-1.2: 1;
preferably, the pulping purification in the step (2) is carried out at the temperature of 0-30 ℃, preferably 10-20 ℃;
preferably, the time of pulping and purifying in the step (2) is 1 to 5 hours, and preferably 2 to 3 hours.
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