CN114644612B - Preparation method of benzodiazepine nerve inhibitor intermediate compound - Google Patents
Preparation method of benzodiazepine nerve inhibitor intermediate compound Download PDFInfo
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- CN114644612B CN114644612B CN202011497787.9A CN202011497787A CN114644612B CN 114644612 B CN114644612 B CN 114644612B CN 202011497787 A CN202011497787 A CN 202011497787A CN 114644612 B CN114644612 B CN 114644612B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 150000001875 compounds Chemical class 0.000 title claims abstract description 18
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 title description 4
- 229940049706 benzodiazepine Drugs 0.000 title description 4
- 239000003112 inhibitor Substances 0.000 title description 3
- 210000005036 nerve Anatomy 0.000 title description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 97
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 91
- 238000006243 chemical reaction Methods 0.000 claims description 70
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 66
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 44
- 239000000706 filtrate Substances 0.000 claims description 37
- 238000003756 stirring Methods 0.000 claims description 33
- 239000000243 solution Substances 0.000 claims description 31
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 27
- 239000012043 crude product Substances 0.000 claims description 22
- 239000011780 sodium chloride Substances 0.000 claims description 22
- 239000011259 mixed solution Substances 0.000 claims description 16
- 238000010992 reflux Methods 0.000 claims description 16
- 238000004537 pulping Methods 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 13
- 238000010438 heat treatment Methods 0.000 claims description 12
- 229940125890 compound Ia Drugs 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
- KHVZPFKJBLTYCC-UHFFFAOYSA-N (2-amino-5-bromophenyl)-pyridin-2-ylmethanone Chemical compound NC1=CC=C(Br)C=C1C(=O)C1=CC=CC=N1 KHVZPFKJBLTYCC-UHFFFAOYSA-N 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 3
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical class CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 2
- 238000010009 beating Methods 0.000 claims 3
- YNAVUWVOSKDBBP-UHFFFAOYSA-O morpholinium Chemical compound [H+].C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-O 0.000 claims 1
- 238000001035 drying Methods 0.000 abstract description 6
- 230000009286 beneficial effect Effects 0.000 abstract description 5
- 238000000605 extraction Methods 0.000 abstract description 4
- 239000012535 impurity Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000003908 quality control method Methods 0.000 abstract description 3
- 238000005406 washing Methods 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 19
- 239000011521 glass Substances 0.000 description 14
- 239000012065 filter cake Substances 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 239000000843 powder Substances 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000001819 mass spectrum Methods 0.000 description 10
- 230000005311 nuclear magnetism Effects 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000012046 mixed solvent Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 6
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 229910017053 inorganic salt Inorganic materials 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 3
- 229940011051 isopropyl acetate Drugs 0.000 description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 3
- 229960005181 morphine Drugs 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000003651 drinking water Substances 0.000 description 2
- 235000020188 drinking water Nutrition 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000007788 liquid 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
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- TWJVNKMWXNTSAP-UHFFFAOYSA-N azanium;hydroxide;hydrochloride Chemical compound [NH4+].O.[Cl-] TWJVNKMWXNTSAP-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of a compound I, in particular to a preparation method of an isomer Ia thereof. The preparation method provided by the invention does not need extraction, washing, drying, concentration and other operations, is simple in post-treatment, is beneficial to industrial production, has high yield, and has only one impurity in the obtained product, thereby being beneficial to subsequent quality control.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry preparation, and in particular relates to a benzodiazepine with a structural formula of
Preparation of the derivatives.
Background
The Rui Malun is a benzodiazepine central nervous inhibitor developed by Paion company in England, and is mainly applied to pre-clinical administration of operational examination; additive administration during operation; and opioid for combined use as intravenous total anesthetics for induction and maintenance; ICU sedation, and the like. The compound shown in the formula I is (S) -3- (7-bromo-2-oxo-5- (pyridin-2-yl) -2, 3-dihydro-1H-benzo [1,4 ]]Diaza-type
-3-yl) methyl propionate is an essential intermediate for synthesizing the Malun, and the quality and efficiency of synthesis directly influence the difficulty of product quality control and the production cost of the product.
At present, the synthesis method of the intermediate Ia of the Rayleigh Malun at home and abroad is as follows:
in patent WO0069836A1, fmoc-L-glutamic acid-5-methyl ester IIIa is used as a starting material, after acylation, the obtained product is reacted with 2- (2-amino-5-bromo-benzoyl) pyridine to prepare IIa, intermediate IIa is stirred in a mixed solution of triethylamine and dichloromethane at 40 ℃ overnight, acetic acid and 1, 2-dichloroethane solvent are added after concentration of the reaction solution, the obtained product is stirred at 40 ℃ overnight, and then the obtained product is subjected to column chromatography to obtain intermediate Ia, wherein the yield of the analogue is 55%. The method has longer reaction time, needs to concentrate the reaction liquid in the process, has complex operation, uses the I-type solvent, has the risk of substandard solvent residue and has low yield.
In patent CN108264499a, fmoc-glutamic acid-5-methyl ester IIIa is used as a starting material, and is reacted with 2- (2-amino-5-bromo-benzoyl) pyridine under the action of condensing agent DCC for 20 hours, intermediate IIa is added into a mixed solution of morpholine and dichloromethane, and then extracted, concentrated, and finally column chromatography is performed to obtain intermediate Ia, with a yield of 48.2%. The method has long reaction time, low synthesis efficiency in the first step, easy exceeding of isomers, time-consuming extraction and concentration in the second step, and finally column chromatography, is not suitable for industrial production, and has low yield.
In view of the deficiencies of the process for preparing the intermediate Ia and in order to meet the demands of industrial production, there is a need for improvement of the existing processes.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a method for preparing an intermediate Ia compound, which mainly improves the quality and yield of the product by changing the reaction system, the post-treatment mode and other ways; the method has simple operation, no extraction, concentration, column chromatography and other operations, short reaction time, and can remarkably improve the yield and quality and meet the industrial mass production.
The invention discloses a preparation method of an intermediate compound I and an isomer thereof, which is characterized in that the preparation method comprises the following steps:
1) Reacting compound II or isomer IIa thereof with an organic solvent under morphine base conditions;
2) Cooling the reaction solution and filtering;
3) Pouring the filtrate into a post-treatment solvent, pulping and suction-filtering to obtain a crude product of the compound I, wherein the post-treatment solvent is one or two mixed solutions selected from water, inorganic salt water solution and alkane;
4) And pulping and refining the crude product in an organic mixed solution to obtain the compound I, wherein the organic mixed solution is a mixed solution of a good solvent and a poor solvent, the good solvent is selected from esters or alcohols, and the poor solvent is selected from alkanes or ethers.
The organic solvent is selected from one or more of N, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone.
Preferably, the organic solvent is N, N-dimethylformamide.
Preferably, the post-treatment step 2) is to cool the reaction solution to 0-10 ℃ and stir and filter.
Preferably, the post-treatment solvent in the post-treatment step 3) is a mixed solution of an inorganic salt aqueous solution and an alkane.
More preferably, the inorganic brine solution has a volume at least 5 times the volume of the filtrate.
More preferably, the inorganic brine solution has a volume 7 times the volume of the filtrate.
More preferably, the aqueous inorganic salt solution is an aqueous sodium chloride solution.
Preferably, the concentration of the sodium chloride aqueous solution is selected to be 5% -20%.
More preferably, the aqueous sodium chloride solution has a concentration of 10%.
Preferably, the good solvent in the post-treatment step 4) is selected from ethyl acetate, isopropyl acetate or methanol, and the poor solvent is selected from n-heptane, petroleum ether or cyclohexane.
Preferably, the volume ratio of the good solvent to the poor solvent in the post-treatment step 4) is 1:1-1:8.
More preferably, the volume ratio of good solvent to poor solvent in post-treatment step 4) is 1:4.
Preferably, the mass ratio of the compound II to the good solvent in the post-treatment step 4) is 1:1-1:5.
More preferably, the mass ratio of compound II to good solvent in the post-treatment step 4) is 1:2.
More preferably, the good solvent in the post-treatment step 4) is ethyl acetate, and the poor solvent is n-heptane.
Preferably, in the post-treatment step 4), the pulping temperature of the organic mixed solution is 40-80 ℃.
More preferably, in the post-treatment step 4), the pulping temperature of the organic mixed solution is 50-60 ℃.
More preferably, in the post-treatment step 4), the pulping temperature of the organic mixed solution is 60 ℃.
Preferably, the intermediate compound I of the present invention is isomer Ia.
Preferably, the present invention discloses a process for the preparation of the intermediate compound isomer Ia, which process is:
preferably, the preparation method of the compound II comprises the following steps:
the compound III or the isomer IIIa thereof is acylated under the action of oxalyl chloride and then reacts with 2- (2-amino-5-bromo-benzoyl) pyridine to obtain the compound II.
Preferably, the preparation of compound IIa is:
preferably, the present invention discloses a process for the preparation of intermediate compound I, in particular isomer Ia thereof, which process comprises:
1) Reacting compound II or isomer IIa thereof with an organic solvent under morphine base conditions;
2) Cooling the reaction liquid to 0-10 ℃, stirring and filtering;
3) Pouring the filtrate into an inorganic salt water solution and an alkane mixed solution for pulping, and then carrying out suction filtration to obtain a crude product of the compound Ia, wherein the inorganic salt water solution is selected from a sodium chloride water solution or an ammonium chloride water solution, and the alkane is selected from n-heptane, petroleum ether or cyclohexane;
4) Pulping and refining the crude product Ia in a mixed solution of a good solvent and a poor solvent, wherein the good solvent is selected from ethyl acetate or isopropyl acetate, the poor solvent is selected from n-heptane, petroleum ether or cyclohexane, and the volume ratio of the good solvent to the poor solvent is 1:1-1:8.
Preferably, the present invention discloses a process for the preparation of intermediate compound I, in particular isomer Ia thereof, which process comprises:
1) Reacting compound II or isomer IIa thereof with an organic solvent under morphine base conditions;
2) Cooling the reaction liquid to 0-10 ℃, stirring and filtering;
3) Pouring the filtrate into a mixed solution of 10% sodium chloride aqueous solution and n-heptane, pulping, and suction-filtering to obtain a crude compound Ia, wherein the volume ratio of the sodium chloride aqueous solution to the filtrate is 7:1, and the volume ratio of the n-heptane to the filtrate is 6:1
4) Mixing the crude product of the compound Ia and ethyl acetate, heating to reflux, adding n-heptane, heating to 60 ℃ for pulping, cooling and crystallizing to obtain the compound Ia, wherein the volume ratio of the ethyl acetate to the n-heptane is 1:4.
Compared with the prior art, the invention has the beneficial effects that:
(1) The preparation process does not need extraction, washing, drying, concentration and other operations, and the post-treatment is simple.
(2) The product treated by the method has only one impurity, which is more beneficial to the subsequent quality control.
(3) The preparation method has high yield, can obviously improve the synthesis efficiency and reduce the production cost.
(4) The method is more beneficial to industrialized mass production.
Detailed Description
The present invention will be described in further detail with reference to the following examples, which are only for illustrating the technical aspects of the present invention and are not intended to limit the present invention, and any equivalent substitutions in the art according to the present disclosure are within the scope of the present invention.
Preparation example
Dichloromethane (3800 g) was added to the reaction flask, fmoc-L-glutamic acid-5-methyl ester (570 g) was added, N-dimethylformamide (10 g) was added with rapid stirring, oxalyl chloride (230 g) was slowly added, after the reaction was completed, cooled to 0-10 ℃,2- (2-amino-5-bromo-benzoyl) pyridine (410 g) was added, N-diisopropylethylamine (190 g) was added dropwise after the addition, and the temperature was controlled to not more than 25 ℃. After the dripping is finished, stirring for 1-2 h, adding drinking water into the reaction liquid after the reaction is finished, stirring and separating liquid, collecting an organic phase, concentrating until no obvious liquid drops drop, adding methanol into oily residues, stirring, refluxing and pulping to obtain an off-white solid, namely an intermediate IIa, and obtaining the yield: 90.3% and purity of more than 98%.
Example 1 preparation of Rayleigh Malun intermediate Ia
N, N-dimethylformamide (14.2 g) was added to the reaction flask, stirring was started, intermediate IIa (7.5 g) was added, the temperature was lowered to 5 to 10℃and morpholine (3.7 g) was added thereto, and the temperature was controlled to 25 to 30℃after the addition was completed, and the reaction was carried out for 2.5 hours. After the reaction is completed, the reaction solution is cooled to 2-6 ℃, stirred for 20min, and filtered by suction to obtain the N, N-dimethylformamide filtrate of Ia. The filtrate was poured into a mixed solvent of 10% aqueous sodium chloride (138 g) and n-heptane (81 g), and stirred at 5 to 10℃for 1 hour. And (3) centrifuging to obtain a crude product of the intermediate Ia.
Ethyl acetate (12.6 g) is added into a glass reaction bottle, a crude intermediate Ia is added, the temperature is raised to reflux, n-heptane (38.4 g) is slowly added, after the addition is finished, the temperature is raised to 60 ℃, the mixture is stirred for 1h, then the system is cooled to 20-30 ℃, the mixture is stirred and crystallized for 2h, the mixture is centrifuged, and a filter cake is dried, so that white-like powder is obtained, and the structure is verified to be intermediate Ia. Yield 89.5%, HPLC:98.91%.
MS m/z(ESI):404.2[M+1]
1 HNMR(400MHz，CDCl 3 ):9.10(s,1H)；8.52(d,1H,J＝4.4)；7.98(d,1H,J＝8.0)；7.76-7.71(m,1H)；7.50(dd,1H,J＝2.0,8.4)；7.43(d,1H,J＝2.4)；7.30-7.28(m,1H)；6.95(d,1H,J＝8.8)；3.68-3.64(m,1H)；3.60(s,3H)；2.62-2.58(m,2H)；2.52-2.43(m,2H).
EXAMPLE 2 preparation of intermediate Ia Malun
N, N-dimethylformamide (15.6 g) was added to the reaction flask, stirring was started, intermediate IIa (8.3 g) was added, the temperature was lowered to 5 to 10℃and morpholine (4.1 g) was added thereto, and the temperature was controlled to 22 to 29℃after the addition was completed, and the reaction was carried out for 2 hours. After the reaction is completed, the reaction solution is cooled to 0-5 ℃, stirred for 20min, and filtered by suction to obtain the N, N-dimethylformamide filtrate of Ia. The filtrate was poured into a mixed solvent of 10% aqueous sodium chloride (152 g) and n-heptane (90 g), and stirred at 0 to 15℃for 1 hour. And (3) centrifuging to obtain a crude product of the intermediate Ia.
Adding ethyl acetate (14 g) into a glass reaction bottle, adding a crude intermediate Ia, heating to reflux, slowly adding n-heptane (85 g), after the addition, heating to 60 ℃, stirring for 1h, cooling the system to 20-30 ℃, stirring for crystallization for 2h, centrifuging, and drying a filter cake to obtain white-like powder, wherein nuclear magnetism and mass spectrum data are the same as those of example 1, namely the intermediate Ia. Yield 89.9%, HPLC:97.11%.
EXAMPLE 3 preparation of Rayleigh Malun intermediate Ia
N, N-dimethylformamide (101 g) is added into a reaction bottle, stirring is started, intermediate IIa (53.5 g) is added, the temperature is reduced to 5-10 ℃, morpholine (26.7 g) is added, the temperature is controlled to 20-30 ℃ after the addition, and the reaction is carried out for 2-3 h. After the reaction is completed, the reaction solution is cooled to 2-8 ℃, stirred for 20min, and filtered by suction to obtain the N, N-dimethylformamide filtrate of Ia. The filtrate was poured into a mixed solvent of 20% aqueous sodium chloride (942 g) and n-heptane (138 g), and stirred at 5 to 15℃for 1 hour. And (3) centrifuging to obtain a crude product of the intermediate Ia.
Ethyl acetate (90 g) is added into a glass reaction bottle, the temperature is raised to reflux, then n-heptane (275 g) is added, after the addition is completed, the temperature is raised to 60 ℃, stirring is carried out for 1h, then the system is reduced to 20-30 ℃, stirring and crystallization are carried out for 2h, centrifugation is carried out, a filter cake is dried, thus obtaining white-like powder, and nuclear magnetism and mass spectrum data are the same as those of the embodiment 1, thus obtaining the intermediate Ia. Yield 81.4%, HPLC:98.01%.
EXAMPLE 4 preparation of Rayleigh Malun intermediate Ia
N, N-dimethylformamide (209 g) is added into a reaction bottle, stirring is started, intermediate IIa (110 g) is added, the temperature is reduced to 5-10 ℃, morpholine (55 g) is added, the temperature is controlled to 20-30 ℃ after the addition, and the reaction is carried out for 2-3 h. After the reaction is completed, the reaction solution is cooled to 5-10 ℃, stirred for 20min, and filtered by suction to obtain the N, N-dimethylformamide filtrate of Ia. The filtrate was poured into a mixed solvent of 5% aqueous sodium chloride (140 g) and n-heptane (81), and stirred at 0 to 15℃for 1 hour. And (3) centrifuging to obtain a crude product of the intermediate Ia.
Ethyl acetate (186 g) is added into a glass reaction bottle, the temperature is raised to reflux, then n-heptane (565 g) is added, after the addition is finished, the temperature is raised to 60 ℃, stirring is carried out for 1h, then the system is reduced to 20-25 ℃, stirring and crystallization are carried out for 2h, centrifugation is carried out, a filter cake is dried, thus obtaining white-like powder, and nuclear magnetism and mass spectrum data are the same as those of the embodiment 1, thus obtaining the intermediate Ia. Yield 79.0%, HPLC >98.64%.
EXAMPLE 5 preparation of Rayleigh Malun intermediate Ia
N, N-dimethylformamide (28.3 g) is added into a reaction bottle, stirring is started, intermediate IIa (15 g) is added, the temperature is reduced to 5-10 ℃, morpholine (7.5 g) is added, the temperature is controlled to 20-30 ℃ after the addition, and the reaction is carried out for 2-3 h. After the reaction is completed, the reaction solution is cooled to 2-7 ℃, stirred for 20min and filtered by suctionObtaining the N, N-dimethylformamide filtrate of Ia. Pouring the filtrate into 10% NH 4 The mixture of the aqueous Cl solution (264 g) and n-heptane (155 g) was stirred at 10 to 15℃for 1 hour. And (3) centrifuging to obtain a crude product of the intermediate Ia.
Ethyl acetate (26 g) is added into a glass reaction bottle, the temperature is raised to reflux, then n-heptane (77 g) is added, after the addition is completed, the temperature is raised to 60 ℃, the mixture is stirred for 1h, then the system is reduced to 20-30 ℃, the mixture is stirred and crystallized for 2h, the mixture is centrifuged, a filter cake is dried, and white-like powder is obtained, and nuclear magnetism and mass spectrum data are the same as those of the embodiment 1, thus obtaining the intermediate Ia. Yield 83.1%, HPLC:98.71%.
EXAMPLE 6 preparation of Rayleigh Malun intermediate Ia
N, N-dimethylformamide (22.7 g) is added into a reaction bottle, stirring is started, intermediate IIa (12 g) is added, the temperature is reduced to 5-10 ℃, morpholine (5.9 g) is added, the temperature is controlled to 20-30 ℃ after the addition, and the reaction is carried out for 2-3 h. After the reaction is completed, the reaction solution is cooled to 0-10 ℃, stirred for 20min, and filtered by suction to obtain the N, N-dimethylformamide filtrate of Ia. The filtrate was poured into a mixed solvent of 10% aqueous sodium chloride (212 g) and cyclohexane (142 g), and stirred at 0 to 15℃for 1 hour. And (3) centrifuging to obtain a crude product of the intermediate Ia.
Adding ethyl acetate (20 g) into a glass reaction bottle, heating to reflux, then adding cyclohexane (70 g), after the addition, heating to 60 ℃, stirring for 1h, then cooling the system to 20-30 ℃, stirring for crystallization for 2h, centrifuging, drying a filter cake to obtain white-like powder, and obtaining intermediate Ia by nuclear magnetism and mass spectrum data in the same way as in example 1. Yield 85.5%, HPLC:98.80%.
EXAMPLE 7 preparation of intermediate Ia of Rayleigh Malun
N, N-dimethylformamide (1.9 g) is added into a reaction bottle, stirring is started, intermediate IIa (1 g) is added, the temperature is reduced to 5-10 ℃, morpholine (0.5 g) is added, the temperature is controlled to 20-30 ℃ after the addition, and the reaction is carried out for 2-3 h. After the reaction is completed, the reaction solution is cooled to 3-9 ℃, stirred for 20min, and filtered by suction to obtain the N, N-dimethylformamide filtrate of Ia. The filtrate was poured into a mixed solvent of 10% aqueous sodium chloride (7.7 g) and petroleum ether (4.3 g), and stirred at 8 to 15℃for 1 hour. And (3) centrifuging to obtain a crude product of the intermediate Ia.
Adding isopropyl acetate (1.6 g) into a glass reaction bottle, heating the crude intermediate Ia to reflux, then adding petroleum ether (5 g), after the addition, heating to 60 ℃, stirring for 1h, then cooling the system to 25-30 ℃, stirring and crystallizing for 2h, centrifuging, drying a filter cake to obtain white-like powder, and obtaining intermediate Ia by nuclear magnetism and mass spectrum data as in example 1. Yield 88.6%, HPLC:98.37%.
Example 8 preparation of intermediate Ia of Rayleigh Malun
N, N-dimethylformamide (23 g) is added into a reaction bottle, stirring is started, intermediate IIa (12 g) is added, the temperature is reduced to 5-10 ℃, morpholine (6 g) is added, the temperature is controlled to 20-30 ℃ after the addition, and the reaction is carried out for 2-3 h. After the reaction is completed, the reaction solution is cooled to 5-10 ℃, stirred for 20min, and filtered by suction to obtain the N, N-dimethylformamide filtrate of Ia. The filtrate was poured into a mixed solvent of 10% aqueous sodium chloride (213 g) and cyclohexane (125 g), and stirred at 5 to 15℃for 1 hour. And (3) centrifuging to obtain a crude product of the intermediate Ia.
Adding methanol (12 g) into a glass reaction bottle, adding a crude intermediate Ia, heating to reflux, then adding n-heptane (63 g), after the addition, heating to 60 ℃, stirring for 1h, then cooling the system to 20-25 ℃, stirring for crystallization for 2h, centrifuging, drying a filter cake to obtain white-like powder, and obtaining the intermediate Ia by using nuclear magnetism and mass spectrum data as in example 1. Yield 70.6%, HPLC:99.23%.
EXAMPLE 9 preparation of Rayleigh Malun intermediate Ia
N, N-dimethylformamide (14.2 g) is added into a reaction bottle, stirring is started, intermediate IIa (7.5 g) is added, the temperature is reduced to 5-10 ℃, morpholine (3.7 g) is added, after the addition, the temperature is controlled to 20-30 ℃ for reaction for 2-3 h. After the reaction is completed, the reaction solution is cooled to 0-7 ℃, stirred for 20min, and filtered by suction to obtain the N, N-dimethylformamide filtrate of Ia. The filtrate was poured into drinking water (140 g) and stirred at 10-15℃for 1h. And (3) centrifuging to obtain a crude product of the intermediate Ia.
Ethyl acetate (13 g) is added into a glass reaction bottle, the temperature is raised to reflux, then n-heptane (37 g) is added, after the addition is completed, the temperature is raised to 60 ℃, the mixture is stirred for 1h, then the system is reduced to 25-30 ℃, the mixture is stirred and crystallized for 2h, the mixture is centrifuged, a filter cake is dried, and white-like powder is obtained, and nuclear magnetism and mass spectrum data are the same as those of the embodiment 1, thus obtaining the intermediate Ia. Yield 61%, HPLC:93.21%.
EXAMPLE 10 preparation of intermediate Ia of Rayleigh Malun
N, N-dimethylformamide (14.2 g) was added to the reaction flask, stirring was started, intermediate IIa (7.5 g) was added, the temperature was lowered to 5 to 10℃and morpholine (3.7 g) was added thereto, and the temperature was controlled to 20 to 30℃after the addition was completed, and the reaction was carried out for 3 hours. After the reaction is completed, the reaction solution is cooled to 3-7 ℃, stirred for 20min, and filtered by suction to obtain the N, N-dimethylformamide filtrate of Ia. The filtrate was poured into a mixed solution of ice water (140 g) and n-heptane (82 g), and stirred at 0 to 15℃for 1 hour. And (3) centrifuging to obtain a crude product of the intermediate Ia.
Ethyl acetate (13 g) is added into a glass reaction bottle, the temperature is raised to reflux, then n-heptane (37 g) is added, after the addition is completed, the temperature is raised to 60 ℃, the mixture is stirred for 1h, then the system is reduced to 20-30 ℃, the mixture is stirred and crystallized for 2h, the mixture is centrifuged, a filter cake is dried, and white-like powder is obtained, and nuclear magnetism and mass spectrum data are the same as those of the embodiment 1, thus obtaining the intermediate Ia. Yield 66%, HPLC:98.37%.
EXAMPLE 11 preparation of Rayleigh Malun intermediate Ia
N, N-dimethylformamide (18.5 g) was added to the reaction flask, stirring was started, intermediate IIa (9.8 g) was added, the temperature was lowered to 5 to 10℃and morpholine (4.8 g) was added thereto, and the temperature was controlled to 20 to 30℃after the addition was completed, and the reaction was carried out for 2.5 hours. After the reaction is completed, the reaction solution is cooled to 6-10 ℃, stirred for 20min, and filtered by suction to obtain the N, N-dimethylformamide filtrate of Ia. The filtrate was poured into ice water (182 g) and stirred at 0 to 5℃for 1 hour. And (3) centrifuging to obtain a crude product of the intermediate Ia.
Ethyl acetate (17 g) is added into a glass reaction bottle, the temperature is raised to reflux, then n-heptane (49 g) is added, after the addition is completed, the temperature is raised to 60 ℃, the mixture is stirred for 1h, then the system is reduced to 20-30 ℃, the mixture is stirred and crystallized for 2h, the mixture is centrifuged, a filter cake is dried, and white-like powder is obtained, and nuclear magnetism and mass spectrum data are the same as those of the embodiment 1, thus obtaining the intermediate Ia. Yield 65%, HPLC:91.11%.
Example 12 preparation of Rayleigh Malun intermediate Ia
N, N-dimethylformamide (190 g) is added into a glass reaction bottle, stirring is started, intermediate IIa (100 g) is added, the temperature is reduced to 5-10 ℃, morpholine (50 g) is added, the temperature is controlled to 20-30 ℃ after the addition, and the reaction is carried out for 2-3 h. After the reaction is completed, the reaction solution is cooled to 0-10 ℃, stirred for 20min, filtered by suction, and the filtrate is poured into 10% sodium chloride aqueous solution and stirred for 1h at 5-15 ℃. And (3) centrifuging to obtain a crude product of the intermediate Ia. The crude product was dissolved in 125ml of isopropanol at 85℃and, after cooling, isolated by filtration and dried to give intermediate Ia (yield 65.1%, HPLC:95%, containing a number of impurities greater than 0.10%).
Example 13 industrialized preparation of Rayleigh Malun intermediate Ia
N, N-dimethylformamide (14.21 kg) was added to a 100L glass reactor, stirring was started at a speed of 120r/min, intermediate IIa (7.48 kg) was added, the temperature was lowered to 10.+ -. 5 ℃ and morpholine (3.74 kg) was added, and after the addition, the temperature was controlled to 25.+ -. 5 ℃ for 2 hours. After completion of the TLC monitoring reaction, the reaction solution was cooled to 5.+ -. 5 ℃, stirred for 25min, suction-filtered, and the filter cake was washed with N, N-dimethylformamide (2.39 kg) to give an N, N-dimethylformamide filtrate of Ia, which was poured into a vessel containing 10% aqueous sodium chloride (122.7 kg) and N-heptane (19.75 kg) and stirred for 1h at 10.+ -. 5 ℃. And (3) centrifuging to obtain a crude product of the intermediate Ia.
Ethyl acetate (12.64 kg) is added into a glass reaction bottle, the temperature of the crude intermediate Ia is raised to reflux, then n-heptane (38.41 kg) is added, after the addition is finished, the temperature is raised to 60 ℃, the mixture is stirred for 1h, then the system is lowered to 20+/-5 ℃, the mixture is stirred and crystallized for 2h, the mixture is centrifuged, and a filter cake is dried to obtain white-like powder, thus obtaining the intermediate Ia. Yield 89.3%, HPLC:97.28%.
The above examples are only illustrative of the invention and are not intended to limit the invention to the particular embodiments thereof. Modifications and improvements in various other forms will occur to those skilled in the art upon the foregoing description. Obvious modifications or improvements are thus extended within the scope of the invention, which is defined in the appended claims.
Claims (14)
1. A process for the preparation of the isomer Ia of intermediate compound I, characterized in that it comprises:
1) Reacting isomer IIa of compound II with an organic solvent under morpholinium conditions;
2) Cooling the reaction solution and filtering;
3) Pouring the filtrate into a post-treatment solvent, pulping and suction-filtering to obtain a crude product of the compound Ia;
4) Mixing the crude product of the compound Ia and ethyl acetate, heating to reflux, adding n-heptane, pulping, cooling and crystallizing to obtain the compound Ia;
the organic solvent is selected from N, N-dimethylformamide;
the post-treatment solvent is a mixed solution of sodium chloride aqueous solution and n-heptane.
2. The process according to claim 1, wherein the process for preparing compound IIa comprises:
the compound III isomer IIIa is acylated with oxalyl chloride and then reacted with 2- (2-amino-5-bromo-benzoyl) pyridine to give compound IIa.
3. The method of claim 1, wherein in step 3), the aqueous sodium chloride solution has a volume of at least 5 times the volume of the filtrate.
4. A method of preparing according to claim 3, wherein the aqueous sodium chloride solution has a volume of 7 times the volume of the filtrate.
5. The method according to claim 3 or 4, wherein the concentration of the aqueous sodium chloride solution is 5% to 20%.
6. The method according to claim 5, wherein the concentration of the aqueous sodium chloride solution is 10%.
7. The method according to claim 1, wherein in the step 4), the volume ratio of ethyl acetate to n-heptane is 1:1-1:8.
8. The process of claim 7, wherein in step 4), the volume ratio of ethyl acetate to n-heptane is 1:4.
9. The process according to claim 1, wherein in step 4) the mass ratio of compound IIa to ethyl acetate is from 1:1 to 1:5.
10. The process according to claim 9, wherein the mass ratio of compound IIa to ethyl acetate is 1:2.
11. The method according to claim 1, wherein in step 4), the beating temperature is 40 to 80 ℃.
12. The method of claim 11, wherein the beating temperature is 50-60 ℃.
13. The method of claim 12, wherein the beating temperature is 60 ℃.
14. The preparation method according to claim 1, characterized in that the preparation method is:
1) Reacting compound II isomer IIa with N, N-dimethylformamide under morpholine conditions;
2) Cooling the reaction liquid to 0-10 ℃, stirring and filtering;
3) Pouring the filtrate into a mixed solution of 10% sodium chloride aqueous solution and n-heptane, pulping, and suction-filtering to obtain a crude compound Ia, wherein the volume ratio of the sodium chloride aqueous solution to the filtrate is 7:1, and the volume ratio of the n-heptane to the filtrate is 6:1, a step of;
4) Mixing the crude product of the compound Ia and ethyl acetate, heating to reflux, adding n-heptane, pulping at 60 ℃, cooling and crystallizing to obtain the compound Ia, wherein the volume ratio of the ethyl acetate to the n-heptane is 1:4.
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