CN117946002A - Synthesis method of rosuvastatin key intermediate - Google Patents
Synthesis method of rosuvastatin key intermediate Download PDFInfo
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- CN117946002A CN117946002A CN202410099728.8A CN202410099728A CN117946002A CN 117946002 A CN117946002 A CN 117946002A CN 202410099728 A CN202410099728 A CN 202410099728A CN 117946002 A CN117946002 A CN 117946002A
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 11
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 title claims description 12
- 229960000672 rosuvastatin Drugs 0.000 title claims description 12
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims abstract description 44
- VFFQGPWQVYUFLV-UHFFFAOYSA-N 4-fluoroisoquinoline Chemical compound C1=CC=C2C(F)=CN=CC2=C1 VFFQGPWQVYUFLV-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000006467 substitution reaction Methods 0.000 claims abstract description 18
- 238000005695 dehalogenation reaction Methods 0.000 claims abstract description 14
- 238000003682 fluorination reaction Methods 0.000 claims abstract description 12
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 11
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 8
- 239000007858 starting material Substances 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 92
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 32
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- 230000035484 reaction time Effects 0.000 claims description 9
- 239000012363 selectfluor Substances 0.000 claims description 8
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 7
- 239000007800 oxidant agent Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 239000012320 chlorinating reagent Substances 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- 150000002978 peroxides Chemical class 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- 150000001263 acyl chlorides Chemical class 0.000 claims description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 2
- 239000012025 fluorinating agent Substances 0.000 claims description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 8
- 230000001590 oxidative effect Effects 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 36
- 230000015572 biosynthetic process Effects 0.000 description 34
- 239000007787 solid Substances 0.000 description 28
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 26
- 238000004128 high performance liquid chromatography Methods 0.000 description 23
- 238000001914 filtration Methods 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 235000005074 zinc chloride Nutrition 0.000 description 13
- 239000011592 zinc chloride Substances 0.000 description 13
- 208000010412 Glaucoma Diseases 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 238000001035 drying Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000004537 pulping Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 4
- QSKQVZWVLOIIEV-NSHDSACASA-N ripasudil Chemical compound C[C@H]1CNCCCN1S(=O)(=O)C1=CC=CC2=CN=CC(F)=C12 QSKQVZWVLOIIEV-NSHDSACASA-N 0.000 description 4
- 229950007455 ripasudil Drugs 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
- 201000004569 Blindness Diseases 0.000 description 2
- 206010010356 Congenital anomaly Diseases 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 210000001742 aqueous humor Anatomy 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 208000030533 eye disease Diseases 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- -1 isoquinoline nitroxide Chemical class 0.000 description 2
- 210000001328 optic nerve Anatomy 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- DTWZAGQENHHNKG-UHFFFAOYSA-N 3-fluoroisoquinoline Chemical compound C1=CC=C2C=NC(F)=CC2=C1 DTWZAGQENHHNKG-UHFFFAOYSA-N 0.000 description 1
- WSUBMVBAMAKLFM-UHFFFAOYSA-N 4-fluoroisoquinolin-5-amine Chemical compound N1=CC(F)=C2C(N)=CC=CC2=C1 WSUBMVBAMAKLFM-UHFFFAOYSA-N 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010018325 Congenital glaucomas Diseases 0.000 description 1
- 206010012565 Developmental glaucoma Diseases 0.000 description 1
- 206010058314 Dysplasia Diseases 0.000 description 1
- 101000669917 Homo sapiens Rho-associated protein kinase 1 Proteins 0.000 description 1
- 101000669921 Homo sapiens Rho-associated protein kinase 2 Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010022941 Iridocyclitis Diseases 0.000 description 1
- 206010067013 Normal tension glaucoma Diseases 0.000 description 1
- 102100039313 Rho-associated protein kinase 1 Human genes 0.000 description 1
- 102100039314 Rho-associated protein kinase 2 Human genes 0.000 description 1
- 206010047555 Visual field defect Diseases 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 201000004612 anterior uveitis Diseases 0.000 description 1
- 230000001746 atrial effect Effects 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- NSNHWTBQMQIDCF-UHFFFAOYSA-N dihydrate;hydrochloride Chemical compound O.O.Cl NSNHWTBQMQIDCF-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000004406 elevated intraocular pressure Effects 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 201000002978 low tension glaucoma Diseases 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 201000003142 neovascular glaucoma Diseases 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000003590 rho kinase inhibitor Substances 0.000 description 1
- 239000011435 rock Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
-
- 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)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a synthesis method of a key intermediate of rosudil, which relates to the technical field of pharmaceutical organic synthesis, and adopts isoquinoline as a starting material to sequentially undergo oxidation reaction, substitution reaction, fluorination reaction, chlorination reaction and dehalogenation reaction to obtain 4-fluoroisoquinoline.
Description
Technical field:
The invention relates to the technical field of pharmaceutical organic synthesis, in particular to a synthesis method of a key intermediate of rosudil.
The background technology is as follows:
Glaucoma (glaucoma) is a group of diseases characterized by atrophy and depression of the disk, visual field defects and vision loss, and pathologic elevated intraocular pressure and insufficient blood supply to the optic nerve are the primary risk factors for its onset, and tolerance of the optic nerve to pressure damage is also associated with the occurrence and progression of glaucoma. Any obstruction of the aqueous humor circulation pathway can lead to pathological changes caused by elevated ocular pressure, but some patients also present with normal tension glaucoma. Glaucoma is one of three general blinding eye diseases that lead to blindness in humans, with a total incidence of 1% in the population, 2% after 45 years of age. Glaucoma is clinically classified into three major categories, primary, secondary and congenital, according to etiology, angle of the room, tonograph, etc.
Secondary glaucoma is caused by interference of normal aqueous humor circulation due to certain eye diseases or systemic diseases, such as glaucoma caused by ocular trauma, neovascular glaucoma, iridocyclitis secondary glaucoma, glucocorticoid glaucoma and the like, and the pathogenic cause of the secondary glaucoma is clear. Congenital glaucoma is due to embryonic dysplasia and congenital variations in the atrial angular structure.
Ripasudil (K-115, rosuvastatin dihydrate hydrochloride) is a ROCK-specific inhibitor capable of inhibiting the activity of ROCK1 and ROCK2, with IC 50 values of 51nM and 19nM, respectively. Ripasudil is Rho kinase inhibitor, has potent ocular tension lowering effect, and can be used for treating glaucoma and intraocular hypertension. Ripasudil has the structural formula:
4-fluoroisoquinoline is a key intermediate of Ripasudil and has the following structural formula:
CN108558758A discloses a synthetic method of 4-fluoroisoquinoline-5-amine, which takes isoquinoline-1-alcohol as a raw material, firstly reacts with Selectfluor to obtain 4-fluoro-3-methoxyisoquinoline-1-alcohol, and then carries out hydrochloric acid hydrolysis reaction, phosphorus oxychloride halogenation reaction and catalytic hydrogenation reaction to obtain 4-fluoroisoquinoline. The synthesis method has the problems of high price of starting materials, complicated steps, low yield and the like, is not beneficial to industrial production, and needs to improve the preparation process.
The invention comprises the following steps:
The invention aims to solve the technical problem of providing a synthesis method of a rosudil key intermediate 4-fluoroisoquinoline, which uses isoquinoline as a starting material, and simplifies the process operation and reduces the process pollution while improving the total yield of a target product through a process route with easily available raw materials and definite control condition parameters.
The technical problems to be solved by the invention are realized by adopting the following technical scheme:
a synthesis method of a key intermediate of rosudil uses isoquinoline as a starting material, an intermediate 1 is obtained through oxidation reaction, an intermediate 2 is obtained through substitution reaction of the intermediate 1, an intermediate 3 is obtained through fluorination reaction of the intermediate 2, an intermediate 4 is obtained through chlorination reaction of the intermediate 3, and 4-fluoroisoquinoline is obtained through dehalogenation reaction of the intermediate 4.
The reaction equation is as follows:
In a further embodiment, the oxidation reaction uses peroxide as the oxidizing agent. The peroxide includes, but is not limited to, at least one of m-chloroperoxybenzoic acid, peroxyacetic acid, hydrogen peroxide. The isoquinoline is oxidized into isoquinoline nitroxide by the oxidation of the oxidizing agent.
In a further technical scheme, the molar ratio of the isoquinoline to the oxidizing agent is 1 (1-3). The dosage of the oxidizing agent needs to be controlled, if the oxidizing agent is excessive, the content of impurities such as m-chlorobenzoic acid in the intermediate 1 product can be increased; if the oxidizing agent is too small, it will result in a relatively large amount of isoquinoline residue.
In a further embodiment, the solvent for the oxidation reaction includes, but is not limited to, at least one of water, methylene chloride, acetonitrile, dimethyl sulfoxide, methanol.
In a further technical scheme, the reaction temperature of the oxidation reaction is 40-120 ℃ and the reaction time is 1-10 h.
In a further embodiment, the substitution reaction uses an acid chloride as a substitution reagent. The acyl chloride includes, but is not limited to, at least one of benzoyl chloride, p-toluenesulfonyl chloride, and methylsulfonyl chloride.
In a further embodiment, the molar ratio of the intermediate 1 to the substitution reagent is 1 (1-3). The dosage of the substitution reagent needs to be controlled, and if the substitution reagent is excessive, the content of impurities such as benzoic acid in the intermediate 2 product can be increased; if the amount of the substitution reagent is too small, the intermediate 1 remains more.
In a further technical scheme, the reaction temperature of the substitution reaction is-10-20 ℃ and the reaction time is 1-5 h.
In a further embodiment, the fluorination reaction uses Selectfluor (N-fluorodimethyl-4-pyridinesulfonamide) as the fluorination reagent.
In a further technical scheme, the molar ratio of the intermediate 2 to the fluorinating agent is1 (1-3).
In a further embodiment, the solvent for the fluorination reaction includes, but is not limited to, at least one of water, methanol, acetonitrile, dimethyl sulfoxide.
In a further technical scheme, the reaction temperature of the fluorination reaction is 40-100 ℃ and the reaction time is 0.5-4 h.
In a further technical scheme, at least one of phosphorus oxychloride, thionyl chloride and phosphorus pentachloride is used as a chlorinating reagent in the chlorination reaction.
In a further technical scheme, the mol ratio of the intermediate 3 to the chlorinating agent is 1 (30-70).
In a further technical scheme, the reaction temperature of the chlorination reaction is 50-90 ℃ and the reaction time is 1-6 h.
In a further embodiment, the dehalogenation acid binding agent includes, but is not limited to, at least one of triethylamine, pyridine, sodium carbonate, and sodium bicarbonate. The hydrogen chloride generated by the dehalogenation reaction forms salt with an acid binding agent, so that the forward progress of the dehalogenation reaction is promoted.
In a further technical scheme, pd/C or Raney Ni is adopted as a hydrogenation catalyst in the dehalogenation reaction.
In a further technical scheme, the mol ratio of the intermediate 4 to the acid binding agent is 1 (1-3); the dosage of the hydrogenation catalyst is 1-20% of the mass of the intermediate 4.
In a further embodiment, the solvent for the dehalogenation reaction includes, but is not limited to, at least one of methanol, acetonitrile, dimethyl sulfoxide.
In a further technical scheme, the reaction temperature of the dehalogenation reaction is 20-60 ℃ and the reaction time is 5-24 h.
The beneficial effects of the invention are as follows: the invention adopts isoquinoline as an initial raw material, and the 4-fluoroisoquinoline is obtained through oxidation reaction, substitution reaction, fluorination reaction, chlorination reaction and dehalogenation reaction in sequence, and the synthesis method has the characteristics of easily obtained raw materials, definite control condition parameters, good process repeatability, high total product yield, and solves the problems of high cost, complex operation, low yield and the like of the existing 4-fluoroisoquinoline synthesis method.
Description of the drawings:
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of the synthesized 4-fluoroisoquinoline of the invention.
The specific embodiment is as follows:
the invention is further described below with reference to specific embodiments and illustrations in order to make the technical means, the creation features, the achievement of the purpose and the effect of the implementation of the invention easy to understand.
Example 1
Synthesis of intermediate 1: isoquinoline (7.7 mol,1 kg) and dichloromethane (2 kg) were added to the reaction vessel, and stirred to dissolve the isoquinoline completely, and then m-chloroperoxybenzoic acid (12.9 mol,2.23 kg) was added to react at room temperature for 4 hours. After the reaction, the temperature was lowered to room temperature to obtain a reaction solution containing intermediate 1 (directly used for the next reaction).
Synthesis of intermediate 2: 8L of water was added to the reaction solution containing intermediate 1, the temperature was lowered to 0 to 5℃and benzoyl chloride (12.7 mol,1.78 kg) was then added thereto, followed by reaction at 0 to 5℃for 2 hours. At the end of the reaction, the solid was collected by filtration and dried in an oven at 40 ℃ to afford intermediate 2. The yield was 80% and the HPLC purity was 94.42%.
Synthesis of intermediate 3: intermediate 2 (6.9 mol,1 kg), water 5L and acetonitrile 10L were added to the reaction vessel, and stirred to dissolve intermediate 2 completely, then SelectFluor (8.3 mol,2.93 kg) was added, and the temperature was raised to 70℃for 2 hours. After the reaction is finished, acetonitrile is distilled off, the temperature is reduced to 0-10 ℃, a large amount of solids are separated out, the solids are filtered, collected, pulped by adding water, filtered, collected and dried in a baking oven at 40 ℃ to obtain the intermediate 3. The yield was 96% and the HPLC purity was 95.97%.
Synthesis of intermediate 4: to the reaction vessel was added phosphorus oxychloride 5L, and intermediate 3 (5.5 mol,1 kg) was slowly added at 0-20 ℃ and stirred for 30min, then heated to 60 ℃ for 2h. After the reaction, removing redundant phosphorus oxychloride by reduced pressure distillation, slowly dripping the residue into water at the temperature of 5-10 ℃ under stirring, filtering, collecting solid, and drying in a baking oven at the temperature of 40 ℃ to obtain the intermediate 4. The yield was 88% and the HPLC purity was 97.05%.
Synthesis of 4-fluoroisoquinoline: to the reaction vessel were added intermediate 4 (5.5 mol,1 kg) and methanol 10L, stirred to dissolve intermediate 4 completely, and then triethylamine (11.1 mol,1.12 kg) and 10% Pd/C (0.1 kg) were added and the mixture was heated to 40℃to react for 12 hours. After the reaction, filtering, collecting filtrate, distilling under reduced pressure to remove methanol, adding 0.5L of water and 10L of ethyl acetate into the residue under stirring, separating an organic phase, spin-drying, pulping under an ice bath at-5-0 ℃ until the mixture becomes solid, and obtaining the 4-fluoroisoquinoline. The yield was 86% and the HPLC purity was 95.47%.
Example 2
Synthesis of intermediate 1: isoquinoline (7.7 mol,1 kg) and dichloromethane (2 kg) were added to the reaction vessel, and stirred to dissolve the isoquinoline completely, and then m-chloroperoxybenzoic acid (7.7 mol,1.33 kg) was added to react at room temperature for 4 hours. After the reaction, the temperature was lowered to room temperature to obtain a reaction solution containing intermediate 1 (directly used for the next reaction).
Synthesis of intermediate 2: 8L of water was added to the reaction solution containing intermediate 1, the temperature was lowered to 0 to 5℃and benzoyl chloride (12.7 mol,1.78 kg) was then added thereto, followed by reaction at 0 to 5℃for 2 hours. At the end of the reaction, the solid was collected by filtration and dried in an oven at 40 ℃ to afford intermediate 2. The yield was 73% and the HPLC purity was 94.18%.
Synthesis of intermediate 3: intermediate 2 (6.9 mol,1 kg), water 5L and acetonitrile 10L were added to the reaction vessel, and stirred to dissolve intermediate 2 completely, then SelectFluor (6.9 mol,2.44 kg) was added, and the temperature was raised to 70℃for 2 hours. After the reaction is finished, acetonitrile is distilled off, the temperature is reduced to 0-10 ℃, a large amount of solids are separated out, the solids are filtered, collected, pulped by adding water, filtered, collected and dried in a baking oven at 40 ℃ to obtain the intermediate 3. The yield was 92% and the HPLC purity was 95.48%.
Synthesis of intermediate 4: to the reaction vessel was added phosphorus oxychloride 5L, and intermediate 3 (5.5 mol,1 kg) was slowly added at 0-20 ℃ and stirred for 30min, then warmed to 70 ℃ for reaction for 3h. After the reaction, removing redundant phosphorus oxychloride by reduced pressure distillation, slowly dripping the residue into water at the temperature of 5-10 ℃ under stirring, filtering, collecting solid, and drying in a baking oven at the temperature of 40 ℃ to obtain the intermediate 4. The yield was 90% and the HPLC purity was 97.42%.
Synthesis of 4-fluoroisoquinoline: to the reaction vessel were added intermediate 4 (5.5 mol,1 kg) and methanol 10L, stirred to dissolve intermediate 4 completely, then triethylamine (11.1 mol,1.12 kg) and 10% Pd/C (0.05 kg) were added, and the temperature was raised to 40℃for reaction for 12 hours. After the reaction, filtering, collecting filtrate, distilling under reduced pressure to remove methanol, adding 0.5L of water and 10L of ethyl acetate into the residue under stirring, separating an organic phase, spin-drying, pulping under an ice bath at-5-0 ℃ until the mixture becomes solid, and obtaining the 4-fluoroisoquinoline. The yield was 81% and the HPLC purity was 95.04%.
Example 3
Synthesis of intermediate 1: isoquinoline (7.7 mol,1 kg) and 2kg of methylene chloride were added to the reaction vessel, and the mixture was stirred to dissolve the isoquinoline completely, and then m-chloroperoxybenzoic acid (23.1 mol,3.99 kg) was added to the reaction vessel, followed by reaction at room temperature for 4 hours. After the reaction, the temperature was lowered to room temperature to obtain a reaction solution containing intermediate 1 (directly used for the next reaction).
Synthesis of intermediate 2: 8L of water was added to the reaction solution containing intermediate 1, the temperature was lowered to 0 to 5℃and benzoyl chloride (12.7 mol,1.78 kg) was then added thereto, followed by reaction at 0 to 5℃for 2 hours. At the end of the reaction, the solid was collected by filtration and dried in an oven at 40 ℃ to afford intermediate 2. The yield was 85% and the HPLC purity 94.27%.
Synthesis of intermediate 3: intermediate 2 (6.9 mol,1 kg), water 5L and acetonitrile 10L were added to the reaction vessel, and stirred to dissolve intermediate 2 completely, then SelectFluor (8.3 mol,2.93 kg) was added, and the temperature was raised to 70℃for 2 hours. After the reaction is finished, acetonitrile is distilled off, the temperature is reduced to 0-10 ℃, a large amount of solids are separated out, the solids are filtered, collected, pulped by adding water, filtered, collected and dried in a baking oven at 40 ℃ to obtain the intermediate 3. The yield was 95% and the HPLC purity was 95.27%.
Synthesis of intermediate 4: to the reaction vessel was added phosphorus oxychloride 4L, and intermediate 3 (5.5 mol,1 kg) was slowly added at 0-20 ℃ and stirred for 30min, then warmed to 70 ℃ for reaction for 3h. After the reaction, removing redundant phosphorus oxychloride by reduced pressure distillation, slowly dripping the residue into water at the temperature of 5-10 ℃ under stirring, filtering, collecting solid, and drying in a baking oven at the temperature of 40 ℃ to obtain the intermediate 4. The yield was 88% and the HPLC purity was 97.82%.
Synthesis of 4-fluoroisoquinoline: to the reaction vessel were added intermediate 4 (5.5 mol,1 kg) and methanol 10L, stirred to dissolve intermediate 4 completely, and then triethylamine (11.1 mol,1.12 kg) and 10% Pd/C (0.1 kg) were added and the mixture was heated to 60℃to react for 12 hours. After the reaction, filtering, collecting filtrate, distilling under reduced pressure to remove methanol, adding 0.5L of water and 10L of ethyl acetate into the residue under stirring, separating an organic phase, spin-drying, pulping under an ice bath at-5-0 ℃ until the mixture becomes solid, and obtaining the 4-fluoroisoquinoline. The yield was 88% and the HPLC purity was 96.25%.
Example 4
Synthesis of intermediate 1: isoquinoline (7.7 mol,1 kg) and dichloromethane (2 kg) were added to the reaction vessel, and stirred to dissolve the isoquinoline completely, and then m-chloroperoxybenzoic acid (12.9 mol,2.23 kg) was added to react at room temperature for 4 hours. After the reaction, the temperature was lowered to room temperature to obtain a reaction solution containing intermediate 1 (directly used for the next reaction).
Synthesis of intermediate 2: 8L of water was added to the reaction solution containing intermediate 1, the temperature was lowered to 0 to 5℃and benzoyl chloride (7.7 mol,1.08 kg) was then added thereto, followed by reaction at 0 to 5℃for 2 hours. At the end of the reaction, the solid was collected by filtration and dried in an oven at 40 ℃ to afford intermediate 2. The yield was 72% and the HPLC purity was 94.58%.
Synthesis of intermediate 3: intermediate 2 (6.9 mol,1 kg), water 5L and acetonitrile 10L were added to the reaction vessel, and stirred to dissolve intermediate 2 completely, then SelectFluor (10.2 mol,3.61 kg) was added, and the temperature was raised to 70℃for 2 hours. After the reaction is finished, acetonitrile is distilled off, the temperature is reduced to 0-10 ℃, a large amount of solids are separated out, the solids are filtered, collected, pulped by adding water, filtered, collected and dried in a baking oven at 40 ℃ to obtain the intermediate 3. The yield was 97% and the HPLC purity was 95.83%.
Synthesis of intermediate 4: to the reaction vessel was added phosphorus oxychloride 5L, and intermediate 3 (5.5 mol,1 kg) was slowly added at 0-20 ℃ and stirred for 30min, then warmed to 90 ℃ for reaction for 3h. After the reaction, removing redundant phosphorus oxychloride by reduced pressure distillation, slowly dripping the residue into water at the temperature of 5-10 ℃ under stirring, filtering, collecting solid, and drying in a baking oven at the temperature of 40 ℃ to obtain the intermediate 4. The yield was 92% and the HPLC purity was 97.90%.
Synthesis of 4-fluoroisoquinoline: to the reaction vessel were added intermediate 4 (5.5 mol,1 kg) and methanol 10L, stirred to dissolve intermediate 4 completely, and then triethylamine (11.1 mol,1.12 kg) and 10% Pd/C (0.1 kg) were added and the mixture was heated to 50℃to react for 24 hours. After the reaction, filtering, collecting filtrate, distilling under reduced pressure to remove methanol, adding 0.5L of water and 10L of ethyl acetate into the residue under stirring, separating an organic phase, spin-drying, pulping under an ice bath at-5-0 ℃ until the mixture becomes solid, and obtaining the 4-fluoroisoquinoline. The yield was 88% and the HPLC purity was 96.31%.
Example 5
Synthesis of intermediate 1: isoquinoline (7.7 mol,1 kg) and dichloromethane (2 kg) were added to the reaction vessel, and stirred to dissolve the isoquinoline completely, and then m-chloroperoxybenzoic acid (12.9 mol,2.23 kg) was added to react at room temperature for 4 hours. After the reaction, the temperature was lowered to room temperature to obtain a reaction solution containing intermediate 1 (directly used for the next reaction).
Synthesis of intermediate 2: 8L of water is added into the reaction solution containing the intermediate 1, the temperature is reduced to 0 to 5 ℃, and then benzoyl chloride (15.4 mol,2.16 kg) is added for reaction for 2 hours at 0 to 5 ℃. At the end of the reaction, the solid was collected by filtration and dried in an oven at 40 ℃ to afford intermediate 2. The yield was 87% and the HPLC purity was 94.49%.
Synthesis of intermediate 3: intermediate 2 (6.9 mol,1 kg), water 5L and acetonitrile 10L were added to the reaction vessel, stirred to dissolve intermediate 2 completely, then SelectFluor (8.3 mol,2.93 kg) was added, and the temperature was raised to 85℃for 2.5 hours. After the reaction is finished, acetonitrile is distilled off, the temperature is reduced to 0-10 ℃, a large amount of solids are separated out, the solids are filtered, collected, pulped by adding water, filtered, collected and dried in a baking oven at 40 ℃ to obtain the intermediate 3. The yield was 97% and the HPLC purity was 96.28%.
Synthesis of intermediate 4: to the reaction vessel was added phosphorus oxychloride 5L, and intermediate 3 (5.5 mol,1 kg) was slowly added at 0-20 ℃ and stirred for 30min, then heated to 80 ℃ for reaction for 3h. After the reaction, removing redundant phosphorus oxychloride by reduced pressure distillation, slowly dripping the residue into water at the temperature of 5-10 ℃ under stirring, filtering, collecting solid, and drying in a baking oven at the temperature of 40 ℃ to obtain the intermediate 4. The yield was 91% and the HPLC purity was 97.73%.
Synthesis of 4-fluoroisoquinoline: to the reaction vessel were added intermediate 4 (5.5 mol,1 kg) and methanol 10L, stirred to dissolve intermediate 4 completely, then triethylamine (11.1 mol,1.12 kg) and 10% Pd/C (0.15 kg) were added, and the temperature was raised to 40℃for reaction for 12 hours. After the reaction, filtering, collecting filtrate, distilling under reduced pressure to remove methanol, adding 0.5L of water and 10L of ethyl acetate into the residue under stirring, separating an organic phase, spin-drying, pulping under an ice bath at-5-0 ℃ until the mixture becomes solid, and obtaining the 4-fluoroisoquinoline. The yield was 88% and the HPLC purity was 95.57%.
Example 6
Example 6 the specific procedure for the synthesis of 4-fluoroisoquinoline was the same as in example 1 except that zinc chloride was added as a catalyst in the synthesis of intermediate 2, and the amount of zinc chloride was 5% by mass of isoquinoline.
Synthesis of intermediate 2: 8L of water is added into the reaction solution containing the intermediate 1, the temperature is reduced to 0 to 5 ℃, benzoyl chloride (12.7 mol,1.78 kg) and 0.05kg of zinc chloride are added, and the mixture is reacted for 2 hours at 0 to 5 ℃. At the end of the reaction, the solid was collected by filtration and dried in an oven at 40 ℃ to afford intermediate 2. The yield was 90% and the HPLC purity was 95.64%.
Example 7
Example 7 the specific procedure for the synthesis of 4-fluoroisoquinoline was the same as in example 1 except that zinc chloride was added as a catalyst in the synthesis of intermediate 2, and the amount of zinc chloride was 10% by mass of isoquinoline.
Synthesis of intermediate 2: 8L of water is added into the reaction solution containing the intermediate 1, the temperature is reduced to 0 to 5 ℃, benzoyl chloride (12.7 mol,1.78 kg) and 0.1kg of zinc chloride are added, and the mixture is reacted for 2 hours at 0 to 5 ℃. At the end of the reaction, the solid was collected by filtration and dried in an oven at 40 ℃ to afford intermediate 2. The yield was 94% and the HPLC purity was 96.32%.
Example 8
Example 8 the specific procedure for the synthesis of 4-fluoroisoquinoline was the same as in example 1 except that zinc chloride was added as a catalyst in the synthesis of intermediate 2, and the amount of zinc chloride was 15% by mass of isoquinoline.
Synthesis of intermediate 2: 8L of water is added into the reaction solution containing the intermediate 1, the temperature is reduced to 0 to 5 ℃, benzoyl chloride (12.7 mol,1.78 kg) and 0.15kg of zinc chloride are added, and the mixture is reacted for 2 hours at 0 to 5 ℃. At the end of the reaction, the solid was collected by filtration and dried in an oven at 40 ℃ to afford intermediate 2. The yield was 95% and the HPLC purity was 96.39%.
The specific steps for preparing intermediate 2 in combination with examples 1, 6, 7 and 8 can be seen that the addition of a proper amount of zinc chloride to the reaction system can enhance the reactivity of the substitution reaction, greatly increasing the yield of intermediate 2, and thus the zinc chloride acts as a catalyst in the substitution reaction. And zinc chloride is not an expensive catalyst, and is suitable for industrial production.
In a further technical scheme, the substitution reaction uses zinc chloride as a catalyst, and the dosage is 5-15% of the mass of isoquinoline.
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of 4-fluoroisoquinoline. From fig. 1, it can be seen that the target product 4-fluoroisoquinoline can be synthesized by adopting the technical scheme of the invention, so that the target product 4-fluoroisoquinoline can be used as an intermediate for preparing Raudil.
The foregoing has shown and described the basic principles and main features of the present invention and the advantages of the present invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and that the above embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the spirit and scope of the invention, which is defined in the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (10)
1. A synthesis method of a key intermediate of rosuvastatin is characterized by comprising the following steps: taking isoquinoline as a starting material, carrying out oxidation reaction to obtain an intermediate 1, carrying out substitution reaction on the intermediate 1 to obtain an intermediate 2, carrying out fluorination reaction on the intermediate 2 to obtain an intermediate 3, carrying out chlorination reaction on the intermediate 3 to obtain an intermediate 4, and carrying out dehalogenation reaction on the intermediate 4 to obtain 4-fluoroisoquinoline;
The reaction equation is as follows:
2. The method for synthesizing a rosuvastatin key intermediate according to claim 1, characterized in that: the oxidation reaction takes peroxide as an oxidizing reagent;
preferably, the peroxide is at least one selected from m-chloroperoxybenzoic acid, peroxyacetic acid and hydrogen peroxide;
preferably, the molar ratio of isoquinoline to oxidizing agent is 1 (1-3).
3. The method for synthesizing a rosuvastatin key intermediate according to claim 1, characterized in that: the solvent for the oxidation reaction is at least one selected from water, dichloromethane, acetonitrile, dimethyl sulfoxide and methanol;
preferably, the reaction temperature of the oxidation reaction is 40-120 ℃ and the reaction time is 1-10 h.
4. The method for synthesizing a rosuvastatin key intermediate according to claim 1, characterized in that: the substitution reaction takes acyl chloride as a substitution reagent;
preferably, the acyl chloride is at least one selected from benzoyl chloride, p-toluenesulfonyl chloride and methylsulfonyl chloride;
preferably, the molar ratio of the intermediate 1 to the substitution reagent is 1 (1-3);
preferably, the reaction temperature of the substitution reaction is-10-20 ℃ and the reaction time is 1-5 h.
5. The method for synthesizing a rosuvastatin key intermediate according to claim 1, characterized in that: the fluorination reaction uses SelectFluor as a fluorination reagent;
Preferably, the molar ratio of the intermediate 2 to the fluorinating agent is 1 (1-3).
6. The method for synthesizing a rosuvastatin key intermediate according to claim 1, characterized in that: the solvent for the fluorination reaction is at least one selected from water, methanol, acetonitrile and dimethyl sulfoxide;
preferably, the reaction temperature of the fluorination reaction is 40-100 ℃ and the reaction time is 0.5-4 h.
7. The method for synthesizing a rosuvastatin key intermediate according to claim 1, characterized in that: the chlorination reaction takes at least one of phosphorus oxychloride, thionyl chloride and phosphorus pentachloride as a chlorinating reagent;
preferably, the molar ratio of the intermediate 3 to the chlorinating agent is 1 (30-70);
Preferably, the reaction temperature of the chlorination reaction is 50-90 ℃ and the reaction time is 1-6 h.
8. The method for synthesizing a rosuvastatin key intermediate according to claim 1, characterized in that: the acid binding agent for the dehalogenation reaction is at least one selected from triethylamine, pyridine, sodium carbonate and sodium bicarbonate;
Preferably, the molar ratio of the intermediate 4 to the acid-binding agent is 1 (1-3).
9. The method for synthesizing a rosuvastatin key intermediate according to claim 1, characterized in that: pd/C or Raney Ni is adopted as a hydrogenation catalyst in the dehalogenation reaction;
Preferably, the hydrogenation catalyst is used in an amount of 1 to 20% by mass of the intermediate 4.
10. The synthesis method according to claim 8 or 9, characterized in that: the solvent for the dehalogenation reaction is at least one selected from methanol, acetonitrile and dimethyl sulfoxide;
preferably, the dehalogenation reaction is carried out at a reaction temperature of 20-60 ℃ for 5-24 hours.
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