CN114163380A - Alavazepam intermediate, preparation method and application thereof - Google Patents
Alavazepam intermediate, preparation method and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 57
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 8
- 230000008569 process Effects 0.000 claims abstract description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 17
- 239000011737 fluorine Substances 0.000 claims description 17
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 15
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 239000003446 ligand Substances 0.000 claims description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 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 compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 9
- 239000012535 impurity Substances 0.000 claims description 9
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 8
- 239000007832 Na2SO4 Substances 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000000460 chlorine Substances 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
- 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 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 230000009467 reduction Effects 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000010948 rhodium Substances 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- LYXHWHHENVLYCN-QMDOQEJBSA-N (1z,5z)-cycloocta-1,5-diene;rhodium;tetrafluoroborate Chemical compound [Rh].F[B-](F)(F)F.C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1 LYXHWHHENVLYCN-QMDOQEJBSA-N 0.000 claims description 3
- YQYGPGKTNQNXMH-UHFFFAOYSA-N 4-nitroacetophenone Chemical compound CC(=O)C1=CC=C([N+]([O-])=O)C=C1 YQYGPGKTNQNXMH-UHFFFAOYSA-N 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 230000008878 coupling Effects 0.000 claims description 3
- 238000010168 coupling process Methods 0.000 claims description 3
- 238000005859 coupling reaction Methods 0.000 claims description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims 2
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims 2
- 229960005370 atorvastatin Drugs 0.000 claims 2
- 239000004912 1,5-cyclooctadiene Substances 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 5
- 239000006227 byproduct Substances 0.000 abstract description 4
- 239000000047 product Substances 0.000 abstract description 3
- 230000036632 reaction speed Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 239000012467 final product Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 206010047115 Vasculitis Diseases 0.000 description 5
- 230000001086 cytosolic effect Effects 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- WELNSIYTQJSNRP-UHFFFAOYSA-N 2-fluoro-6-methylbenzoic acid Chemical compound CC1=CC=CC(F)=C1C(O)=O WELNSIYTQJSNRP-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000003760 magnetic stirring Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003862 glucocorticoid Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 229960004618 prednisone Drugs 0.000 description 2
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 2
- -1 rhodium (I) bis (1, 5-cyclooctadiene) tetrafluoroborate Chemical compound 0.000 description 2
- WMJNKBXKYHXOHC-PMACEKPBSA-N (2S,3S)-2,3-dihydroxy-2,3-bis(2-methylbenzoyl)butanedioic acid Chemical compound C=1(C(=CC=CC1)C(=O)[C@]([C@](C(=O)O)(O)C(=O)C=1C(=CC=CC1)C)(O)C(=O)O)C WMJNKBXKYHXOHC-PMACEKPBSA-N 0.000 description 1
- 208000018359 Systemic autoimmune disease Diseases 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000008816 organ damage Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1845—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing phosphorus
- B01J31/185—Phosphites ((RO)3P), their isomeric phosphonates (R(RO)2P=O) and RO-substitution derivatives thereof
- B01J31/186—Mono- or diamide derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/60—Reduction reactions, e.g. hydrogenation
- B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
- B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
- B01J2231/645—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of C=C or C-C triple bonds
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/822—Rhodium
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides an alvarazepam intermediate (a compound shown in a formula I), and the compound can be used as an alvarazepam raw material or intermediate to synthesize alvarazepam. The invention also provides a preparation method of the alvarazepam intermediate compound I, the target product alvarazepam intermediate compound I is obtained through 3 steps of reaction, the whole route is novel in design, the chiral resolution process adopted in the prior art is avoided, the practicability is high, the yield is high, the reaction speed is high, the number of byproducts is small, and the preparation method is very suitable for industrial application.
Description
Technical Field
The invention relates to alvarazepam, in particular to an alvarazepam intermediate, a preparation method and application thereof.
Background
Alvacepam is a drug developed by Katemenches GmbH in the United states for the treatment of severe active anti-neutrophil cytoplasmic autoantibody associated vasculitis. Severe active anti-neutrophil cytoplasmic autoantibody associated vasculitis is a rare systemic autoimmune disease involving small blood vessels. Glucocorticoids have been used for decades to treat severe active anti-neutrophil cytoplasmic autoantibody associated vasculitis, and although the prognosis of patients improves with continued optimization of treatment, organ damage and other toxic reactions resulting from long-term use of the hormone threaten patient health. The clinical trial data of alvaconazole III phase show that the relief effect of alvaconazole in treating patients with severe active anti-neutrophil cytoplasmic autoantibody related vasculitis in 26 weeks is similar to that of prednisone, and the sustained relief effect in 52 weeks is obviously better than that of prednisone. Therefore, the fact that alvacepam can reduce the use of glucocorticoid and even replace hormone will open a new era for the treatment of severe active anti-neutrophil cytoplasmic autoantibody associated vasculitis.
The structural formula of alvarepam is as follows:
CN106999481A discloses a preparation method of alvacam, which not only has long preparation steps, but also needs to be resolved by using ditoluoyl-L-tartaric acid, and the yield of the final product is low.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a compound (formula I), which can be used as an alvarazepam raw material or intermediate to synthesize the alvarazepam.
Except for special description, the parts are parts by weight, and the percentages are mass percentages.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a compound of formula I having the following structural formula:
wherein R is1Is halogen; r2Is COR4；R4Is halogen or OC1-C6Alkoxy group of (2).
In one embodiment, the halogen is selected from fluorine, chlorine, bromine or iodine; fluorine, chlorine or bromine are preferred.
In one embodiment, the OC1-C6The alkoxy group of (a) is selected from methoxy or ethoxy.
In one embodiment, R1Is fluorine.
In one embodiment, R4Is methoxy.
In one embodiment, R1Is fluorine; r2Is COR4；R4Is methoxy.
In one embodiment, the invention also provides the use of a compound of formula I as a starting material or intermediate for alvarazepam.
In one embodiment, the compound of formula I may occur as an impurity in the final product of alvarazepam, and the invention therefore also provides the use of a compound of formula I as a control for an impurity in alvarazepam.
A compound of formula II having the following structural formula:
wherein R is1Is halogen; r2Is COR4；R3Is nitro or amino; r4Is halogen or OC1-C6Alkoxy group of (2).
In one embodiment, the halogen is selected from fluorine, chlorine, bromine or iodine; fluorine, chlorine or bromine are preferred.
In one embodiment, the OC1-C6The alkoxy group of (a) is selected from methoxy or ethoxy.
In one embodiment, R1Is fluorine.
In one embodiment, R4Is methoxy.
In one embodiment, R1Is fluorine; r2Is COR4；R3Is nitro; r4Is methoxy.
In one embodiment, the compound of formula II may appear as an impurity in the final product of the compound of formula I, and the invention therefore also provides the use of the compound of formula II as a control for the impurity in the compound of formula I.
In one embodiment, the compounds of formula I of the present invention are prepared by reduction of a compound of formula II.
The compound of formula I is prepared by reducing the compound of formula II, wherein two chiral positions are involved, and nitro reduction is carried out at the same time. It has been found that different catalysts and ligands have a great influence on the reaction, and that if the control is not good, many by-products, low yield and low ee value may occur. In addition, the reaction conditions also influence the yield and ee value of the product. Inventor(s):after a number of experiments, it was found that rhodium (I) bis (1, 5-cyclooctadiene) tetrafluoroborate (Rh (COD))2BF4The (R) -Ligand 1 is a Ligand of the catalyst, the dichloromethane is a solvent, the reaction is carried out for 12 to 24 hours at the temperature of between 20 and 30 ℃ in hydrogen with the atmospheric pressure of 1, the byproducts are less, the yield of the final product, namely the compound shown in the formula II is higher, and the ee value is high.
The structural formula of the (R) -Ligand 1 is as follows:
a compound of formula IV having the general formula:
wherein R is1Is halogen.
In one embodiment, the compound of formula II of the present invention is prepared by coupling a compound of formula III with a compound of formula IV, according to the following reaction scheme:
in one embodiment, the compounds of formula II of the present invention are prepared by a process comprising: dissolving compound III in anhydrous acetone, adding K2CO3And DMF solution with compound IV dissolved, stirring at room temperature for reaction for 30-40 hr, adding anhydrous Na2SO4Then continuously stirring and reacting for 2-5 hours at 40-60 ℃, and then separating to obtain the compound II.
The compound of formula IV may appear as an impurity in the final product of the compound of formula II and the invention therefore also provides the use of the compound of formula IV as a control for the impurity of the compound of formula II.
In one embodiment, the compound of formula IV is prepared by reacting a compound of formula VI with a compound of formula V, as follows:
in one embodiment, the compounds of formula IV of the present invention are prepared by a process comprising: dissolving a compound V (2-fluoro-6-methylbenzoic acid) by using anhydrous THF, cooling to-5-0 ℃ in a low-temperature reaction tank, dropwise adding a THF solution of oxalyl chloride, transferring to room temperature after adding, stirring and reacting for 1-3 hours, cooling a reaction system to-5-0 ℃, dropwise adding a THF solution containing pyridine and a compound VI, transferring to room temperature after adding, continuing stirring and reacting for 3-5 hours, and separating to obtain a compound IV.
The preparation method of the compound III comprises the following steps: under the protection of nitrogen, a THF solution containing methyl chloroformate is dripped into a THF solution dissolved with NaH and p-nitroacetophenone, then the mixture is refluxed for 2 to 4 hours, the reaction system is cooled to room temperature, acetic acid is used for stopping the reaction, and the compound III is obtained by separation.
Has the advantages that:
the invention provides a compound (formula I), which can be used as an alvarazepam raw material or an intermediate to synthesize the alvarazepam. The method has the advantages of novel design of the whole route, avoidance of a chiral resolution process adopted in the prior art, strong practicability, high yield, high reaction speed and few byproducts, and is very suitable for industrial application. The invention uses bis (1, 5-cyclooctadiene) rhodium (I) tetrafluoroborate (Rh (COD)2BF4The compound of the formula II is prepared by chiral reduction in hydrogen with 1 atmospheric pressure at 20-30 ℃ for 12-24 hours by taking (R) -Ligand 1 as a Ligand of the catalyst and dichloromethane as a solvent, and the final product has high yield and high ee value. The compound of formula I as an intermediate of alvacam is obtained through 3 steps of reaction, and the total yield can reach 63.59 percent (calculated by 2-fluoro-6-methylbenzoic acid). In conclusion, the preparation method is simple, the raw materials are cheap and easy to obtain, the reaction conditions are mild, large-scale equipment is not needed, the yield of the final product is high, the purity is high, and the method is suitable for industrial production.
Detailed Description
The present invention is described in detail below with reference to specific examples, which are given for the purpose of further illustrating the invention and are not to be construed as limiting the scope of the invention, and the invention may be modified and adapted by those skilled in the art in light of the above disclosure. The raw materials and reagents used in the invention are all commercial products.
EXAMPLE 1 Synthesis of Compound I
A compound of formula II (R)1Is fluorine; r2Is COR4；R3Is nitro; r4Is methoxy) reduction to prepare the compound of formula I (R)1Is fluorine; r2Is COR4；R4Methoxy) reaction scheme is:
comprising bis (1, 5-cyclooctadiene) rhodium (I) tetrafluoroborate (Rh (COD)2BF481mg, 0.2mmol) and Ligand (R) -Ligand 1(174mg, 0.4mmol) in dichloromethane (20mL) was added a solution of compound II (4g, 10mmol) in isopropanol (40 mL). Then stirred at room temperature for 18 hours under 1 atmosphere of hydrogen and TLC showed the reaction was complete. The reaction solution was diluted with 200mL of ethyl acetate and then with saturated NaHCO respectively3The aqueous solution (100mL X2) and saturated aqueous NaCl solution (100mL X2) were washed, and the organic layer was washed with anhydrous Na2SO4After drying, concentration under reduced pressure was carried out, and the residue was separated by means of a silica gel column (ethyl acetate/petroleum ether ═ 1/5) to give 3.6g of compound I as a white solid in 96% yield and 98.8% ee. H1 NMR (400MHz, CDCl 3): δ (ppm): 7.52(M,1H), 7.32-6.99(M,4H),6.61(M, 2H), 4.18(M,1H),3.76(s,3H),3.61-3.32(M,4H),2.88(M, 1H), 2.46(s, 3H), 2.12(M,1H),1.78-1.61(M,3H). MS (M/z)371(M +1).
EXAMPLE 2 Synthesis of Compound II
A compound of formula II (R)1Is fluorine; r2Is COR4；R3Is nitro; r4Is methoxy) from a compound of formula III (R)2Is COR4；R3Is nitro; r4Is methoxy) and a compound of the formula IV (R)1Fluorine) is prepared by coupling, and the reaction formula is as follows:
4.9g (22mmol) of Compound III are dissolved in 100mL of anhydrous acetone, followed by addition of 4.2g (30mmol) of K2CO3And 5.5g (20mmol) of Compound IV in 10mL of DMF, followed by stirring at room temperature for 36 hours by adding 5g of anhydrous Na2SO4Then stirring was continued at 50 ℃ for 3 hours and TLC showed the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the residue was added to 200mL of ethyl acetate, washed with saturated aqueous NaCl (100mL of X2), and the organic layer was washed with anhydrous Na2SO4After drying, the concentrated crude product was filtered and separated by silica gel column separation (ethyl acetate/petroleum ether ═ 1/10) to give 6.3g of compound II as a yellow solid in 72% yield. Yellow solid. H1 NMR (400MHz, CDCl 3): δ (ppm): 8.38(d, J ═ 8.7Hz,2H),8.01(d, J ═ 8.7Hz,2H),7.51(M,1H),7.31-7.03(M,2H),3.87-3.60(M, 5H),2.79-2.52(M,5H),1.78-1.55(M,2H). MS (M/z)399(M +1).
EXAMPLE 3 Synthesis of Compound IV
IV Compound (R)1Is fluorine) from compounds of formula VI and compounds of formula V (R)1Fluorine) is prepared by the following reaction formula:
50mL of anhydrous THF and 0.2mL of anhydrous DMF, and 3.1g (20mmol) of the compound V (2-fluoro-6-methylbenzoic acid) were charged into a 250mL dry three-necked flask with magnetic stirring, and after cooling to 0 ℃ in a low-temperature reaction tank, a solution of 1.7mL (20mmol) of oxalyl chloride in THF (15mL) was added dropwise, and after completion of the addition, the mixture was allowed to stand at room temperature and stirred for 2 hours. After the reaction system was cooled to 0 deg.C, a solution of 1.7mL (40mmol) of pyridine and 2.8g (20mmol) of Compound VI in THF (20mL) was added dropwise, after which time the reaction was allowed to warm to room temperature and stirred for 4 hours, and TLC indicated completion of the reaction. Diluted with 200mL ethyl acetate, washed with water (100mL X2), 2M aqueous NaOH (100mL X2), and saturated NaHCO3Washing with aqueous solution (100mL X2), washing with saturated aqueous NaCl solution (100mL X2), and washing with organic solventLayer channel anhydrous Na2SO4After drying, concentration gave 5g of compound IV as a white solid in 92% yield. H1 NMR(400 MHz,CDCl3)：δ(ppm)：9.12(s,1H),7.43(m，1H),7.21-6.96(m,2H),3.55-3.39(m,4H), 2.38(s,3H),2.20-2.14(m,2H).MS(m/z)274(M+1),276(M+1).
EXAMPLE 4 Synthesis of Compound III (2-fluoro-6-methylbenzoic acid)
A150 mL three-necked reaction flask equipped with magnetic stirring and nitrogen blanketing was charged with 1.2g (20mmol, 60%) NaH and 3.3g (20mmol) of p-nitroacetophenone, respectively, in 40mL THF, and then a solution of 2.1g (22mmol) of methyl chloroformate in 20mL THF was added dropwise over about 10 minutes under magnetic stirring. Reflux was continued for 3 hours with magnetic stirring and TLC showed the reaction was complete. The reaction system is cooled to room temperature, the reaction is stopped by acetic acid, 200mL of ethyl acetate is added for dilution, and then the mixture is washed by saturated NaCl aqueous solution (100mL of X4) and then is added with Na2SO4After drying and concentration, the crude product obtained was separated by silica gel column separation (ethyl acetate/petroleum ether ═ 1/20) to give 3.2g of compound III as a yellow solid with a yield of 72%. H1 NMR(400MHz,CDCl3): enolic δ (ppm): 12.22(s,1H),8.32(d, J ═ 8.9Hz,2H), 7.96(d, J ═ 8.9Hz,2H),5.78(s,1H),3.84(s,3H), MS (M/z)224(M +1).
Claims (10)
1. A compound of formula I having the following structural formula:
wherein R is1Is halogen; r2Is COR4；R4Is halogen or OC1-C6Alkoxy group of (2).
2. A compound of formula II having the following structural formula:
wherein R is1Is halogen; r2Is COR4；R3Is nitro or amino; r4Is halogen or OC1-C6Alkoxy group of (2).
3. A compound according to claim 1 or 2, wherein: the halogen is selected from fluorine, chlorine, bromine or iodine; preferably fluorine, chlorine or bromine; the OC1-C6The alkoxy group of (a) is selected from methoxy or ethoxy.
4. A compound according to claim 1 or 2, wherein: r1Is fluorine; r2Is COR4；R4Is methoxy.
5. A compound of formula IV having the general formula:
wherein R is1Is halogen.
6. Use of a compound of formula I according to claim 1 as a starting material or intermediate for atorvastatin; or the use of a compound of formula I as a control for an impurity in atorvastatin.
7. Use of a compound of formula II according to claim 2 as a control for impurities in a compound of formula I.
8. Use of a compound of formula IV according to claim 5 as a control for impurities of a compound of formula II.
9. A process for the preparation of compounds of formula I according to claim 1, characterized in that: reducing the compound of the formula II to obtain a compound of a formula I; the catalyst used for the reduction was bis (1, 5-cyclooctadiene) rhodium (I) tetrafluoroborate (Rh (COD)2BF4The Ligand of the catalyst is (R) -Ligand 1, and the solvent isDichloromethane, reacting for 12-24 hours at 20-30 ℃ in hydrogen with 1 atmospheric pressure; the structural formula of the (R) -Ligand 1 is as follows:
10. a process for the preparation of a compound of formula I according to claim 9, characterized in that: the compound of formula II is prepared by coupling a compound of formula III and a compound of formula IV, and the reaction formula is as follows:
dissolving compound III in anhydrous acetone, adding K2CO3And DMF solution with compound IV dissolved therein, reacting at room temperature for 30-40 hr, adding anhydrous Na2SO4Then continuously reacting for 2-5 hours at 40-60 ℃, and then separating to obtain a compound II; the compound IV is prepared by reacting a compound of a formula VI with a compound of a formula V, wherein the reaction formula is as follows:
dissolving a compound V by using anhydrous THF, cooling to-5-0 ℃ in a low-temperature reaction tank, dropwise adding a THF solution of oxalyl chloride, transferring to room temperature for reaction for 1-3 hours after adding, cooling a reaction system to-5-0 ℃, dropwise adding a THF solution containing pyridine and a compound VI, transferring to room temperature for continuous reaction for 3-5 hours after adding, and separating to obtain a compound IV;
the preparation method of the compound III comprises the following steps: under the protection of nitrogen, a THF solution containing methyl chloroformate is dripped into a THF solution dissolved with NaH and p-nitroacetophenone, then the mixture is refluxed for 2 to 4 hours, the reaction system is cooled to room temperature, acetic acid is used for stopping the reaction, and the compound III is obtained by separation.
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