CN114671737B - Preparation method of posaconazole main ring intermediate - Google Patents
Preparation method of posaconazole main ring intermediate Download PDFInfo
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- CN114671737B CN114671737B CN202210404095.8A CN202210404095A CN114671737B CN 114671737 B CN114671737 B CN 114671737B CN 202210404095 A CN202210404095 A CN 202210404095A CN 114671737 B CN114671737 B CN 114671737B
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- difluorobenzene
- posaconazole
- main ring
- ring intermediate
- bromopropyl
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- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 title claims abstract description 47
- 229960001589 posaconazole Drugs 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000005977 Ethylene Substances 0.000 claims abstract description 27
- 125000005997 bromomethyl group Chemical group 0.000 claims abstract description 27
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 35
- 238000000034 method Methods 0.000 claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 239000007789 gas Substances 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 230000001681 protective effect Effects 0.000 claims description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- QEWHNJPLPZOEKU-UHFFFAOYSA-N 1-(2,4-difluorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(F)C=C1F QEWHNJPLPZOEKU-UHFFFAOYSA-N 0.000 claims description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- 239000012046 mixed solvent Substances 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 6
- 150000007522 mineralic acids Chemical class 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 238000006555 catalytic reaction Methods 0.000 claims description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 239000001307 helium Substances 0.000 claims description 2
- 229910052734 helium Inorganic materials 0.000 claims description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 239000000047 product Substances 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 13
- 238000010586 diagram Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XSROFNLUQOGWON-UHFFFAOYSA-N 2,4-difluoro-1-prop-1-en-2-ylbenzene Chemical compound CC(=C)C1=CC=C(F)C=C1F XSROFNLUQOGWON-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- -1 1, 2, 4-triazol-1-ylmethyl Chemical group 0.000 description 1
- VEHMGPJUOWKYRJ-UHFFFAOYSA-N 1-(3-bromoprop-1-en-2-yl)-2,4-difluorobenzene Chemical compound FC1=CC=C(C(=C)CBr)C(F)=C1 VEHMGPJUOWKYRJ-UHFFFAOYSA-N 0.000 description 1
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 1
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical class O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 1
- VHHPDZDTKZOHTB-UHFFFAOYSA-M [Br-].[Mg+]C.C1CCOC1 Chemical compound [Br-].[Mg+]C.C1CCOC1 VHHPDZDTKZOHTB-UHFFFAOYSA-M 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- 229940096325 posaconazole oral suspension Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/35—Preparation of halogenated hydrocarbons by reactions not affecting the number of carbon or of halogen atoms in the reaction
- C07C17/358—Preparation of halogenated hydrocarbons by reactions not affecting the number of carbon or of halogen atoms in the reaction by isomerisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/35—Preparation of halogenated hydrocarbons by reactions not affecting the number of carbon or of halogen atoms in the reaction
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
- C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
- C07C29/40—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing carbon-to-metal bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/64—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by simultaneous introduction of -OH groups and halogens
-
- 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
Abstract
The invention discloses a preparation method of posaconazole main ring intermediate, which sequentially prepares 2- (2, 4-difluorobenzene) propane-2-alcohol, 1- (1-propylene-2-yl) -2, 4-difluorobenzene and 1-bromo-2- (2, 4-difluorobenzene) -isopropanol to finally prepare a target product 1- [1- (bromomethyl) ethylene ] -2, 4-difluoro-benzene and an isomer 1- [ (1E) -1-bromopropyl-1-alkene-2-yl ] -2, 4-difluorobenzene, and then converts the isomer 1- [ (1E) -1-bromopropyl-1-alkene-2-yl ] -2, 4-difluorobenzene into the target product. According to the preparation method provided by the invention, the solvent and the catalyst which are economical are selected, and the isomer is converted into the target product, so that the yield of the target product can be improved, and the production cost can be reduced. The invention can be used for preparing the posaconazole main ring intermediate, and the prepared posaconazole main ring intermediate is further applied to the production of posaconazole.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry synthesis, and relates to a preparation method of a posaconazole intermediate, in particular to a preparation method of a posaconazole main ring intermediate.
Background
Posaconazole (Posaconazole) is a derivative of itraconazole, is a second-generation triazole high-lipophilicity antifungal drug which is first appeared and marketed in Germany in 10 months and 25 days 2005, and has the advantages of high efficiency, lower toxic and side effects, wide antibacterial spectrum and the like. The posaconazole oral suspension and the posaconazole enteric-coated tablet are successfully obtained and batched into the Chinese market in 6 months in 2013 and 12 months in 2018 respectively, and the posaconazole is first-line medicine with very large clinical demand in China at present.
Posaconazole with a chemical name of 4- [4- [4- [ -4- [ [ (3R, 5R) -5- (2, 4-difluorophenyl) -5- (1, 2, 4-triazol-1-ylmethyl) oxapent-3-yl]Methoxy group]Phenyl group]Piperazin-1-yl]Phenyl group]-2- [ (2S, 3S) -2-hydroxypentan-3-yl]-1,2, 4-triazole-3-one, the structural formula of which is shown in figure 1. The current economic route for preparing posaconazole bulk drug is formed by reacting a main ring and a side chain, wherein the structural formula of the main ring is shown in figure 2, and the structural formula of the side chain is shown in figure 3.1- [1- (bromomethyl) ethylene]2, 4-difluoro-benzene is an important intermediate which is indispensable in the economical process route for preparing posaconazole main ring,its molecular formula C 9 H 7 BrF 2 Molecular weight 233.05, structural formula is shown in FIG. 4, but 1- [1- (bromomethyl) ethylene is synthesized at present]The cost of the 2, 4-difluoro-benzene is high, and the isomer of the target product is often generated in the synthesis process, so that the conversion rate of the reaction is greatly reduced, and the green chemical idea is not met.
Disclosure of Invention
The invention aims to solve the technical problem of providing a preparation method of a posaconazole main ring intermediate, in particular to a preparation method of 1- [1- (bromomethyl) ethylene ] -2, 4-difluoro-benzene, and aims to reduce the manufacturing cost of the posaconazole main ring, further reduce the production cost of posaconazole bulk drug, enhance market competitiveness and bring greater social benefit.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
a preparation method of posaconazole main ring intermediate, which comprises the following steps in sequence:
preparation of S1.2- (2, 4-difluorobenzene) propan-2-ol
Adding tetrahydrofuran solution of methyl magnesium bromide and 2, 4-difluoroacetophenone into methyl tertiary butyl ether solvent, and reacting in a protective gas environment to prepare 2- (2, 4-difluorobenzene) propane-2-ol;
preparation of S2.1- (1-propen-2-yl) -2, 4-difluorobenzene
2- (2, 4-difluorobenzene) propane-2-alcohol reacts with inorganic acid in a protective gas environment to prepare 1- (1-propylene-2-yl) -2, 4-difluorobenzene;
preparation of S3.1-bromo-2- (2, 4-difluorobenzene) -isopropanol
1- (1-propylene-2-yl) -2, 4-difluorobenzene reacts with dibromohydantoin in a mixed solvent under the environment of protective gas to prepare 1-bromo-2- (2, 4-difluorobenzene) -isopropanol;
preparation of posaconazole Main Ring intermediate 1- [1- (bromomethyl) ethylene ] -2, 4-difluoro-benzene and isomer 1- [ (1E) -1-bromopropyl-1-en-2-yl ] -2, 4-difluorobenzene
Adding concentrated acid into 1-bromo-2- (2, 4-difluorobenzene) -isopropanol, and reacting in a protective gas environment to obtain a mixture of posaconazole main ring intermediate 1- [1- (bromomethyl) ethylene ] -2, 4-difluoro-benzene and isomer 1- [ (1E) -1-bromopropyl-1-en-2-yl ] -2, 4-difluorobenzene;
rectifying the mixture, and respectively collecting a posaconazole main ring intermediate 1- [1- (bromomethyl) ethylene ] -2, 4-difluoro-benzene and an isomer 1- [ (1E) -1-bromopropyl-1-en-2-yl ] -2, 4-difluorobenzene;
s5 conversion of the isomer 1- [ (1E) -1-bromopropyl-1-en-2-yl ] -2, 4-difluorobenzene to the desired product
The isomer 1- [ (1E) -1-bromopropyl-1-alkene-2-yl ] -2, 4-difluorobenzene collected in the step S4 is added into an organic solvent, and is subjected to catalytic reaction in a protective gas environment, and is purified to form the posaconazole main ring intermediate 1- [1- (bromomethyl) ethylene ] -2, 4-difluoro-benzene.
As one limitation of the invention, the system temperature is 0-5 ℃ when 2, 4-difluoroacetophenone is added in the step S1;
the reaction temperature is 10-20 DEG C
The concentration of the tetrahydrofuran solution of the methyl magnesium bromide is 2.0-4.0 mol/L;
the mass ratio of the tetrahydrofuran solution of 2, 4-difluoroacetophenone, methyl tertiary butyl ether and methyl magnesium bromide is 1: 4-6:3-5.
As another limitation of the invention, the reaction temperature in the step S2 is 50-60 ℃;
the inorganic acid comprises 85% of phosphoric acid by mass or 98% of sulfuric acid by mass;
the mass ratio of the 2- (2, 4-difluorobenzene) propane-2-alcohol to the inorganic acid is 1:1-2.
As a third limitation of the invention, the reaction temperature in the step S3 is 20 to 30 ℃;
the mixed solvent consists of dimethyl sulfoxide and water in a mass ratio of 7-9:1;
the mass ratio of 1- (1-propylene-2-yl) -2, 4-difluorobenzene to dibromohydantoin is 2:1 to 3.
As a fourth limitation of the invention, the concentrated acid in the step S4 is concentrated sulfuric acid with a mass fraction of 95-98%; the vacuum degree of rectification is-0.08 to-0.09 MPa, the collection temperature of 1- [1- (bromomethyl) ethylene ] -2, 4-difluoro-benzene is 90-93 ℃, and the collection temperature of 1- [ (1E) -1-bromopropyl-1-alkene-2-yl ] -2, 4-difluoro-benzene is 95-100 ℃.
As a fifth limitation of the invention, the organic solvent in the step S5 includes acetonitrile and tetrahydrofuran;
the catalyst for the catalytic reaction is concentrated sulfuric acid, and the reaction temperature is 50-60 ℃;
the mass ratio of the catalyst to the 1- [ (1E) -1-bromopropyl-1-en-2-yl ] -2, 4-difluorobenzene to the organic solvent is 1:2-3: 9 to 11.
As a sixth limitation of the present invention, the protective gas in the production method may be at least one of nitrogen, hydrogen, helium, and argon.
As a further limitation to the second limitation of the invention, the reaction temperature in step S3 is 20 to 30 ℃;
the mixed solvent consists of dimethyl sulfoxide and water in a mass ratio of 7-9:1;
the mass ratio of 1- (1-propylene-2-yl) -2, 4-difluorobenzene to dibromohydantoin is 2:1 to 3.
As another limitation of the second limitation of the invention, the concentrated acid in the step S4 is concentrated sulfuric acid with a mass fraction of 95-98%;
the rectification vacuum degree is-0.08 to-0.09 MPa;
the collection temperature of posaconazole main ring intermediate 1- [1- (bromomethyl) ethylene ] -2, 4-difluoro-benzene is 90-93 ℃, and the collection temperature of isomer 1- [ (1E) -1-bromopropyl-1-en-2-yl ] -2, 4-difluoro-benzene is 95-100 ℃.
As a further limitation to the second limitation of the present invention, the organic solvent in S5 includes acetonitrile, tetrahydrofuran;
the catalyst for the catalytic reaction is concentrated sulfuric acid, and the reaction temperature is 50-60 ℃;
the mass ratio of the catalyst to the isomer 1- [ (1E) -1-bromopropyl-1-en-2-yl ] -2, 4-difluorobenzene to the organic solvent is 1:2-3: 9 to 11.
By adopting the technical scheme, compared with the prior art, the invention has the following technical progress:
(1) the invention selects more economical solvent and catalyst: such as methyl tertiary butyl ether, 85% phosphoric acid, concentrated sulfuric acid, dibromohydantoin and the like, so that the production cost is greatly reduced;
(2) the invention converts the isomer 1- [ (1E) -1-bromopropyl-1-alkene-2-yl ] -2, 4-difluorobenzene of the target product into the target product, reduces the generation of byproducts, and obviously improves the yield of the target product.
In summary, the preparation method of posaconazole main ring intermediate provided by the invention selects the more economical solvent and catalyst, and converts the isomer into the target product, thereby fully utilizing the resources, obviously improving the yield of the target product and reducing the production cost.
The preparation method of the posaconazole main ring intermediate provided by the invention can be used for preparing the posaconazole main ring intermediate 1- [1- (bromomethyl) ethylene ] -2, 4-difluoro-benzene, and the prepared 1- [1- (bromomethyl) ethylene ] -2, 4-difluoro-benzene can be further applied to the production of posaconazole.
Drawings
The invention will be described in more detail below with reference to the accompanying drawings and specific examples.
FIG. 1 is a diagram of the structural formula of posaconazole in the background of the invention;
fig. 2 is a structural diagram of a posaconazole main ring in the background of the invention;
FIG. 3 is a side chain structural diagram of posaconazole in the background of the invention;
FIG. 4 is a diagram of the structural formula of 1- [1- (bromomethyl) vinyl ] -2, 4-difluoro-benzene in the background of the invention;
FIG. 5 is an HPGC diagram of step S1 of example 1 of the present invention;
FIG. 6 is an HPGC diagram of example 1, step S2 of the present invention;
FIG. 7 is an HPGC diagram of example 1, step S3 of the present invention;
FIG. 8 is a HPLC chart of the target product in step S4 of example 1 of the present invention;
FIG. 9 is an HPLC chart of the isomer in step S4 of example 1 of the present invention;
fig. 10 is a process flow diagram of the present invention.
Detailed Description
The invention is further illustrated by the following examples. It should be understood that the described embodiments are only for explaining the present invention and do not limit the present invention.
Materials, reagents, and the like used in the examples of the present invention are commercially available unless otherwise specified. The experimental methods for which specific conditions are not specified in the examples are generally conducted under conventional conditions or under conditions recommended by the manufacturer.
Example 1 preparation method of posaconazole Main Ring intermediate
The embodiment is a preparation method of a posaconazole main ring intermediate, which comprises the following steps in sequence:
preparation of S1.2- (2, 4-difluorobenzene) propan-2-ol
100.0kg of methyl tertiary butyl ether is taken and placed in a 300L reaction kettle, a temperature control system is started under the environment of protective gas nitrogen, the temperature of the reaction kettle is controlled to be minus 5 ℃, 80.0kg of 3mol/L methyl magnesium bromide tetrahydrofuran solution is added at a rotating speed of 85rpm, the temperature of the system is controlled to be 3 ℃, 20.0kg of 2, 4-difluoroacetophenone is added dropwise, and the temperature of the system is controlled to be 0-5 ℃ during dropwise addition. After the dripping is completed, controlling the system temperature to 15-20 ℃, monitoring the reaction progress through a TLC method, after the reaction is completed, dripping 30L of 5% hydrochloric acid, slowly quenching, layering, standing for 30min, separating an organic phase, adding 50.0kg of purified water into the organic phase, collecting the organic phase, and evaporating under reduced pressure at 50 ℃ and minus 0.085Mpa to obtain 21.6kg of 2- (2, 4-difluorobenzene) propane-2-ol.
5mL of the prepared 2- (2, 4-difluorobenzene) propane-2-alcohol is filtered by a microporous filter membrane to remove impurities, injected into a gas chromatograph, and analyzed and calculated to obtain the purity and yield of the 2- (2, 4-difluorobenzene) propane-2-alcohol.
Detection conditions: the temperature of the sample inlet is 260 ℃, the sample inlet volume is 5 mu L, and the split ratio is 10:1;
chromatographic column: SE54 (60.0 m.times.0.32 mm.times.0.5 μm);
chromatographic conditions: the initial temperature was 100deg.C, and 50deg.C/min was raised to 200deg.C. Then, heating to 260 ℃ at 20 ℃/min, and preserving heat for 5min;
detector temperature: 270 ℃.
The purity of 2- (2, 4-difluorobenzene) propane-2-ol was 99.5% and the yield relative to 2, 4-difluoroacetophenone was 98.0% by HPGC analysis, the HPGC spectrum being shown in FIG. 5.
Preparation of S2.1- (1-propen-2-yl) -2, 4-difluorobenzene
Placing 2- (2, 4-difluorobenzene) propane-2-ol prepared in S1 into a 200L reaction kettle, controlling the rotating speed to be 85rpm, starting a temperature control system in a nitrogen environment, enabling the temperature in the kettle to be raised to 55 ℃, dropwise adding 30.0kg of phosphoric acid with the mass fraction of 85%, controlling the system temperature of the reaction at 50-55 ℃, monitoring the reaction process by a TLC method, dropwise adding 40.0kg of purified water after the reaction is completed, dropwise adding 30.0kg of methyl tertiary butyl ether, stirring for 30min, layering, standing for 15min, separating an organic phase, adding 30.0kg of purified water into the organic phase, collecting the organic phase, and evaporating for 8h under reduced pressure at 40 ℃ and minus 0.085MPa to obtain 18.1kg of 1- (1-propylene-2-yl) -2, 4-difluorobenzene.
5mL of the prepared 1- (1-propylene-2-yl) -2, 4-difluorobenzene is filtered by a microporous filter membrane to remove impurities, and is injected into a gas chromatograph to analyze and calculate the purity and yield of the 1- (1-propylene-2-yl) -2, 4-difluorobenzene.
Detection conditions: the temperature of the sample inlet is 260 ℃, the sample inlet volume is 5 mu L, and the split ratio is 10:1;
chromatographic column: SE54 (60.0 m.times.0.32 mm.times.0.5 μm);
chromatographic conditions: the initial temperature was 100deg.C, and 50deg.C/min was raised to 200deg.C. Then, heating to 260 ℃ at 20 ℃/min, and preserving heat for 5min;
detector temperature: 270 ℃.
The purity of 1- (1-propen-2-yl) -2, 4-difluorobenzene was 96.1% by HPGC analysis, the yield relative to 2- (2, 4-difluorobenzene) propan-2-ol was 93.8%, and the HPGC spectrum is shown in FIG. 6.
Preparation of S3.1-bromo-2- (2, 4-difluorobenzene) -isopropanol
Placing 1- (1-propylene-2-yl) -2, 4-difluorobenzene prepared in S2 into a 300L reaction kettle, controlling the system temperature of the reaction at 25-30 ℃, adding a mixed solvent consisting of 40.0kg of dimethyl sulfoxide and 5.0kg of water, adding 10.0kg of dibromohydantoin in a nitrogen environment at a rotating speed of 85rpm, monitoring the reaction progress by a TLC method, dripping 50.0kg of purified water after the reaction is completed, dripping 50.0kg of methyl tertiary butyl ether, standing for layering, adding 50.0kg of water washing into an organic phase, collecting the organic phase, and evaporating the organic phase to dryness under reduced pressure at 50 ℃ and minus 0.085MPa for 6 hours to obtain 29.3kg of oily 1-bromo-2- (2, 4-difluorobenzene) -isopropanol.
5mL of the prepared 1-bromo-2- (2, 4-difluorobenzene) -isopropanol is filtered by a microporous filter membrane to remove impurities, and is injected into a gas chromatograph to analyze and calculate the purity and yield of the 1-bromo-2- (2, 4-difluorobenzene) -isopropanol.
Detection conditions: the temperature of the sample inlet is 260 ℃, the sample inlet volume is 5 mu L, and the split ratio is 10:1;
chromatographic column: SE54 (60.0 m.times.0.32 mm.times.0.5 μm);
chromatographic conditions: the initial temperature was 100deg.C, and 50deg.C/min was raised to 200deg.C. Then, heating to 260 ℃ at 20 ℃/min, and preserving heat for 5min;
detector temperature: 270 ℃.
The purity of 1-bromo-2- (2, 4-difluorobenzene) -isopropanol was 96.1% by HPGC analysis, and the yield relative to 1- (1-propen-2-yl) -2, 4-difluorobenzene was 100.0%, with the HPGC spectrum shown in FIG. 7.
S4.1- [1- (bromomethyl) ethylene ] -2, 4-difluoro-benzene and preparation and purification of the isomer 1- [ (1E) -1-bromopropyl-1-en-2-yl ] -2, 4-difluorobenzene
Placing 50.0kg of 98% concentrated sulfuric acid in a 300L reaction kettle, controlling the rotating speed at 85rpm, starting a temperature control system in a protective gas nitrogen environment, controlling the system temperature to 25-30 ℃ in the reaction process, dropwise adding 1-bromo-2- (2, 4-difluorobenzene) -isopropanol prepared by S3, reacting at 25-30 ℃ after the dropwise adding, monitoring the reaction progress through a TLC method, cooling to 5-10 ℃ after the reaction is completed, dropwise adding 100.0kg of purified water, adding 60.0kg of methyl tert-butyl ether, adding 50.0kg of water washing and layering organic phase, collecting the organic phase, evaporating the organic phase at 50 ℃ under-0.085 MPa under reduced pressure for 8h, and obtaining 27.0kg of a mixture of 1- [1- (bromomethyl) ethylene ] -2, 4-difluoro-benzene and isomer 1- [ (1E) -1-bromopropyl-1-en-2-yl ] -2, 4-difluorobenzene, wherein the yield is 100.0% relative to 1-bromo-2- (2, 4-difluorobenzene) -isopropanol.
1- [1- (bromomethyl) ethylene ] -2, 4-difluoro-benzene and isomer 1- [ (1E) -1-bromopropyl-1-en-2-yl ] -2, 4-difluorobenzene mixture are added into a rectifying still, vacuum degree is kept at-0.085 Mpa, temperature in the still is carefully controlled, and fractions with the temperature of 90-93 ℃ and 95-100 ℃ are respectively collected. The target product 1- [1- (bromomethyl) ethylene ] -2, 4-difluoro-benzene 21.3kg was obtained.
The prepared 1- [1- (bromomethyl) ethylene ] -2, 4-difluoro-benzene 5mL is filtered by a microporous membrane to remove impurities, injected into a liquid chromatograph, and analyzed and calculated the purity of the 1- [1- (bromomethyl) ethylene ] -2, 4-difluoro-benzene.
Chromatographic column: agilent XDB-C18 (250 cm. Times.4.6 mm. Times.5 μm);
chromatographic conditions: gradient elution was performed with methanol as mobile phase a and water as mobile phase B, as specified in table 1; the column temperature is 25 ℃; the detection wavelength is 254nm, the flow rate is 1mL/min, and the sample injection amount is 10 mu L.
TABLE 1 liquid phase elution procedure
The purity of 1- [1- (bromomethyl) ethylene ] -2, 4-difluoro-benzene was 98.8% by HPLC analysis, and the HPLC spectrum is shown in FIG. 8.
5.7kg of isomer 1- [ (1E) -1-bromopropyl-1-en-2-yl ] -2, 4-difluorobenzene was obtained, 5mL of the obtained isomer 1- [ (1E) -1-bromopropyl-1-en-2-yl ] -2, 4-difluorobenzene was subjected to impurity removal by a microporous filter membrane, and was injected into a liquid chromatograph for analysis and calculation of the isomer purity.
Chromatographic column: agilent XDB-C18 (250 cm. Times.4.6 mm. Times.5 μm);
chromatographic conditions: gradient elution was performed with methanol as mobile phase a and water as mobile phase B, as specified in table 1 above; the column temperature is 25 ℃; the detection wavelength is 254nm, the flow rate is 1mL/min, and the sample injection amount is 10 mu L.
The purity of the isomer 1- [ (1E) -1-bromopropyl-1-en-2-yl ] -2, 4-difluorobenzene was 96.3% by HPLC analysis, and the HPLC chart is shown in FIG. 9.
S5 conversion of the isomer 1- [ (1E) -1-bromopropyl-1-en-2-yl ] -2, 4-difluorobenzene to the desired product
Placing 30.0kg of organic solvent acetonitrile and isomer 1- [ (1E) -1-bromopropyl-1-en-2-yl ] -2, 4-difluorobenzene 5.7kg into a 100L reaction kettle, controlling the rotating speed to be 85rpm, dropwise adding 2.8kg of concentrated sulfuric acid under the environment of protective gas nitrogen, starting a temperature control system, controlling the temperature of the reaction system to be 50-60 ℃, monitoring the reaction progress through HPLC, evaporating the solvent at 30-35 ℃ and-0.09 MPa after the reaction is completed, cooling to room temperature, adding 30.0kg of methyl tertiary butyl ether, adding 20.0kg of water, stirring for 30min, layering, discarding a water layer, washing an organic phase with 20.0kg of water, evaporating the solvent at 30-35 ℃ and-0.09 MPa to obtain a target product of 5.1kg, wherein the purity is 90.0%, and the yield of the step is 90.0%.
The posaconazole main ring intermediate 1- [1- (bromomethyl) ethylene ] -2, 4-difluoro-benzene provided in this example was prepared to finally obtain 26.4kg of the target product, which is 88.4% relative to the total yield of 2, 4-difluoro acetophenone.
Fig. 10 is a process flow diagram of the present invention.
Examples 2-7 preparation of posaconazole Main Ring intermediate
Examples 2-7 are the same as example 1, except that the raw materials and the process parameters are different, the raw materials are shown in table 2, and the process parameters of the different preparation steps are shown in table 3.
Table 2 raw material usage amount for examples 2 to 7
Table 3 table of process parameters for the steps of examples 2 to 7
Examples 2-7 summary of the yields of 1- [1- (bromomethyl) ethylene ] -2, 4-difluoro-benzene of the desired product was obtained starting from 2, 4-difluoroacetophenone and the specific data are shown in Table 4.
TABLE 4 summary of target product yields
As can be seen from Table 4, the overall yield of the preparation method of the posaconazole main ring intermediate 1- [1- (bromomethyl) ethylene ] -2, 4-difluoro-benzene provided by the invention is relatively high, and the overall yield of the target product relative to the 2, 4-difluoro acetophenone is more than 83% in the experimental range of the invention.
It is to be understood that the above examples of the present invention are provided by way of illustration only and not by way of limitation of the embodiments of the present invention. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. Not all embodiments are exhaustive. All obvious changes or modifications which come within the spirit of the invention are desired to be protected.
Claims (8)
1. The preparation method of the posaconazole main ring intermediate is characterized by comprising the following steps in sequence:
preparation of S1.2- (2, 4-difluorobenzene) propan-2-ol
Adding tetrahydrofuran solution of methyl magnesium bromide and 2, 4-difluoroacetophenone into methyl tertiary butyl ether solvent, and reacting in a protective gas environment to prepare 2- (2, 4-difluorobenzene) propane-2-ol;
preparation of S2.1- (1-propen-2-yl) -2, 4-difluorobenzene
2- (2, 4-difluorobenzene) propane-2-alcohol reacts with inorganic acid in a protective gas environment to prepare 1- (1-propylene-2-yl) -2, 4-difluorobenzene;
preparation of S3.1-bromo-2- (2, 4-difluorobenzene) -isopropanol
1- (1-propylene-2-yl) -2, 4-difluorobenzene reacts with dibromohydantoin in a mixed solvent under the environment of protective gas to prepare 1-bromo-2- (2, 4-difluorobenzene) -isopropanol;
preparation of posaconazole Main Ring intermediate 1- [1- (bromomethyl) ethylene ] -2, 4-difluoro-benzene and isomer 1- [ (1E) -1-bromopropyl-1-en-2-yl ] -2, 4-difluorobenzene
Adding concentrated acid into 1-bromo-2- (2, 4-difluorobenzene) -isopropanol, and reacting in a protective gas environment to obtain a mixture of posaconazole main ring intermediate 1- [1- (bromomethyl) ethylene ] -2, 4-difluoro-benzene and isomer 1- [ (1E) -1-bromopropyl-1-en-2-yl ] -2, 4-difluorobenzene; the concentrated acid is concentrated sulfuric acid with the mass fraction of 95-98%;
rectifying the mixture, and respectively collecting a posaconazole main ring intermediate 1- [1- (bromomethyl) ethylene ] -2, 4-difluoro-benzene and an isomer 1- [ (1E) -1-bromopropyl-1-en-2-yl ] -2, 4-difluorobenzene;
s5, converting isomer 1- [ (1E) -1-bromopropyl-1-alkene-2-yl ] -2, 4-difluorobenzene into a target product, adding isomer 1- [ (1E) -1-bromopropyl-1-alkene-2-yl ] -2, 4-difluorobenzene collected in the step S4 into an organic solvent, carrying out catalytic reaction in a protective gas environment, and purifying to obtain posaconazole main ring intermediate 1- [1- (bromomethyl) ethylene ] -2, 4-difluoro-benzene;
the organic solvent in the step S5 comprises acetonitrile and tetrahydrofuran; the catalyst for the catalytic reaction is concentrated sulfuric acid, and the reaction temperature is 50-60 ℃; the mass ratio of the catalyst to the 1- [ (1E) -1-bromopropyl-1-en-2-yl ] -2, 4-difluorobenzene to the organic solvent is 1:2-3: 9 to 11.
2. The method for preparing posaconazole main ring intermediate according to claim 1, wherein the system temperature is 0-5 ℃ when 2, 4-difluoroacetophenone is added in step S1; the reaction temperature is 10-20 ℃; the concentration of the tetrahydrofuran solution of the methyl magnesium bromide is 2.0-4.0 mol/L; the mass ratio of the tetrahydrofuran solution of 2, 4-difluoroacetophenone, methyl tertiary butyl ether and methyl magnesium bromide is 1: 4-6:3-5.
3. The method for preparing posaconazole main ring intermediate according to claim 1 or 2, wherein the reaction temperature in step S2 is 50-60 ℃; the inorganic acid comprises 85% of phosphoric acid by mass or 98% of sulfuric acid by mass; the mass ratio of the 2- (2, 4-difluorobenzene) propane-2-alcohol to the inorganic acid is 1:1-2.
4. The method for preparing posaconazole main ring intermediate according to claim 1 or 2, wherein the reaction temperature in step S3 is 20-30 ℃; the mixed solvent consists of dimethyl sulfoxide and water in a mass ratio of 7-9:1; the mass ratio of 1- (1-propylene-2-yl) -2, 4-difluorobenzene to dibromohydantoin is 2:1 to 3.
5. The method according to claim 1 or 2, wherein the rectification vacuum degree in the step S4 is-0.08 to-0.09 mpa, the collection temperature of 1- [1- (bromomethyl) ethylene ] -2, 4-difluoro-benzene is 90-93 ℃, and the collection temperature of 1- [ (1E) -1-bromopropyl-1-en-2-yl ] -2, 4-difluorobenzene is 95-100 ℃.
6. The method for preparing posaconazole main ring intermediate according to claim 1, wherein the shielding gas is at least one of nitrogen, hydrogen, helium and argon.
7. The method for preparing posaconazole main ring intermediate according to claim 3, wherein the reaction temperature in step S3 is 20 to 30 ℃; the mixed solvent consists of dimethyl sulfoxide and water in a mass ratio of 7-9:1; the mass ratio of 1- (1-propylene-2-yl) -2, 4-difluorobenzene to dibromohydantoin is 2:1 to 3.
8. The method according to claim 7, wherein the rectification vacuum degree in the step S4 is-0.08 to-0.09 MPa, the collection temperature of the posaconazole main ring intermediate 1- [1- (bromomethyl) ethylene ] -2, 4-difluoro-benzene is 90-93 ℃, and the collection temperature of the isomer 1- [ (1E) -1-bromopropyl-1-en-2-yl ] -2, 4-difluorobenzene is 95-100 ℃.
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