CN116496180A - Method for producing Lin Zage intermediate - Google Patents
Method for producing Lin Zage intermediate Download PDFInfo
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- CN116496180A CN116496180A CN202310515137.XA CN202310515137A CN116496180A CN 116496180 A CN116496180 A CN 116496180A CN 202310515137 A CN202310515137 A CN 202310515137A CN 116496180 A CN116496180 A CN 116496180A
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- 238000004519 manufacturing process Methods 0.000 title abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- 238000000034 method Methods 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 86
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 84
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 239000002904 solvent Substances 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 238000002360 preparation method Methods 0.000 claims description 20
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 7
- 238000006396 nitration reaction Methods 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 238000010511 deprotection reaction Methods 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 229960000583 acetic acid Drugs 0.000 claims description 5
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 5
- 239000012346 acetyl chloride Substances 0.000 claims description 5
- 239000012362 glacial acetic acid Substances 0.000 claims description 5
- 229910017604 nitric acid Inorganic materials 0.000 claims description 5
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical group OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- 239000012320 chlorinating reagent Substances 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 230000001546 nitrifying effect Effects 0.000 claims 1
- 238000006722 reduction reaction Methods 0.000 claims 1
- 230000003321 amplification Effects 0.000 abstract description 4
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 4
- 239000012535 impurity Substances 0.000 abstract description 3
- 238000007086 side reaction Methods 0.000 abstract description 3
- 238000001212 derivatisation Methods 0.000 abstract description 2
- 238000011112 process operation Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 239000012065 filter cake Substances 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 238000001816 cooling Methods 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- 206010046798 Uterine leiomyoma Diseases 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000002386 leaching Methods 0.000 description 4
- 201000010260 leiomyoma Diseases 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 3
- 101100132433 Arabidopsis thaliana VIII-1 gene Proteins 0.000 description 2
- 101100459319 Arabidopsis thaliana VIII-2 gene Proteins 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000004973 liquid crystal related substance Substances 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- 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 description 1
- XXZCIYUJYUESMD-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-3-(morpholin-4-ylmethyl)pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)CN1CCOCC1 XXZCIYUJYUESMD-UHFFFAOYSA-N 0.000 description 1
- BMAAMIIYNNPHAB-UHFFFAOYSA-N 3-[5-[(2,3-difluoro-6-methoxyphenyl)methoxy]-2-fluoro-4-methoxyphenyl]-2,4-dioxo-1h-thieno[3,4-d]pyrimidine-5-carboxylic acid Chemical compound COC1=CC(F)=C(N2C(C3=C(C(O)=O)SC=C3NC2=O)=O)C=C1OCC1=C(OC)C=CC(F)=C1F BMAAMIIYNNPHAB-UHFFFAOYSA-N 0.000 description 1
- 208000005641 Adenomyosis Diseases 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000008238 LHRH Receptors Human genes 0.000 description 1
- 108010021290 LHRH Receptors Proteins 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 201000009274 endometriosis of uterus Diseases 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 201000007954 uterine fibroid Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Compared with the prior art, the method improves the production efficiency, reduces the total cost of production, has simple and controllable reaction, high yield and less side reaction, avoids the follow-up transfer and derivatization of isomer impurities, has simple and convenient process operation, and is more suitable for production and amplification.
Description
1. Technical field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to synthesis of a Lin Zage intermediate.
2. Background art
Lin Zage (Linnogolix) is a novel oral GnRH receptor antagonist originally developed by Kissei Pharmaceutical (abbreviated as "Kissei"), and currently developed indications are endometriosis, adenomyosis and uterine leiomyomas (also known as uterine fibroids). 11 months 2015, kissei delegated Lin Zage to ObsEva the global exclusive rights in areas other than asian countries such as japan; month 9 of 2021, kissei granted rights to shanghai in China to develop and commercialize Lin Zage benefits.
Day 14, 2022, 06, lin Zage tablets (trade name: yselty, specification: 100mg, 200 mg) were first available in the european union for the treatment of moderate to severe symptoms of uterine fibroids in adult women of child-bearing age. Furthermore, lin Zage tablets were also used for the treatment of uterine fibroids in iceland, leydig, norway and uk.
WO2014042176A1 discloses a Lin Zage-way intermediate preparation route, as shown below, wherein the 5 steps of the synthesis route are linear design (the total route yield is 72.0%), the material cost is high, and the production time is long; and in the fifth step, raney-Nickel and hydrogen which are easy to burn in the air are used for reduction, and special equipment is needed, so that the amplification is not facilitated.
Therefore, the inventor researches a method for preparing Lin Zage good intermediate with simple operation, high reaction purity and yield, short production time and lower process cost to meet the requirements of mass production and quality control.
3. Summary of the invention
Compared with the prior art, the method improves the production efficiency, reduces the total cost of production, has simple and controllable reaction, high yield and less side reaction, avoids the follow-up transfer and derivatization of isomer impurities, has simple and convenient process operation, and is more suitable for production and amplification.
The invention provides a preparation method of a key intermediate compound I of linagole, which comprises the following steps:
(1) The compound of the formula (VIII) is subjected to hydroxy protection, nitration and deprotection reaction to obtain the compound of the formula (VII),
(2) The compound of formula (VII) undergoes reduction in a solvent to give the compound of formula (VI),
(3) Protecting amino groups of the compound of formula (VI) in a solvent to obtain a compound of formula (V);
(4) Reacting a compound of formula (V) with a compound of formula (III) in a solvent under the action of alkali to obtain a compound of formula (II);
(5) The compound of the formula (II) is in a solvent, and under the action of acid, the compound of the formula (I) is obtained;
wherein R is as follows 1 And R is 2 Each independently is a hydrogen atom, boc, cbz, fmoc, acetyl, and R 1 And R is 2 Not both hydrogen atoms. Preferably, R 1 And R is 2 Each independently is a hydrogen atom or Boc, and R 1 And R is 2 Not both hydrogen atoms.
Wherein, the liquid crystal display device comprises a liquid crystal display device,
in the step (1), the compound of formula (VIII) and an acylating reagent are subjected to hydroxyl protection reaction in a solvent to obtain the compound of formula (VIII-1), wherein the solvent is one or more selected from dichloromethane, tetrahydrofuran and ethyl acetate, preferably dichloromethane, and the acylating reagent is one or two selected from acetyl chloride and acetic anhydride, preferably acetyl chloride; carrying out nitration reaction on the compound of the formula (VIII-1) in a solvent to obtain the compound of the formula (VIII-2), wherein the solvent is one or two of glacial acetic acid and concentrated sulfuric acid, preferably glacial acetic acid, and the nitration reagent is one or two of concentrated nitric acid and fuming nitric acid, preferably concentrated nitric acid; deprotection of a compound of formula (VIII-2) in a solvent selected from one or more of methanol, ethanol, isopropanol, acetonitrile, preferably methanol, to give a compound of formula (VII); the deprotected base is selected from one or more of sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide, preferably sodium bicarbonate.
In the step (2), the solvent is selected from one or more of methanol, ethanol, isopropanol and tetrahydrofuran, preferably methanol; the reducing agent is hydrazine hydrate, active carbon and ferric trichloride; the reaction temperature is 40-60 ℃ and the reaction time is 4-8 h.
In the step (3), the solvent is selected from one or more of ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile and toluene, preferably ethyl acetate.
In the step (4), the solvent is selected from one or more of ethyl acetate and acetonitrile, preferably ethyl acetate; the alkali is selected from one or more of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, preferably sodium carbonate; the reaction temperature is 60-80 ℃ and the reaction time is 6-10 h.
In the step (5), the solvent is selected from one or more of ethyl acetate and acetonitrile, preferably ethyl acetate; the acid is concentrated hydrochloric acid, the reaction temperature is 40-60 ℃, and the reaction time is 1-4 h.
Further, the invention also comprises the step of preparing the compound of the formula (III) from the compound of the formula (IV), wherein the compound of the formula (IV) is reacted with a chloro reagent in a solvent to obtain the compound of the formula (III);
wherein the solvent is DCM; the chlorinating agent is selected from one or two of thionyl chloride and phosphorus oxychloride, preferably thionyl chloride; the reaction temperature is-10 to 10 ℃.
The beneficial technical effects of the invention are as follows:
1. the design of a polymerization reaction route, namely directly separating liquid after the completion of the second-step reaction, directly performing a third-step reaction on an organic phase after the liquid separation, and directly performing deprotection reaction after the completion of the fourth-step reaction to obtain the compound of the formula (I), wherein the application is a convergent reaction, and the compound of the formula (III) can be prepared while the compound of the formula (V) is prepared; the operation is simplified, the production period is shortened, the production efficiency is improved, and the total production cost is reduced;
2. the preparation of the compound of the formula (V) from the compound of the formula (VIII) is mostly changed in protecting groups, the reaction is simple and controllable, the yield loss is low, and the three-step reaction yield from the compound of the formula (VIII) to the compound of the formula (V) is 85.6%;
3. the nitration reaction and the nitroreduction are both placed at the front end of the route, so that theoretical reaction sites are reduced, side reactions are few, and the phenomenon that isomer impurities are difficult to clear and are transmitted and derived subsequently is avoided;
4. the reaction uses cheap and easily available reagents, the process is simple and convenient to operate, the yield of each step is higher than 90%, the total yield of the route is 81.4%, and the total yield of the preparation by the second step to the sixth step is 86% higher than that of other patent routes (72.0% of the total yield of WO2014042176A 1);
5. the route has reasonable design and cost advantage, and is more suitable for production and amplification.
4. Description of the drawings
FIG. 1 shows a compound of formula (I) prepared in example 12 1 HNMR。
5. Detailed description of the preferred embodiments
The following detailed description of specific embodiments of the invention is provided for purposes of illustration only and is not to be construed as limiting the invention.
EXAMPLE 1 preparation of the Compound of formula (VII)
20g of compound of formula (VIII) is added with 200ml of DCM and triethylamine (17.1 g, 1.2 rq), the temperature is reduced to 0 ℃, acetyl chloride (12.1 g, 1.1 eq) is added dropwise, the temperature T is less than or equal to 10 ℃, the temperature is kept at 0-10 ℃ after the addition, and the reaction is completed. 200ml of water is added into the system, the mixture is stirred and separated, the organic phase is concentrated to dryness under reduced pressure at 40 ℃, 100ml of glacial acetic acid is added, the temperature is raised to 60 ℃, 60% concentrated nitric acid (19.2 g, 1.3 eq) is added dropwise, the temperature is kept between 55 ℃ and 65 ℃ for reaction for 2 hours, and the reaction is completed. Cooling to 20 ℃, adding 150ml of water, precipitating a large amount of solids, filtering, and leaching the filter cake with 20ml of water. The filter cake prepared was added with 100ml of methanol, sodium bicarbonate (23.6 g, 2.0 eq) and reacted at 20℃to 25℃for 2.5h, the reaction being complete. The system is added with 150ml of water, the pH=5 is regulated by concentrated hydrochloric acid, the temperature T is less than 30 ℃, a large amount of solid is separated out, the filtration is carried out, the filter cake is leached by 20ml of water, and the yellow solid compound of the formula (VII) is obtained by 24.0g after drying, and the yield is 91%.
EXAMPLE 2 preparation of the Compound of formula (VI)
24g of the compound of formula (VII) prepared in example 1 was added with 120ml of methanol, iron trichloride (2.1 g, 0.1 rq) and activated carbon (2.4 g), the temperature was raised to 50℃and hydrazine hydrate (27.9 g, 3 eq) was added dropwise thereto, and the reaction was carried out at 50-60℃for 5 hours after the addition. Cooling to 40 ℃, filtering with diatomite, eluting a filter cake with 50ml of methanol at 40 ℃, concentrating the filtrate at 40 ℃ under reduced pressure, adding 100ml of isopropyl ether, pulping, filtering, and drying to obtain 19.3g of red solid compound of formula (VI), wherein the yield is 96%.
EXAMPLE 3 (V) conversionPreparation of the Compounds
19.3g of the compound of formula (VI) prepared in example 2 was added to 100ml of ethyl acetate and 54ml of an aqueous solution of sodium hydroxide (5.4 g, 1.1 eq) and di-tert-butyl dicarbonate (32 g, 1.2 eq) was added dropwise thereto, and the reaction was carried out at 20℃to 30℃for 3 hours after the addition was completed. The system was separated, washed 1 time with 50ml of 10% aqueous citric acid solution, and concentrated under reduced pressure at 40℃to give 31g of a pale-red solid compound of formula (V) in 98% yield.
EXAMPLE 4 preparation of Compounds of formula (III)
21g of compound of formula (IV) and 210ml of dichloromethane, cooling to 2 ℃ in cold hydrazine, dropwise adding thionyl chloride (4.5 g, 1.2 eq), controlling the temperature T to be less than or equal to 5 ℃, and after the addition, preserving the temperature for 0-5 ℃ for 2h, thus finishing the reaction. 170ml of water was added to the system, the mixture was stirred and separated, the organic phase was washed with 85ml of saturated aqueous sodium hydrogencarbonate solution for 1 time, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 85ml of ethyl acetate solution of the compound of formula (III) (120.61 mmol) in place of methylene chloride.
EXAMPLE 5 preparation of Compounds of formula (II)
85ml of ethyl acetate was added to 85ml of the ethyl acetate solution of the compound (120.61 mmol) of formula (III) prepared in example 4, and 85ml of the compound V (31 g, 1.0 eq) prepared in example 3 was added, sodium carbonate (15.4 g, 1.2 eq) and tetrabutylammonium bromide (7.7 g, 0.2 eq) were added, and the reaction was warmed to reflux for 10 hours, to complete the reaction. The temperature was lowered and insoluble salts were removed by filtration to give 170ml of Compound II (120.61 mmol) as ethyl acetate solution.
EXAMPLE 6 preparation of the Compound of formula (I)
170ml of ethyl acetate solution of the compound (120.61 mmol) of the formula (II) prepared in example 5 is heated to 40 ℃, 36% of concentrated hydrochloric acid (30.6 g, 2.5 eq) is added dropwise, a large amount of white solid is precipitated in the process of adding dropwise, the temperature is raised to 60 ℃ after adding, and the reaction is completed for 1 h. Cooling to 20 ℃, filtering to obtain a white solid, and leaching a filter cake by using 10ml of ethyl acetate. The filter cake was added to methanol: in 100ml of water=1:1, the pH value of 10% sodium hydroxide aqueous solution is regulated to be=9-10, the mixture is stirred for 1h, the mixture is filtered, a filter cake is leached by 10ml of water, 36.2g of a pale red solid compound in the formula (I) is obtained after drying, and the total yield is 96.1%. Examples 1 to 6: the total yield was 81.4%.
EXAMPLE 7 preparation of the Compound of formula (VII)
80g of compound of formula (VIII) is added with 800ml of DCM and triethylamine (68 g, 1.2 rq), the temperature is reduced to 0 ℃, acetyl chloride (49 g, 1.1 eq) is added dropwise, the temperature T is less than or equal to 10 ℃, the temperature is kept between 0 ℃ and 10 ℃ after the addition, the reaction is completed for 2 hours. 800ml of water is added into the system, the mixture is stirred and separated, the organic phase is concentrated to dryness under reduced pressure at 40 ℃, 400ml of glacial acetic acid is added, the temperature is raised to 60 ℃, 60% concentrated nitric acid (77 g, 1.3 eq) is added dropwise, the temperature is kept between 55 ℃ and 65 ℃ for reaction for 2 hours, and the reaction is completed. Cooling to 20 ℃, adding 600ml of water, precipitating a large amount of solids, filtering, and leaching the filter cake with 80ml of water. 400ml of methanol and sodium bicarbonate (95 g, 2.0 eq) are added into the prepared filter cake, and the reaction is carried out for 2.5h at 20-25 ℃ under the condition of heat preservation, and the reaction is complete. The system was added with 600ml of water, pH=5 was adjusted with concentrated hydrochloric acid, temperature T < 30 ℃, a large amount of solids precipitated, filtered, and the filter cake was rinsed with 20ml of water to give 126.4g (562.86 mmol) of the compound of formula (VII) in 120% yield.
EXAMPLE 8 preparation of the Compound of formula (VI)
126.4g of the compound of the formula (VII) prepared in example 7 (100% yield according to the previous step) was added with 632ml of methanol, 632ml of ferric trichloride (9.1 g, 0.1 rq) and 12.6g of activated carbon, the temperature was raised to 50℃and hydrazine hydrate (122 g, 3 eq) was added dropwise thereto, and the reaction was completed at 50 to 60℃for 5 hours. Cooling to 20 ℃, filtering with celite, concentrating the filtrate under reduced pressure at 40 ℃, adding 400ml of ethyl acetate, washing 1 time with 400ml of 10% saline solution, to obtain 400ml of ethyl acetate solution of the compound of formula (VI) (562.86 mmol).
EXAMPLE 9 preparation of Compound of formula (V)
400ml of ethyl acetate solution of the compound (562.86 mmol) of the formula (VI) produced in example 8 was added with 250ml of aqueous sodium hydroxide (25 g, 1.1 eq) solution, di-tert-butyl dicarbonate (147 g, 1.2 eq) was added dropwise, and the reaction was carried out at 20-30℃for 3 hours after the addition, thereby completing the reaction. The system was separated, and 200ml of a 10% aqueous solution of citric acid was washed 1 time to obtain 400ml of an ethyl acetate solution of the compound (562.86 mmol) of the formula (V).
EXAMPLE 10 preparation of Compounds of formula (III)
98g of compound of formula (IV) and 980ml of dichloromethane, cooling to 2 ℃ in cold hydrazine, dropwise adding thionyl chloride (80 g, 1.2 eq), controlling the temperature T to be less than or equal to 5 ℃, and after the addition, preserving the temperature for 0-5 ℃ for 2h, thus finishing the reaction. 800ml of water was added to the system, the mixture was stirred and separated, the organic phase was washed with 400ml of saturated aqueous sodium hydrogencarbonate solution for 1 time, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 400ml of ethyl acetate solution of the compound of formula (III) (562.86 mmol) in place of methylene chloride.
EXAMPLE 11 preparation of Compounds of formula (II)
400ml of the ethyl acetate solution of the compound (III) prepared in example 10 (562.86 mmol) was added to 400ml of the ethyl acetate solution of the compound (562.86 mmol) prepared in example 9 (V), sodium carbonate (72 g, 1.2 eq) and tetrabutylammonium bromide (36 g, 0.2 eq) were added, and the reaction was warmed to reflux for 10 hours, and the reaction was completed. The temperature was lowered and insoluble salts were removed by filtration to give 800ml of a solution of the compound of formula (II) (562.86 mmol) in ethyl acetate.
EXAMPLE 12 preparation of Compounds of formula (I)
800ml of ethyl acetate solution of the compound (562.86 mmol) of the formula (II) prepared in example 11 was heated to 40℃and a large amount of white solid was precipitated during the dropwise addition of 36% (143 g, 2.5 eq) of concentrated hydrochloric acid, and the reaction was completed after the addition was heated to 60℃for 1 hour. Cooling to 20 ℃, filtering to obtain a white solid, and leaching a filter cake by using 50ml of ethyl acetate. The filter cake was added to methanol: in water=1:1 400ml,10% sodium hydroxide aqueous solution by mass fraction adjusts pH=9-10, stir for 1h, filter cake is rinsed with water 50ml, dry to get pale red solid 151g, total yield 86%. 1 H NMR(400MHz,DMSO-d6)δ9.61(s,2H),7.48(q,J＝9.7Hz,1H),7.19(d,J＝7.7Hz,1H),7.11(d,J＝12.0Hz,1H),6.92(ddd,J＝9.4,3.7,1.9Hz,1H),5.00(s,2H),3.82(s,3H),3.75(s,3H).
Claims (10)
1. A preparation method of a linagole key intermediate compound of formula (I), which is characterized by comprising the following steps:
(1) The compound of formula (VIII) is subjected to hydroxy protection, nitration and deprotection reaction to obtain the compound of formula (VII):
(2) Carrying out reduction reaction on the compound of the formula (VII) in a solvent to obtain the compound of the formula (VI):
(3) Protecting the amino group of the compound of formula (VI) in a solvent to give a compound of formula (V):
(4) Reacting a compound of formula (V) with a compound of formula (III) in a solvent under the action of a base to obtain a compound of formula (II):
(5) The compound of formula (II) is in solvent, under the action of acid, the compound of formula (I) is obtained:
wherein R is as follows 1 And R is 2 Each independently is a hydrogen atom, boc, cbz, fmoc, acetyl, and R 1 And R is 2 Not both hydrogen atoms.
2. The method of claim 1, wherein R is 1 And R is 2 Each independently is a hydrogen atom or Boc, and R 1 And R is 2 Not both hydrogen atoms.
3. The preparation method according to claim 1, wherein the hydroxy protection reaction in the step (1) is that the compound of formula (VIII) is reacted with an acylating agent in a solvent to obtain the compound of formula (VIII), wherein the solvent is one or more selected from dichloromethane, tetrahydrofuran and ethyl acetate; the acylating agent is one or two selected from acetyl chloride and acetic anhydride.
4. The preparation method according to claim 1, wherein the nitration reaction in the step (1) is a nitration reaction of the compound of formula (viii-1) in a solvent to obtain the compound of formula (viii-2), wherein the solvent is one or two selected from glacial acetic acid and concentrated sulfuric acid; the nitrifying reagent is one or two selected from concentrated nitric acid and fuming nitric acid.
5. The preparation method according to claim 1, wherein the deprotection reaction in the step (1) is a deprotection reaction of a compound of formula (viii-2) in a solvent to obtain a compound of formula (vii), wherein the solvent is one or more selected from methanol, ethanol, isopropanol and acetonitrile; the deprotected base is selected from one or more of sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide.
6. The method according to claim 1, wherein in the step (2), the solvent is one or more selected from the group consisting of methanol, ethanol, isopropanol, and tetrahydrofuran; the reducing agent is hydrazine hydrate, active carbon and ferric trichloride;
the reaction temperature is 40-60 ℃ and the reaction time is 4-8 h.
7. The method according to claim 1, wherein in the step (3), the solvent is one or more selected from ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile and toluene.
8. The process according to claim 1, wherein the compound of formula (III) in step (3) is obtained by reacting a compound of formula (IV):
wherein the solvent is DCM; the chlorinating agent is selected from one or two of thionyl chloride and phosphorus oxychloride; the reaction temperature is-10 to 10 ℃.
9. The method according to claim 1, wherein in the step (4), the solvent is one or both of ethyl acetate and acetonitrile; the alkali is selected from one or more of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide; the reaction temperature is 60-80 ℃ and the reaction time is 6-10 h.
10. The preparation method according to claim 1, wherein in the step (5), the solvent is one or both of ethyl acetate and acetonitrile; the acid is concentrated hydrochloric acid; the reaction temperature is 40-60 ℃ and the reaction time is 1-4 h.
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