CN111517939B - Preparation method and intermediate of fused tricyclic derivative - Google Patents
Preparation method and intermediate of fused tricyclic derivative Download PDFInfo
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- CN111517939B CN111517939B CN201911353162.2A CN201911353162A CN111517939B CN 111517939 B CN111517939 B CN 111517939B CN 201911353162 A CN201911353162 A CN 201911353162A CN 111517939 B CN111517939 B CN 111517939B
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- C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
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Abstract
The invention provides a preparation method of a fused tricyclic derivative intermediate. The intermediate has a structure represented by formula (4-7). The preparation method has the advantages of easily available raw materials and simple steps, and is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the field of medicines, in particular to a preparation method and an intermediate of a fused tricyclic derivative.
Background
The voltage-gated calcium channel is composed of an alpha 1 subunit and accessory protein alpha 2 delta, beta, gamma subunits. α 2 δ protein can modulate the density of calcium channels and the calcium channel voltage-dependent kinetics (Felix et al (199) j. Neuroscience 17. Compounds that exhibit high affinity binding to the voltage-dependent calcium channel subunit α 2 δ have been shown to be effective in the treatment of pain, such as pregabalin and gabapentin. In mammals, there are 4 subtypes of α 2 δ protein, each encoded by a different gene. The α 2 δ subtypes 1 and 2 show high affinity with pregabalin, while the α 2 δ subtypes 3 and 4 have no significant drug binding force.
However, the proportion of gabapentin that greatly ameliorates the pain in diabetic peripheral neuropathy patients is about 60% (Acta neurol. Scand.101:359-371, 2000), and pregabalin, although it is better tolerated than gabapentin, is less safe and has the potential to abuse or cause patient dependence (Am J Health Syst Pharm.2007;64 (14): 1475-1482).
There is still a great need to develop new compounds that show high affinity binding to the voltage-dependent calcium channel subunit α 2 δ.
PCT/CN2017/101364 patent application discloses a fused tricyclic gamma-amino acid derivative, a preparation method and medical application thereof, which have good biological activity, and also discloses an intermediate compound shown in formula (I) for preparing the derivative and a preparation method thereof,
disclosure of Invention
It is an object of the present invention to provide a process for the preparation of fused tricyclic derivatives.
It is another object of the present invention to provide a process for the preparation of intermediates of fused tricyclic derivatives.
The invention relates to a preparation method of a compound shown in a formula (4-7) and a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound shown in the formula (4-6) is used as a raw material for preparation
Some embodiments of the present invention are a process for preparing a compound of formula (4-7) and stereoisomers or pharmaceutically acceptable salts thereof, wherein a compound of formula (4-6) is reacted with cyclopropyl (ylidene) malonate to obtain a compound of formula (4-7).
Some embodiments of the present invention are a method for preparing a compound represented by formula (4-7) and stereoisomers or pharmaceutically acceptable salts thereof, wherein a compound represented by formula (4-6) is reacted with cyclopropyl (ylidene) malonate to prepare a compound represented by formula (4-7) using a base selected from the group consisting of triethylamine, diisopropylethylamine;
some embodiments of the present invention are a method for preparing a compound represented by formula (4-7) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound represented by formula (4-6) is reacted with cycloisopropyl malonate to obtain the compound represented by formula (4-7), and the solvent used in the reaction is selected from formic acid.
Some embodiments of the present invention are a process for preparing a compound of formula (4-7) and stereoisomers or pharmaceutically acceptable salts thereof, wherein a compound of formula (4-6) is reacted with cycloisopropyl malonate to obtain a compound of formula (4-7), wherein the molar ratio of the compound of formula (4-6) to the cycloisopropyl malonate is 1.
Some embodiments of the present invention are a method for preparing a compound represented by formula (4-7) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound represented by formula (4-6) is reacted with cycloisopropyl malonate to obtain the compound represented by formula (4-7) at a temperature of 0 ℃ to reflux.
Some embodiments of the present invention are a process for preparing a compound of formula (4-7), and stereoisomers or pharmaceutically acceptable salts thereof, wherein a compound of formula (4-6) is reacted with cyclopropyl (ylidene) malonate to obtain a compound of formula (4-7),
the base used in the reaction is selected from triethylamine and diisopropylethylamine;
the solvent used in the reaction is selected from formic acid
The molar ratio of the compound of formula (4-6) to the isopropylidene malonate ring is 1-1;
the reaction temperature is 0 ℃ to reflux.
The invention relates to a preparation method of a compound shown in a formula (4-6) and a stereoisomer or pharmaceutically acceptable salt thereof, which comprises the steps of preparing the compound shown in the formula (4-6) by using a compound shown in the formula (4-5) as a raw material,
some embodiments of the present invention are a process for preparing a compound of formula (4-6) and stereoisomers or pharmaceutically acceptable salts thereof, wherein
The compound of formula (4-6) is prepared by taking the compound of formula (4-5) as a raw material and reacting with an oxidant.
Some embodiments of the present invention are a method for preparing a compound represented by formula (4-6) and a stereoisomer or a pharmaceutically acceptable salt thereof, comprising the steps of reacting a compound represented by formula (4-5) with an oxidizing agent to obtain a compound represented by formula (4-6); the oxidant is selected from PCC (pyridinium chlorochromate), diiodoyl benzoic acid, pyridinium dichromate, 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone, manganese dioxide, potassium permanganate, iodobenzene acetate, silver oxide, iodobenzene trifluoroacetate, potassium persulfate and hydrogen peroxide.
Some embodiments of the present invention are a process for preparing a compound of formula (4-6) and stereoisomers or pharmaceutically acceptable salts thereof, by reaction with a solvent selected from the group consisting of dichloromethane, acetone, tetrahydrofuran, water, acetic acid, maple, 1, 4-dioxane.
Some embodiments of the present invention are a method for preparing a compound represented by formula (4-6) and a stereoisomer or a pharmaceutically acceptable salt thereof, comprising the steps of reacting a compound represented by formula (4-5) with an oxidizing agent to obtain a compound represented by formula (4-6); the molar ratio of the compound of formula (4-5) to the oxidizing agent is 1:1-1:3.
some embodiments of the present invention are methods for preparing a compound represented by formula (4-6) and a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (4-5) is used as a raw material, and is reacted with an oxidant to prepare the compound represented by formula (4-6), wherein the reaction temperature is selected from 0-50 ℃.
Some embodiments of the present invention are a process for preparing a compound of formula (4-6) and stereoisomers or pharmaceutically acceptable salts thereof, wherein
Reacting a compound of a formula (4-5) serving as a raw material with an oxidant to prepare a compound of a formula (4-6);
the oxidant is selected from PCC (pyridinium chlorochromate), diiodoyl benzoic acid, pyridinium dichromate, 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone, manganese dioxide, potassium permanganate, iodobenzene acetate, silver oxide, iodobenzene trifluoroacetate, potassium persulfate and hydrogen peroxide;
the solvent used in the reaction is selected from dichloromethane, acetone, tetrahydrofuran, water, acetic acid, dimethyl sulfoxide and 1, 4-dioxane;
the molar ratio of the compound of formula (4-5) to the oxidizing agent is 1:1-1:3.
the invention relates to a preparation method of a compound shown in a formula (4-5) and a stereoisomer or a pharmaceutically acceptable salt thereof, which comprises the steps of preparing the compound shown in the formula (4-5) by using the compound shown in the formula (4-4) as a raw material,
some embodiments of the present invention are a method for preparing a compound represented by formula (4-5) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound represented by formula (4-4) is used as a raw material, and is reacted with a reducing agent to prepare the compound represented by formula (4-5).
Some embodiments of the present invention are a method for preparing a compound represented by formula (4-5) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (4-5) is prepared by reacting a compound represented by formula (4-4) with a reducing agentThe further reducing agent is selected from LiAlH 4 、NaBH 4 LiBH4, sodium triacetoxyborohydride, borane, red aluminum, raney's nickel, pressurized catalytic hydrogenation.
Some embodiments of the present invention are a method for preparing a compound represented by formula (4-5) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (4-4) is used as a raw material, and reacts with a reducing agent to prepare the compound represented by formula (4-5), and the reaction solvent is selected from diethyl ether, tetrahydrofuran, water, methanol and ethanol.
Some embodiments of the present invention are methods for preparing a compound represented by formula (4-5) and stereoisomers or pharmaceutically acceptable salts thereof, wherein a compound represented by formula (4-4) is used as a raw material, and is reacted with a reducing agent to prepare a compound represented by formula (4-5), wherein the molar ratio of the compound represented by formula (4-4) to the reducing agent is 1:1-1:3.
some embodiments of the present invention are methods for preparing a compound of formula (4-5) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (4-4) is used as a raw material, and is reacted with a reducing agent to prepare the compound of formula (4-5), wherein the reaction temperature is selected from 0 ℃ to reflux.
Some embodiments of the present invention are methods for preparing a compound of formula (4-5) and stereoisomers or pharmaceutically acceptable salts thereof, wherein a compound of formula (4-4) is used as a starting material, and reacted with a reducing agent to obtain a compound of formula (4-5), wherein the reducing agent is selected from LiAlH 4 、NaBH 4 、LiBH 4 Sodium triacetoxyborohydride, borane, red aluminum, raney nickel, pressurized catalytic hydrogenation; the reaction solvent is selected from diethyl ether, tetrahydrofuran, water, methanol and ethanol; the molar ratio of the compound of formula (4-4) to the reducing agent is 1:1-1:3; the reaction temperature is selected from 0 ℃ to reflux.
The invention relates to a preparation method of a compound shown in a formula (4-4) and a stereoisomer or pharmaceutically acceptable salt thereof, which comprises the steps of preparing the compound shown in the formula (4-4) by using the compound shown in the formula (4-3) as a raw material,
some embodiments of the present invention are a method for preparing a compound represented by formula (4-4) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (4-4) is prepared by reacting a compound represented by formula (4-3) with NaCN.
Some embodiments of the present invention are methods for preparing a compound represented by formula (4-4) and stereoisomers or pharmaceutically acceptable salts thereof, wherein a compound represented by formula (4-3) is used as a raw material, and is reacted with NaCN to prepare a compound represented by formula (4-4), and a reaction solvent is selected from DMSO, N-dimethylformamide, acetone, tetrahydrofuran, 1, 4-dioxane, acetonitrile, and dichloromethane.
Some embodiments of the present invention are a method for preparing a compound represented by formula (4-4) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein a compound represented by formula (4-3) is used as a raw material, and reacts with NaCN to prepare a compound represented by formula (4-4), wherein the molar ratio of the compound represented by formula (4-3) to the NaCN is 1:1-1:3.
some embodiments of the present invention are methods for preparing a compound represented by formula (4-4) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein a compound represented by formula (4-3) is used as a raw material, and reacts with NaCN to prepare a compound represented by formula (4-4), wherein the reaction temperature is selected from 0 ℃ to reflux.
The invention relates to a preparation method of a compound shown in a formula (4-3) and a stereoisomer or a pharmaceutically acceptable salt thereof, which comprises the steps of preparing the compound shown in the formula (4-3) by using a compound shown in the formula (4-2) as a raw material,
some embodiments of the present invention are methods for preparing a compound represented by formula (4-3), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein a compound represented by formula (4-2) is used as a raw material, and reacts with methanesulfonyl chloride under alkaline conditions to prepare a compound represented by formula (4-3).
Some embodiments of the present invention are a method for preparing a compound represented by formula (4-3), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein a compound represented by formula (4-2) is used as a raw material, and reacts with methanesulfonyl chloride under an alkaline condition to prepare a compound represented by formula (4-3); the alkali is selected from organic alkali or inorganic alkali, preferably triethylamine, diisopropylethylamine, imidazole, sodium carbonate, sodium bicarbonate, potassium carbonate and sodium hydroxide;
some embodiments of the present invention are a method for preparing a compound represented by formula (4-3), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein a compound represented by formula (4-2) is used as a raw material, and reacts with methanesulfonyl chloride under an alkaline condition to prepare a compound represented by formula (4-3); the solvent used in the reaction is selected from dichloromethane, N-dimethylformamide, acetone, tetrahydrofuran, 1, 4-dioxane, acetonitrile and dimethyl sulfoxide.
Some embodiments of the present invention are a method for preparing a compound represented by formula (4-3), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein a compound represented by formula (4-2) is used as a raw material, and reacts with methanesulfonyl chloride under an alkaline condition to prepare a compound represented by formula (4-3); the molar ratio of the compound of formula (4-2) to methanesulfonyl chloride is 1:1-1:5, preferably 1:1-1:2, more preferably 1:1-1:1.5.
some embodiments of the present invention are methods for preparing a compound represented by formula (4-3) and stereoisomers or pharmaceutically acceptable salts thereof, wherein a compound represented by formula (4-2) is used as a raw material, and reacts with methanesulfonyl chloride under alkaline conditions to prepare a compound represented by formula (4-3), wherein the reaction temperature is selected from 0 to 50 ℃.
Some embodiments of the present invention are a method for preparing a compound represented by formula (4-3), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein a compound represented by formula (4-2) is used as a raw material, and reacts with methanesulfonyl chloride under an alkaline condition to prepare a compound represented by formula (4-3);
the alkali is selected from organic alkali or inorganic alkali, preferably triethylamine, diisopropylethylamine, imidazole, sodium carbonate, sodium bicarbonate, potassium carbonate and sodium hydroxide;
the solvent used in the reaction is selected from dichloromethane, N-dimethylformamide, acetone, tetrahydrofuran, 1, 4-dioxane, acetonitrile and dimethyl sulfoxide.
The invention relates to a preparation method of a compound shown in a formula (4-2) and a stereoisomer or a pharmaceutically acceptable salt thereof, which comprises the steps of preparing the compound shown in the formula (4-2) by using the compound shown in the formula (4-1) as a raw material,
some embodiments of the present invention are a method for preparing a compound represented by formula (4-2) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (4-2) is prepared by reacting a compound represented by formula (4-1) with a reducing agent.
Some embodiments of the present invention are a method for preparing a compound represented by formula (4-2) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound represented by formula (4-2) is prepared by reacting a compound represented by formula (4-1) with a reducing agent selected from LiAlH 4 、NaBH 4 、LiBH 4 Sodium triacetoxyborohydride, borane, red aluminum, raney nickel, pressurized catalytic hydrogenation.
Some embodiments of the present invention are a method for preparing a compound represented by formula (4-2) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein a compound represented by formula (4-1) is used as a raw material, and is reacted with a reducing agent to prepare a compound represented by formula (4-2), and a solvent used in the reaction is selected from tetrahydrofuran, diethyl ether, water, methanol and ethanol.
Some embodiments of the present invention are methods for preparing a compound represented by formula (4-2) and stereoisomers or pharmaceutically acceptable salts thereof, wherein a compound represented by formula (4-1) is used as a raw material, and is reacted with a reducing agent to prepare a compound represented by formula (4-2), wherein the molar ratio of the compound represented by formula (4-1) to the reducing agent is 1:1-1:5, preferably 1:2-1:4.
some embodiments of the present invention are methods for preparing a compound of formula (4-2) and stereoisomers or pharmaceutically acceptable salts thereof, wherein a compound of formula (4-1) is used as a raw material, and is reacted with a reducing agent to prepare a compound of formula (4-2), wherein the reaction temperature is selected from 0 to 50 ℃.
Some embodiments of the present invention are a process for preparing a compound of formula (4-2) and stereoisomers or pharmaceutically acceptable salts thereof, wherein
Reacting a compound of a formula (4-1) serving as a raw material with a reducing agent to prepare a compound of a formula (4-2);
the reducing agent is selected from LiAlH 4 、NaBH 4 、LiBH 4 Sodium triacetoxyborohydride, borane, red aluminum, raney nickel, pressurized catalytic hydrogenation;
the solvent used in the reaction is selected from tetrahydrofuran, diethyl ether, water, methanol and ethanol.
The invention relates to a preparation method of a compound shown in a formula (4-7) and a stereoisomer or a pharmaceutically acceptable salt thereof, wherein
a, taking a compound of a formula (4-1) as a raw material, and reacting the compound with a reducing agent to prepare a compound of a formula (4-2);
b, taking the compound of the formula (4-2) as a raw material, and reacting the compound with methanesulfonyl chloride under an alkaline condition to prepare a compound of the formula (4-3);
c, reacting a compound of a formula (4-3) serving as a raw material with NaCN to prepare a compound of a formula (4-4);
d, taking the compound of the formula (4-4) as a raw material, and reacting the compound with a reducing agent to prepare a compound of the formula (4-5);
e, taking the compound of the formula (4-5) as a raw material, and reacting the compound of the formula (4-6) with an oxidant to prepare a compound of the formula;
f, taking the compound of the formula (4-6) as a raw material, and reacting the compound with the malonic acid cyclo (ylidene) isopropyl ester to prepare the compound of the formula (4-7);
some embodiments of the present invention are a process for preparing a compound of formula (4-7) and stereoisomers or pharmaceutically acceptable salts thereof, wherein
a, the reducing agent is selected from LiAlH 4 、NaBH 4 、LiBH 4 Sodium triacetoxyborohydride borane, red aluminum,Raney nickel, pressure catalytic hydrogenation, further reaction using solvent selected from tetrahydrofuran, diethyl ether, water, methanol, ethanol;
the base is selected from organic base or inorganic base, preferably triethylamine, diisopropylethylamine, imidazole, sodium carbonate, sodium bicarbonate, potassium carbonate and sodium hydroxide, and the solvent used in the reaction is selected from dichloromethane, N-dimethylformamide, acetone, tetrahydrofuran, 1, 4-dioxane, acetonitrile and dimethyl maple;
c, selecting a reaction solvent from DMSO, N-dimethylformamide, acetone, tetrahydrofuran, 1, 4-dioxane, acetonitrile and dichloromethane;
d, the reducing agent is LiAlH 4 、NaBH 4 、LiBH 4 Sodium triacetoxyborohydride, borane, red aluminum, raney nickel and pressurized catalytic hydrogenation, wherein the reaction solvent is selected from diethyl ether, tetrahydrofuran, water, methanol and ethanol;
the oxidant is selected from PCC (pyridinium chlorochromate), diiodo-acylbenzoic acid, pyridinium dichromate, 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone, manganese dioxide, potassium permanganate, iodobenzene acetate, silver oxide, iodobenzene trifluoroacetate, potassium persulfate and hydrogen peroxide; the solvent used for further reaction is selected from dichloromethane, acetone, tetrahydrofuran, water, acetic acid, dimethyl sulfoxide, 1, 4-dioxane;
f, using a base selected from triethylamine and diisopropylethylamine; the solvent used for the further reaction is selected from formic acid.
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
When the compound of the general formula has a chiral center, the compound of the general formula can be a racemate or an optical isomer except for clear marks.
When the present invention relates to a substituent substituted with a plurality of substituents, each substituent may be the same or different.
When the present invention relates to a compound containing a plurality of hetero atoms, the hetero atoms may be the same or different.
The elements carbon, hydrogen, and the like involved in the groups and compounds of the invention,The oxygen, sulfur, nitrogen or halogen includes their isotopes, and the elements carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the invention are optionally further replaced by 1 to 5 of their corresponding isotopes, wherein isotopes of carbon include 12 C、 13 C and 14 c, isotopes of hydrogen including protium (H), deuterium (D, also called deuterium), tritium (T, also called deuterium), isotopes of oxygen including 16 O、 17 O and 18 isotopes of O, sulfur including 32 S、 33 S、 34 S and 36 isotopes of S, nitrogen including 14 N and 15 isotopes of N, F 19 Isotopes of F, chlorine including 35 Cl and 37 isotopes of Cl, bromine including 79 Br and 81 Br。
Detailed Description
The following detailed description is provided for the purpose of illustrating the invention and the resulting beneficial effects, and is not intended to limit the scope of the invention.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift (. Delta.) at 10 -6 The units in (ppm) are given. NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometers in deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), deuterated acetonitrile (CD) 3 CN) internal standard Tetramethylsilane (TMS).
Agilent 6120B (ESI) and Agilent 6120B (APCI) were used for MS measurement.
HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18X 4.6 mm).
The thin-layer chromatography silica gel plate adopts a cigarette platform yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the thin-layer chromatography (TLC) is 0.15 mm-0.20 mm, and the specification of the thin-layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
Known starting materials of the present invention can be synthesized by methods known in the art or can be purchased from companies such as Tatan technology, annaiji chemistry, shanghai Demer, chengdulong chemistry, shaoyuan chemistry, and Bailingwei technology.
The proportion shown by the silica gel column chromatography is volume ratio.
PCC: pyridinium chlorochromate;
ms: a methanesulfonyl group;
example 1
The first step is as follows: 1-hydroxymethyl-3-cyclopentene (4-2)
cyclopent-3-en-1-ylmethanol
At 0 ℃ under a nitrogen atmosphere to LiAlH 4 To (2.3 g,60.0 mmol) was added THF (30 mL). A solution of 3-cyclopentene-1-carboxylic acid (2.2g, 20.0 mmol) in THF (5 mL) was slowly added dropwise to the reaction through a constant pressure funnel. After the addition was complete, the reaction was warmed to room temperature and stirred for 1 hour. The reaction was cooled to 0 ℃ and water (2.3 mL), a 15% aqueous NaOH solution (2.3 mL) and water (2.3 mL) were gradually added dropwise to the reaction in this order, and after stirring for 15 minutes, the reaction mixture was filtered, the filtrate was washed with THF (15 mL) and dichloromethane (15 mL) in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-hydroxymethyl-3-cyclopentene (4-2) (1.2g, 60.0%) as a yellow liquid.
1 H NMR(400MHz,CDCl 3 )δ5.64(s,2H),3.52(d,J＝5.7Hz,2H),2.52-2.36(m,3H),2.19(br s,1H),2.15-1.99(m,2H).
The second step: 1-methanesulfonic acid methyl ester-3-cyclopentene (4-3)
cyclopent-3-en-1-ylmethyl methanesulfonate
CH was added to 1-hydroxymethyl-3-cyclopentene (4-2) (1.2g, 12.0 mmol) at 0 ℃ under a nitrogen atmosphere 2 Cl 2 (50 mL). Et was added thereto successively 3 N (1.5g, 14.4 mmol), methanesulfonyl chloride (1.5g, 13.2mmol). After stirring at 0 ℃ for 30 minutes, the reaction was warmed to room temperature and stirred for 6 hours. Saturated NaHCO was added dropwise thereto 3 Aqueous (50 mL), dichloromethane (100 mL), extraction, aqueous phase with dichloromethane (100 mL) back extraction, combined organic phase with anhydrous sodium sulfate drying, vacuum concentration to obtain yellow liquid methyl 1-methane sulfonate-3-cyclopentene (4-3) (1.9g, 90.0%).
1 H NMR(400MHz,CDCl 3 )δ5.65(br,s,2H),4.12-4.10(d,2H),3.05(s,3H),2.73-2.71(m,1H),2.63-2.45(m,2H),2.35-2.10(m,2H).
LCMS m/z＝199.1[M+23]
The third step: 2- (3-cyclopenten-1-yl) acetic acid (4-4)
2-(cyclopent-3-en-1-yl)acetic acid
DMSO (40 mL) was added to methyl 1-methanesulfonate-3-cyclopentene (4-3) (1.9g, 10.8mmol) at room temperature under a nitrogen atmosphere. NaCN (1.0 g,21.6 mmol) was added thereto, and the reaction was stirred for 48 hours while the temperature was raised to 50 ℃. After the reaction was cooled to room temperature, water (100 mL), etOAc (150 mL) was added, extracted, the aqueous phase was back-extracted with EtOAc (100 mL), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a yellow liquid. EtOH (45 mL), water (15 mL), and NaOH (1.7 g, 43.2mmol) were added to the resulting yellow liquid in that order, and the reaction was heated to reflux and stirred for 12 hours. After the reaction was cooled to 0 deg.C, hydrochloric acid (1N, 45mL) was added dropwise thereto, the residue was extracted with EtOAc (100 mL. Times.2), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2- (3-cyclopenten-1-yl) acetic acid (4-4) (0.76g, 56.0%) as a yellow liquid.
1 H NMR(CDCl 3 ,400MHz)δ11.75(br,s,1H),5.62(s,2H),2.70-2.63(m,1H),2.59-2.55(m,2H),2.42-2.41(d,2H),2.04-2.01(m,2H).
The fourth step: 2- (3-cyclopenten-1-yl) ethanol (4-5)
2-(cyclopent-3-en-1-yl)ethan-1-ol
At 0 ℃ under a nitrogen atmosphere to LiAlH 4 (0.38g, 10.0mmol) to the reaction solution was added Et 2 O (10 mL). To the reaction was slowly added dropwise Et (0.76g, 6.0 mmol) of 2- (3-cyclopenten-1-yl) acetic acid (4-4) (0.76g, 6.0 mmol) through a constant pressure funnel 2 O (5 mL) solution. After the dropwise addition, the reaction was heated and stirred under reflux for 1 hour. The reaction was cooled to 0 ℃ and water (0.4 mL), a 15% aqueous NaOH solution (0.4 mL) and water (0.4 mL) were added slowly and dropwise to the reaction in this order, and after stirring for 15 minutes, the reaction mixture was filtered, and the filtrate was successively treated with Et 2 O (5 mL), dichloromethane (5 mL), anhydrous sodium sulfate drying, and concentration under reduced pressure gave 2- (3-cyclopenten-1-yl) ethanol (4-5) (0.60g, 89.0%) as a yellow liquid.
1 H NMR(CDCl 3 ,400MHz)δ5.64(br,s,2H),3.60-3.52(d,2H),2.65-2.03(m,5H),1.60-1.26(m,2H).
The fifth step: 2- (3-cyclopenten-1-yl) acetaldehyde (4-6)
2-(cyclopent-3-en-1-yl)acetaldehyde
CH was added to 2- (3-cyclopenten-1-yl) ethanol (4-5) (0.60g, 5.4 mmol) at room temperature under a nitrogen atmosphere 2 Cl 2 (10 mL). PCC (2.15g, 10.0 mmol) was added thereto, and the reaction was stirred at room temperature for 3 hours. Filtering through diatomaceous earth, filtering the cake with CH 2 Cl 2 Washing (10 mL. Times.2), and concentrating under reduced pressure gave 2- (3-cyclopenten-1-yl) acetaldehyde (4-6) (0.45g, 76.0%) as a yellow liquid.
1 H NMR(CDCl 3 ,400MHz)δ9.75-9.74(d,1H),5.64-5.62(m,2H),2.85-2.53(m,5H),2.40-1.95(m,2H).
And a sixth step: 4- (3-cyclopenten-1-yl) butanoic acid (4-7)
4-(cyclopent-3-en-1-yl)butanoic acid
Et was added dropwise to formic acid (2.1g, 45.0 mmol) at 0 ℃ under a nitrogen atmosphere 3 N (2.0 g,20.0 mmol), and after stirring for 10 minutes, the mixed solution was dropwise added to 2- (3-cyclopenten-1-yl) acetaldehyde (4-6) (0.45g, 4.0 mmol) and cyclo (ylidene) malonate (0.56g, 4.0 mmol), and the reaction was warmed to 100 ℃ and stirred for 5 hours. After the reaction was cooled to room temperature, 2M NaOH (40 mL) was added dropwise, the residue was extracted with EtOAc (50 mL. Times.3), the combined filter cakes were adjusted to pH 4 with 5M hydrochloric acid, and the aqueous phase was treated with CH 2 Cl 2 (40 mL. Times.2), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4- (3-cyclopenten-1-yl) butyric acid (4-7) (0.4 g, 65.0%) as a yellow liquid.
1 H NMR(400MHz,CDCl 3 )δ5.66(s,2H),2.48(dd,J＝14.1,8.7Hz,2H),2.40–2.31(m,2H),2.30–2.18(m,1H),1.97(dd,J＝13.7,6.4Hz,2H),1.66(dt,J＝12.2,7.5Hz,2H),1.51–1.39(m,2H).
Claims (16)
1. A preparation method of the compound shown in the formula (4-7), wherein the compound shown in the formula (4-6) is used as a raw material to prepare
Wherein
Reacting the compound of formula (4-6) with cyclopropyl (ylidene) malonate to obtain the compound of formula (4-7).
2. The method of claim 1, wherein
The base used in the reaction is selected from triethylamine and diisopropylethylamine;
the solvent used for the reaction is selected from formic acid.
3. The production process according to any one of claims 1 to 2, which further comprises producing a compound of the formula (4-6) by using a compound of the formula (4-5) as a starting material,
4. the method of claim 3, wherein
Taking a compound of a formula (4-5) as a raw material, and reacting the compound with an oxidant to prepare a compound of a formula (4-6);
the oxidant is selected from PCC (pyridinium chlorochromate), diiodoyl benzoic acid, pyridinium dichromate, 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone, manganese dioxide, potassium permanganate, iodobenzene acetate, silver oxide, iodobenzene trifluoroacetate, potassium persulfate and hydrogen peroxide;
the solvent used in the reaction is selected from dichloromethane, acetone, tetrahydrofuran, water, acetic acid, dimethyl sulfoxide and 1, 4-dioxane.
5. The process according to claim 3, which further comprises preparing a compound of the formula (4-5) by starting from the compound of the formula (4-4),
6. the method according to claim 5, wherein
Reacting a compound of a formula (4-4) serving as a raw material with a reducing agent to prepare a compound of a formula (4-5); the reducing agent is selected from LiAlH 4 、NaBH 4 LiBH4, sodium triacetoxyborohydride, borane, red aluminum, raney nickel and pressurized catalytic hydrogenation;
the reaction solvent is selected from diethyl ether, tetrahydrofuran, water, methanol, and ethanol.
7. The process according to claim 5, further comprising preparing the compound of formula (4-4) by using the compound of formula (4-3) as a starting material,
8. the method of claim 7, wherein
Taking a compound of a formula (4-3) as a raw material, and reacting with NaCN to prepare a compound of a formula (4-4);
the reaction solvent is selected from DMSO, N-dimethylformamide, acetone, tetrahydrofuran, 1, 4-dioxane, acetonitrile, and dichloromethane.
9. The process according to claim 7, which further comprises preparing the compound of the formula (4-3) by using the compound of the formula (4-2) as a starting material,
10. the method of claim 9, wherein
Taking a compound of a formula (4-2) as a raw material, and reacting the compound with methane sulfonyl chloride under an alkaline condition to prepare a compound of a formula (4-3);
the alkali is selected from organic alkali or inorganic alkali;
the solvent used in the reaction is selected from dichloromethane, N-dimethylformamide, acetone, tetrahydrofuran, 1, 4-dioxane, acetonitrile and dimethyl sulfoxide.
11. The method of claim 10, wherein
The alkali is selected from triethylamine, diisopropylethylamine, imidazole, sodium carbonate, sodium bicarbonate, potassium carbonate and sodium hydroxide.
12. The process according to claim 9, which further comprises preparing the compound of the formula (4-2) by using the compound of the formula (4-1) as a starting material,
13. the method of claim 12, wherein
Taking a compound of a formula (4-1) as a raw material, and reacting the compound with a reducing agent to prepare a compound of a formula (4-2);
the reducing agent is selected from LiAlH 4 、NaBH 4 、LiBH 4 Sodium triacetoxyborohydride, borane, red aluminum, raney nickel and pressurized catalytic hydrogenation;
the solvent used in the reaction is selected from tetrahydrofuran, diethyl ether, water, methanol and ethanol.
14. A process for the preparation of a compound of formula (4-7) wherein
a, taking a compound of a formula (4-1) as a raw material, and reacting the compound with a reducing agent to prepare a compound of a formula (4-2);
b, taking the compound of the formula (4-2) as a raw material, and reacting the compound with methanesulfonyl chloride under an alkaline condition to prepare a compound of the formula (4-3);
c, taking the compound of the formula (4-3) as a raw material, and reacting with NaCN to prepare the compound of the formula (4-4);
d, taking the compound of the formula (4-4) as a raw material, and reacting the compound of the formula (4-4) with a reducing agent to prepare a compound of the formula (4-5);
e, taking the compound of the formula (4-5) as a raw material, and reacting the compound of the formula (4-6) with an oxidant to prepare a compound of the formula;
and f, reacting the compound of the formula (4-6) serving as a raw material with the cyclopropyl (trimethylene) malonate to obtain the compound of the formula (4-7).
15. The method of claim 14, wherein
a, the reducing agent is selected from LiAlH 4 、NaBH 4 、LiBH 4 Sodium triacetoxyborohydride, borane, red aluminum, raney nickel and pressurized catalytic hydrogenation, wherein a solvent used in the reaction is selected from tetrahydrofuran, diethyl ether, water, methanol and ethanol;
the alkali is selected from organic alkali or inorganic alkali;
c, selecting a reaction solvent from DMSO, N-dimethylformamide, acetone, tetrahydrofuran, 1, 4-dioxane, acetonitrile and dichloromethane;
d, the reducing agent is LiAlH 4 、NaBH 4 、LiBH 4 Sodium triacetoxyborohydride, borane, red aluminum, raney nickel, and pressurized catalytic hydrogenation, wherein the reaction solvent is selected from diethyl ether, tetrahydrofuran, water, methanol and ethanol;
the oxidant is selected from PCC (pyridinium chlorochromate), diiodo-acyl benzoic acid, pyridinium dichromate, 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone, manganese dioxide, potassium permanganate, iodobenzene acetate, silver oxide, iodobenzene trifluoroacetate, potassium persulfate and hydrogen peroxide; the solvent used in the reaction is selected from dichloromethane, acetone, tetrahydrofuran, water, acetic acid, dimethyl sulfoxide and 1, 4-dioxane;
f, using a base selected from triethylamine and diisopropylethylamine; the solvent used for the reaction is selected from formic acid.
16. The method of claim 15, wherein
And b, the alkali is selected from triethylamine, diisopropylethylamine, imidazole, sodium carbonate, sodium bicarbonate, potassium carbonate and sodium hydroxide, and a solvent used in the reaction is selected from dichloromethane, N-dimethylformamide, acetone, tetrahydrofuran, 1, 4-dioxane, acetonitrile and dimethyl maple.
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