CN103483293B - Synthesis method of lasofoxifene precursor of nafoxidine - Google Patents
Synthesis method of lasofoxifene precursor of nafoxidine Download PDFInfo
- Publication number
- CN103483293B CN103483293B CN201310372314.XA CN201310372314A CN103483293B CN 103483293 B CN103483293 B CN 103483293B CN 201310372314 A CN201310372314 A CN 201310372314A CN 103483293 B CN103483293 B CN 103483293B
- Authority
- CN
- China
- Prior art keywords
- phenyl
- dialin
- methoxyl group
- nafoxidine
- add
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 0 C(CC1)CC1C1**C(O*2CCCC2)=CC1 Chemical compound C(CC1)CC1C1**C(O*2CCCC2)=CC1 0.000 description 4
- ITAFANKKHOYILJ-UHFFFAOYSA-N BrC(CC1)CC1OC1=CCC1 Chemical compound BrC(CC1)CC1OC1=CCC1 ITAFANKKHOYILJ-UHFFFAOYSA-N 0.000 description 1
- HLNRRPIYRBBHSQ-UHFFFAOYSA-N CCCN1CCCC1 Chemical compound CCCN1CCCC1 HLNRRPIYRBBHSQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of the lasofoxifene precursor of nafoxidine (1). The synthesis method comprises the following steps of: reacting 6-methoxy-2-phenyl-1-tetralone (2) with perfluoro butanesulfonylfluoride to obtain 6-methoxy-2-phenyl-3,4-dialin-1-perfluorobutane sulfonate (3), and carrying out coupling reaction on the 6-methoxy-2-phenyl-3,4-dialin-1-perfluorobutane sulfonate (3) and a compound in the general formula 4 in the presence of cuprous chloride, lithium chloride, and an iron catalyst, to obtain the nafoxidine (1). The synthesis method disclosed by the invention is simple and efficient, needs mild and easily controllable reaction conditions, and is high yield, and the product is easily separated.
Description
Technical field
The invention belongs to chemosynthesis technical field, be specifically related to treat postmenopausal women osteoporosis agents lasofoxifene precursor of nafoxidine (
1) a kind of synthetic method.
Background technology
D-lasofoxifene tartrate (lasofoxifene D-tartrate) is a kind of partial oestrogen agonist of Pfizer's exploitation, and its listing formulation is thin membrane coated tablet, and commodity are called Fablyn.It has the effect blocking bone loss, reduce cholesterol, go on the market in Europe at present, every per daily dose only needs 0.5mg, the partial oestrogen agonist [Wang Wei that there is blocking-up bone loss, reduce effect of cholesterol the most potent at present, Ai Min. the new drug Lasofoxifene for the treatment of osteoporosis
pharmacy is in progress,
2005, 29 (2): 2-3].Its II phase is clinical compares the RALOXIFENE HCL (raloxifene that D-lasofoxifene tartrate and Li Lai company develop, 60mg/ day) curative effect, D-lasofoxifene tartrate increases lumbar spine bmd, is all better than RALOXIFENE HCL with the effect reducing low density lipoprotein cholesterol.
D-lasofoxifene tartrate (lasofoxifene D-tartrate)
Nafoxidine (
1) be a kind of non steroidal estrogen antagonist found the sixties in 20th century, but unsuccessful as medicinal, but due to synthetic route that D-lasofoxifene tartrate is the most succinct be with nafoxidine (
1) be raw material, through over hydrogenation, demethylation, split obtain with D-tartaric acid [US005552412A and Tong Ling, Zhu Xueyan, Yuan Zhedong.
chinese Journal of Pharmaceuticals,
2011, 42 (7): 481-483], however synthesis difficult point not at rear three-step reaction, and be its precursor nafoxidine (
1) synthesis.So nafoxidine (
1) synthesis attract attention again.
Reported in literature nafoxidine (
1) many synthetic routes [Li Dan, Wang Zhefeng, Wang little Mei, Shi Huilin. lasofoxifene tartrate synthesis scheme.
chinese Journal of Pharmaceuticals.
2010, 41 (6): 468-471], wherein comparatively succinct, representative route has two: respectively with 6-methoxyl group-2-phenyl-ALPHA-tetralone (
2) or 6-methoxyl group-ALPHA-tetralone be starting raw material.
route 1: with 6-methoxyl group-2-phenyl-ALPHA-tetralone (2) for starting raw material.
Early stage United States Patent (USP) (US3274213,1966) has been reported, in anhydrous THF, 1-(2-(4-bromine phenoxy group) ethyl) tetramethyleneimine has been made Grignard reagent, then backflow condition under with 6-methoxyl group-2-phenyl-ALPHA-tetralone (
2) carry out grignard addition, obtain nafoxidine (
1), yield is only 24%(condition A).
Patent WO2012/159981 A2 have employed identical route, but processing condition are different, under low temperature (-78 DEG C), use n-Butyl Lithium, 1-(2-(4-bromine phenoxy group) ethyl) tetramethyleneimine is made organolithium reagent, and under the existence of anhydrous cerous compounds, with 6-methoxyl group-2-phenyl-ALPHA-tetralone (
2) carry out addition reaction, obtain nafoxidine (
1), yield is 28%(condition B).This reaction needed is carried out under low temperature (-78 DEG C), and last handling process needs to use high vacuum underpressure distillation (0.2mmHg) removes impurity, operates comparatively loaded down with trivial details, and very high to the requirement of equipment, makes the with high costs of this operational path.Compare Article 1 route, yield does not significantly improve, and does not also have the advantage on cost, but constant product quality.
route 2: with 6-methoxyl group-ALPHA-tetralone for starting raw material.
United States Patent (USP) (US005552412A, 1996) report and use n-Butyl Lithium that 1-(2-(4-bromine phenoxy group) ethyl) tetramethyleneimine is made organolithium reagent in anhydrous THF, under the existence of anhydrous cerous compounds, carry out addition reaction with cheap 6-methoxyl group-ALPHA-tetralone, and remove impurity by high vacuum underpressure distillation (0.15mmHg).Re-use pyridinium tribromide and carry out bromo-reaction.Last and phenylo boric acid carries out Suzuki coupling, obtain nafoxidine (
1), the bromination reaction by product in this route is more, and is difficult to be separated, and the catalyzer cost of Suzuki linked reaction is higher and cannot reclaim.This route total recovery is 37% (condition A).
Tong Ling etc. [Tong Ling, Zhu Xueyan, Yuan Zhedong.
chinese Journal of Pharmaceuticals,
2011, 42 (7): 481-483] route in patent US005552412A is optimized, make total recovery be promoted to 50%.
US Patent No. 2012/0045648 A1 have employed identical route, and just the processing condition of the first step reaction are different, adopts Grignard reagent to replace organolithium reagent to react, but concrete temperature of reaction and separation method not mentioned.This route total recovery is 42% (condition B).
Summary of the invention
The object of the present invention is to provide lasofoxifene precursor of nafoxidine (
1) a kind of synthetic method.
The present invention with 6-methoxyl group-2-phenyl-ALPHA-tetralone (
2) as raw material, under the existence of DBU, react with perfluoro butyl sulfonic acid fluoride, obtain 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3), then at cuprous chloride, under the existence of lithium chloride and iron catalyst, with general formula
4compound carry out linked reaction, obtain nafoxidine (
1), reaction formula is as follows:
1) 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) synthesis
The preparation method of usual perfluoro butyl sulphonate is: at tetrahydrofuran (THF) or methylene dichloride, by perfluoro butyl sulfonic acid fluoride under the existence of organic bases (DBU, triethylamine, hmds lithium etc.), be obtained by reacting with carbonyl compound, this reaction is at room temperature carried out usually.Perfluoro butyl sulfonic acid fluoride is by electrolysis process industrially tons of scale operation in recent years, with low cost, and nontoxic pollution-free.[Science?Update，
E-Newsletter.?
2003.9
:?3-6?/?Michael?Alexander?Kolja?Vogel,?
Dissertation，Freie?
?Berlin，
2009,?30-33]。
In the present invention by 6-methoxyl group-2-phenyl-ALPHA-tetralone (
2) be dissolved in organic solvent, at room temperature add DBU, more slowly add perfluoro butyl sulfonic acid fluoride, stirring reaction 4-60h.Add water washing organic phase, then add and wash with the dilute hydrochloric acid solution of DBU equivalent, finally with saturated nacl aqueous solution washing, pressure reducing and steaming solvent, obtain 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3).
Wherein, described organic solvent is tetrahydrofuran (THF) or methylene dichloride, selects methylene dichloride effect better.Solvent load and 6-methoxyl group-2-phenyl-ALPHA-tetralone (
2) Ratio control at 5-15, usually reaction adopts ratio 8.
Described step 1) 6-methoxyl group-2-phenyl-ALPHA-tetralone (
2) be 1:1 ~ 5 with the molar ratio range of perfluoro butyl sulfonic acid fluoride, the best is 1:1.4.
2) nafoxidine (
1) synthesis
Grignard reagent linked reaction, be by thiazolinyl or aryl substituent under the existence of metal catalyst, carry out linked reaction with Grignard reagent; Metal catalyst is palladium, nickel.
The reaction type that palladium is applied due to it with nickel and other heavy metal catalysts is more extensive, and it is comparatively ripe, and the parent being subject to people looks at, but it is high owing to there is price, poisonous and harmful, usual needs use the Phosphine ligands of severe toxicity to participate in, and the substrate of the linked reaction of palladium and nickel catalysis is generally comparatively unstable bromide and iodide.Large quantity research shows in recent years, the advantages such as iron catalyst not only has efficiently, low toxicity, environmental protection, and reaction substrate not only can use bromide and iodide, can also use stable and cheap muriate and sulphonate [Wang Chen, Fu Yao etc.
organic chemistry,
2007, 27:703-723], and reaction conditions does not have the heavy metal catalyst such as palladium and nickel so harsh.Therefore iron catalyst is widely applied in organic synthesis.
Reference literature method of the present invention [Michael Alexander Kolja Vogel,
dissertation. Freie
berlin,
2009: 55-64], adopt iron catalyst, develop prepare nafoxidine (
1) novel process.
To general formula
4compound THF solution in, add cuprous chloride and lithium chloride, then add 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) THF solution and iron catalyst, at-30 DEG C ~ 40 DEG C react 0.5 ~ 5h.Reaction solution is poured in saturated ammonium chloride, solids removed by filtration, collect filtrate.Point to anhydrate phase, and extract by ethyl acetate, merge organic phase, finally with saturated sodium-chloride washing, anhydrous sodium sulfate drying, filters, pressure reducing and steaming solvent, obtain nafoxidine (
1).
Wherein, described step 2) general formula
4compound in, M is MgBr or Li.
Described step 2) general formula
4compound and 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) molar ratio range be 1:0.5 ~ 2, the best is 1:1; Cuprous chloride and 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) molar ratio range be 1:0.5 ~ 3, the best is 1:1; Iron catalyst and 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) molar ratio range be 1:0.5 ~ 5, the best is 1:1; The molar ratio range of cuprous chloride and lithium chloride is 1:1 ~ 5, and the best is 1:2; The temperature of linked reaction is-30 DEG C ~ 40 DEG C, and the reaction times is 0.5 ~ 5h.
Described step 2) iron catalyst is one in iron(ic) chloride, iron bromide, ferric acetyl acetonade.When using ferric acetyl acetonade to do, reaction effect is best.Ferric acetyl acetonade and 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) Ratio control at 0.5-2, when ratio is 1, reaction yield is the highest.
Described step 2) THF and 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) Ratio control at 5-15, usually reaction adopts ratio 8.
Advantage of the present invention and innovative point are:
The invention provides a kind of succinct nafoxidine efficiently (
1) synthetic method: use the nontoxic and perfluoro butyl sulfonic acid fluoride of safety, cheap free of contamination iron catalyst reacts, and reaction conditions gentleness is easy to control, and the high and product of yield is easily separated.Solve operational path in prior art loaded down with trivial details, complicated operation, the problems such as by product is many, separation difficulty.What also solve D-lasofoxifene tartrate raw material carrys out source problem simultaneously.
Accompanying drawing explanation
Fig. 1 be 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3)
1h NMR
Fig. 2 be 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3)
13c NMR
Fig. 3 be nafoxidine (
1)
1h NMR
Embodiment
The present invention will be further described by the following examples, but the present invention is not limited only to this.
Embodiment 1:
At room temperature by 6-methoxyl group-2-phenyl-ALPHA-tetralone (
2) (15.0g, 59.5mmol) be dissolved in methylene dichloride (120mL), adds DBU(12.6g, 83.3mmol).In reaction solution, slowly add perfluoro butyl sulfonic acid fluoride (25.2g, 83.3mmol), about 20min adds.At room temperature stir 16h.The washing of distilled water 120mL × 2 is added in reaction solution, and add 0.5N hydrochloric acid soln 167mL, divide phase of anhydrating, and extract with methylene dichloride 100mL × 2, merge organic phase, saturated nacl aqueous solution 100mL washs, anhydrous sodium sulfate drying, filter, concentrated filtrate obtain 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) 30.0g, pale yellow oil, productive rate 94.3%.
6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3)
1h NMR (500 MHz, CDCl
3) see Fig. 1: δ 7.51 (d,
j=8.5 Hz, 1H), 7.49 – 7.43 (m, 4H), 7.43 – 7.34 (m, 1H), 6.89 (dd,
j=8.6/2.6 Hz, 1H), 6.85 (d, J=2.4 Hz, 1H), 3.88 (s, 3H), 3.03 (t, J=7.8 Hz, 2H), 2.83 (t, J=7.9 Hz, 2H).
6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3)
13c NMR (126 MHz, CDCl
3) see Fig. 2: δ 160.13,141.27,138.00,136.46,129.64,129.20,128.44,123.68,123.07,113.86,111.48,55.28,30.35,28.27, in product, 4 carbon of perfluoro butyl exist
13overlap is had in C NMR, [Shekhar S consistent with document description, Dunn T B, Kotecki B J, et al. A General Method for Palladium-Catalyzed Reactions of Primary Sulfonamides with Aryl Nonaflates.
j Org Chem,
2011, 76 (11): 4552 – 4563].
Embodiment 2:
At room temperature by 6-methoxyl group-2-phenyl-ALPHA-tetralone (
2) (3.00g, 11.9mmol) be dissolved in THF(25mL) in, add DBU(2.53g, 16.7mmol).In reaction solution, slowly add perfluoro butyl sulfonic acid fluoride (5.03g, 16.7mmol), about 15min adds.At room temperature stir 16h.Pressure reducing and steaming THF, in residue, add methylene dichloride 30mL, distilled water 30mL × 2 are washed, and add 0.5N hydrochloric acid soln 33.3mL, divide phase of anhydrating, and extract with methylene dichloride 10mL, merge organic phase, saturated nacl aqueous solution 30mL washs, anhydrous sodium sulfate drying, filter, concentrated filtrate obtain 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) 5.89g, pale yellow oil, productive rate 92.7%.
Embodiment 3:
At 0 DEG C, toward (4-(2-(1-pyrrolidyl) oxyethyl group) phenyl-magnesium-bromide (
4) (M=MgBr) (11.2mmol) THF solution (48mL) in, add CuCl(1.11g, 11.2mmol), anhydrous LiCl(0.940g, 22.5mmol), stir 1h, add 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) (6.00g, 11.2mmol) and ferric acetyl acetonade (3.97g, 11.2mmol), continue to stir 2h at 0 DEG C.Reaction solution is poured in saturated ammonium chloride solution (50mL), solids removed by filtration, collect filtrate.Divide phase of anhydrating, and extract with ethyl acetate 20mL × 2, merge organic phase, pressure reducing and steaming solvent.Distilled water 40mL is added in residue, and add 2N hydrochloric acid, make pH be 2 ~ 3, add mixed solution 20mL × 2(1:3 v/v of ether and methyltetrahydrofuran) extract, divide and go organic phase, and extract with 0.5N hydrochloric acid 30mL, merge aqueous phase, add 4N sodium hydroxide solution, make pH be 11 ~ 12, add ethyl acetate 30mL × 2 to extract, divide phase of anhydrating.Organic phase adds saturated nacl aqueous solution 50mL and washs, and organic phase, through anhydrous sodium sulfate drying, is filtered, concentrated nafoxidine (
1) 4.23g, white crystals, productive rate 88.6%.
Nafoxidine (
1)
1h NMR (500 MHz, CDCl
3) as shown in Figure 3, δ 7.13 (t,
j=7.4 Hz, 2H), 7.09 – 7.03 (m, 3H), 6.99 (d,
j=8.5 Hz, 2H), 6.80 (m, 4H), 6.63 (dd,
j=8.6,2.7 Hz, 1H), 4.10 (t,
j=6.0 Hz, 2H), 3.82 (s, 3H), 2.99 – 2.95 (m, 2H), 2.92 (t,
j=6.0 Hz, 2H), 2.81 (dd,
j=9.2,6.3 Hz, 2H), 2.66 (s, 4H), 1.87 – 1.82 (m, 4H) [consistent with patent WO2012/159981 A2]
Embodiment 4:
At-10 DEG C, toward (4-(2-(1-pyrrolidyl) oxyethyl group) phenyl-magnesium-bromide (
4) (M=MgBr) (7.49mmol) THF solution (32mL) in, add CuCl(0.740g, 7.49mmol), LiCl(0.630g, 15.0mmol), stir 1h, add 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) (4.00g, 7.49mmol) and iron(ic) chloride (1.31g, 7.91mmol), continue to stir 3h at-10 DEG C.Reaction solution is poured in saturated ammonium chloride solution (40mL), solids removed by filtration, collect filtrate.Divide phase of anhydrating, and extract with ethyl acetate 15mL × 2, merge organic phase, pressure reducing and steaming solvent.In residue, add distilled water 30mL, and add 2N hydrochloric acid, make pH be 2 ~ 3, and add mixed solution 15 mL × 2(1:3 v/v of ether and methyltetrahydrofuran) extract, divide and go organic phase, and extract with 0.5N hydrochloric acid 20mL, merge aqueous phase, add 4N sodium hydroxide solution, make pH be 11 ~ 12, add ethyl acetate 20mL × 2 to extract, divide phase of anhydrating, organic phase adds L saturated nacl aqueous solution 35m and washs, anhydrous sodium sulfate drying, filter, concentrated filtrate obtain nafoxidine (
1) 2.68g, white crystals, productive rate 84.2%.
Embodiment 5:
At 25 DEG C, toward (4-(2-(1-pyrrolidyl) oxyethyl group) phenyl-magnesium-bromide (
4) (M=MgBr) (37.5mmol) THF solution (160mL) in, add CuCl(3.70g, 37.5mmol), LiCl(3.15g, 74.9mmol), stir 0.5h, add 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) (20.0g, 37.5mmol) and iron bromide (11.6g, 39.3mmol), continue to stir 0.5h at 40 DEG C.Reaction solution is poured in saturated ammonium chloride solution (200mL), solids removed by filtration, collect filtrate.Divide phase of anhydrating, and extract with ethyl acetate 75mL × 2, merge organic phase, pressure reducing and steaming solvent.In residue, add distilled water 150mL, and add 2N hydrochloric acid, make pH be 2 ~ 3, and add mixed solution 75mL × 2(1:3 v/v of ether and methyltetrahydrofuran) extract, divide and go organic phase, and extract with 0.5N hydrochloric acid 100mL, merge aqueous phase, add 4N sodium hydroxide solution, make pH be 11 ~ 12, add ethyl acetate 75mL × 2 to extract, divide phase of anhydrating, organic phase adds saturated nacl aqueous solution 175mL and washs, anhydrous sodium sulfate drying, filter, concentrated filtrate obtain nafoxidine (
1) 13.3g, white crystals, productive rate 83.3%.
Embodiment 6:
At-30 DEG C, toward (4-(2-(1-pyrrolidyl) oxyethyl group) phenyl lithium (
4) (M=Li) (14.1mmol) THF solution (60mL) in, add CuCl(1.39g, 14.0mmol), LiCl(1.18g, 28.1mmol), stir 2h, add 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) (7.50g, 14.0mmol) and ferric acetyl acetonade (4.96g, 14.0mmol), continue to stir 5h at-30 DEG C.Reaction solution is poured in saturated ammonium chloride solution (60mL), solids removed by filtration, collect filtrate.Divide phase of anhydrating, and extract with ethyl acetate 20mL × 2, merge organic phase, pressure reducing and steaming solvent.In residue, add distilled water 50mL, and add 2N hydrochloric acid, make pH be 2 ~ 3, and add mixed solution 25mL × 2(1:3 v/v of ether and methyltetrahydrofuran) extract, divide and go organic phase, and extract with 0.5N hydrochloric acid 30mL, merge aqueous phase, add 4N sodium hydroxide solution, make pH be 11 ~ 12, add ethyl acetate 30mL × 2 to extract, divide phase of anhydrating, organic phase adds saturated nacl aqueous solution 50mL and washs, anhydrous sodium sulfate drying, filter, concentrated filtrate obtain nafoxidine (
1) 5.33g, white crystals, productive rate 89.3%.
Embodiment 7:
At-20 DEG C, toward (4-(2-(1-pyrrolidyl) oxyethyl group) phenyl lithium (
4) (M=Li) (225mmol) THF solution (1L) in add CuCl(22.2g, 225mmol), LiCl(18.9g, 450 mmol), stir 1.5h, add 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) (120 g, 225mmol) and iron(ic) chloride (39.0g, 236mmol), continue at-20 DEG C to stir 3h.Reaction solution is poured in saturated ammonium chloride solution (1L), solids removed by filtration, collect filtrate.Divide phase of anhydrating, and extract with ethyl acetate 300mL × 2, merge organic phase, pressure reducing and steaming solvent.In residue, add distilled water 700mL, and add 2N hydrochloric acid, make pH be 2 ~ 3, and add mixed solution 250mL × 2(1:3 v/v of ether and methyltetrahydrofuran) extract, divide and go organic phase, and extract with 0.5N hydrochloric acid 300mL, merge aqueous phase, add 4N sodium hydroxide solution, make pH be 11 ~ 12, add ethyl acetate 350mL × 2 to extract, divide phase of anhydrating, organic phase adds saturated nacl aqueous solution 500mL and washs, anhydrous sodium sulfate drying, filter, concentrated filtrate obtain nafoxidine (
1) 83.4g, white crystals, productive rate 87.3%.
Embodiment 8:
At-30 DEG C, the lithium reagent of 1-(2-(4-bromine phenoxy group) ethyl) tetramethyleneimine (
4) (M=Li) (3.74mmol) THF solution (16mL) in add CuCl(0.370g, 3.74mmol), LiCl(0.310g, 7.48mmol), stir 2h, add 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) (2.00g, 3.74mmol) and iron bromide (1.11g, 3.74mmol), continue at 0 DEG C to stir 1h.Reaction solution is poured in saturated ammonium chloride solution (16mL), solids removed by filtration, collect filtrate.Divide phase of anhydrating, and extract with ethyl acetate 10mL × 2, merge organic phase, pressure reducing and steaming solvent.In residue, add distilled water 10mL, and add 2N hydrochloric acid, make pH be 2 ~ 3, and add mixed solution 10mL × 2(1:3 v/v of ether and methyltetrahydrofuran) extract, divide and go organic phase, and extract with 0.5N hydrochloric acid 15mL, merge aqueous phase, add 4N sodium hydroxide solution, make pH be 11 ~ 12, add ethyl acetate 10mL × 2 to extract, divide phase of anhydrating, organic phase adds saturated nacl aqueous solution 15mL and washs, anhydrous sodium sulfate drying, filter, concentrated filtrate obtain nafoxidine (
1) 1.35g, white crystals, productive rate 84.9%.
Claims (3)
1. the synthetic method of lasofoxifene precursor of nafoxidine, it is characterized in that: 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (3) is under the existence of cuprous chloride, lithium chloride and iron catalyst, carry out linked reaction with the compound of general formula 4, obtain nafoxidine (1); Wherein, in the compound of general formula 4, M is MgBr or Li; Iron catalyst is the one in iron(ic) chloride, iron bromide, ferric acetyl acetonade.
2. the synthetic method of lasofoxifene precursor of nafoxidine according to claim 1, it is characterized in that: the compound of described general formula 4 and the molar ratio range of 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (3) are 1:0.5 ~ 2; The molar ratio range of cuprous chloride and 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (3) is 1:0.5 ~ 3; The molar ratio range of iron catalyst and 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (3) is 1:0.5 ~ 5; The molar ratio range of cuprous chloride and lithium chloride is 1:1 ~ 5; The temperature of linked reaction is-30 DEG C ~ 40 DEG C, and the reaction times is 0.5 ~ 5h.
3. the synthetic method of lasofoxifene precursor of nafoxidine according to claim 1 and 2, it is characterized in that: the compound of described general formula 4 and mol ratio the best of 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (3) are 1:1; Mol ratio the best of cuprous chloride and 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (3) is 1:1; Mol ratio the best of iron catalyst and 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (3) is 1:1; Mol ratio the best of cuprous chloride and lithium chloride is 1:2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310372314.XA CN103483293B (en) | 2013-08-24 | 2013-08-24 | Synthesis method of lasofoxifene precursor of nafoxidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310372314.XA CN103483293B (en) | 2013-08-24 | 2013-08-24 | Synthesis method of lasofoxifene precursor of nafoxidine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103483293A CN103483293A (en) | 2014-01-01 |
| CN103483293B true CN103483293B (en) | 2015-01-07 |
Family
ID=49823942
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310372314.XA Active CN103483293B (en) | 2013-08-24 | 2013-08-24 | Synthesis method of lasofoxifene precursor of nafoxidine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103483293B (en) |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6608212B1 (en) * | 2002-06-04 | 2003-08-19 | Pfizer, Inc. | Process for preparing vinylaromatic compounds |
| DE102005043337A1 (en) * | 2005-09-12 | 2007-03-15 | Ludwig-Maximilians-Universität München | Nickel- or iron-catalyzed carbon-carbon coupling reaction of arylenes, alkenes, and alkynes |
| JP5212931B2 (en) * | 2006-01-26 | 2013-06-19 | 学校法人東京理科大学 | Method for producing lasofoxifene and its analogs |
| EP2524908A1 (en) * | 2011-05-20 | 2012-11-21 | LEK Pharmaceuticals d.d. | Process for the preparation of alfa-substituted ketones and their application in synthesis of pharmaceutically active compounds |
| CN103113323B (en) * | 2013-02-05 | 2015-11-11 | 南京华威医药科技开发有限公司 | The preparation method of Lasofoxifene tartrate intermediate |
-
2013
- 2013-08-24 CN CN201310372314.XA patent/CN103483293B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN103483293A (en) | 2014-01-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Kaye et al. | The Use of Catalytic Amounts of CuCl and Other Improvements in the Benzyne Route to Biphenyl‐Based Phosphine Ligands | |
| CN103087105B (en) | Chiral phosphine ligand and comprise the metal catalyst of this part and their application | |
| EP2235023B1 (en) | An efficient process to induce enantioselectivity in procarbonyl compounds | |
| CN105408302B (en) | The method for preparing the amines of purified form | |
| CN106146459A (en) | A kind of preparation method of bilastine | |
| CN104844399A (en) | Method for synthetizing 2-fluoro phenol compound | |
| CN104098607B (en) | Containing single phosphine list N-heterocyclic carbine nickel (II) title complex and the application thereof of tricyclohexyl phosphine | |
| CN103880762B (en) | A kind of preparation method of 1,2,3-triazole compound | |
| CN103483293B (en) | Synthesis method of lasofoxifene precursor of nafoxidine | |
| CN103694153B (en) | The method of styracin and arylsulfinate Reactive Synthesis alkenyl sulfone compound | |
| CN101591360B (en) | Ionic liquid type monophosphine monoimidazolium salt nickel (II) complex and preparation and application thereof | |
| Dai et al. | Nickel-Catalyzed Cross-Coupling of Aryl 2-Pyridyl Ethers with Organozinc Reagents: Removal of the Directing Group via Cleavage of the Carbon–Oxygen Bonds | |
| JP6096465B2 (en) | Method for preparing 2-alkoxy-5- (pyridin-2-yl) pyridine, an intermediate of peranpanel | |
| JP2001507348A (en) | Method for producing organozinc reagent | |
| CN109096119A (en) | A method of preparing cinacalcet hydrochloride | |
| CN102584512B (en) | Method for synthesizing benzofuran derivatives in one pot process | |
| CN110803985B (en) | Preparation method of bilastine intermediate | |
| CN102249962B (en) | Preparation method of 1,1-disulfur-1-olefin | |
| CN103864567A (en) | Method for preparing coupled arene compound | |
| CN106588779A (en) | Method for synthesizing dexmedetomidine hydrochloride intermediate | |
| US7109349B2 (en) | Process for obtaining Cizolirtine and its enantiomers | |
| CN102786427A (en) | Synthetic method of bis-(2-dimethylaminoethyl)ether | |
| CN109232282B (en) | Synthetic method of 2-aminobenzophenone compound | |
| CN102827080B (en) | Novel synthetic method of ivabradine and novel intermediate product of ivabradine | |
| US20060135787A1 (en) | Process for obtaining enantiomers of thienylazolylalcoxyethanamines |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20201211 Address after: No.279, Zhongxia, Gushan Town, Jin'an District, Fuzhou City, Fujian Province Patentee after: FUZHOU NEPTUNUS FUYAO PHARMACEUTICAL Co.,Ltd. Address before: 350007 No. 25, progressive Road, Cangshan District, Fujian, Fuzhou Patentee before: FUJIAN INSTITUTE OF MICROBIOLOGY |