CN100480224C - Preparation of nabumetone - Google Patents
Preparation of nabumetone Download PDFInfo
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- CN100480224C CN100480224C CNB2005101113900A CN200510111390A CN100480224C CN 100480224 C CN100480224 C CN 100480224C CN B2005101113900 A CNB2005101113900 A CN B2005101113900A CN 200510111390 A CN200510111390 A CN 200510111390A CN 100480224 C CN100480224 C CN 100480224C
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- nabumetone
- naphthyl
- methoxyl group
- hours
- ketone
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- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 229960004270 nabumetone Drugs 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 31
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- 239000000047 product Substances 0.000 claims description 19
- 239000012043 crude product Substances 0.000 claims description 17
- 238000001953 recrystallisation Methods 0.000 claims description 17
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 150000001555 benzenes Chemical class 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- VZBLASFLFFMMCM-UHFFFAOYSA-N 6-methoxynaphthalene-2-carbaldehyde Chemical compound C1=C(C=O)C=CC2=CC(OC)=CC=C21 VZBLASFLFFMMCM-UHFFFAOYSA-N 0.000 claims 1
- WDJHALXBUFZDSR-UHFFFAOYSA-M acetoacetate Chemical compound CC(=O)CC([O-])=O WDJHALXBUFZDSR-UHFFFAOYSA-M 0.000 claims 1
- 238000005903 acid hydrolysis reaction Methods 0.000 claims 1
- IAQRGUVFOMOMEM-UHFFFAOYSA-N butene Natural products CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- 239000011259 mixed solution Substances 0.000 claims 1
- IAQRGUVFOMOMEM-ONEGZZNKSA-N trans-but-2-ene Chemical compound C\C=C\C IAQRGUVFOMOMEM-ONEGZZNKSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 20
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 abstract description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- 238000005984 hydrogenation reaction Methods 0.000 description 27
- 229960000935 dehydrated alcohol Drugs 0.000 description 16
- 238000001816 cooling Methods 0.000 description 15
- 239000013078 crystal Substances 0.000 description 15
- 238000001035 drying Methods 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- 230000007062 hydrolysis Effects 0.000 description 15
- 238000006460 hydrolysis reaction Methods 0.000 description 15
- 239000000843 powder Substances 0.000 description 15
- 238000006073 displacement reaction Methods 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000010531 catalytic reduction reaction Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 4
- 229940043232 butyl acetate Drugs 0.000 description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical class C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 238000003512 Claisen condensation reaction Methods 0.000 description 2
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- PJKVFARRVXDXAD-UHFFFAOYSA-N 2-naphthaldehyde Chemical compound C1=CC=CC2=CC(C=O)=CC=C21 PJKVFARRVXDXAD-UHFFFAOYSA-N 0.000 description 1
- 206010070840 Gastrointestinal tract irritation Diseases 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000001741 anti-phlogistic effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- GVIIRWAJDFKJMJ-UHFFFAOYSA-N propan-2-yl 3-oxobutanoate Chemical compound CC(C)OC(=O)CC(C)=O GVIIRWAJDFKJMJ-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
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- Catalysts (AREA)
- Quinoline Compounds (AREA)
Abstract
本发明涉及一种萘丁美酮的制备方法，与现有方法相比，该方法在催化氢化制备中间体3-烷氧羰基-4-(6-甲氧基-2-萘基)丁-2-酮时，采用Raney-Ni Wn(n＝2～7)、Raney Cu或Raney Co作为催化剂，具有成本低，反应条件温和，设备腐蚀性小，工艺简单等优点。The present invention relates to a kind of preparation method of nabumetone, compared with existing method, this method is in catalytic hydrogenation preparation intermediate 3-alkoxycarbonyl-4-(6-methoxy-2-naphthyl) butane- For 2-ketone, Raney-Ni Wn (n=2-7), Raney Cu or Raney Co is used as the catalyst, which has the advantages of low cost, mild reaction conditions, less corrosive equipment, and simple process.
Description
Technical field
The present invention relates to the preparation method of nabumetone.Be specifically related to that catalytic reduction method prepares improving one's methods of intermediate 3-carbalkoxy-4-(6-methoxyl group-2-naphthyl) fourth-2-ketone in a kind of nabumetone building-up process.
Background technology
Nabumetone is Maxicom again, chemistry 4-(6-methoxyl group-2-naphthyl) by name-2-butanone, be Britain Beecham company research and develop a kind of NSAID (non-steroidal anti-inflammatory drug), go on the market the beginning of the eighties in last century, rheumatic and rheumatoid arthritis etc. there is mitigation preferably, suitable with the effect of broad spectrum antiphlogistic medicine Naproxen Base, and do not have carbonyl because of intramolecularly, very little to GI irritation, obtain higher rating clinically.In recent years the domestic and international market demand grows by a large margin every year, and development prospect is very optimistic.
The synthetic route of nabumetone report is more, and methoxyl group-the 2-naphthaldehyde is initial feed and acetoacetic ester condensation to adopt 6-at present usually, is that catalyzer carries out catalytic reduction and obtains nabumetone (U.S. Patent application US4247709 and US4061779 with the palladium charcoal again; J.Med.Chem.1978,21:1260; Chinese Journal of Pharmaceuticals 1990,21 (3): 194), though this method step is less, but adopt the palladium charcoal to make catalyzer, defectives such as the palladium charcoal exists itself and costs an arm and a leg, and selectivity is relatively poor, and the preparation of palladium charcoal in the industry at home, use and reclaim technologies such as circulation immature, unprofessional, not system, less stable, cause the shared aborning cost of palladium charcoal higher, thereby be unfavorable for suitability for industrialized production.
Other has report to adopt 6-methoxyl group-2-acetonaphthone or 6-methoxyl group-2-brooethyl naphthalene is raw material, with acetylacetic ester or acetone reaction, is that catalyzer carries out catalytic reduction and obtains nabumetone (U.S. Patent application US4221741 with the palladium charcoal again; UK Patent Application BR8201004; Canadian patent application CA1049039), these methods also have complex process, complex operation, and selectivity is relatively poor during with the reaction of acetylacetic ester or acetone, reaction yield is low and shortcoming such as cost height, is difficult to realize large-scale commercial production.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of nabumetone, this method prepares intermediate 3-carbalkoxy-4-(6-methoxyl group-2-naphthyl) fourth-2-ketone step to catalytic reduction method among the existing preparation method and improves, cost an arm and a leg defectives such as poor selectivity, instability, production cost height and purification process complexity to overcome the catalyzer that exists in the prior art.
When the characteristics of the inventive method are that catalytic reduction prepares intermediate 3-carbalkoxy-4-(6-methoxyl group-2-naphthyl) fourth-2-ketone, adopt Raney-Ni W
n(n=2～7), Raney Cu or Raney Co are as catalyzer.
The inventive method may further comprise the steps: with 6-methoxyl group-2-naphthaldehyde is initial feed, generate 3-carbalkoxy-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone (III) with acetoacetic ester condensation, catalytic hydrogenation makes 3-carbalkoxy-4-(6-methoxyl group-2-naphthyl) fourth-2-ketone (II) in organic solvent, acidolysis obtains nabumetone (I) crude product, obtains qualified pure product through the dehydrated alcohol recrystallization purifying.
The reaction scheme of the inventive method is as follows:
When the present invention prepares intermediate 3-carbalkoxy-4-(6-methoxyl group-2-naphthyl) fourth-2-ketone in catalytic hydrogenation, adopt Raney-Ni W
n(n=2～7), Raney Cu or Raney Co be as catalyzer, wherein preferred Raney-Ni W
n(n=2～7), catalyst consumption are 5-10% (weight ratio) of 3-carbalkoxy-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone consumption.
During catalytic hydrogenation, pressure and temperature is all influential to the yield of product, and pressure is too big, and temperature is too high, causes carbonyl to be reduced easily, and it is many to generate by product; But the too little temperature of pressure is too low, and speed of response is slow, and extend reaction time.Suitable catalytic hydrogenation pressure is 0.1～4.0MPa (gauge pressure) among the present invention, wherein preferred 0.1～1.0MPa (gauge pressure); Suitable temperature is 20～100 ℃, wherein preferred 20～60 ℃; The catalytic hydrogenation time is 2-20 hour, is preferably 2-5 hours; Solvent can be selected C1-C8 alcohols (as methyl alcohol, ethanol, Virahol, propyl carbinol etc.) for use; Ester class (as butylacetate, ethyl acetate etc.); Benzene and substituted benzene (as toluene, dimethylbenzene etc.); The mixture of alkanes (hexanaphthene, normal hexane, sherwood oil, low boiling point solvent wet goods) or above solvent, wherein particular methanol, ethanol or propyl carbinol.The amount ratio of organic solvent and 3-carbalkoxy-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone is 1～5ml:1g.
Beneficial effect
That 1, utilizes that the inventive method prepares nabumetone has productive rate height (two step overall yields reaches more than 80%), a product purity advantages of higher.
2, the raw material that the inventive method adopted is easy to get, cost is low, used catalyzer is inexpensive, selectivity good, operating procedure is simple, reliable, efficient and reaction conditions is gentle, little to the corrodibility of equipment, can be used for industrialization and commercially produce and have a production cost advantage.
Embodiment
Below in conjunction with embodiment the inventive method is further elaborated, but does not limit the present invention:
Embodiment 1
With 80g 6-methoxyl group-2-naphthaldehyde, the 56g methyl acetoacetate is dissolved in the 350ml hexanaphthene, add toluylic acid piperidinium salt 5g, refluxed 5 hours, boil off solvent, add the 160ml methanol crystallization in the residue, filter, dry 3-methoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone 110g, the productive rate 90% of getting.
In the autoclave of 500ml capacity, add 60g 3-methoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone, 6g Raney Ni (W-2), 300ml methyl alcohol is used H
2Air three times in the displacement still, hydrogenation be to gauge pressure 1.0Mpa, 40 ℃ of temperature, continuous hydrogenation, it is constant to keep reaction pressure, reacts 15 hours, TLC detects to track to and reacts completely, and filters, and adds 100ml hydrochloric acid in the filtrate, back hydrolysis 5 hours, product is separated out in cooling, filter crude product, the dehydrated alcohol recrystallization filters, drying obtains white crystal powder nabumetone 42.3g.Overall yield reaches 87.6%, mp79.5～81 ℃, GC content 〉=99%.
Embodiment 2
Prepare 3-methoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone according to embodiment 1 described method, in the autoclave of 500ml capacity, add 60g 3-methoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone, 6gRaney Ni (W-2), 280ml methyl alcohol is used H
2Air three times in the displacement still, hydrogenation be to gauge pressure 0.1Mpa, 40 ℃ of temperature, continuous hydrogenation, it is constant to keep reaction pressure, reacts about 20 hours, and TLC detects to track to and reacts completely, filter, add 100ml hydrochloric acid, back hydrolysis 5 hours in the filtrate, the cooling, separate out product, filter crude product, the dehydrated alcohol recrystallization filters drying, obtain white crystal powder nabumetone 39.5g, overall yield is 81.8%, GC content 〉=99%.
Embodiment 3
Prepare 3-methoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone according to embodiment 1 described method, in the autoclave of 500ml capacity, add 60g 3-methoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone, 6gRaney Ni (W-2), 150ml butylacetate and 120ml toluene are used H
2Air is three times in the displacement still, and hydrogenation to gauge pressure is 3.0Mpa, 40 ℃ of temperature, continuous hydrogenation, it is constant to keep reaction pressure, reacts about 8 hours, and TLC detects to track to and reacts completely, filter, add 100ml hydrochloric acid, back hydrolysis 5 hours in the filtrate, the cooling, separate out product, filter crude product, the dehydrated alcohol recrystallization filters drying, obtain white crystal powder nabumetone 38.6g, overall yield is 80%, GC content 〉=99%.
Embodiment 4
Prepare 3-methoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone according to embodiment 1 described method, in the autoclave of 500ml capacity, add 60g 3-methoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone, 6gRaney Ni (w-2), 300ml methyl alcohol is used H
2Air three times in the displacement still, hydrogenation be to gauge pressure 1.0Mpa, 25 ℃ of temperature, continuous hydrogenation, it is constant to keep reaction pressure, reacts 20 hours, and TLC detects to track to and reacts completely, filter, add 100ml hydrochloric acid, back hydrolysis 5 hours in the filtrate, the cooling, separate out product, filter crude product, the dehydrated alcohol recrystallization filters drying, obtain white crystal powder nabumetone 39.6g, overall yield is 82%, GC content 〉=99%
Embodiment 5
Prepare 3-methoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone according to embodiment 1 described method, in the autoclave of 500ml capacity, add 60g 3-methoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone, 6gRaney Ni (W-2), 260ml toluene is used H
2Air three times in the displacement still, hydrogenation be to gauge pressure 1.0Mpa, 80 ℃ of temperature, continuous hydrogenation, it is constant to keep reaction pressure, reacts about 10 hours, TLC detects to track to and reacts completely, and adds 100ml hydrochloric acid, back hydrolysis 5 hours in the filtrate, the cooling, separate out product, filter crude product, the dehydrated alcohol recrystallization filters drying, obtain white crystal powder nabumetone 38.5g, overall yield is 80%, GC content 〉=99%.
Embodiment 6
Prepare 3-methoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone according to embodiment 1 described method, in the autoclave of 500ml capacity, add 60g 3-methoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone, 5gRaney Ni (W-4), 300ml methyl alcohol is used H
2Air three times in the displacement still, hydrogenation be to gauge pressure 1.0Mpa, 30 ℃ of temperature, continuous hydrogenation, it is constant to keep reaction pressure, reacts 5 hours, and TLC detects to track to and reacts completely, filter, add 100ml hydrochloric acid, back hydrolysis 5 hours in the filtrate, the cooling, separate out product, filter crude product, the dehydrated alcohol recrystallization filters drying, obtain white crystal powder nabumetone 39.0g, overall yield is 81%, GC content 〉=99%.
Embodiment 7
Prepare 3-methoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone according to embodiment 1 described method, in the autoclave of 500ml capacity, add 60g 3-methoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone, 6gRaney Ni (W-6), 300ml methyl alcohol is used H
2Air three times in the displacement still, hydrogenation be to gauge pressure 0.1Mpa, 25 ℃ of temperature, continuous hydrogenation, it is constant to keep reaction pressure, reacts about 5 hours, and TLC detects to track to and reacts completely, filter, add 100ml hydrochloric acid, back hydrolysis 5 hours in the filtrate, the cooling, separate out product, filter crude product, the dehydrated alcohol recrystallization filters drying, obtain white crystal powder nabumetone 39.0g, overall yield is 81%, GC content 〉=99%.
Embodiment 8
Prepare 3-methoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone according to embodiment 1 described method, in the autoclave of 500ml capacity, add 60g3-methoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone, 4gRaney Ni (W-7), 300ml methyl alcohol is used H
2Air three times in the displacement still, hydrogenation be to gauge pressure 0.1Mpa, 30 ℃ of temperature of reaction, continuous hydrogenation, it is constant to keep reaction pressure, reacts about 2 hours, and TLC detects to track to and reacts completely, filter, add 100ml hydrochloric acid, back hydrolysis 5 hours in the filtrate, the cooling, separate out product, filter crude product, the dehydrated alcohol recrystallization filters drying, obtain white crystal powder nabumetone 39.0g, overall yield is 81%, GC content 〉=99%.
Embodiment 9
Prepare 3-methoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone according to embodiment 1 described method, in the autoclave of 500ml capacity, add 60g 3-methoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone, 3gRaney Ni (W-7), the 260ml butylacetate is used H
2Air three times in the displacement still, hydrogenation be to gauge pressure 1.0Mpa, 40 ℃ of temperature of reaction, continuous hydrogenation, it is constant to keep reaction pressure, reacts about 15 hours, and TLC detects to track to and reacts completely, filter, add 100ml hydrochloric acid, back hydrolysis 5 hours in the filtrate, the cooling, separate out product, filter crude product, the dehydrated alcohol recrystallization filters drying, obtain white crystal powder nabumetone 39.0g, overall yield is 81%, GC content 〉=99%.
Embodiment 10
Prepare 3-methoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone according to embodiment 1 described method, in the autoclave of 500ml capacity, add 60g 3-methoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone, 6gRaney Cu, 300ml methyl alcohol is used H
2Air three times in the displacement still, hydrogenation be to gauge pressure 2.0Mpa, 60 ℃ of temperature, continuous hydrogenation, it is constant to keep reaction pressure, reacts about 20 hours, and TLC detects to track to and reacts completely, and filters, add 100ml hydrochloric acid in the filtrate, back hydrolysis 5 hours, cooling, separate out product, filter crude product, the dehydrated alcohol recrystallization, filter, drying obtains white crystal powder nabumetone 38.6g, overall yield reaches 73%, mp79.5～81 ℃, GC content 〉=99%.
Embodiment 11
Prepare 3-methoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone according to embodiment 1 described method, in the autoclave of 500ml capacity, add 60g 3-methoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone, the fresh RaneyNi W of 6g
2, 300ml methyl alcohol, normal pressure feeds hydrogen, 40 ℃ of temperature, continuous hydrogenation reacted about 5 hours, TLC detects, and TLC detects to track to and reacts completely, and filters, add 100ml hydrochloric acid in the filtrate, back hydrolysis 5 hours, cooling, separate out product, filter crude product, the dehydrated alcohol recrystallization, filter, drying obtains white crystal powder nabumetone 39g.Overall yield reaches 83%, mp79.5～81 ℃, GC content 〉=99%.
Embodiment 12
Prepare 3-methoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone according to embodiment 1 described method, in the autoclave of 500ml capacity, add 60g 3-methoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone, the fresh Raney Co of 6g, 300ml methyl alcohol, normal pressure feeds hydrogen, 40 ℃ of temperature, continuous hydrogenation, reacted about 15 hours, TLC detects to track to and reacts completely, and filters, and adds 100ml hydrochloric acid in the filtrate, back hydrolysis 5 hours, the cooling, separate out product, filter crude product, the dehydrated alcohol recrystallization, filter, drying obtains white crystal powder nabumetone 38.2g.Overall yield reaches 79%, mp79.5～81 ℃, GC content 〉=99%.
Embodiment 13
Prepare 3-methoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone according to embodiment 1 described method, in the autoclave of 500ml capacity, add 60g 3-methoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone, the fresh Raney Ni of 6g W
2, 200ml methyl alcohol and 80ml butylacetate, normal pressure feeds hydrogen, 40 ℃ of temperature, continuous hydrogenation reacted about 5 hours, TLC detects to track to and reacts completely, and filters, and adds 100ml hydrochloric acid in the filtrate, back hydrolysis 5 hours, product is separated out in cooling, filter crude product, the dehydrated alcohol recrystallization filters, drying obtains white crystal powder nabumetone 39g.Overall yield reaches 83%, mp79.5～81 ℃, GC content 〉=99%.
Embodiment 14
With 80g 6-methoxyl group-2-naphthaldehyde, the 63g methyl aceto acetate is dissolved in the 350ml hexanaphthene, add toluylic acid piperidinium salt 5g, refluxed 5 hours, boil off solvent, add the 160ml methanol crystallization in the residue, filter, dry 3-ethoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone 115g, the productive rate 89.8% of getting.
In the autoclave of 500ml capacity, add 60g 3-ethoxycarbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone, 6g RaneyNi (W-2), 300ml methyl alcohol is used H
2Air three times in the displacement still, hydrogenation be to gauge pressure 1.0Mpa, 40 ℃ of temperature, continuous hydrogenation, it is constant to keep reaction pressure, reacts 15 hours, TLC detects to track to and reacts completely, and filters, and adds 100ml hydrochloric acid in the filtrate, back hydrolysis 5 hours, product is separated out in cooling, filter crude product, the dehydrated alcohol recrystallization filters, drying obtains white crystal powder nabumetone 38.1g.Overall yield reaches 83%, mp79.5～81 ℃, GC content 〉=99%.
Embodiment 15
With 80g 6-methoxyl group-2-naphthaldehyde, the 70g ISOPROPYL ACETOACETATE is dissolved in the 380ml hexanaphthene, add toluylic acid piperidinium salt 5g, refluxed 5 hours, boil off solvent, add the 160ml methanol crystallization in the residue, filter, dry 3-isopropyl carbonyl-4-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone 122.5g, the productive rate 91.3% of getting.
In the autoclave of 500ml capacity, add the different third oxygen carbonyl-4-of 60g 3-(6-methoxyl group-2-naphthyl) but-2-ene-2-ketone, 6g RaneyNi (W-2), 300ml methyl alcohol is used H
2Air three times in the displacement still, hydrogenation be to gauge pressure 1.0Mpa, 40 ℃ of temperature, continuous hydrogenation, it is constant to keep reaction pressure, reacts 15 hours, TLC detects to track to and reacts completely, and filters, and adds 100ml hydrochloric acid in the filtrate, back hydrolysis 5 hours, product is separated out in cooling, filter crude product, the dehydrated alcohol recrystallization filters, drying obtains white crystal powder nabumetone 43.5g.Overall yield reaches 85%, mp79.5～81 ℃, GC content 〉=99%.
Claims (5)
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