CN1272487A - New synthesizing method of 2-(2-substituting ethyl) cyclohexanone - Google Patents
New synthesizing method of 2-(2-substituting ethyl) cyclohexanone Download PDFInfo
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Abstract
The present invention relates to a new method for synthesizing intermediate 2-(2-substituted ethyl) cyclohexanone by using lipoic acid or lipoamide. Said method uses acetyl-gamma-butyrolactone as raw material, makes it produce Michael addition reaction with acrolein and makes intramolecular Aldol condensation to produce spiro compound 2-oxapiro [4.5] decane-8-hydroxy-1,6-diketone (IV), then makes it undergo the process of dehydration to obtain 2-oxaspiro [4.5] decane-1,6-diketone (VI) and makes hydrolysis to remove carbon dioxide so as to obtain the invented 2-(2-substituted ethyl) cyclohexanone (I). Said invention is simple and convenient, moderate reaction condition, and its yield is high.
Description
The invention relates to the new synthesis method of pharmaceutical intermediate, the novel synthesis of the synthetic intermediate 2-of specifically a kind of Thioctic Acid and derivative Thioctamide thereof (2-replaces ethyl) pimelinketone.
Thioctic Acid is a kind of natural product that physiologically active is arranged, and the oxidative decarboxylation that participates in alpha-ketoacid in the tricarboxylic acid cycle as coenzyme is reacted, and Thioctamide is converted into Thioctic Acid in vivo and works.As hepatoprotective, German in recent years approved Thioctic Acid is used for the treatment of diabetic neuropathy clinically for Thioctic Acid and Thioctamide.
The Thioctic Acid Thioctamide
Synthetic two class methods that adopt usually of Thioctic Acid: (1) is starting raw material with the hexanodioic acid, and (2) are raw material with the pimelinketone, referring to Yadav J.S., J.Sci.Ind.Res.1990,49,400.(1) with the hexanodioic acid is raw material
It is raw material that present industrial process generally adopts with the hexanodioic acid, referring to Reed L.J.J.Am.Chem.Soc.1955,77,416; Acker D.S.J.Am.Chem.Soc.1957,79,6483.Its chemical process is as follows:
Must use ethene and a large amount of aluminum chloride in this method, environmental pollution is serious; And each intermediate character is close in preparation process, and separation difficulty influences quality product.However, because of its raw material is easy to get, still adopt for some factories.(2) with the pimelinketone be raw material
Just because of be some shortcomings of starting raw material with the hexanodioic acid, many chemist's exploitations are the synthetic method of raw material with the pimelinketone, its key intermediate is 2-(2-replaces an ethyl) pimelinketone, react the skeleton structure that just obtains Thioctic Acid through Baeyer-Villiger, difficult point is that pimelinketone intramolecularly introducing 2-replaces ethyl.
Ubatani M. is prepared in reaction Thioctic Acid (day disclosure special permission 1965:19939) in the presence of sodium amide with pimelinketone and bromoethyl ether; But reaction easily generates polysubstituted product, purifies for separation and brings difficulty.
Paust J. obtains 2-(2-ethoxyethyl) pimelinketone (DE 1994:4229914 A1) with pimelinketone and ethyl vinyl ether in the presence of tert-butyl peroxide.The synthetic route of this method is simple and direct, and the alkylated reaction yield can reach 69%, but owing at high temperature use a large amount of superoxide, wayward on the industrial production.
The objective of the invention is to overcome above-mentioned weak point, design 2-(2-replaces ethyl) the pimelinketone synthetic method that another kind of suitability for industrialized is produced.With the suitability for industrialized production vitamins B that is easy to get
1Raw material acetyl-Υ-butyrolactone make initiator, be built into the pimelinketone that band 2-position replaces ethyl through some reactions, become through Baeyer-Villiger reaction then that synthetic Thioctic Acid or Thioctamide institute are prerequisite to have a corresponding substituent carbon skeleton, its chemical process is as follows:
X represents halogen, hydroxyl, OR or OCOR, and wherein R represents C
1-C
4Alkyl or C
3-C
6Cycloalkyl.
Above-mentioned chemical process is described below respectively by the operation step:
(1) Michael reaction formation compound III takes place with propenal in acetyl-Υ-butyrolactone under organic bases or inorganic base catalyst effect in organic solvent, intramolecularly Aldol condensation takes place subsequently generate 2-oxaspiro [4.5] decane-8-hydroxyl-1,6-diketone (IV);
(2) spirocyclic compound (IV) dehydration in the presence of the organic acid salt of organic acid or organic bases and water-fast organic solvent generates 2-oxaspiro [4.5]-7-decylene-1, and the 6-diketone (the conjugation ketenes, V);
(3) conjugation ketenes (V) hydrogenation in the presence of catalyzer obtains 2-oxaspiro [4.5] decane-1,6-diketone (VI);
(4) spirocyclic compound (VI) is under the mineral acid effect, and the lactonic ring cracking is also sloughed carbonic acid gas, forms target compound 2-of the present invention (2-replaces ethyl) pimelinketone (I).
Compound I can make Thioctic Acid or Thioctamide by currently known methods.
Catalyst system therefor is triethylamine, pyridine, 1 in the above-mentioned chemical process (1), 8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU), 1, mineral alkalis such as the oxyhydroxide of organic basess such as 5-diazabicylo [4.3.0] carbon in the ninth of the ten Heavenly Stems-5-alkene (DBN), triethylenediamine (DABCO), tetramethyl guanidine or basic metal, alkaline-earth metal and oxide compound, wherein preferred catalyzer is pyridine and DBU, catalyst consumption is 0.01～0.1 mol ratio, and optimum is 0.02～0.06 mol ratio; Organic solvent can be with halogenated alkane such as tetracol phenixin, trichloromethane, methylene dichloride, ethylene dichloride, aromatic hydrocarbons such as benzene,toluene,xylene, and organic acid acetic such as ethyl acetate, butylacetate etc., wherein preferred solvent is toluene and butylacetate.
Dehydration catalyst in the above-mentioned chemical process (2) can adopt low-molecular-weight fatty sulfonic acid such as C
1-C
4Sulfonic acid, substituted aroma sulfonic acid such as Phenylsulfonic acid, toluenesulphonic acids, oxalic acid, the organic acid salt of organic bases is such as PAA salt, pyridine oxalate, DBU oxalate; Used organic solvent is with chemical process (1), and wherein preferred solvent is toluene and butylacetate.
Hydrogenation catalyst is Pd/C, Pd/CaCO in the above-mentioned chemical process (3)
3, Pd/BaSO
4, Raney-Ni, active nickel, the hydrogenation absolute pressure is 0.1～1.0MPa, is preferably 0.1～0.3MPa, temperature of reaction is 0～100 ℃, is preferably 20～50 ℃; Solvent for use is low-molecular-weight alcohols such as methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol, low-molecular-weight ester class such as ethyl acetate, butylacetate.
Mineral acid is hydrochloric acid, Hydrogen bromide, hydroiodic acid HI in the above-mentioned chemical process (4); the hydrolysis decarbonation is halo simultaneously; obtain 2-(2-halogenated ethyl) pimelinketone, then obtain 2-(2-hydroxyethyl) pimelinketone, obtain 2-(2-acetyl oxygen ethyl) pimelinketone with the ethanoyl protection with sulfuric acid or phosphoric acid.
The inventive method refuse generation is less, can be rated as the environmental friendliness chemical process; The carbonatoms that participates in reaction process is only lost one, and Atom economy is good.The inventive method raw material is cheap and easy to get, the reaction conditions gentleness, and the yield height does not have harsh requirement to equipment, is suitable for suitability for industrialized production.
The inventive method midbody compound IV comprises two chiral centres, forms two groups of diastereomer IV
AAnd IV
B, can be through column chromatography for separation.IV
A, IV
B, V and VI be the new compound of not seeing bibliographical information.Classify the compound IV that the inventor measures through instrumental analysis down as
A, IV
B, V, VI spectral data.Compound IV
A
And enantiomer
2-Oxaspiro[4.5]decane-8-hydroxy-1，6-dione
2-oxaspiro [4.5] decane-8-hydroxyl-1,6-diketone IR (neat oil): ν
Max3415 (OH), 1758 (COO-), 1708 (CO-) cm
-1 1H NMR (CDCl
3, 300MHz): δ 4.51 (m, 1H ,-CHOH-), 4.32 (m, 2H ,-COOCH
2-), 3.14 (m, 1H ,-COCH
2-), 3.04 (m, 1H ,-COCH
2-), 2.56 (m, 3H ,-OH and-CH
2-), 2.16 (m, 2H), 1.95 (m, 1H), 1.82 (m, 1H)
13C NMR (CDCl
3, 75MHz, DEPT): δ 203.85 (CO), 175.21 (COO), 69.23 (CH), 66.20 (CH
2), 57.08 (C), 46.94 (CH
2), 31.42 (CH
2), 30.72 (CH
2), 27.95 (CH
2) EIMS (m/z, %): 184 (M
+, 100), 166 (25.08), 142 (31.47), 138 (53.24), 120 (39.24), 107 (24.23), 99 (42.65), 94 (21.92), 86 (44.12), 81 (47.85), 68 (20.04), 53 (22.14), 42 (8.27) EI HRMS:calcd for C
9H
10O
4184.0736, found 184.0731 compound IV
B
And enantiomer
2-Oxaspiro[4.5]decane-8-hydroxy-1，6-dione
2-oxaspiro [4.5] decane-8-hydroxyl-1,6-diketone IR (KBr): ν
Max3446 (OH), 1775 (COO-), 1705 (CO-) cm
-1 1H NMR (CDCl
3), 300MHz): δ 4.32 (m, 2H ,-COOCH
2-), 4.03 (m, 1H ,-CHOH-), 2.90 (m, 3H ,-OH and-COCH
2-), 2.36 (m, 2H), 2.04 (m, 4H), 1.68 (m, 1H)
13C NMR (CDCl
3, 75MHz, DEPT): δ 202.50 (CO), 174.71 (COO), 69.50 (CH), 65.99 (CH
2), 56.08 (C), 48.41 (CH
2), 31.37 (CH
2), 30.84 (CH
2), 29.74 (CH
2) EIMS (m/z, %): 184 (M
+, 0.91), 165 (1.63), 138 (20.23), 120 (28.51), 107 (12.06), 94 (4.37), 91 (6.22), 68 (100), 42 (5.59) EI HRMS:calcd for C
9H
10O
4184.0736, found 184.0730 compound V:
2-Oxaspiro[4.5]-7-decene-1，6-dione
2-oxaspiro [4.5]-7-decylene-1,6-diketone IR (neat oil): ν
Max1770 (COO-), 1665 (CO-) cm
-1 1H NMR (CDCl
3, 300MHz): δ 7.12 (m, 1H ,-CH=CH-), 6.06 (m, 1H ,-CH=CH-), 4.37 (m, 2H ,-COOCH
2-), 2.70 (m, 2H), 2.48 (m, 2H), 2.12 (m, 2H)
13C NMR (CDCl
3, 75MHz, DEPT): δ 194.45 (CO-), 175.33 (COO-), 151.66 (=CH-), 127.30 (HC=), 65.73 (CH
2), 53.76 (C), 32.36 (CH
2), 30.54 (CH
2), 22.88 (CH
2) EIMS (m/z, %): 165 (M
+-1,2.51), 138 (27.57), 120 (33.48), 107 (14.97), 94 (4.93), 91 (7.18), 68 (100), 53 (6.58), 42 (12.29) EI HRMS:calcd for C
9H
10O
3166.0630, found 166.0625 compound VI:
2-Oxaspiro[4.5]decane-1，6-dione
2-oxaspiro [4.5] decane-1,6-diketone IR (neat oil): ν
Max1770 (COO-), 1708 (CO-) cm
-1 1H NMR (CDCl
3, 300MHz): δ 4.27 (m, 2H ,-COOCH
2-), 2.90 (m, 2H ,-COCH
2-), 2.50 (m, 1H), 2.32 (m, 2H), 2.06 (m, 1H), 1.94 (m, 1H), 1.75 (m, 3H)
13C NMR (CDCl
3, 75MHz, DEPT): δ 205.46 (CO), 175.21 (COO), 65.85 (CH
2), 57.43 (C), 39.12 (CH
2), 36.66 (CH
2), 32.13 (CH
2), 26.71 (CH
2), 20.88 (CH
2) EIMS (m/z, %): 168 (M
+, 12.47), 140 (100), 122 (14.49), 112 (83.83), 99 (13.47), 95 (28.59), 86 (12.04), 81 (31.65), 67 (8.37), 55 (10.89) EI HRMS:calcd for C
9H
12O
3168.0786, found 168.0784 examples one
Be equipped with in the 500ml four-hole round-bottomed flask of mechanical stirrer, thermometer, reflux exchanger and dropping funnel one, acetyl-Υ-butyrolactone 25.6g (0.2mol) is dissolved among the toluene 400ml, add catalyzer DBU 1.0g (0.0066mol), stir down and drip propenal 12.4g (0.22mol), dropwised in about 0.5 hour.Continue stir about reacted completely in 2 hours.Reaction solution can through pickling, washing back concentrating under reduced pressure recovery solvent as for, reaction product IV is IV
AAnd IV
BMixture, the available silicon plastic column chromatography separate (elutriant is a sherwood oil: ethyl acetate=1: 1), yield 91% (IV
A+ IV
B).Compound IV
AIR (neat oil): ν
Max3415 (OH), 1758 (COO-), 1708 (CO-) cm
-1 1H NMR (CDCl
3, 300MHz): δ 4.51 (m, 1H ,-CHOH-), 4.32 (m, 2H ,-COOCH
2-), 3.14 (m, 1H ,-COCH
2-), 3.04 (m, 1H ,-COCH
2-), 2.56 (m, 3H ,-OH and-CH
2-), 2.16 (m, 2H), 1.95 (m, 1H), 1.82 (m, 1H)
13C NMR (CDCl
3, 75MHz, DEPT): δ 203.85 (CO), 175.21 (COO), 69.23 (CH), 66.20 (CH
2), 57.08 (C), 46.94 (CH
2), 31.42 (CH
2), 30.72 (CH
2), 27.95 (CH
2) EIMS (m/z, %): 184 (M
+, 100), 166 (25.08), 142 (31.47), 138 (53.24), 120 (39.24), 107 (24.23), 99 (42.65), 94 (21.92), 86 (44.12), 81 (47.85), 68 (20.04), 53 (22.14), 42 (8.27) EI HRMS:calcd for C
9H
12O
4184.0736, found 184.0731 compound IV
BIR (KBr): ν
Max3446 (OH), 1775 (COO-), 1705 (CO-) cm
-1 1H NMR (CDCl
3, 300MHz): δ 4.32 (m, 2H ,-COOCH
2-), 4.03 (m, 1H ,-CHOH-), 2.90 (m, 3H ,-OH and-COCH
2-), 2.36 (m, 2H), 2.04 (m, 4H), 1.68 (m, 1H)
13C NMR (CDCl
3, 75MHz, DEPT): δ 202.50 (CO), 174.71 (COO), 69.50 (CH), 65.99 (CH
2), 56.08 (C), 48.41 (CH
2), 31.37 (CH
2), 30.84 (CH
2), 29.74 (CH
2) EIMS (m/z, %): 184 (M
+, 0.91), 165 (1.63), 138 (20.23), 120 (28.51), 107 (12.06), 94 (4.37), 91 (6.22), 68 (100), 42 (5.59) EI HRMS:calcd for C
9H
12O
4184.0736 found 184.0730
Reaction solution also can carry out the next step after pickling, washing; Also can directly carry out next step dehydration reaction.Example two
Catalyzer in the example one is changed to pyridine, and solvent is changed to butylacetate, and all the other are with example one operation, and effect is suitable with example one.Example three
Prolong in example one or the example two is changed to the reflux condensing tube of band water trap.Add tosic acid 2.0g in example one after the washing or example two reaction solutions, stir down reflux and tell the water that reaction produces, till no longer including moisture and going out.Reaction solution washes with water removes catalyzer, decompression and solvent recovery, and (elutriant is a sherwood oil: ethyl acetate=1: 1) obtain V, yield 89% with purification by silica gel column chromatography.Compound V:IR (neat oil): ν
Max1770 (COO-), 1665 (CO-) cm
-1 1H NMR (CDCl
3, 300MHz): δ 7.12 (m, 1H ,-CH=CH-), 6.06 (m, 1H ,-CH=CH-), 4.37 (m, 2H ,-COOCH
2-), 2.70 (m, 2H), 2.48 (m, 2H), 2.12 (m, 2H)
13C NMR (CDCl
3, 75MHz, DEPT): δ 194.45 (CO), 175.33 (COO), 151.66 (=CH), 127.30 (HC=), 65.73 (CH
2), 53.76 (C), 32.36 (CH
2), 30.54 (CH
2), 22.88 (CH
2) EIMS (m/z, %): 165 (M
+-1,2.51), 138 (27.57), 120 (33.48), 107 (14.97), 94 (4.93), 91 (7.18), 68 (100), 53 (6.58), 42 (12.29) EI HRMS:calcd for C
9H
10O
3166.0630 found 166.0625
Finish behind the branch water reaction solution also the used water eccysis remove catalyzer, reclaim to add behind the solvent to be directly used in down behind the ethanol and go on foot hydrogenation; If solvent is a butylacetate, can after washing, be directly used in down the step hydrogenation.Example four
To directly add oxalic acid 2.0g in the reaction solution in example one or the example two, all the other are with example three operations.Reaction solution washes with water removes catalyzer, adds ethanol behind the recovery solvent and is used for step hydrogenation down; If solvent is a butylacetate, can after washing, be directly used in down the step hydrogenation, effect is suitable with example three.Example five
Concentrated solution in example three or the example four is transferred in the 500ml hydrogenation still, adds ethanol 200ml, 10%Pd/C 2.0g, logical hydrogen hydrogenation is until no longer inhaling hydrogen.After reaction is finished, remove by filter catalyzer (catalyzer of recovery can be reused), (elutriant was a sherwood oil: ethyl acetate=1: 1) obtain VI, yield 95% with purification by silica gel column chromatography after filtrate was reclaimed solvent.Compound VI: IR (neat oil): ν
Max1770 (COO-), 1708 (CO-) cm
-1 1H NMR (CDCl
3, 300MHz): δ 4.27 (m, 2H ,-COOCH
2-), 2.90 (m, 2H ,-COCH
2-), 2.50 (m, 1H), 2.32 (m, 2H), 2.06 (m, 1H), 1.94 (m, 1H), 1.75 (m, 3H)
13C NMR (CDCl
3, 75MHz, DEPT): δ 205.46 (CO), 175.21 (COO), 65.85 (CH
2), 57.43 (C), 39.12 (CH
2), 36.66 (CH
2), 32.13 (CH
2), 26.71 (CH
2), 20.88 (CH
2) EIMS (m/z, %): 168 (M
+, 12.47), 140 (100), 122 (14.49), 112 (83.83), 99 (13.47), 95 (28.59), 86 (12.04), 81 (31.65), 67 (8.37), 55 (10.89) EI HRMS:calcd for C
9H
12O
3168.0786 found 168.0784
Raw product VI also can be directly used in down the reaction of one-step hydrolysis decarbonation.Example six
If solvent for use is a butylacetate in example three or the example four, can wash the back and directly add Pd/C, all the other are with example five operations.The reaction concentrated solution can be directly used in down the reaction of one-step hydrolysis decarbonation, and effect is suitable with example five.Example seven
Catalyst P d/C in example five or the example six is changed to Raney-Ni, and all the other are with example five operation, and effect and example five, example six are suitable.Example eight
Concentrated solution in example five, example six or the example seven is transferred in the 100ml single port bottle, adds concentrated hydrochloric acid 20ml, on reinstall stream prolong and airway, airway inserts in the beaker that is filled with water.Under the magnetic stirrer violent stirring, oil bath heat gradually temperature rising reflux react no longer emerge to carbonic acid gas till.Reaction is chilled to room temperature after finishing, and thin up is with toluene extraction three times.Extraction liquid is used saturated aqueous common salt and water washing respectively, reclaims the toluene underpressure distillation, collect 88-92 ℃/4mmHg cut and get colourless transparent liquid 19.3g, for 2-(2-chloroethyl) pimelinketone (Compound I, X=Cl), yield 78%.Compound I (X=Cl):
1H NMR (CDCl
3, 300MHz): δ 3.62 (t, J=6.3Hz, 2H ,-CH
2Cl), 2.61 (m, 1H ,-CH-), 2.33-1.31 (m, 10H) EIMS (m/z, %): 162 (M
++ 1,6.50), 160 (M
+-1,22.10), 124 (9.09, M
+-HCl), and 117 (33.23), 98 (68.07), 83 (35.17), 81 (43.56), 69 (13.29), 55 (100) examples nine
Hydrochloric acid in the example eight is changed to Hydrogen bromide, can get 2-(2-bromotrifluoromethane) pimelinketone (Compound I, X=Br), yield 75%.Compound I (X=Br):
1H NMR (CDCl
3, 300MHz): δ 3.49 (t, J=6.3Hz, 2H ,-CH
2Br), 2.63 (m, 1H ,-CH-), 2.41-1.35 (m, 10H) EIMS (m/z, %): 206 (M
++ 1,9.02), 204 (M
+-1,9.43), 163 (6.85), 161 (11.41), 124 (50.37, M
+-HBr), 96 (100), 81 (57.91), 69 (7.55), 55 (47.59) examples ten
Hydrochloric acid in the example eight is changed to dilute sulphuric acid or dilute phosphoric acid, and (Compound I X=OH), gets 2-(2-acetoxyl group) pimelinketone (Compound I, X=OCOCH after the acetylize of usefulness diacetyl oxide can to get 2-(2-hydroxyethyl) pimelinketone
3), yield 68%.Compound I (X=OCOCH
3):
1H NMR (CDCl
3, 300MHz): δ 4.10 (m, 2H ,-COOCH
2-), 2.41-2.39 (m, 3H ,-CH
2COCH-), 2.04 (s, 3H ,-CH
3), 2.20-1.46 (m, 8H) EIMS (m/z, %): 184 (M
+, 3.84), 124 (M
+-CH
3COOH), 98 (100), 80 (12.48), 68 (4.51), 55 (16.46) examples 11
From the starting raw material to the final product, each goes on foot intermediate without separation and purification, and reaction obtains 2-(2-chloroethyl) pimelinketone successively, and total recovery counts 60% with acetyl-gamma-butyrolactone.
Claims (6)
1, the method for a kind of Synthetic 2-(2-replaces ethyl) pimelinketone is characterized in that present method comprises the following steps:
(1) Michael reaction formation compound (III) takes place with propenal in acetyl-gamma-butyrolactone under organic bases or inorganic base catalyst effect in organic solvent, intramolecularly Aldol condensation takes place subsequently generate 2-oxaspiro [4.5] decane-8-hydroxyl-1,6-diketone (IV);
(2) spirocyclic compound (IV) dehydration in the presence of the organic acid salt of organic acid or organic bases and water-fast organic solvent generates 2-oxaspiro [4.5]-7-decylene-1, and the 6-diketone (the conjugation ketenes, V);
(3) conjugation ketenes (V) hydrogenation in the presence of catalyzer obtains 2-oxaspiro [4.5] decane-1,6-diketone (VI);
(4) spirocyclic compound (VI) is under the mineral acid effect, and the lactonic ring cracking is also sloughed carbonic acid gas, forms target compound 2-of the present invention (2-replaces ethyl) pimelinketone (I); Its chemical process is as follows:
X represent halogen, hydroxyl, OR or-OCOR, wherein R represents C
1-C
4Alkyl or C
3-C
6Cycloalkyl;
2, the method of a kind of Synthetic 2 according to claim 1-(2-replaces ethyl) pimelinketone, it is characterized in that chemical process in the wherein said aforesaid method (1) catalyst system therefor is a triethylamine, pyridine, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU), 1,5-diazabicylo [4.3.0] carbon in the ninth of the ten Heavenly Stems-5-alkene (DBN), triethylenediamine (DABCO), organic bases or basic metal such as tetramethyl guanidine, mineral alkalis such as the oxyhydroxide of alkaline-earth metal and oxide compound, wherein preferred catalyzer is pyridine and DBU, catalyst consumption is 0.01～0.1 mol ratio, and optimum is 0.02～0.06 mol ratio; Organic solvent can be with halogenated alkane such as tetracol phenixin, trichloromethane, methylene dichloride, ethylene dichloride, aromatic hydrocarbons such as benzene,toluene,xylene, and organic acid acetic such as ethyl acetate, butylacetate etc., wherein preferred solvent is toluene and butylacetate;
3, the method for a kind of Synthetic 2 according to claim 1-(2-replaces ethyl) pimelinketone is characterized in that the dehydration catalyst of chemical process in the wherein said aforesaid method (2) can adopt low-molecular-weight fatty sulfonic acid such as C
1-C
4Sulfonic acid, substituted aroma sulfonic acid such as Phenylsulfonic acid, toluenesulphonic acids, oxalic acid, the organic acid salt of organic bases is such as PAA salt, pyridine oxalate, DBU oxalate; Used organic solvent is with chemical process (1), and wherein preferred solvent is toluene and butylacetate;
4, the method for a kind of Synthetic 2 according to claim 1-(2-replaces ethyl) pimelinketone, the hydrogenation catalyst that it is characterized in that chemical process in the wherein said aforesaid method (3) is Pd/C, Pd/CaCO
3, Pd/BaSO
4, Raney-Ni, active nickel, the hydrogenation absolute pressure is 0.1～1.0MPa, is preferably 0.1～0.3MPa, temperature of reaction is 0～100 ℃, is preferably 20～50 ℃; Solvent for use is low-molecular-weight alcohols such as methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol, low-molecular-weight ester class such as ethyl acetate, butylacetate;
5, the method for a kind of Synthetic 2 according to claim 1-(2-replaces ethyl) pimelinketone, the mineral acid that it is characterized in that chemical process in the wherein said aforesaid method (4) is hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, hydrolysis decarbonation halo simultaneously obtains 2-(2-halogenated ethyl) pimelinketone, then obtain 2-(2-hydroxyethyl) pimelinketone with sulfuric acid or phosphoric acid, obtain 2-(2-acetyl oxygen ethyl) pimelinketone through the ethanoyl protection;
6, the method for a kind of Synthetic 2 according to claim 1-(2-replaces ethyl) pimelinketone is characterized in that wherein said midbody compound IV (IV
AAnd IV
B), V, VI be new compound.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN99113667A CN1094119C (en) | 1999-04-29 | 1999-04-29 | New synthesizing method of 2-(2-substituting ethyl) cyclohexanone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN99113667A CN1094119C (en) | 1999-04-29 | 1999-04-29 | New synthesizing method of 2-(2-substituting ethyl) cyclohexanone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1272487A true CN1272487A (en) | 2000-11-08 |
| CN1094119C CN1094119C (en) | 2002-11-13 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102850200A (en) * | 2012-09-11 | 2013-01-02 | 西安彩晶光电科技股份有限公司 | Method for industrialized production of 4-hydroxyl cyclohexanone |
| CN101223122B (en) * | 2005-07-19 | 2013-02-27 | 弗门尼舍有限公司 | Substituted cyclohexanones |
| CN106365973A (en) * | 2015-07-20 | 2017-02-01 | 江苏同禾药业有限公司 | Thioctic acid intermediate synthesis method |
| CN110963916A (en) * | 2018-09-29 | 2020-04-07 | 上海现代制药股份有限公司 | Preparation method of 2- (acetoxyethyl) cyclohexanone |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2696933B2 (en) * | 1987-06-16 | 1998-01-14 | 日産化学工業株式会社 | Substituted cyclic ketones and substituted cyclic enones and methods for their preparation |
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1999
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101223122B (en) * | 2005-07-19 | 2013-02-27 | 弗门尼舍有限公司 | Substituted cyclohexanones |
| CN102850200A (en) * | 2012-09-11 | 2013-01-02 | 西安彩晶光电科技股份有限公司 | Method for industrialized production of 4-hydroxyl cyclohexanone |
| CN102850200B (en) * | 2012-09-11 | 2015-09-30 | 西安彩晶光电科技股份有限公司 | A kind of method of suitability for industrialized production 4-hydroxy-cyclohexanone |
| CN106365973A (en) * | 2015-07-20 | 2017-02-01 | 江苏同禾药业有限公司 | Thioctic acid intermediate synthesis method |
| CN106365973B (en) * | 2015-07-20 | 2018-12-11 | 江苏同禾药业有限公司 | A kind of synthetic method of lipoic acid intermediate |
| CN110963916A (en) * | 2018-09-29 | 2020-04-07 | 上海现代制药股份有限公司 | Preparation method of 2- (acetoxyethyl) cyclohexanone |
| CN110963916B (en) * | 2018-09-29 | 2022-11-04 | 上海现代制药股份有限公司 | Preparation method of 2- (acetoxyethyl) cyclohexanone |
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| CN1094119C (en) | 2002-11-13 |
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