CN102050714B - Method for synthesizing Teprenone - Google Patents
Method for synthesizing Teprenone Download PDFInfo
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- CN102050714B CN102050714B CN201010578339.1A CN201010578339A CN102050714B CN 102050714 B CN102050714 B CN 102050714B CN 201010578339 A CN201010578339 A CN 201010578339A CN 102050714 B CN102050714 B CN 102050714B
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- DJAHKBBSJCDSOZ-AJLBTXRUSA-N (5z,9e,13e)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one;(5e,9e,13e)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CC\C(C)=C/CCC(C)=O.CC(C)=CCC\C(C)=C\CC\C(C)=C\CC\C(C)=C\CCC(C)=O DJAHKBBSJCDSOZ-AJLBTXRUSA-N 0.000 title claims abstract description 51
- 229950006156 teprenone Drugs 0.000 title claims abstract description 51
- 238000000034 method Methods 0.000 title claims abstract description 47
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- 229910052782 aluminium Inorganic materials 0.000 claims abstract description 22
- 239000003054 catalyst Substances 0.000 claims abstract description 16
- 238000000926 separation method Methods 0.000 claims abstract description 16
- 238000006563 Carroll rearrangement reaction Methods 0.000 claims abstract description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 12
- 238000004821 distillation Methods 0.000 claims abstract description 10
- 230000008569 process Effects 0.000 claims abstract description 10
- 238000004945 emulsification Methods 0.000 claims abstract description 8
- 238000000746 purification Methods 0.000 claims abstract description 8
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000002576 ketones Chemical class 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims description 21
- CCCXGQLQJHWTLZ-UHFFFAOYSA-N geranyl linalool Natural products CC(=CCCC(=CCCCC(C)(O)CCC=C(C)C)C)C CCCXGQLQJHWTLZ-UHFFFAOYSA-N 0.000 claims description 21
- IQDXAJNQKSIPGB-HQSZAHFGSA-N geranyllinalool Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CCC(C)(O)C=C IQDXAJNQKSIPGB-HQSZAHFGSA-N 0.000 claims description 21
- -1 organo aluminum Chemical compound 0.000 claims description 18
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 17
- 125000005907 alkyl ester group Chemical group 0.000 claims description 17
- 238000005406 washing Methods 0.000 claims description 11
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical group [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 claims description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 9
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 7
- 238000005292 vacuum distillation Methods 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000004411 aluminium Substances 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- CATSNJVOTSVZJV-UHFFFAOYSA-N heptan-2-one Chemical compound CCCCCC(C)=O CATSNJVOTSVZJV-UHFFFAOYSA-N 0.000 claims description 6
- 206010019332 Heat exhaustion Diseases 0.000 claims description 5
- 206010019345 Heat stroke Diseases 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical group CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 4
- 239000011521 glass Substances 0.000 claims description 4
- KILURZWTCGSYRE-LNTINUHCSA-K (z)-4-bis[[(z)-4-oxopent-2-en-2-yl]oxy]alumanyloxypent-3-en-2-one Chemical group CC(=O)\C=C(\C)O[Al](O\C(C)=C/C(C)=O)O\C(C)=C/C(C)=O KILURZWTCGSYRE-LNTINUHCSA-K 0.000 claims description 3
- BMTAFVWTTFSTOG-UHFFFAOYSA-N Butylate Chemical group CCSC(=O)N(CC(C)C)CC(C)C BMTAFVWTTFSTOG-UHFFFAOYSA-N 0.000 claims description 3
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 3
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims description 3
- 229940093858 ethyl acetoacetate Drugs 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 238000002203 pretreatment Methods 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 238000001577 simple distillation Methods 0.000 claims description 3
- 238000000638 solvent extraction Methods 0.000 claims description 3
- 239000003039 volatile agent Substances 0.000 claims description 3
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 claims description 2
- 239000011260 aqueous acid Substances 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- CGZZMOTZOONQIA-UHFFFAOYSA-N cycloheptanone Chemical compound O=C1CCCCCC1 CGZZMOTZOONQIA-UHFFFAOYSA-N 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 238000000199 molecular distillation Methods 0.000 claims description 2
- 238000012856 packing Methods 0.000 claims description 2
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 claims description 2
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- 229940079593 drug Drugs 0.000 abstract description 8
- 238000005516 engineering process Methods 0.000 abstract description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 abstract description 3
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- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000007086 side reaction Methods 0.000 abstract description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 abstract 1
- 239000001569 carbon dioxide Substances 0.000 abstract 1
- 230000003247 decreasing effect Effects 0.000 abstract 1
- 238000007865 diluting Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 17
- 150000001298 alcohols Chemical class 0.000 description 10
- 230000002902 bimodal effect Effects 0.000 description 10
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 9
- 238000000605 extraction Methods 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000002775 capsule Substances 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000004364 calculation method Methods 0.000 description 4
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 101150041968 CDC13 gene Proteins 0.000 description 2
- 206010061164 Gastric mucosal lesion Diseases 0.000 description 2
- 208000007882 Gastritis Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 230000000767 anti-ulcer Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
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- 125000001475 halogen functional group Chemical group 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
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- 150000003180 prostaglandins Chemical class 0.000 description 2
- 238000005201 scrubbing Methods 0.000 description 2
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- 231100000397 ulcer Toxicity 0.000 description 2
- 102000003886 Glycoproteins Human genes 0.000 description 1
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
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- 150000001335 aliphatic alkanes Chemical group 0.000 description 1
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- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 1
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- 150000004702 methyl esters Chemical class 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses an improved process for synthesizing Teprenone with Carroll reaction and a separation and purification method. In the method, aiming at the condition that alcohol byproducts which are difficult to separate are always produced in reaction, a treated organic aluminum catalyst is adopted, a ketone solvent is added for diluting; and low vacuum is adopted in the reaction process for rapidly transferring the low-level alcohol and the carbon dioxide generated in the reaction, and therefore, the reaction temperature is reduced, the side reaction is well controlled, the generation of the alcohol byproducts is decreased and the reaction conversion rate is higher than 95%. According to the invention, the emulsification problem in the purification process is solved so that the yield of the product before the rectification is increased to be higher than 87%, the short-distance distillation is well realized, the separated Teprenone completely meets the standards on the marketed drugs, the purity is not less than 99.0% and the yield of the high-purity product is above 66%. The improved process and the post-treatment and separation technology are simple for operation, easy for control, good in stability, achieve high reaction conversion rate and stable quality and are easy for industrialized production.
Description
Technical field
The present invention relates to a kind of method of synthetic teprenone, particularly, is a kind of technique and separating and purifying technology with the synthetic teprenone of Carroll reaction.
Background technology
Teprenone (teprenone, geranylgeranylacetone), a kind of for terpenes, has another name called Teprenone, chemistry geranylgeranylacetone by name, structural formula is as follows:
Japan's listing in 1984, within 1994, FDA is granted, and 2000 are domestic from Japanese import capsule, and material (China) pharmaceutcal corporation, Ltd approval capsule in 2009 is defended in bulk drug import in 2006, produces without competition.Teprenone is to have wide spectrum anti-ulcer medicament, various experimental ulcer and gastric mucosal lesion is had to the improvement effect of stronger antiulcer action and gastric mucosal lesion.This medicine can promote the synthetic and secretion of regeneration defense factor main in stomach mucous membrane, gastric mucus, polymer glycoprotein, phosphatide, improves the hydrocarbonate in gastric mucus.Because this medicine can improve the reduction of stomach mucous membrane hyperplasia district's hyperplasia ability in hydrocortisone induced ulcer, maintain the balance of mucosal hyperplasia cellular regions, therefore can promote the healing of gastric mucosa injury.Improve the biosynthesis ability of prostaglandin(PG) in stomach mucous membrane: this medicine can improve the biosynthesis ability of prostaglandin(PG) (PGE2, I2) in normal rat body of stomach and pyloric region mucous membrane.Improve gastric mucosal blood flow.Treat clinically acute gastritis and chronic gastritis Acute Exacerbation Period, stomach ulcer.
Owing to going on the market, drug standard teprenone requirement purity is greater than 99.0%, single cis (5Z, 9E, 13E) and alltrans (5E, 9E, 13E) isomer ratio is 0.61～0.68, and teprenone technical difficulty synthetic and purifying high quality standards is large, domesticly without producer, applies for this products material and preparation listing license.At present, two kinds of methods of synthetic main employing of the teprenone of report: method one, geranyl linalool and Acetacetic acid alkyl ester carry out Carroll reaction; Carroll reaction refers to beta, gamma-unsaturated alcohol compounds and the compound (as beta-ketoester) with active methylene group, and under the condition existing at catalyzer, reaction forms γ, δ-saturated ketone.Its reaction mechanism is:
Method two, halo tetramethyl-16 carbon tetraenes and Acetacetic acid alkyl ester sodium carry out substitution reaction in saponification depickling.In method two, it is two kinds of isomer mixtures (3: 2) that its halo tetramethyl-16 carbon tetraenes must meet, and the synthetic upper difficulty that increases, therefore adopts Carroll reaction the most practical.
But, in the Carroll reaction of existing report, existence due to organo aluminum catalyst, the inevitable by-product alcohols that produces, and the by-product alcohols generating is difficult to separation, and in last handling process, after solvent extraction separating, washing, emulsion is comparatively serious, can not obtain highly purified product, the transformation efficiency of reaction is lower, thereby has caused the yield of finished product lower.And Carroll reaction adopts logical nitrogen or air distillation to get rid of in reaction process and produces lower alcohol (methyl alcohol, ethanol etc.) and carbonic acid gas, temperature of reaction is all over 170 ℃, and pyrogenic distillation also can cause impurity to increase.Japan defends material patent WO0203981A1 and discloses, and uses normal hexane to do to extract separated solvent, constantly adds methyl alcohol, ethanol or Virahol, the low easy distillation of this solvent system boiling point, but water-soluble large, demulsification is undesirable, can not realize preferably industrialization.
Summary of the invention
A kind of method that the object of this invention is to provide synthetic teprenone, the method is improved existing Carroll reaction, reduces the generation of impurity in reaction process, improves the purity of product; The post-processing technology of optimizing product, improves demulsification, is conducive to the suitability for industrialized production of teprenone.
A kind of method that the invention provides synthetic teprenone, the method has following steps:
A, get geranyl linalool, Acetacetic acid alkyl ester, organo aluminum catalyst, wherein, geranyl linalool and Acetacetic acid alkyl ester consumption mol ratio are 1: 1.0-2.0, organo aluminum catalyst consumption is the 0.5-10%mol of geranyl linalool consumption;
B, pre-treatment organo aluminum catalyst: get the 19.9%-50% of Acetacetic acid alkyl ester total amount, add organo aluminum catalyst, be dissolved into mixed solution in 40-120 ℃, vacuum distillation, discards and slip out liquid, obtains pretreated catalyzer; Wherein, the pretreatment temperature of catalyzer is low, is conducive to realize industrialization.
C, get geranyl linalool, the pretreated organo aluminum catalyst of b step, remaining Acetacetic acid alkyl ester, carry out Carroll reaction, heat up, except the lower alcohol and the CO that generate in dereaction
2, stopped reaction, cooling, obtain the thick product of teprenone;
D, the thick product of the teprenone that c step is made carry out after separation, re-refine and obtain sterling teprenone.
Further, the geranyl linalool described in a step and Acetacetic acid alkyl ester consumption mol ratio are 1: 1.2-1.6.
Further, described organo aluminum catalyst is aluminum isopropylate, aluminium secondary butylate, aluminium acetylacetonate, tri ethylacetoacetate aluminium, is preferably aluminum isopropylate.
Further, the alkyl in described Acetacetic acid alkyl ester is low alkyl group, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, is preferably methyl esters, ethyl.
Wherein, before the Carroll reaction described in c step, add the ketones solvent of 2-100% geranyl linalool weight.
Further, described ketones solvent is butanone, pentanone, hexanone, heptanone, cyclopentanone, pimelinketone, suberone or Methyl amyl ketone.
Wherein, the intensification described in c step is the highest is no more than 160 ℃.
Further, described temperature-rising method is for progressively heating up: be first warmed up to 125 ℃ ± 10 ℃ reaction 1-2 hour, then progressively bring up to 150 ℃ ± 5 ℃ reaction 2-4 hour.
Wherein, in step c, adopt 0.01-0.05MPa vacuum distilling except the lower alcohol and the CO that produce in dereaction
2, described lower alcohol refers to the alkane chain alcohol that Acetacetic acid alkyl ester generates in reaction.
Wherein, at the separation method described in d step, be: get teprenone mixture prepared by c step, add part by propyl carbinol 50-100, the separated solvent extraction that isopropyl ether or normal hexane 0-50 part form; Successively with 5% aqueous acid and the washing of 10% weak base aqueous solution, be then washed to neutrality again, anhydrous sodium sulfate drying, filters, and distillation, except desolventizing, obtains the thick product of teprenone; Wherein, extract and washing process in, add propyl carbinol or repeatedly freezingly add heat collapse emulsification layering, the add-on of propyl carbinol and the number of times of freezing heating be take and realized preferably demulsification as index.
Further, the separated solvent of described extraction is by propyl carbinol 50-80 part, and isopropyl ether or normal hexane 20-50 part form.
Wherein, the process for purification described in d step is:
(1) product, after the d step of learning from else's experience separation, adopts molecular distillation to carry out simple distillation, and its parameter is set to: input speed 1ml/min, and opening for feed is no more than 80 ℃ of temperature, Heating temperature 100-160 ℃, vacuum tightness 1.1-30pa; And/or
(2), adopt packing tower rectifying, its condition is: vacuum tightness 10-100pa, glass filler, rectifying reflux ratio was progressively brought up to 5: 2 and is controlled separated front-end volatiles effect from 50: 1, be no more than 195 ℃ at the bottom of rectifying tower.
By the present invention, improve the teprenone that synthetic method obtains and meet the listing drug standard completely, the ratio of single cis (5Z, 9E, 13E) and alltrans (5E, 9E, 13E) isomer is 0.61～0.68, by anhydride, containing C
23h
38o is no less than 99.0%, and other are always mixed and be less than 1%.
Adopt improvement synthesis technique of the present invention, catalyzer is carried out to pre-treatment, reduce temperature of reaction, controlled preferably the generation of side reaction in traditional C arroll reaction, suppressed the generation of by-product alcohols, in the thick product of reaction gained, the purity of teprenone just can reach more than 95%, then passes through separating step of the present invention, purification step, further improve product purity, gained teprenone quality standard meets the listing drug standard completely; Adopt moderate boiling point, dissolve applicable propyl carbinol, isopropyl ether or normal hexane mixed extraction separated, and adopt breaking method of the present invention, demulsification is good, be beneficial to layering, and can go out organic layer by subzero fractionation, before solving distillation, extract the emulsification difficult problem in sepn process, the yield of the front product of rectifying has been brought up to more than 87%; The fine short-path distillation of having realized, isolated teprenone meets the listing drug standard completely, and purity is no less than 99.0%, and high purity product yield more than 66%, has been realized industrialization preferably.
Accompanying drawing explanation
Fig. 1 Tetrenone (Japan defends the commercially available capsule of material) gas chromatogram
Fig. 2 rectifying product-1 gas chromatogram
Fig. 3 rectifying product-2 gas chromatogram
Fig. 4 rectifying product-3 gas chromatogram
Embodiment
Synthetic, the separation method of embodiment 1 teprenone of the present invention
First, at 40-100 ℃, 5.0g (24.5mmol) aluminum isopropylate is dissolved in 20g (0.172mol) methyl acetoacetate, vacuum distillation at 40-120 ℃ then, pressure is 0.03MPa, discards and slips out liquid, obtains pretreated catalyzer.In there-necked flask, add geranyl linalool 120g (0.413mol), methyl acetoacetate 38g (0.327mol), pimelinketone 40g and pretreated catalyzer, stir and heat up, in 125 ℃ of reaction 30-60 minute, be increased to again 135 ℃ of reaction 30-60 minute, at 150 ℃, react 2-4 hour again, simultaneously water pump 0.03MPa vacuum distilling methyl alcohol and eliminating CO
2, stopped reaction, cooling fast, obtain the thick product of teprenone, residual raw material geranyl linalool 0.85% in GC assaying reaction liquid, product 95.76% (bimodal), by-product alcohols accounts for 0.12% (bimodal), reaction solution directly joins and in 1L separating funnel, adds 600ml n-butanol extraction again, use respectively twice of 5% sulfuric acid scrubbing, 10% sodium bicarbonate washing once, then be washed to neutrality, in extraction and washing process, add propyl carbinol or repeatedly freezingly add heat collapse emulsification layering, anhydrous sodium sulfate drying spends the night, filter, water pump underpressure distillation solvent, n-butanol, after separation, obtain product 121g, yield 88.61%.The method of calculation of this yield are:
121/[(120/290.49)*330.55]＝88.61％。
Synthetic, the separation method of embodiment 2 teprenones of the present invention
First, at 40-100 ℃, 5.0g (24.5mmol) aluminum isopropylate is dissolved in 38.4g (0.330mol) methyl acetoacetate, vacuum distillation at 40-120 ℃ then, pressure is 0.03MPa, discards and slips out liquid, obtains pretreated catalyzer.In there-necked flask, add geranyl linalool 120g (0.413mol), methyl acetoacetate 38.4g (0.330mol), Methyl amyl ketone 100g and pretreated catalyzer, stir and heat up, in 125 ℃ of reactions 30 minutes, be increased to again 135 ℃ of reactions 60 minutes, at 150 ℃, react 3 hours again, simultaneously water pump 0.03MPa vacuum distilling methyl alcohol and eliminating CO
2, stopped reaction, cooling fast, obtain the thick product of teprenone, residual raw material geranyl linalool 0.65% in GC assaying reaction liquid, product 95.9% (bimodal), by-product alcohols accounts for 0.09% (bimodal), reaction solution directly joins in 1L separating funnel, the isopropyl ether or the normal hexane extraction that add 600ml to contain 50% propyl carbinol are used respectively 5% hydrochloric acid washed twice again, 10% sodium bicarbonate washing once, then be washed to neutrality, in extraction and washing process, add propyl carbinol or repeatedly freezingly add heat collapse emulsification layering, anhydrous sodium sulfate drying spends the night, filter, water pump underpressure distillation solvent, after separation, obtain product 122g, yield 89.34%.The method of calculation of yield:
122/[(120/290.49)*330.55]＝89.34％。
Synthetic, the separation method of embodiment 3 teprenones of the present invention
First, at 40-100 ℃, 5.0g (24.5mmol) aluminum isopropylate is dissolved in 19g (0.165mol) methyl acetoacetate, vacuum distillation at 40-120 ℃ then, pressure is 0.03MPa, discards and slips out liquid, obtains pretreated catalyzer.In there-necked flask, add geranyl linalool 120g (0.413mol), methyl acetoacetate 77g (0.661mol), heptanone 20g and pretreated catalyzer, in 125 ℃ of reaction 30-60 minute, be increased to again 135 ℃ of reaction 30-60 minute, at 150 ℃, react 2-4 hour again, simultaneously water pump 0.03MPa vacuum distilling methyl alcohol and eliminating CO
2, stopped reaction, cooling fast, obtain the thick product of teprenone, residual raw material geranyl linalool 0.98% in GC assaying reaction liquid, product 95.3% (bimodal), by-product alcohols accounts for 0.16% (bimodal), reaction solution directly joins in 1L separating funnel, add again 600ml to contain isopropyl ether or the normal hexane extraction of 80% propyl carbinol, use respectively twice of 5% sulfuric acid scrubbing, 10% sodium bicarbonate washing once, then be washed to neutrality, in extraction and washing process, add propyl carbinol or repeatedly freezingly add heat collapse emulsification layering, anhydrous sodium sulfate drying spends the night, filter, water pump underpressure distillation solvent, after separation, obtain product 119g, yield 87.14%.The method of calculation of this yield are: 119/[(120/290.49) * 330.55]=87.14%.
In embodiment 1-3, vacuum distillation adopts conventional vacuum distillation device in organic synthesis; Organo aluminum catalyst all aluminium secondary butylate, aluminium acetylacetonate, the tri ethylacetoacetate aluminium of available equimolar amount substitutes aluminum isopropylate; Acetacetic acid alkyl ester can substitute methyl acetoacetate with methyl aceto acetate, etheric acid n-propyl ester, etheric acid isopropyl esters, etheric acid acetyl n-butyl, etheric acid sec-butyl ester, the tert-butyl acetoacetate of equimolar amount, can reach identical effect.
The process for purification of embodiment 4 teprenones of the present invention
The thick products molecule rectifying of embodiment 1-3 gained and/or tower rectifying purifying are obtained respectively to teprenone rectifying product 1-3, be respectively 95g, 101g, 91g, yield is respectively 69.57%, 73.96%, 66.64%.Concrete process for purification is as follows:
(1) adopt molecule rectifying (short-path distillation) simple distillation, its parameter is set to: input speed 1ml/min, opening for feed temperature is no more than 80 ℃, Heating temperature 100-160 ℃, vacuum tightness 1.1-30pa.
(2) adopt the interior rectification under vacuum of the high 600mm rectifying tower of diameter 80mm of glass filler, vacuum tightness 10-100pa, rectifying reflux ratio is progressively brought up to 5: 2 from 50: 1 (mol ratio) and is controlled separated front-end volatiles effect, is no more than 195 ℃ at the bottom of rectifying tower.
The structural confirmation of embodiment 6 products
With HNMR, IR, MS, confirm the structure of rectifying product 1:
HNMR(CDC13)6：1.61-1.65(15H，S，19，20，21，22，23-CH3)，1.87(6H，m，7，11，15-CH2)，2.07(6H，m，8，12，16-CH2)，2.13(3H，S，1-CH3)，2.27(2H，m，3-CH2)，5.2(4H，m，5，9，13，17-CH＝)。
CNMR(CDC13)6：5.89-43.87{[6(-CH)+8(-CH2-)]×2}122.53-124.32[4(＝CH-)×2]130.97-136.34[4(＞C＝)×2]，208.18，208.27[(＞C＝O)×2]。
IR(KBr)V(cm)：3423，3035，2966，2919，2856，1721，1669，1446，1377，1358，1159，984，837，740。
MS(m/z)：330。
Embodiment 7
Adopt gas Chromatographic Determination aforesaid method products obtained therefrom, and compare with the teprenone synthetic method of Tetrenone (Japan defends the commercially available capsule of material), prior art report.
Comparative example: adopt prior art to prepare teprenone:
Add geranyl linalool 100g (0.345mol), methyl acetoacetate 44g (0.379mol) and 1g (4.9mmol) aluminum isopropylate in there-necked flask after, stirring heats up in 140 ℃ of reactions 4 hours, simultaneously distillating carbinol and eliminating CO
2be warming up to again 170 ℃ of reactions 2 hours, stopped reaction, cooling fast, adopt GC to measure, residual raw material geranyl linalool 2.5%, product 87.86% (bimodal), by product alcohols accounts for 0.87% (bimodal), reaction solution is not treated directly to be joined with rectification under vacuum vacuum tightness 1.5mmHg in the high 600mm rectifying tower of diameter 80mm of glass filler, collects 188-198 ℃ of main distillate fraction 85g, purity 96.85% (bimodal), yield 74.69%, by-product alcohols is increased to 1.69% (bimodal).The method of calculation of this yield are: 85/[(100/290.49) * 330.55]=74.69%.
Chromatographic condition:
Chromatographic column: FFAP capillary column 30mX0.32mmX0.25 μ m;
Column temperature: temperature programming to 180 ℃-220 ℃;
Detector temperature: 280 ℃; 250 ℃ of injector temperatures; Sample size: direct injection 1 μ l;
Splitting ratio: 20: 1.
Need testing solution: get testing sample and make every ml approximately containing the sample of 5mg with normal hexane dilution, obtain.
Color atlas is shown in Fig. 1-4, and its chromatographic data is in Table 1-4, and measurement result is in Table 5.
Table 1 Tetrenone (Japan defends the commercially available capsule of material) data from gas chromatography
| Retention time | Peak area | Peak area % | Peak height | Theoretical plate number (USP) |
| 2.395 | 3433 | 0.01 | 1505 | 25325 |
| 4.275 | 3646 | 0.01 | 976 | 31732 |
| 4.427 | 19876 | 0.07 | 3351 | 12870 |
| 7.378 | 11424 | 0.04 | 2887 | 76273 |
| 7.502 | 4462 | 0.02 | 1240 | 97435 |
| 8.432 | 35635 | 0.12 | 9315 | 117717 |
| 9.222 | 8676 | 0.03 | 2126 | 122061 |
| 9.413 | 9393 | 0.03 | 2599 | 158923 |
| 10.150 | 8337 | 0.03 | 1608 | 151053 |
| 10.940 | 5394 | 0.02 | 1554 | 240043 |
| 11.043 | 5224 | 0.02 | 1501 | 245644 |
| 11.648 | 5174 | 0.02 | 878 | 97886 |
| 12.370 | 10336 | 0.04 | 2262 | 161130 |
| 12.720 | 6925 | 0.02 | 1205 | 103662 |
| 12.898 | 6461 | 0.02 | 1199 | 105000 |
| 13.158 | 35533 | 0.12 | 6206 | 120619 |
| 13.567 | 11083940 | 38.68 | 1796747 | 107032 |
| 13.920 | 31787 | 0.11 | 8427 | 107091 |
| 14.325 | 17286637 | 60.33 | 2537495 | 101696 |
| 14.860 | 32110 | 0.11 | 3951 | 81160 |
| 15.717 | 39307 | 0.14 | 5195 | 97271 |
| Sum | 28653745 | 100.00 | 4392227 |
Table 2 rectifying product-1 data from gas chromatography
| Retention time | Peak area | Peak area % | Peak height | Theoretical plate number (USP) |
| 4.288 | 8250 | 0.03 | 1418 | 11715 |
| 5.665 | 2555 | 0.01 | 566 | 42998 |
| 8.423 | 4044 | 0.01 | 1072 | 111621 |
| 9.070 | 2457 | 0.01 | 614 | 140229 |
| 9.255 | 3676 | 0.01 | 1018 | 164450 |
| 9.432 | 4317 | 0.01 | 900 | 88316 |
| 9.987 | 2652 | 0.01 | 767 | 207279 |
| 11.085 | 9011 | 0.03 | 1768 | 89931 |
| 11.892 | 19452 | 0.06 | 3684 | 112528 |
| 12.143 | 21997 | 0.07 | 3337 | 80661 |
| 12.487 | 43584 | 0.13 | 7922 | 109948 |
| 12.643 | 26731 | 0.08 | 5573 | 158373 |
| 12.913 | 20382 | 0.06 | 3587 | 117331 |
| 13.295 | 12194804 | 37.72 | 2027811 | 104763 |
| 13.640 | 37977 | 0.12 | 6158 | 112828 |
| 14.028 | 19908422 | 61.58 | 2935199 | 93140 |
| 14.377 | 4927 | 0.02 | 942 | 175727 |
| 14.532 | 4443 | 0.01 | 812 | 169919 |
| 15.375 | 11785 | 0.04 | 1637 | 101098 |
| Sum | 32331465 | 100.00 | 5002958 |
Table 3 rectifying product-2 data from gas chromatography
| Retention time | Peak area | Peak area % | Peak height | Theoretical plate number (USP) |
| 3.068 | 2953 | 0.01 | 1465 | 56804 |
| 7.178 | 3740 | 0.01 | 839 | 58595 |
| 9.053 | 5347 | 0.02 | 1488 | 158150 |
| 9.245 | 10515 | 0.04 | 2932 | 168436 |
| 9.408 | 5149 | 0.02 | 1260 | 115960 |
| 11.082 | 5411 | 0.02 | 1176 | 124513 |
| 11.438 | 2865 | 0.01 | 687 | 168909 |
| 11.873 | 17808 | 0.06 | 3615 | 121941 |
| 12.482 | 60384 | 0.21 | 11346 | 120412 |
| 12.638 | 50490 | 0.18 | 10781 | 148566 |
| 12.908 | 11195 | 0.04 | 2067 | 110512 |
| 13.287 | 10798399 | 38.37 | 1857397 | 110157 |
| 13.627 | 8693 | 0.03 | 1684 | 161971 |
| 14.018 | 17073362 | 60.66 | 2586799 | 98047 |
| 14.373 | 4034 | 0.01 | 1003 | 302862 |
| 14.547 | 28255 | 0.10 | 4709 | 138774 |
| 15.368 | 57815 | 0.21 | 7953 | 101287 |
| Sum | 28146415 | 100.00 | 4497201 |
Table 4 rectifying product-3 data from gas chromatography
| Retention time | Peak area | Peak area % | Peak height | Theoretical plate number (USP) |
| 1.877 | 4336 | 0.01 | 1634 | 15261 |
| 2.835 | 17483 | 0.05 | 4170 | 11933 |
| 3.408 | 4253 | 0.01 | 1017 | 17782 |
| 4.387 | 16265 | 0.05 | 2651 | 12435 |
| 4.853 | 2131 | 0.01 | 465 | 26556 |
| 5.690 | 2187 | 0.01 | 303 | 0 |
| 6.280 | 6872 | 0.02 | 1143 | 25449 |
| 7.535 | 4343 | 0.01 | 606 | 22532 |
| 8.857 | 4651 | 0.01 | 564 | 31732 |
| 9.070 | 3609 | 0.01 | 626 | 46525 |
| 11.433 | 3841 | 0.01 | 487 | 0 |
| 11.703 | 5606 | 0.02 | 643 | 33313 |
| 12.412 | 23117 | 0.07 | 2003 | 24763 |
| 12.762 | 18408 | 0.05 | 1665 | 25800 |
| 14.207 | 13574507 | 39.00 | 1005962 | 24804 |
| 14.820 | 2215 | 0.01 | 318 | 119493 |
| 15.125 | 8021 | 0.02 | 757 | 39857 |
| 15.863 | 21069363 | 60.54 | 1435934 | 24575 |
| 16.853 | 33545 | 0.10 | 2389 | 31220 |
| Sum | 34804753 | 100.00 | 2463337 |
Table 5 teprenone sample and the contrast of comparative sample quality standard
As can be seen from the above embodiments, in the existing Carroll reaction described in comparative example, adopt undressed catalyzer, reaction conversion ratio is lower, and by-product alcohols increases on the contrary in last handling process, and target level of product quality does not reach the listing drug standard.Adopt improvement synthesis technique of the present invention and separation purification method to reduce below temperature of reaction to 160 ℃, greatly reduce the generation of by-product alcohols in existing Carroll reaction, in the thick product of reaction gained, the purity of teprenone just can reach more than 95%, the present invention has also solved the emulsification difficult problem in purge process, and the yield of the front product of rectifying has been brought up to more than 87%; The fine short-path distillation of having realized, isolated teprenone meets the listing drug standard completely, and purity is no less than 99.0%, and high purity product yield is more than 66%.This technological operation is simple, is easy to control good stability, steady quality, easily suitability for industrialized production.
Claims (1)
1. a method for synthetic teprenone, is characterized in that: the method has following steps:
A, get geranyl linalool, Acetacetic acid alkyl ester, organo aluminum catalyst, wherein, geranyl linalool and Acetacetic acid alkyl ester consumption mol ratio are 1:1.0-2.0; Organo aluminum catalyst consumption is the 0.5-10%mol of geranyl linalool consumption;
B, pre-treatment organo aluminum catalyst: get the 19.9%-50% of Acetacetic acid alkyl ester gross weight, add organo aluminum catalyst, be dissolved into mixed solution in 40-100 ℃, vacuum distillation, discards and slip out liquid, obtains pretreated catalyzer;
C, get geranyl linalool, the pretreated organo aluminum catalyst of b step, remaining Acetacetic acid alkyl ester, carry out Carroll reaction, heat up, except the lower alcohol and the CO that generate in dereaction
2, stopped reaction, cooling, obtain the thick product of teprenone;
D, the thick product of the teprenone that c step is made carry out after separation, re-refine and obtain sterling teprenone;
Wherein, before the Carroll reaction described in c step, add the ketones solvent of 10-100% geranyl linalool weight; In step c, adopt 0.01-0.05MPa vacuum distilling except the lower alcohol and the CO that produce in dereaction
2;
Wherein, the separation method described in d step is:
Get the thick product of teprenone prepared by c step, add part by propyl carbinol 50-100, the separated solvent extraction that isopropyl ether or normal hexane 0-50 part form; Successively with 5% aqueous acid and the washing of 10% weak base aqueous solution, be then washed to neutrality again, anhydrous sodium sulfate drying, filters, and distillation is except desolventizing; Wherein, extract and washing process in, add propyl carbinol or repeatedly freezingly add heat collapse emulsification layering.
2. the method for synthetic teprenone according to claim 1, is characterized in that: the geranyl linalool described in a step and Acetacetic acid alkyl ester consumption mol ratio are 1:1.2-1.6.
3. the method for synthetic teprenone according to claim 1, is characterized in that: described organo aluminum catalyst is aluminum isopropylate, aluminium secondary butylate, aluminium acetylacetonate, tri ethylacetoacetate aluminium.
4. the method for synthetic teprenone according to claim 3, is characterized in that: described organo aluminum catalyst is aluminum isopropylate.
5. the method for synthetic teprenone according to claim 1, is characterized in that: the alkyl in described Acetacetic acid alkyl ester is low alkyl group; This low alkyl group is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl.
6. the method for synthetic teprenone according to claim 5, is characterized in that: the alkyl in described Acetacetic acid alkyl ester is methyl, ethyl.
7. the method for synthetic teprenone according to claim 1, is characterized in that: described ketones solvent is butanone, pentanone, hexanone, heptanone, cyclopentanone, pimelinketone, suberone or Methyl amyl ketone.
8. the method for synthetic teprenone according to claim 1, is characterized in that: intensification described in c step is the highest is no more than 160 ℃.
9. the method for synthetic teprenone according to claim 8, is characterized in that: described temperature-rising method is for progressively heating up: be first warmed up to 125 ℃ ± 10 ℃ reaction 1-2 hour, then progressively bring up to 150 ℃ ± 5 ℃ reaction 2-4 hour.
10. the method for synthetic teprenone according to claim 1, is characterized in that: the ratio of described separated solvent is: propyl carbinol 50-80 part, isopropyl ether or normal hexane 20-50 part.
The method of 11. synthetic teprenones according to claim 1, is characterized in that: the process for purification described in d step is:
(1), get the product after separation, adopt molecular distillation to carry out simple distillation, its parameter is set to: input speed 1ml/min, opening for feed is no more than 80 ℃ of temperature, Heating temperature 100-160 ℃, vacuum tightness 1.1-30pa; And/or
(2), adopt packing tower rectifying, its condition is: vacuum tightness 10-100pa, glass filler, rectifying reflux ratio is progressively brought up to 5:2 from 50:1 and is controlled separated front-end volatiles effect, is no more than 195 ℃ at the bottom of rectifying tower.
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