CN1062901A - The novel process of not separating geometrical isomer direct production tamoxifen citrate - Google Patents
The novel process of not separating geometrical isomer direct production tamoxifen citrate Download PDFInfo
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- CN1062901A CN1062901A CN 91107302 CN91107302A CN1062901A CN 1062901 A CN1062901 A CN 1062901A CN 91107302 CN91107302 CN 91107302 CN 91107302 A CN91107302 A CN 91107302A CN 1062901 A CN1062901 A CN 1062901A
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- tamoxifen citrate
- dehydrate
- tamoxifen
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Abstract
The present invention is a kind of method for preparing the anti-breast cancer medicines tamoxifen citrate.Present method does not need the geometric separation isomer, directly prepares the tamoxifen citrate medicine from dehydrate, and yield is brought up to 85.7%-87.5%.This processing method is simple, and agents useful for same is easy to get inexpensive, and quality product is qualified, is suitable for medicine industry production.
Description
The present invention belongs to a kind of anti-breast cancer medicine-tamoxifen citrate (chemical name: (Z)-2-[4-(1,2-phenylbenzene-1-butylene base) phenoxy group]-N, N-dimethyl amine citrate 1: 1) new production process.
The production method of producing at present both at home and abroad tamoxifen citrate be with deoxy-through Ge Shi, dehydrate that dehydration reaction obtained after the separation of E, two kinds of isomer of Z again salify make finished product.
Its reaction formula is as follows:
The common drawback of these aspects is: owing to contain two kinds of isomer of the similar E of physico-chemical property, Z and some other more difficult isolating impurity in the dehydrate, and the physiologically active of these two kinds of isomer is opposite fully, therefore in order to obtain to meet the finished product that drug quality requires.(E content must not surpass 1% in the pharmacopeia regulation finished product), must take some relatively separation ways of very complicated, the E-isomer of getting must abandon as refuse again, and yield is low, and final product quality is difficult for stable.
Report as Chinese patent 86 1 07840 A, 1610 gram dehydrates will be used twice in hexane recrystallization, use the heptane recrystallization again three times, just get tamoxifen free alkali 700 grams of purity more than 99.2%, the sixth of the twelve Earthly Branches, the alkane mother liquor was concentrated into dried, the pure recrystallization of first, remove the E configuration, methanol mother liquor and heptane mother liquor are concentrated into dried respectively, residuum merges, and uses heptane recrystallization in the sixth of the twelve Earthly Branches again, repeats secondary, again about pure Z type product 200 grams, therefore restrain from 610 and get 903 gram Z type free alkalis the dehydrates, yield 56.09%, this patent and report get 1.4～1.5 kilograms tamoxifen citrate behind 1 kilogram of free alkali salify, yield is that 96～99%, two steps merging yield is 53.85～55.53%.
The objective of the invention is to set up a kind of dehydrate and need not carry out E, Z isomer separation, directly be prepared into the production technique of the tamoxifen citrate that meets the drug quality requirement fully.
The present invention adopts following steps:
Earlier with the dehydrate of industrial production gained through aliphatics or aromatic hydrocarbon solvent and proper amount of active carbon pre-treatment purifying such as sherwood oil, Skellysolve A, hexanes, remove the impurity beyond two kinds of isomer, guarantee that final product quality can meet the pharmacopeia requirement.
Will be through the dehydrate of above-mentioned processing with water-soluble strong acid such as concentrated hydrochloric acid or sulfuric acid, 30～60 ℃ of following reacting by heating are more than 19 hours in the aqueous solution, pour into then and separate out precipitation in the frozen water, filter washing on a small quantity, get white precipitate, filter the gained solid, add mineral alkalis such as 4% aqueous sodium hydroxide solution or potassium hydroxide, it is above in 60～65 ℃ of reactions two hours, filtration, washing, drying to keep pH12, get pure Z type tamoxifen free alkali, yield 99.2%.
This pure Z type tamoxifen free alkali is again with aliphatics or aromatic hydrocarbon solvent recrystallizations such as sherwood oil or Skellysolve As, recrystallization is put rate 90%, the free alkali fusing point is 95～97 ℃, E type content 0.2～0.4%, this free alkali can be directly used in Citric Acid salify in acetone and prepare tamoxifen citrate, salify yield 96～98%, quality meet the pharmacopeia requirement.
From dehydrate to the finished product total recovery is 85.7～87.5%.
Advantage of the present invention:
1, need not separate E type and Z type geometrical isomer, directly prepare tamoxifen citrate from dehydrate, therefore no longer produce the E-isomer that goes out of use, make yield bring up to 85.7～87.5% from 53.85～55.83% of Chinese patent 86,1 07840A report.
2, because the isomer separation step of having cut off very complicated makes technology simple and easy to do, be suitable for industrial production.Reduce three wastes discharge amount, improved labour protection.
3, agents useful for same is cheap and easy to get, and along with the raising of yield, cost significantly descends.
4, final product quality is stable, and (145～146.5 ℃ of molten points), E-isomer content is lower than 0.4%, (pharmacopeia regulation 1%).
Embodiment one
The pre-treatment of dehydrate and purifying
The dehydrate hydrochloride crude product (production unit provides) of gained in the enchashment row industrial production, with in the excessive 4% NaOH aqueous solution and after, filtering precipitate, be washed to neutrality, again with 15 times of amount sherwood oils (60～90 ℃) and an amount of activated carbon, reflux 0.5 hour is taken advantage of hot filtration under diminished pressure after the drying, steam solvent to the greatest extent, promptly get the dehydrate behind the purifying.This method almost can eliminate other impurity except that two kinds of isomer of E, Z in the dehydrate crude product (foreign matter content account for dehydrate hydrochloride crude product 15～20%), and the not loss of two kinds of foreign body objects of E, Z.
Embodiment two
The preparation of Z-type tamoxifen free alkali
Get dehydrate 20 grams behind the above-mentioned pre-treatment purifying, add 80 milliliters of concentrated hydrochloric acids, in 50～60 ℃, insulated and stirred reaction 19 hours, in the impouring 240 gram frozen water, stir, filter, a small amount of washing, filter white precipitate, add the 4% NaOH aqueous solution, keep more than the PH12, in 60～65 ℃ of stirring reactions 2 hours, filter, get tamoxifen Z type free alkali crude product after the drying, off-white color crystallization 19.84 grams, 95～96 ℃ of fusing points, yield 99.2%, then with 15 times of sherwood oils and an amount of activated carbon recrystallization, once get white, needle-shaped crystals 17.86 grams, fusing point 95～96.5 ℃ of (E type content (0.2～0.4%), recrystallization yields 90%.
Embodiment three
The preparation of tamoxifen citrate
The above-mentioned tamoxifen Z type free alkali of 15 grams is dissolved in 100 milliliters of acetone.
In addition 9.55 gram Citric Acids are dissolved in 55 milliliters of acetone, under agitation add tamoxifen Z type free alkali acetone soln then, stirring at room for a moment, separate out a large amount of white crystals, place down for 0 ℃ and spend the night, filter, with a small amount of cold acetone clean, after the drying tamoxifen citrate 2.23 restrains, 145～146.5 ℃ of fusing points (E type content＜0.4%), yield 97.81%.
Claims (1)
- A kind of need not separate production technique that E type and Z type geometrical isomer directly prepare the tamoxifen citrate medicine comprising:--will be raw material with the deoxy-, through Ge Shi, eliminate dehydrate that reaction makes with aliphatics and aromatic hydrocarbon solvent and proper amount of active carbon pre-treatment purifying such as sherwood oil, Skellysolve A, normal hexanes, remove the impurity beyond two kinds of isomer.--with water-soluble strong acid such as the dehydrate behind the purifying and concentrated hydrochloric acid or sulfuric acid, more than 19 hours, precipitate in the impouring frozen water then 30～60 ℃ of following reacting by heating.--mineral alkalis such as throw out hydro-oxidation sodium or potassium hydroxide are kept more than the pH12 60～65 ℃ of reactions 2 hours.--with alkali-treated tamoxifen free alkali, with behind aliphatics such as oil fan, Skellysolve A, normal hexane or the aromatic hydrocarbon solvent recrystallization with Citric Acid salify and prepare the tamoxifen citrate medicine in acetone.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 91107302 CN1062901A (en) | 1991-01-05 | 1991-01-05 | The novel process of not separating geometrical isomer direct production tamoxifen citrate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 91107302 CN1062901A (en) | 1991-01-05 | 1991-01-05 | The novel process of not separating geometrical isomer direct production tamoxifen citrate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1062901A true CN1062901A (en) | 1992-07-22 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 91107302 Pending CN1062901A (en) | 1991-01-05 | 1991-01-05 | The novel process of not separating geometrical isomer direct production tamoxifen citrate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1062901A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0677507A1 (en) * | 1993-10-25 | 1995-10-18 | Taiho Pharmaceutical Company Limited | Process for producing acid-addition salt of z-isomer of triphenylethylene compound |
| CN103450036A (en) * | 2013-08-15 | 2013-12-18 | 凯莱英医药集团（天津）股份有限公司 | Preparation method of high-purity tamoxifen citrate |
| CN109293519A (en) * | 2017-07-25 | 2019-02-01 | 北京斯利安药业有限公司 | A kind of preparation method of tamoxifen citrate crystal form A |
| CN111362816A (en) * | 2020-03-09 | 2020-07-03 | 扬子江药业集团江苏海慈生物药业有限公司 | Preparation method of tamoxifen related substance |
| CN114133334A (en) * | 2021-11-09 | 2022-03-04 | 北京京丰制药(山东)有限公司 | Industrial preparation process of tamoxifen citrate |
-
1991
- 1991-01-05 CN CN 91107302 patent/CN1062901A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0677507A1 (en) * | 1993-10-25 | 1995-10-18 | Taiho Pharmaceutical Company Limited | Process for producing acid-addition salt of z-isomer of triphenylethylene compound |
| EP0677507A4 (en) * | 1993-10-25 | 1996-04-10 | Taiho Pharmaceutical Co Ltd | Process for producing acid-addition salt of z-isomer of triphenylethylene compound. |
| CN103450036A (en) * | 2013-08-15 | 2013-12-18 | 凯莱英医药集团（天津）股份有限公司 | Preparation method of high-purity tamoxifen citrate |
| CN109293519A (en) * | 2017-07-25 | 2019-02-01 | 北京斯利安药业有限公司 | A kind of preparation method of tamoxifen citrate crystal form A |
| CN109293519B (en) * | 2017-07-25 | 2021-09-28 | 北京斯利安药业有限公司 | Preparation method of tamoxifen citrate crystal form A |
| CN111362816A (en) * | 2020-03-09 | 2020-07-03 | 扬子江药业集团江苏海慈生物药业有限公司 | Preparation method of tamoxifen related substance |
| CN111362816B (en) * | 2020-03-09 | 2022-03-22 | 扬子江药业集团江苏海慈生物药业有限公司 | Preparation method of tamoxifen related substance |
| CN114133334A (en) * | 2021-11-09 | 2022-03-04 | 北京京丰制药(山东)有限公司 | Industrial preparation process of tamoxifen citrate |
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| C01 | Deemed withdrawal of patent application (patent law 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |