CN110563789A - clean production preparation method of testosterone propionate - Google Patents
clean production preparation method of testosterone propionate Download PDFInfo
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- CN110563789A CN110563789A CN201910946493.0A CN201910946493A CN110563789A CN 110563789 A CN110563789 A CN 110563789A CN 201910946493 A CN201910946493 A CN 201910946493A CN 110563789 A CN110563789 A CN 110563789A
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- Prior art keywords
- testosterone
- water
- weight ratio
- testosterone propionate
- propionate
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- PDMMFKSKQVNJMI-BLQWBTBKSA-N Testosterone propionate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CC)[C@@]1(C)CC2 PDMMFKSKQVNJMI-BLQWBTBKSA-N 0.000 title claims abstract description 40
- 229960001712 testosterone propionate Drugs 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 16
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 claims abstract description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 41
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 30
- 229960003604 testosterone Drugs 0.000 claims abstract description 21
- 239000002253 acid Substances 0.000 claims abstract description 19
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 18
- 239000002699 waste material Substances 0.000 claims abstract description 18
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 9
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 claims abstract description 9
- 235000010334 sodium propionate Nutrition 0.000 claims abstract description 9
- 239000004324 sodium propionate Substances 0.000 claims abstract description 9
- 229960003212 sodium propionate Drugs 0.000 claims abstract description 9
- 239000006227 byproduct Substances 0.000 claims abstract description 5
- 238000005886 esterification reaction Methods 0.000 claims abstract description 5
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 4
- 230000032050 esterification Effects 0.000 claims abstract description 3
- 239000002994 raw material Substances 0.000 claims abstract description 3
- 238000007670 refining Methods 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 238000000967 suction filtration Methods 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 16
- 239000012043 crude product Substances 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 14
- 239000000463 material Substances 0.000 claims description 13
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 10
- 239000000706 filtrate Substances 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 239000012065 filter cake Substances 0.000 claims description 6
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 claims description 6
- 235000019260 propionic acid Nutrition 0.000 claims description 6
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 238000012544 monitoring process Methods 0.000 claims description 4
- 238000004809 thin layer chromatography Methods 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 238000005516 engineering process Methods 0.000 claims description 2
- 230000003472 neutralizing effect Effects 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000002351 wastewater Substances 0.000 abstract description 2
- 239000000047 product Substances 0.000 abstract 1
- 238000004064 recycling Methods 0.000 abstract 1
- 238000007599 discharging Methods 0.000 description 4
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 241000605447 Anemarrhena Species 0.000 description 1
- 208000032467 Aplastic anaemia Diseases 0.000 description 1
- 206010011498 Cryptorchism Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 206010039984 Senile osteoporosis Diseases 0.000 description 1
- 206010046798 Uterine leiomyoma Diseases 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000001548 androgenic effect Effects 0.000 description 1
- 229930191283 anemarrhena Natural products 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 201000000160 cryptorchidism Diseases 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 201000003585 eunuchism Diseases 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 208000037106 male hypogonadism Diseases 0.000 description 1
- 208000007106 menorrhagia Diseases 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0018—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
- C07J1/0022—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
- C07J1/0025—Esters
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a clean production preparation method of testosterone propionate, which takes testosterone as a raw material, and obtains the testosterone propionate with the product purity of more than or equal to 99.5 percent through esterification and refining, and waste acid water generated in the preparation process is neutralized by sodium carbonate, decolored by active carbon, filtered and concentrated to prepare a sodium propionate byproduct, thereby reducing the pollution of waste water to the environment. According to the invention, while high-purity testosterone propionate is prepared, the by-product sodium propionate is obtained by effectively recycling the components in the waste acid water, so that the cost is reduced, and the clean production of testosterone propionate is realized.
Description
Technical Field
The invention belongs to the technical field of steroid medicine preparation, and particularly relates to a clean production preparation method of testosterone propionate.
background
testosterone propionate, also known as testosterone propionate and androgenic drugs, is clinically suitable for the symptoms of anemarrhena, cryptorchidism and male hypogonadism; gynecological diseases such as menorrhagia and hysteromyoma; senile osteoporosis, aplastic anemia, etc.
According to the search, the preparation method of testosterone propionate refers to the acylation synthesis by reacting testosterone with propionic anhydride, and in the process of implementing the invention, the inventor finds that at least the following problems exist in the prior art: in the reaction process of the propionic anhydride, the 3-position ketone group and the 17-position hydroxyl group of the testosterone can simultaneously generate diester impurities, and after the reaction, the propionic anhydride can generate a large amount of acid water, so that the treatment cost of the waste acid water is high.
Disclosure of Invention
In order to solve the problems of low purity, large amount of waste acid water and high treatment cost in testosterone propionate production in the prior art, the invention provides a clean production preparation method of testosterone propionate.
Therefore, the technical scheme of the invention is as follows: a clean production preparation method of testosterone propionate comprises the following steps:
the method is characterized in that:
Testosterone is taken as a raw material, and esterification and refining are carried out to obtain testosterone propionate with the purity of more than or equal to 99.5 percent;
neutralizing waste acid water generated in the preparation with sodium carbonate, decoloring with active carbon, performing suction filtration and concentration to obtain a sodium propionate byproduct;
the specific clean production preparation method comprises the following steps:
Step A: adding propionic acid and testosterone into a reaction bottle, uniformly stirring, adding propionyl chloride, heating to reflux, and monitoring the reaction process by using a TLC (thin layer chromatography) technology until the esterification reaction is complete; after the reaction is completed, slowly dripping the reaction solution into a beaker filled with water for elutriation, stirring uniformly, carrying out suction filtration, washing a filter cake with water, then draining the discharged material, drying to obtain a testosterone propionate crude product, and collecting waste acid water for treatment;
And B: adding methanol, activated carbon and the testosterone propionate crude product prepared in the step A into a reaction bottle, heating to reflux for decoloring, then performing suction filtration, concentrating the filtrate to obtain the residual methanol, cooling for crystallization, performing suction filtration, draining the discharged material, and drying to constant weight to obtain testosterone propionate;
and C: and C, adding the waste acid water collected in the step A into a reaction bottle, adding sodium carbonate to adjust the pH value, adding activated carbon, uniformly stirring, carrying out suction filtration, concentrating the filtrate to the rest part of water, cooling, crystallizing, carrying out suction filtration, and draining the discharged material to obtain the sodium propionate.
the weight ratio of the propionic acid to the testosterone in the step A is 6 ~ 8:1, the weight ratio of the propionyl chloride to the testosterone is 0.3 ~ 0.5:1, the reaction time is 2 ~ 3 hours, the weight ratio of water for elutriation to the testosterone is 60 ~ 80:1, the filter cake is washed by water until the pH value of filtrate ranges from 6 to 7, the weight ratio of the water for washing the filter cake to the testosterone is 20 ~ 30:1, and the temperature of a drying material is controlled at 60 ~ 65 ℃.
the weight ratio of the methanol to the testosterone propionate crude product in the step B is 10 ~ 12:1, the weight ratio of the activated carbon to the testosterone propionate crude product is 0.03 ~ 0.05:1, the reflux decoloring time is 0.5 ~ 1h, the mixture is concentrated until the weight ratio of the rest methanol to the testosterone propionate crude product is 1 ~ 1.5:1, the crystallization temperature is 0 ~ 5 ℃, the crystallization time is 2 ~ 4h, and the material drying temperature is controlled at 60 ~ 65 ℃.
and C, adjusting the weight ratio of sodium carbonate to testosterone in the step C to be 4 ~ 6:1, adjusting the pH value to be 8 ~ 9, adjusting the weight ratio of activated carbon to testosterone to be 0.08 ~ 0.1:1, concentrating until the weight ratio of residual water to waste acid water is 1.0 ~ 1.5:10, controlling the crystallization temperature to be 15 ~ 20 ℃ and controlling the crystallization time to be 8 ~ 10 hours.
Has the advantages that:
The clean production preparation method of testosterone propionate provided by the invention is easy to operate and high-efficiency, and has the following advantages:
1) the purity of the obtained testosterone propionate is more than or equal to 99.5 percent, and the yield is more than or equal to 110 percent;
2) the waste acid water is comprehensively treated to obtain a byproduct sodium propionate, so that the environmental pollution caused by waste water is reduced, the components in the waste acid water are effectively recycled, the cost is reduced, and the clean production of testosterone propionate is realized.
Detailed Description
The technical solution of the present invention is clearly and completely described below by the following specific examples, but the examples should not be construed as limiting the present invention.
The first embodiment is as follows:
(1) Adding 60g of propionic acid and 10g of testosterone into a reaction bottle, uniformly stirring, adding 3g of propionyl chloride, heating to reflux for 3 hours, monitoring by TLC, and completely reacting; adding 600g of water into a beaker, slowly dropwise adding the reaction solution in the reaction bottle into the water while stirring, uniformly stirring, performing suction filtration, washing the material with 200g of water until the pH value is 6, draining, discharging, drying to obtain 11.7g of a testosterone propionate crude product, and simultaneously collecting 850g of waste acid water;
(2) adding 117g of methanol, 0.351g of activated carbon and 11.7g of testosterone propionate crude product into a reaction bottle, heating up, refluxing and decoloring for 1h, performing suction filtration, concentrating the filtrate until 11.7g of methanol is remained, cooling to 5 ℃, stirring and crystallizing for 4h, performing vacuum filtration, draining the discharged material, and drying at 60 ℃ to constant weight to obtain 11.3g of testosterone propionate with the purity of 99.6%;
(3) Adding 850g of waste acid water into a reaction bottle, adding 40g of sodium carbonate to adjust the pH value to 8, adding 0.8g of activated carbon, uniformly stirring, carrying out suction filtration to remove the activated carbon, concentrating the filtrate until the residual 85g of water is obtained, cooling to 15 ℃, crystallizing for 8h, carrying out suction filtration, and carrying out suction drying and discharging to obtain 65g of sodium propionate.
example two:
(1) Adding 80g of propionic acid and 10g of testosterone into a reaction bottle, uniformly stirring, adding 5g of propionyl chloride, heating to reflux for 2 hours, monitoring by TLC, and completely reacting; adding 800g of water into a beaker, slowly dropwise adding the reaction solution in the reaction bottle into the water while stirring, uniformly stirring, carrying out suction filtration, washing the material with 300g of water until the pH value is 7, draining, discharging, drying to obtain 11.5g of a testosterone propionate crude product, and simultaneously collecting 1170g of waste acid water;
(2) adding 138g of methanol, 0.575g of activated carbon and 11.5g of testosterone propionate crude product into a reaction bottle, heating, refluxing and decoloring for 0.5h, performing suction filtration, concentrating the filtrate until 17.25g of methanol remains, cooling to 0 ℃, stirring and crystallizing for 2h, filtering, draining the discharged material, and drying at 65 ℃ to constant weight to obtain 11.2g of testosterone propionate with the purity of 99.8%;
(3) Adding 1170g of waste acid water into a reaction bottle, adding 60g of sodium carbonate to adjust the pH value to 9, adding 1.0g of activated carbon, stirring uniformly, carrying out suction filtration to remove the activated carbon, concentrating the filtrate until 175g of water remains, cooling to 15 ℃, crystallizing for 10 hours, carrying out suction filtration, and carrying out suction drying and discharging to obtain 90g of sodium propionate.
those skilled in the art will appreciate that the details of the present invention are not described in detail herein.
it will be understood that modifications and variations can be made by persons skilled in the art in light of the above teachings and all such modifications and variations are intended to be included within the scope of the invention as defined in the appended claims.
Claims (4)
1. A clean production preparation method of testosterone propionate comprises the following steps:
the method is characterized in that:
testosterone is taken as a raw material, and esterification and refining are carried out to obtain testosterone propionate with the purity of more than or equal to 99.5 percent;
neutralizing waste acid water generated in the preparation with sodium carbonate, decoloring with active carbon, performing suction filtration and concentration to obtain a sodium propionate byproduct;
the specific clean production preparation method comprises the following steps:
Step A: adding propionic acid and testosterone into a reaction bottle, uniformly stirring, adding propionyl chloride, heating to reflux, and monitoring the reaction process by using a TLC (thin layer chromatography) technology until the esterification reaction is complete; after the reaction is completed, slowly dripping the reaction solution into a beaker filled with water for elutriation, stirring uniformly, carrying out suction filtration, washing a filter cake with water, then draining the discharged material, drying to obtain a testosterone propionate crude product, and collecting waste acid water for treatment;
and B: adding methanol, activated carbon and the testosterone propionate crude product prepared in the step A into a reaction bottle, heating to reflux for decoloring, then performing suction filtration, concentrating the filtrate to obtain the residual methanol, cooling for crystallization, performing suction filtration, draining the discharged material, and drying to constant weight to obtain testosterone propionate;
And C: and C, adding the waste acid water collected in the step A into a reaction bottle, adding sodium carbonate to adjust the pH value, adding activated carbon, uniformly stirring, carrying out suction filtration, concentrating the filtrate to the rest part of water, cooling, crystallizing, carrying out suction filtration, and draining the discharged material to obtain the sodium propionate.
2. the clean production and preparation method of testosterone propionate according to claim 1, wherein the weight ratio of propionic acid to testosterone in the step A is 6 ~ 8:1, the weight ratio of propionyl chloride to testosterone is 0.3 ~ 0.5:1, the reaction time is 2 ~ 3h, the weight ratio of water for elutriation to testosterone is 60 ~ 80:1, the pH value of a filter cake is washed by water until the pH value of a filtrate ranges from 6 to 7, the weight ratio of water for washing the filter cake to testosterone ranges from 20 ~ 30:1, and the temperature of a drying material is controlled at 60 ~ 65 ℃.
3. the clean production preparation method of testosterone propionate according to claim 1 or 2, characterized in that the weight ratio of methanol to testosterone propionate crude product in the step B is 10 ~ 12:1, the weight ratio of active carbon to testosterone propionate crude product is 0.03 ~ 0.05:1, the reflux decoloring time is 0.5 ~ 1h, the mixture is concentrated until the weight ratio of the residual methanol to testosterone propionate crude product is 1 ~ 1.5:1, the crystallization temperature is 0 ~ 5 ℃, the crystallization time is 2 ~ 4h, and the drying temperature is controlled at 60 ~ 65 ℃.
4. the clean production preparation method of testosterone propionate according to claim 3, characterized in that the weight ratio of sodium carbonate to testosterone in the step C is 4 ~ 6:1, the pH is adjusted to 8 ~ 9, the weight ratio of activated carbon to testosterone is 0.08 ~ 0.1:1, the mixture is concentrated until the weight ratio of residual water to waste acid water is 1.0 ~ 1.5:10, the crystallization temperature is controlled to 15 ~ 20 ℃, and the crystallization time is controlled to 8 ~ 10 hours.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201910946493.0A CN110563789B (en) | 2019-10-05 | 2019-10-05 | Clean production preparation method of testosterone propionate |
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| CN201910946493.0A CN110563789B (en) | 2019-10-05 | 2019-10-05 | Clean production preparation method of testosterone propionate |
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| CN110563789A true CN110563789A (en) | 2019-12-13 |
| CN110563789B CN110563789B (en) | 2022-03-25 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111875655A (en) * | 2020-06-19 | 2020-11-03 | 浙江神洲药业有限公司 | Preparation method of testosterone propionate |
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| CN102924553A (en) * | 2012-09-26 | 2013-02-13 | 宜城市共同药业有限公司 | High-yield synthesis method of trenbolone acetate |
| CN105732754A (en) * | 2014-12-01 | 2016-07-06 | 台湾永光化学工业股份有限公司 | Synthesis method of alkyl acid testosterone compound |
| CN107312055A (en) * | 2017-06-08 | 2017-11-03 | 江苏正大清江制药有限公司 | A kind of new preparation method of rocuronium |
| CN107540719A (en) * | 2016-06-26 | 2018-01-05 | 浙江仙琚制药股份有限公司 | A kind of 17 α acetoxyl groups（8,13）The preparation method of the α hydroxyl progesterones of alkene 11 |
-
2019
- 2019-10-05 CN CN201910946493.0A patent/CN110563789B/en active Active
Patent Citations (4)
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| CN102924553A (en) * | 2012-09-26 | 2013-02-13 | 宜城市共同药业有限公司 | High-yield synthesis method of trenbolone acetate |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111875655A (en) * | 2020-06-19 | 2020-11-03 | 浙江神洲药业有限公司 | Preparation method of testosterone propionate |
| CN111875655B (en) * | 2020-06-19 | 2021-12-21 | 浙江神洲药业有限公司 | Preparation method of testosterone propionate |
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| CN110563789B (en) | 2022-03-25 |
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