CN109438345A - A kind of synthetic method of two deuterated primaquine - Google Patents
A kind of synthetic method of two deuterated primaquine Download PDFInfo
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- CN109438345A CN109438345A CN201811350876.3A CN201811350876A CN109438345A CN 109438345 A CN109438345 A CN 109438345A CN 201811350876 A CN201811350876 A CN 201811350876A CN 109438345 A CN109438345 A CN 109438345A
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- China
- Prior art keywords
- primaquine
- deuterated
- synthetic method
- reaction
- heavy water
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/40—Nitrogen atoms attached in position 8
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Abstract
The technical problems such as the present invention relates to a kind of synthetic method of two deuterated primaquine, it is long mainly to solve route existing for existing synthetic method, at high cost, cumbersome, and yield is low.The present invention is achieved through the following technical solutions: a kind of synthetic method of two deuterated primaquine, it is characterized in that, using primaquine phosphate as starting material, heavy water is solvent, and the acid of catalytic amount, heating reaction is added, it pours into buck after reaction, extraction, it is dry, two deuterated primaquine are obtained after concentration.The present invention has route simple, and raw material is easy to get, high income, at low cost, convenient post-treatment and the advantages that obtain the purity and high D abundance of product.
Description
Technical field
The present invention relates to a kind of synthetic methods of two deuterated primaquine, belong to deuterated drug production field.
Background technique
In many cases, carbon deuterium key can be slowed down with deuterium for a small number of hydrogen atoms in drug to be enzymatically decomposed, can stopped in vivo
For more time, while the formation of toxic metabolic products is reduced.Therefore, in general, compared to not deuterated drug, deuterated drug has
Toxic side effect is reduced, increases medicine stability, heightens the effect of a treatment, extends the effects of drug biological half-life.In April, 2017, ladder watt
The AUSTEDO (deutetrabenazine) of company becomes first deuterated drug ratified by FDA.Deuterated drug
Research and development cause the broad interest of domestic and international medicine enterprise.
(WO 2011091035) according to the literature, two deuterated primaquine are using p-nitrophenol as starting material, by 8
Step reaction synthesis key intermediate quinoline ring, and pass through number step and react final synthesising target compound, which has route long,
It is at high cost, cumbersome, the disadvantages such as yield is low.
Summary of the invention
The purpose of the present invention is to provide a kind of synthetic methods of deuterated primaquine.Existing synthetic method is mainly solved to exist
Route it is long, at high cost, cumbersome, the technical problems such as yield is low.
The present invention is achieved through the following technical solutions: a kind of synthetic method of two deuterated primaquine, which is characterized in that
Using primaquine phosphate as starting material, heavy water is solvent, and the acid of catalytic amount is added, and buck is poured into heating reaction after reaction
In, it extracts, it is dry, two deuterated primaquine are obtained after concentration.
As optimal technical scheme, in above-mentioned reaction, heavy water dosage is 5-15 times of primaquine phosphate weight, preferably 10
Times.
In above-mentioned reaction, reaction temperature is 55-110 DEG C, preferably 90-100 DEG C.
In above-mentioned reaction, reaction time 4-24 hour, preferably 8-10 hour.
In above-mentioned reaction, acid used is sulfuric acid.
In above-mentioned reaction, it is molten that buck used is selected from saturated sodium carbonate solution, unsaturated carbonate potassium solution or saturated sodium bicarbonate
One of liquid, preferably saturated sodium carbonate solution.
Concrete technology route of the present invention is as follows:
Beneficial effects of the present invention: compared with the existing technology, the present invention has route simple to technical solution of the present invention, and raw material is easy
, yield is up to 95%, at low cost, convenient post-treatment and the advantages that obtain the purity and high D abundance of product.
Specific embodiment
Present pre-ferred embodiments are given below, in order to explain the technical scheme of the invention in detail.
Embodiment 1
Primaquine phosphate (200 mg) is added into there-necked flask, heavy water (2 mL) is added the concentrated sulfuric acid (0.1mL), is heated to 95 DEG C,
8h is reacted, is poured into saturated sodium carbonate solution after reaction (20 mL), ethyl acetate extracts (20 mL x 2), anhydrous slufuric acid
Sodium is dry, and two deuterated primaquine (109 mg, 95% yield) are obtained after concentration.1H NMR (300MHz, DMSO-d6):8.21
(dd, J = 4.5Hz,1.2Hz, 1H), 8.01 (dd, J = 8.4Hz,1.2Hz, 1H), 7.31 (dd, J =
8.4Hz,4.5Hz, 1H),3.44(s, 3H), 3.19(m, 1H), 2.70 (m, 2H), 1.40(m, 4H), 0.91
(d, J= 6.0 Hz, 3H)；13C NMR (75MHz, DMSO-d6): 159.76, 144.28, 138.92, 138.07,
131.04, 124.54, 121.33, 55.60, 48.65, 39.33, 31.59, 23.26, 18.20。
Embodiment 2
Primaquine phosphate (200 mg) is added into there-necked flask, heavy water (2 mL) is added the concentrated sulfuric acid (0.1mL), is heated to 55 DEG C,
Reaction for 24 hours, is poured into saturated sodium carbonate solution (20 mL) after reaction, and ethyl acetate extracts (20 mL x 2), anhydrous sulphur
Sour sodium is dry, and two deuterated primaquine (103 mg, 90% yield) are obtained after concentration.
Embodiment 3
Primaquine phosphate (200 mg) is added into there-necked flask, heavy water (2 mL) is added the concentrated sulfuric acid (0.1mL), is heated to 110
DEG C, 4h is reacted, is poured into saturated sodium carbonate solution after reaction (20 mL), ethyl acetate extracts (20 mL x 2), anhydrous
Sodium sulphate is dry, and two deuterated primaquine (102 mg, 89% yield) are obtained after concentration.
Claims (10)
1. a kind of synthetic method of two deuterated primaquine, which is characterized in that using primaquine phosphate as starting material, heavy water is molten
The acid of catalytic amount is added in agent, and heating reaction is poured into buck after reaction, extracted, dry, and two deuterated primary are obtained after concentration
Ammonia quinoline.
2. a kind of synthetic method of two deuterated primaquine according to claim 1, which is characterized in that heavy water dosage is phosphoric acid
5-15 times of primaquine weight.
3. a kind of synthetic method of two deuterated primaquine according to claim 2, which is characterized in that heavy water dosage is 10
Times.
4. a kind of synthetic method of two deuterated primaquine according to claim 1, which is characterized in that reaction temperature 55-
110℃。
5. a kind of synthetic method of two deuterated primaquine according to claim 4, which is characterized in that reaction temperature 90-
100℃。
6. a kind of synthetic method of two deuterated primaquine according to claim 1, which is characterized in that the reaction time, 4-24 was small
When.
7. a kind of synthetic method of two deuterated primaquine according to claim 6, which is characterized in that the reaction time, 8-10 was small
When.
8. a kind of synthetic method of two deuterated primaquine according to claim 1, which is characterized in that acid used is sulphur
Acid.
9. a kind of synthetic method of two deuterated primaquine according to claim 1, which is characterized in that buck used is selected from full
One of with sodium carbonate liquor, unsaturated carbonate potassium solution or saturated sodium bicarbonate solution.
10. a kind of synthetic method of two deuterated primaquine according to claim 9, which is characterized in that buck used is full
And sodium carbonate liquor.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811350876.3A CN109438345A (en) | 2018-11-14 | 2018-11-14 | A kind of synthetic method of two deuterated primaquine |
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|---|---|---|---|
| CN201811350876.3A CN109438345A (en) | 2018-11-14 | 2018-11-14 | A kind of synthetic method of two deuterated primaquine |
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|---|---|
| CN109438345A true CN109438345A (en) | 2019-03-08 |
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| CN201811350876.3A Pending CN109438345A (en) | 2018-11-14 | 2018-11-14 | A kind of synthetic method of two deuterated primaquine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112724087A (en) * | 2021-02-04 | 2021-04-30 | 康化（上海）新药研发有限公司 | Synthesis method of dideuterotrimethoprim |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011091035A1 (en) * | 2010-01-19 | 2011-07-28 | Concert Pharmaceuticals, Inc. | Aminoquinoline derivatives |
| CN102392267A (en) * | 2011-09-19 | 2012-03-28 | 华东理工大学 | 8, 9-tetradeuterium cetane and preparation method thereof |
| CN106892790A (en) * | 2017-03-16 | 2017-06-27 | 南京工业大学 | The method that a kind of utilization microchannel reaction unit prepares deuterated amino benzenes compounds |
-
2018
- 2018-11-14 CN CN201811350876.3A patent/CN109438345A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011091035A1 (en) * | 2010-01-19 | 2011-07-28 | Concert Pharmaceuticals, Inc. | Aminoquinoline derivatives |
| CN102392267A (en) * | 2011-09-19 | 2012-03-28 | 华东理工大学 | 8, 9-tetradeuterium cetane and preparation method thereof |
| CN106892790A (en) * | 2017-03-16 | 2017-06-27 | 南京工业大学 | The method that a kind of utilization microchannel reaction unit prepares deuterated amino benzenes compounds |
Non-Patent Citations (2)
| Title |
|---|
| ANDREW MARTINS，等: "A Simple, Cost-Effective Method for the Regioselective Deuteration of Anilines", 《ORGANIC LETTERS》 * |
| JUN XU，等: "Copper(II)-catalyzed C5 and C7 halogenation of quinolines using sodium halides under mild conditions", 《ORG. BIOMOL. CHEM.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112724087A (en) * | 2021-02-04 | 2021-04-30 | 康化（上海）新药研发有限公司 | Synthesis method of dideuterotrimethoprim |
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Application publication date: 20190308 |