CN109761913A - A kind of method that Organometallic Palladium catalyzes and synthesizes elagolix intermediate - Google Patents
A kind of method that Organometallic Palladium catalyzes and synthesizes elagolix intermediate Download PDFInfo
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Abstract
The invention discloses a kind of method that Organometallic Palladium catalyzes and synthesizes elagolix intermediate, the structure of elagolix intermediate as shown in formula I,The synthetic route of type I compound is as follows:
Description
Technical field
The present invention relates to machine synthesis and medicine intermediate technical field, specifically a kind of Organometallic Palladium to catalyze and synthesize
The method of elagolix intermediate.
Background technique
Pain caused by Eagolix conduct is treated because of endometriosis, the structure of elagolix are as follows:
(R)-(2- (5- (the fluoro- 3- methoxyphenyl of 2-) -3- (2- fluoro- 6- (trifluoromethyl) benzyl) -4- methyl -2,6- two
- 1 (2H)-yl of oxo -3,6- dihydro-pyrimidin) -1- phenethyl) key centre of the t-butyl carbamate as synthesis elagolix
Body, structure are as follows:
Patent No.: WO2009062087 discloses the synthetic method about the compound, and synthetic route is as follows:
The patent document synthesizes to obtain using Formula II compound as starting material after multisteps such as bromination, N- alkylation, couplings
Target compound.
However, the route prepares target product with multistep reaction, not only process costs are high, and the production cycle is long, and energy
Consumption is big.
Therefore, a kind of low energy consumption, economic, green, environmentally friendly elagolix intermediate as noted above synthesis are developed
Technique can significantly improve the industrialized production and application of elagolix bulk pharmaceutical chemicals.
Summary of the invention
Technical problem to be solved by the present invention lies in: a kind of Organometallic Palladium is provided and catalyzes and synthesizes elagolix intermediate
Method, to solve the technological deficiency that existing synthetic route yield is low, pollution is big, step is long.
The present invention is to solve above-mentioned technical problem by the following technical programs:
A kind of method that Organometallic Palladium catalyzes and synthesizes elagolix intermediate, structure is as shown in formula I；
The synthetic route of the type I compound is as follows:
The synthetic method of type I compound the following steps are included:
The synthesis of S1, VIII compound of formula: weighing 0.5-1.5g, and VII compound of 1.0equiv. formula is added in reactor
After THF 5-15mL, VI compound of formula, the 0.05- of 1.2-1.4equiv. are sequentially added in terms of VII compound, in reactor
The palladium catalyst of 0.15equiv., the alkali of 1.5-2.5equiv., after being warming up to 45-55 DEG C, insulation reaction 16-20h, reaction knot
Reaction solution is concentrated to dryness by Shu Hou, and concentration residue is distributed in methylene chloride and 0.5-1.5N aqueous hydrochloric acid solution, is separated organic
Phase, successively with after saturated sodium bicarbonate aqueous solution and saturated common salt water washing organic phase, organic phase is dried and concentrated with sodium sulphate,
Concentrate obtains VIII compound of formula through column chromatography for separation；
The synthesis of S2, Ⅹ compound of formula: weighing 0.5-1.5g, and VIII compound of formula of 1.0equiv. is added in reactor
After the Isosorbide-5-Nitrae of 5-15mL-dioxane dissolution, in terms of VIII compound of formula, the formula of 1.2-1.4equiv. is successively added into reactor
IX compound, the alkali of 1.6-2.0equiv., 0.05-0.15equiv. catalyst after, reaction system is warming up to 65-75 DEG C, protects
Reaction solution is concentrated to dryness by temperature reaction 16-20h after reaction, and concentration residue is in methylene chloride and 0.5-1.5N hydrochloric acid water
It is distributed in solution, separates organic phase, after successively using saturated sodium bicarbonate aqueous solution and saturated common salt water washing organic phase, organic phase
It is dried and concentrated with sodium sulphate, concentrate obtains Ⅹ compound of formula through column chromatography for separation；
The synthesis of S3, type I compound: 0.5-1.5g is weighed, the Formula X compound of 1.0equiv. is in reactor, with formula Ⅹ
The formula IV compound of 1.2-1.4equiv. is added into reactor compound meter, under room temperature, successively by 1.0-
The triphenylphosphine of 2.0equiv. and the activator of 1.0-2.5equiv. are added into reactor, and reaction response is stirred at room temperature
After 4.5-5.5h, reaction solution is concentrated to dryness, and concentration residue is distributed in ethyl acetate and 0.5-1.5N aqueous hydrochloric acid solution, separation
Organic phase, successively with after saturated sodium bicarbonate aqueous solution and saturated common salt water washing organic phase, organic phase is dry simultaneously with sodium sulphate
Concentration, concentrate obtain type I compound through column chromatography for separation.
Preferably, the alkali in the step S1, step S2 is potassium carbonate.
Preferably, the palladium catalyst in the step S1 is Pd (PPh3)4。
Preferably, 1.0g is weighed in the step S1, THF10mL is added in reactor in VII compound of 1.0equiv. formula
Afterwards, VI compound of formula of 1.2equiv., the Pd (PPh of 0.1equiv. are sequentially added in terms of VII compound, in reactor3)4、
The potassium carbonate of 2.0equiv., after being warming up to 50 DEG C, reaction solution is concentrated to dryness by insulation reaction 18h after reaction, is concentrated residual
Excess distributes in methylene chloride and 0.1N aqueous hydrochloric acid solution, separates organic phase.
Preferably, the catalyst in the step S2 is any one in TBAI, TBAB.
Preferably, 1.0g is weighed in the step S2,10mL is added in reactor in VIII compound of formula of 1.0equiv.
Isosorbide-5-Nitrae-dioxane dissolution after, in terms of VIII compound of formula, successively into reactor be added 1.2equiv. Formula IX compound,
After the alkali of 1.8equiv., the catalyst of 0.1equiv., reaction system is warming up to 70 DEG C, insulation reaction 18h, after reaction,
Reaction solution is concentrated to dryness, concentration residue is distributed in methylene chloride and 1.0N aqueous hydrochloric acid solution.
Preferably, 1.0g is weighed in the step S, the Formula X compound of 1.0equiv. is in reactor, with Ⅹ chemical combination of formula
The formula IV compound of 1.2equiv. is added into reactor object meter, under room temperature, successively by the triphenyl of 1.5equiv.
The activator of phosphine and 1.5equiv. are added into reactor, and after reaction response 5.0h is stirred at room temperature, reaction solution is concentrated to dryness,
Concentration residue is distributed in ethyl acetate and 1.0N aqueous hydrochloric acid solution, separates organic phase, successively molten with saturated sodium bicarbonate water
After liquid and saturated common salt water washing organic phase, organic phase is dried and concentrated with sodium sulphate, and concentrate obtains formula I through column chromatography for separation
Compound.
Preferably, the activator is DIAD.
The present invention has the advantage that compared with prior art
The present invention discloses a kind of method that the Organometallic Palladium as shown in formula I catalyzes and synthesizes elagolix intermediate, compares
With traditional synthetic route, process route disclosed by the invention is not only cheap and easy to get on synthesis material, and synthetic route green
Environmental protection is avoided using mesyl chloride, easy to operate.
Specific embodiment
It elaborates below to the embodiment of the present invention, the present embodiment carries out under the premise of the technical scheme of the present invention
Implement, the detailed implementation method and specific operation process are given, but protection scope of the present invention is not limited to following implementation
Example.
Embodiment 1
A kind of method that Organometallic Palladium catalyzes and synthesizes elagolix intermediate, structure is as shown in formula I；
The synthetic route of the type I compound is as follows:
The synthetic method of type I compound the following steps are included:
The synthesis of S1, VIII compound of formula: weighing 1.0g, and VII compound of 1.0equiv. formula is added in reactor
After THF10mL, VI compound of formula of 1.2equiv., the Pd of 0.1equiv. are sequentially added in terms of VII compound, in reactor
(PPh3)4, 2.0equiv. potassium carbonate, after being warming up to 50 DEG C, reaction solution is concentrated by insulation reaction 18h after reaction
Dry, concentration residue is distributed in methylene chloride and 0.1N aqueous hydrochloric acid solution, is separated organic phase, is successively used saturated sodium bicarbonate water
After solution and saturated common salt water washing organic phase, organic phase is dried and concentrated with sodium sulphate, and concentrate is obtained through column chromatography for separation
VIII compound of formula, yield 75%, high resolution mass spectrum (ESI+): C12H12FN2O3 +, 251.0832；
The synthesis of S2, Ⅹ compound of formula: weighing 1.0g, and 10mL is added in reactor in VIII compound of formula of 1.0equiv.
Isosorbide-5-Nitrae-dioxane dissolution after, in terms of VIII compound of formula, successively into reactor be added 1.2equiv. Formula IX compound,
After the alkali of 1.8equiv., the catalyst of 0.1equiv., reaction system is warming up to 70 DEG C, insulation reaction 18h, after reaction,
Reaction solution is concentrated to dryness, concentration residue is distributed in methylene chloride and 1.0N aqueous hydrochloric acid solution, is separated organic phase, is successively used
After saturated sodium bicarbonate aqueous solution and saturated common salt water washing organic phase, organic phase is dried and concentrated with sodium sulphate, concentrate warp
Column chromatography for separation obtains Ⅹ compound of formula, yield 83%, high resolution mass spectrum (ESI+): C20H16F5N2O3 +, 427.1084；
The synthesis of S3, type I compound: weighing 1.0g, and the Formula X compound of 1.0equiv. is in reactor, with Ⅹ chemical combination of formula
The formula IV compound of 1.2equiv. is added into reactor object meter, under room temperature, successively by the triphenyl of 1.5equiv.
The DIAD of phosphine and 2.5equiv. are added into reactor, and after reaction response 5.0h is stirred at room temperature, reaction solution is concentrated to dryness, dense
Contracting residue distributes in ethyl acetate and 1.0N aqueous hydrochloric acid solution, separates organic phase, successively uses saturated sodium bicarbonate aqueous solution
After saturated common salt water washing organic phase, organic phase is dried and concentrated with sodium sulphate, and concentrate obtains formula I through column chromatography for separation and changes
Close object, yield 80%, high resolution mass spectrum (ESI+): C33H33F5N3O5 +, 646.2340.
Embodiment 2
A kind of method that Organometallic Palladium catalyzes and synthesizes elagolix intermediate, structure is as shown in formula I；
The synthetic route of the type I compound is as follows:
The synthetic method of type I compound the following steps are included:
The synthesis of S1, VIII compound of formula: weighing 0.5g, and THF is added in reactor in VII compound of 1.0equiv. formula
After 5mL, VI compound of formula of 1.2equiv., the Pd of 0.15equiv. are sequentially added in terms of VII compound, in reactor
(PPh3)4, the potassium carbonate of 1.5equiv., after being warming up to 45 DEG C, reaction solution is concentrated by insulation reaction 20h after reaction
Dry, concentration residue is distributed in methylene chloride and 1.5N aqueous hydrochloric acid solution, is separated organic phase, is successively used saturated sodium bicarbonate water
After solution and saturated common salt water washing organic phase, organic phase is dried and concentrated with sodium sulphate, and concentrate is obtained through column chromatography for separation
VIII compound of formula, yield 74.2%, high resolution mass spectrum (ESI+): C12H12FN2O3 +, 251.0832；
The synthesis of S2, Ⅹ compound of formula: weighing 1.5g, and 15mL is added in reactor in VIII compound of formula of 1.0equiv.
Isosorbide-5-Nitrae-dioxane dissolution after, in terms of VIII compound of formula, successively into reactor be added 1.4equiv. Formula IX compound,
After the potassium carbonate of 2.0equiv., the TBAB of 0.05equiv., reaction system is warming up to 70 DEG C, and insulation reaction 16h, reaction terminates
Afterwards, reaction solution being concentrated to dryness, concentration residue is distributed in methylene chloride and 0.5N aqueous hydrochloric acid solution, organic phase is separated, according to
After secondary use saturated sodium bicarbonate aqueous solution and saturated common salt water washing organic phase, organic phase is dried and concentrated with sodium sulphate, concentration
Object obtains Ⅹ compound of formula, yield 82.4%, high resolution mass spectrum (ESI+): C through column chromatography for separation20H16F5N2O3 +, 427.1084；
The synthesis of S3, type I compound: weighing 1.5g, and the Formula X compound of 1.0equiv. is in reactor, with Ⅹ chemical combination of formula
The formula IV compound of 1.4equiv. is added into reactor object meter, under room temperature, successively by the triphenyl of 2.0equiv.
The DIAD of phosphine and 2.0equiv. are added into reactor, and after reaction response 5.5h is stirred at room temperature, reaction solution is concentrated to dryness, dense
Contracting residue distributes in ethyl acetate and 1.5N aqueous hydrochloric acid solution, separates organic phase, successively uses saturated sodium bicarbonate aqueous solution
After saturated common salt water washing organic phase, organic phase is dried and concentrated with sodium sulphate, and concentrate obtains formula I through column chromatography for separation and changes
Close object, yield 79.7%, high resolution mass spectrum (ESI+): C33H33F5N3O5 +, 646.2340.
Embodiment 3
A kind of method that Organometallic Palladium catalyzes and synthesizes elagolix intermediate, structure is as shown in formula I；
The synthetic route of the type I compound is as follows:
The synthetic method of type I compound the following steps are included:
The synthesis of S1, VIII compound of formula: weighing 1.5g, and THF is added in reactor in VII compound of 1.0equiv. formula
After 15mL, VI compound of formula of 1.4equiv., the Pd of 0.15equiv. are sequentially added in terms of VII compound, in reactor
(PPh3)4, the potassium carbonate of 2.5equiv., after being warming up to 55 DEG C, reaction solution is concentrated by insulation reaction 16h after reaction
Dry, concentration residue is distributed in methylene chloride and 0.5N aqueous hydrochloric acid solution, is separated organic phase, is successively used saturated sodium bicarbonate water
After solution and saturated common salt water washing organic phase, organic phase is dried and concentrated with sodium sulphate, and concentrate is obtained through column chromatography for separation
VIII compound of formula, yield 74.1%, high resolution mass spectrum (ESI+): C12H12FN2O3 +, 251.0832；
The synthesis of S2, Ⅹ compound of formula: weighing 0.5g, and 5mL is added in reactor in VIII compound of formula of 1.0equiv.
Isosorbide-5-Nitrae-dioxane dissolution after, in terms of VIII compound of formula, successively into reactor be added 1.2equiv. Formula IX compound,
After the potassium carbonate of 1.6equiv., the TBAI of 0.05equiv., reaction system is warming up to 75 DEG C, and insulation reaction 20h, reaction terminates
Afterwards, reaction solution being concentrated to dryness, concentration residue is distributed in methylene chloride and 1.5N aqueous hydrochloric acid solution, organic phase is separated, according to
After secondary use saturated sodium bicarbonate aqueous solution and saturated common salt water washing organic phase, organic phase is dried and concentrated with sodium sulphate, concentration
Object obtains Ⅹ compound of formula, yield 82.8%, high resolution mass spectrum (ESI+): C through column chromatography for separation20H16F5N2O3 +, 427.1084；
The synthesis of S3, type I compound: weighing 0.5g, and the Formula X compound of 1.0equiv. is in reactor, with Ⅹ chemical combination of formula
The formula IV compound of 1.2equiv. is added into reactor object meter, under room temperature, successively by the triphenyl of 1.0equiv.
The DIAD of phosphine and 1.0equiv. are added into reactor, and after reaction response 4.5h is stirred at room temperature, reaction solution is concentrated to dryness, dense
Contracting residue distributes in ethyl acetate and 0.5-1.5N aqueous hydrochloric acid solution, separates organic phase, successively uses saturated sodium bicarbonate water
After solution and saturated common salt water washing organic phase, organic phase is dried and concentrated with sodium sulphate, and concentrate is obtained through column chromatography for separation
Type I compound, yield 79.6%, high resolution mass spectrum (ESI+): C33H33F5N3O5 +, 646.2340.
Embodiment 4
A kind of method that Organometallic Palladium catalyzes and synthesizes elagolix intermediate, structure is as shown in formula I；
The synthetic route of the type I compound is as follows:
The synthetic method of type I compound the following steps are included:
The synthesis of S1, VIII compound of formula: weighing 1.2g, and THF is added in reactor in VII compound of 1.0equiv. formula
After 10mL, VI compound of formula of 1.3equiv., the Pd of 0.12equiv. are sequentially added in terms of VII compound, in reactor
(PPh3)4, the potassium carbonate of 2.0equiv., after being warming up to 52 DEG C, reaction solution is concentrated by insulation reaction 18h after reaction
Dry, concentration residue is distributed in methylene chloride and 1.2N aqueous hydrochloric acid solution, is separated organic phase, is successively used saturated sodium bicarbonate water
After solution and saturated common salt water washing organic phase, organic phase is dried and concentrated with sodium sulphate, and concentrate is obtained through column chromatography for separation
VIII compound of formula, yield 74.7%, high resolution mass spectrum (ESI+): C12H12FN2O3 +, 251.0832；
The synthesis of S2, Ⅹ compound of formula: weighing 1.2g, and 12mL is added in reactor in VIII compound of formula of 1.0equiv.
Isosorbide-5-Nitrae-dioxane dissolution after, in terms of VIII compound of formula, successively into reactor be added 1.3equiv. Formula IX compound,
After the potassium carbonate of 1.8equiv., the TBAI of 0.08equiv., reaction system is warming up to 68 DEG C, and insulation reaction 18h, reaction terminates
Afterwards, reaction solution being concentrated to dryness, concentration residue is distributed in methylene chloride and 1.2N aqueous hydrochloric acid solution, organic phase is separated, according to
After secondary use saturated sodium bicarbonate aqueous solution and saturated common salt water washing organic phase, organic phase is dried and concentrated with sodium sulphate, concentration
Object obtains Ⅹ compound of formula, yield 82.2%, high resolution mass spectrum (ESI+): C through column chromatography for separation20H16F5N2O3 +, 427.1084；
The synthesis of S3, type I compound: weighing 0.9g, and the Formula X compound of 1.0equiv. is in reactor, with Ⅹ chemical combination of formula
The formula IV compound of 1.3equiv. is added into reactor object meter, under room temperature, successively by the triphenyl of 1.8equiv.
The DIAD of phosphine and 1.8equiv. are added into reactor, and after reaction response 4.8h is stirred at room temperature, reaction solution is concentrated to dryness, dense
Contracting residue distributes in ethyl acetate and 1.2N aqueous hydrochloric acid solution, separates organic phase, successively uses saturated sodium bicarbonate aqueous solution
After saturated common salt water washing organic phase, organic phase is dried and concentrated with sodium sulphate, and concentrate obtains formula I through column chromatography for separation and changes
Close object, yield 79.3%, high resolution mass spectrum (ESI+): C33H33F5N3O5 +, 646.2340.
Embodiment 5
In the preparation process of Formula VIII compound, reaction condition is affected to reaction effect, in order to filter out preferably
Reaction condition finally screens preferable reality as shown in Table 1 according to technical solution disclosed in embodiment 1 (reaction condition is variable)
Test parameter:
Table 1
The data disclosed in table 1: Pd (PPh is used3)4As catalyst, potassium carbonate be alkali, tetrahydrofuran is solvent,
When reacting 18h, reaction condition is preferable.
Embodiment 6
In the preparation process of Formula X compound, reaction condition is affected to reaction effect, in order to filter out preferable reaction
Condition finally screens preferable experiment ginseng as shown in Table 2 according to technical solution disclosed in embodiment 1 (response parameter is variable)
Number:
Table 2
The data disclosed in table 2: the potassium carbonate of 1.8 equivalents is as alkali, and Isosorbide-5-Nitrae-dioxane is as solvent, reaction
18h, reaction effect are preferable.
Embodiment 7
In the preparation process of type I compound, reaction condition is affected to reaction effect, in order to filter out preferable reaction
Condition finally screens preferable experiment ginseng as shown in table 3 according to technical solution disclosed in embodiment 1 (response parameter is variable)
Number:
Table 3
The data disclosed in table 3: the DIAD of 1.5-2.5 equivalent is as activator, and Isosorbide-5-Nitrae-dioxane is as molten
Agent, reacts 5h, and reaction effect is preferable.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Made any modifications, equivalent replacements, and improvements etc., should all be included in the protection scope of the present invention within mind and principle.
Claims (9)
1. a kind of method that Organometallic Palladium catalyzes and synthesizes elagolix intermediate, which is characterized in that structure is as shown in formula I；
The synthetic route of the type I compound is as follows:
2. the method that Organometallic Palladium according to claim 1 catalyzes and synthesizes elagolix intermediate, which is characterized in that packet
Include following steps:
The synthesis of S1, VIII compound of formula: weighing 0.5-1.5g, and THF 5- is added in reactor in VII compound of 1.0equiv. formula
After 15mL, VI compound of formula, the 0.05-0.15equiv. of 1.2-1.4equiv. are sequentially added in terms of VII compound, in reactor
Palladium catalyst, the alkali of 1.5-2.5equiv., after being warming up to 45-55 DEG C, insulation reaction 16-20h will react after reaction
Liquid is concentrated to dryness, and concentration residue is distributed in methylene chloride and 0.5-1.5N aqueous hydrochloric acid solution, separates organic phase, successively with full
After sodium bicarbonate aqueous solution and saturated common salt water washing organic phase, organic phase is dried and concentrated with sodium sulphate, and concentrate is through column
Chromatography obtains VIII compound of formula；
The synthesis of S2, Ⅹ compound of formula: weighing 0.5-1.5g, and 5- is added in reactor in VIII compound of formula of 1.0equiv.
After the Isosorbide-5-Nitrae of 15mL-dioxane dissolution, in terms of VIII compound of formula, the Formula IX of 1.2-1.4equiv. is successively added into reactor
Compound, the alkali of 1.6-2.0equiv., 0.05-0.15equiv. catalyst after, reaction system is warming up to 65-75 DEG C, heat preservation
Reaction solution is concentrated to dryness by reaction 16-20h after reaction, and concentration residue is water-soluble in methylene chloride and 0.5-1.5N hydrochloric acid
Distributed in liquid, separate organic phase, successively with after saturated sodium bicarbonate aqueous solution and saturated common salt water washing organic phase, organic phase with
Sodium sulphate is dried and concentrated, and concentrate obtains Ⅹ compound of formula through column chromatography for separation；
The synthesis of S3, type I compound: weighing 0.5-1.5g, and the Formula X compound of 1.0equiv. is in reactor, with Ⅹ chemical combination of formula
The formula IV compound of 1.2-1.4equiv. is added into reactor object meter, under room temperature, successively by 1.0-2.0equiv.
Triphenylphosphine and the activator of 1.0-2.5equiv. be added into reactor, reaction response 4.5-5.5h is stirred at room temperature
Afterwards, reaction solution is concentrated to dryness, and concentration residue is distributed in ethyl acetate and 0.5-1.5N aqueous hydrochloric acid solution, separates organic phase,
Successively with after saturated sodium bicarbonate aqueous solution and saturated common salt water washing organic phase, organic phase is dried and concentrated with sodium sulphate, dense
Contracting object obtains type I compound through column chromatography for separation.
3. the method that Organometallic Palladium according to claim 2 catalyzes and synthesizes elagolix intermediate, which is characterized in that institute
Stating the alkali in step S1, step S2 is potassium carbonate.
4. the method that Organometallic Palladium according to claim 3 catalyzes and synthesizes elagolix intermediate, which is characterized in that institute
Stating the palladium catalyst in step S1 is Pd (PPh3)4。
5. the method that Organometallic Palladium according to claim 4 catalyzes and synthesizes elagolix intermediate, which is characterized in that institute
It states and weighs 1.0g in step S1, VII compound of 1.0equiv. formula is in reactor, after THF10mL is added, in terms of VII compound,
VI compound of formula of 1.2equiv., the Pd (PPh of 0.1equiv. are sequentially added in reactor3)4, 2.0equiv. potassium carbonate,
After being warming up to 50 DEG C, reaction solution is concentrated to dryness by insulation reaction 18h after reaction, concentration residue in methylene chloride and
It is distributed in 0.1N aqueous hydrochloric acid solution, separates organic phase.
6. the method that Organometallic Palladium according to claim 5 catalyzes and synthesizes elagolix intermediate, which is characterized in that institute
It is any in TBAI, TBAB for stating the catalyst in step S2.
7. the method that Organometallic Palladium according to claim 6 catalyzes and synthesizes elagolix intermediate, which is characterized in that institute
It states and weighs 1.0g in step S2, Isosorbide-5-Nitrae-dioxane dissolution of 10mL is added in reactor in VIII compound of formula of 1.0equiv.
Afterwards, in terms of VIII compound of formula, be successively added into reactor the Formula IX compound of 1.2equiv., 1.8equiv. alkali,
After the catalyst of 0.1equiv., reaction system is warming up to 70 DEG C, and reaction solution is concentrated by insulation reaction 18h after reaction
Dry, concentration residue is distributed in methylene chloride and 1.0N aqueous hydrochloric acid solution.
8. the method that Organometallic Palladium according to claim 6 catalyzes and synthesizes elagolix intermediate, which is characterized in that institute
It states and weighs 1.0g in step S, the Formula X compound of 1.0equiv. is in reactor, in terms of Ⅹ compound of formula, by 1.2equiv.'s
Formula IV compound is added into reactor, under room temperature, successively by the triphenylphosphine of 1.5equiv. and 1.5equiv.
Activator is added into reactor, and after reaction response 5.0h is stirred at room temperature, reaction solution is concentrated to dryness, and concentration residue is in acetic acid second
It is distributed in ester and 1.0N aqueous hydrochloric acid solution, separates organic phase, successively use saturated sodium bicarbonate aqueous solution and saturated common salt water washing
After organic phase, organic phase is dried and concentrated with sodium sulphate, and concentrate obtains type I compound through column chromatography for separation.
9. the method that Organometallic Palladium according to claim 8 catalyzes and synthesizes elagolix intermediate, which is characterized in that institute
Stating activator is DIAD.
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| CN110669014A (en) * | 2019-11-14 | 2020-01-10 | 重庆医药高等专科学校 | Preparation method of oxalagogri intermediate |
| CN110759870A (en) * | 2019-12-06 | 2020-02-07 | 上海博璞诺科技发展有限公司 | Synthesis method of oxalagogri intermediate |
| WO2021054896A1 (en) | 2019-09-18 | 2021-03-25 | Scinopharm Taiwan, Ltd. | Process for preparing elagolix sodium and intermediates thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021054896A1 (en) | 2019-09-18 | 2021-03-25 | Scinopharm Taiwan, Ltd. | Process for preparing elagolix sodium and intermediates thereof |
| EP4031533A4 (en) * | 2019-09-18 | 2023-09-06 | ScinoPharm Taiwan, Ltd. | Process for preparing elagolix sodium and intermediates thereof |
| CN110669014A (en) * | 2019-11-14 | 2020-01-10 | 重庆医药高等专科学校 | Preparation method of oxalagogri intermediate |
| CN110669014B (en) * | 2019-11-14 | 2021-04-30 | 重庆医药高等专科学校 | Preparation method of oxalagogri intermediate |
| CN110759870A (en) * | 2019-12-06 | 2020-02-07 | 上海博璞诺科技发展有限公司 | Synthesis method of oxalagogri intermediate |
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