CN105884760B - A kind of preparation method than his intermediate of department - Google Patents
A kind of preparation method than his intermediate of department Download PDFInfo
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- CN105884760B CN105884760B CN201610414991.7A CN201610414991A CN105884760B CN 105884760 B CN105884760 B CN 105884760B CN 201610414991 A CN201610414991 A CN 201610414991A CN 105884760 B CN105884760 B CN 105884760B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
It is a kind of to be related to field of medicinal chemistry than the preparation method for taking charge of his intermediate, the preparation method of compound shown in formula (A),Its step are as follows: after (S)-(-)-alpha-amido-gamma-butyrolacton (2) or its salt and triphosgene are dissolved in halogenated hydrocarbons, carbonate solution is added to be reacted, [2- isopropyl -4- (((N- methyl) amido) methyl) thiazole (5) or the progress condensation reaction of its salt are added after completion of the reaction
Description
Technical field
The present invention relates to field of medicinal chemistry, and in particular to a kind of than the preparation method for taking charge of his intermediate.
Background technique
Than him is taken charge of, cobicistat (GS-9350) is a kind of pharmacodynamics enhancing of lucky moral (Gilead) exploitation
Agent, trade name Tybost improve the blood concentration of specific HIV drug as pharmacokinetics reinforcing agent once a day.
Tybost is intended as hiv protease inhibitor atazanavir (atazanavir, 300mg, once a day) and darunavir
The reinforcing agent of (darunavir, 800mg, once a day) is used for HIV-1 as a part of antiretroviral conjoint therapy
The treatment of adult the infected.
PCT Patent Application WO2014057498 discloses the preparation method than Si Ta and its intermediate, wherein shown in formula (1)
Compound is the comparable key intermediate for taking charge of him of synthesis,
Shown in formula (1)
Compound shown in formula (A) occurs nucleophilic substitution with morpholine after bromotrimethylsilane bromination and is made
The existing preparation process of compound shown in formula (A) is L- amino lactone (2) and carbonyl dimidazoles (3) in methylene chloride
In, reaction obtains intermediate 4, intermediate 4 and 3-4- (Methylaminomethyl) thiazole in the presence of organic base diisopropylethylamine
Compound shown in formula (A) is made in hydrochloride (5) under organic base catalytic, and reaction equation is as follows:
The process requirement of compound shown in existing synthesis formula (A) uses a large amount of methylene chloride and organic amine such as diisopropyl second
Amine or triethylamine, easily emulsify, and cause to post-process cumbersome, and the purity of product is low, is not suitable for industrialized production.
Summary of the invention
The object of the present invention is to provide one kind to take water as a solvent, post-processing is simple, purity is high and be suitble to it is industrial can
Than taking charge of his intermediate, its chemical name is N- [N- methyl-N- [(2- isopropyl -4- thiazolyl) methyl] amino carbonyl]-L- is high
Serine lactone, structure preparation method as shown in formula (A)
In order to realize the purpose, technical scheme is as follows:
It is a kind of than taking charge of his intermediate, the preparation method of compound shown in formula (A),
Its step are as follows: after (S)-(-)-alpha-amido-gamma-butyrolacton (2) or its salt and triphosgene are dissolved in halogenated hydrocarbons, adding
Enter carbonate solution to be reacted, after completion of the reaction be added [2- isopropyl -4- (((N- methyl) amido) methyl) thiazole (5) or
Its salt carries out condensation reaction
Further, the molar ratio of described (S)-(-)-alpha-amido-gamma-butyrolacton (2) or its salt and triphosgene can be 1:1
~1:2, in one embodiment, the molar ratio of (S)-(-)-alpha-amido-gamma-butyrolacton (2) or its salt and triphosgene are 1.2.
Further, the halogenated hydrocarbons is selected from methylene chloride, chloroform, carbon tetrachloride or 1, and one in 2- dichloroethanes
Kind or combinations thereof；The molal volume ratio of (S)-(-)-alpha-amido-gamma-butyrolacton (2) or its salt or its salt and halogenated hydrocarbons is
1.0mol/L is hereinafter, it is preferred that 0.4~0.8mol/L；The carbonate solution can be sodium bicarbonate solution, potassium bicarbonate solution, carbon
One of acid sodium solution or solution of potassium carbonate or combinations thereof；The molar concentration of the carbonate solution can be 1.0~2.0mol/
L, in one embodiment, the molar concentration of the carbonate solution can be 1.2mol/L；The sodium bicarbonate solution with it is halogenated
The volume ratio of hydrocarbon can be 2.0:1.0, and in one embodiment, the volume ratio of the sodium bicarbonate solution and halogenated hydrocarbons is about 1.5.
Further, the adding manner that carbonate solution is added, which can be, is added at one time, a several batches is divided to be added
Or continuous dropwise addition or interval are added dropwise, and preferably continuous to be added dropwise, dropping temperature is about 15~35 DEG C, and preferably 20~25 DEG C；Carbonate is molten
It after liquid is added dropwise, is warming up to 30 DEG C or more and is reacted, preferably 33~35 DEG C are being reacted, after reaction 0.5h~for 24 hours
[2- isopropyl -4- (((N- methyl) amido) methyl) thiazole (5) or its salt carry out condensation reaction, and the condensation reaction exists for addition
It is carried out at 33~35 DEG C.
In a preferred embodiment, described than taking charge of his intermediate, the preparation method of compound shown in formula (A),
Its operating procedure is as follows: 1 mole of (S)-(-)-alpha-amido-gamma-butyrolacton (2) hydrobromate and 1.2 moles of triphosgenes are dissolved in 1
In~2ml methylene chloride, 1.5~3ml of sodium bicarbonate solution of 1.2mol/L is added dropwise thereto at 20~25 DEG C, about 1.5 is small
When add, after adding, be warming up to 33~35 DEG C, insulated and stirred 1 hour, 1.02mmol is then added at 33~35 DEG C, and [2- was different
Propyl -4- (((N- methyl) amido) methyl) thiazole dihydrochloride], 35 DEG C of insulation reaction 1h after adding.
Compared with the existing technology, the invention has the following advantages that
The present invention substitutes organic base using inorganic alkali solution, reduces emulsion, and reduce cost, realizes two phase reaction,
Accelerate reaction speed, reaction process is also to remove the process of impurity, simplifies post-processing, product purity is improved, especially suitable for work
Industry metaplasia produces.Water consumption substitution major part organic solvent reduces the dosage of organic solvent, environmentally protective.
Specific embodiment
In order to make those skilled in the art more fully understand technical solution of the present invention, disclose further below some non-
Limiting embodiment, the present invention is described in further detail.
1 N- of embodiment [N- methyl-N- [(2- isopropyl -4- thiazolyl) methyl] amino carbonyl]-L- homoserine lactone
The preparation of (formula A)
Into 1000ml four-hole bottle, by (S)-(-)-alpha-amido-gamma-butyrolacton (2) or its salt 32.4g (178mmol) and
21.6g triphosgene (218.3mmol) is dissolved in 270ml methylene chloride, under nitrogen protection, is added dropwise thereto at 25 DEG C
The sodium bicarbonate solution 400ml of 1.2mol/L is added for about 1.5 hours, after adding, is warming up to 33~35 DEG C, insulated and stirred one is small
When, 43.8g [2- isopropyl -4- (((N- methyl) amido) methyl) thiazole dihydrochloride] then is added at 33~35 DEG C
(182.3mmol), 35 DEG C of insulation reaction 1h after adding；HPLC is monitored after the reaction was completed, and liquid separation, water phase is extracted with 100g methylene chloride
It takes, then washed once with 10% citric acid solution of 120g；Liquid separation, merges organic phase, and organic phase is washed with 5% sodium carbonate liquor again
It washs, liquid separation, organic phase is washed with 10% sodium chloride solution, liquid separation, and organic phase evaporated under reduced pressure obtains about 45g light yellow oil
Body, the as product of title, yield 85%, it is 99.5% that HPLC, which detects purity,.
2 N- of embodiment [N- methyl-N- [(2- isopropyl -4- thiazolyl) methyl] amino carbonyl]-L- homoserine lactone
The preparation of (formula A)
Into 1000ml four-hole bottle, by (S)-(-)-alpha-amido-gamma-butyrolacton (2) or its salt 32.4g (178mmol) and
21.6g triphosgene (218.3mmol) is dissolved in 270ml methylene chloride, under nitrogen protection, is added dropwise thereto at 15 DEG C
The potassium bicarbonate solution 400ml of 2.0mol/L is added for about 1.5 hours, after adding, is warming up to 33~35 DEG C, insulated and stirred one is small
When, 43.8g [2- isopropyl -4- (((N- methyl) amido) methyl) thiazole dihydrochloride] then is added at 33~35 DEG C
(182.3mmol), 35 DEG C of insulation reaction 1h after adding；HPLC is monitored after the reaction was completed, and liquid separation, water phase is extracted with 100g methylene chloride
It takes, then washed once with 10% citric acid solution of 140g；Liquid separation, merges organic phase, and organic phase is washed with 5% sodium carbonate liquor again
It washs, liquid separation, organic phase is washed with 10% sodium chloride solution, liquid separation, and organic phase evaporated under reduced pressure obtains about 43.8g pale yellowish oil
Object, the as product of title, it is 99.1% that HPLC, which detects purity,.
3 N- of embodiment [N- methyl-N- [(2- isopropyl -4- thiazolyl) methyl] amino carbonyl]-L- homoserine lactone
The preparation of (formula A)
Into 1000ml four-hole bottle, by (S)-(-)-alpha-amido-gamma-butyrolacton (2) or its salt 32.4g (178mmol) and
21.6g triphosgene (218.3mmol) is dissolved in 270ml carbon tetrachloride, under nitrogen protection, is added dropwise thereto at 15 DEG C
The sodium carbonate liquor 400ml of 1.0mol/L is added for about 1.5 hours, after adding, is warming up to 33~35 DEG C, and insulated and stirred one hour,
Then 43.8g [2- isopropyl -4- (((N- methyl) amido) methyl) thiazole dihydrochloride] is added at 33~35 DEG C
(182.3mmol), 35 DEG C of insulation reaction 1h after adding；HPLC is monitored after the reaction was completed, and liquid separation, water phase is extracted with 100g methylene chloride
It takes, then washed once with 10% citric acid solution of 140g；Liquid separation, merges organic phase, and organic phase is washed with 5% sodium carbonate liquor again
It washs, liquid separation, organic phase is washed with 10% sodium chloride solution, liquid separation, and organic phase evaporated under reduced pressure obtains about 43g light yellow oil
Body, the as product of title, it is 98.5% that HPLC, which detects purity,.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair
Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (5)
1. a kind of preparation method than compound shown in his intermediate formula (A) of department,
It is characterized by: the formula (A) are as follows:
Its step are as follows: after (S)-(-)-alpha-amido-gamma-butyrolacton (2) or its salt and triphosgene are dissolved in halogenated hydrocarbons, carbon is added
Acid salt solution is reacted, and [2- isopropyl -4- (((N- methyl) amido) methyl) thiazole (5) or its salt are added after completion of the reaction
Carry out condensation reaction
Mole of the carbonate solution
Concentration is 1.0~2.0mol/L, and the carbonate is sodium bicarbonate solution, the volume ratio of the sodium bicarbonate solution and halogenated hydrocarbons
It for 2.0:1.0, or is 1.5.
2. a kind of than the preparation method for taking charge of compound shown in his intermediate formula (A) as described in claim 1, it is characterised in that:
The molar ratio of (S)-(-)-alpha-amido-gamma-butyrolacton (2) or its salt and triphosgene is 1:1~1:2, or is 1.2.
3. a kind of than the preparation method for taking charge of compound shown in his intermediate formula (A) as described in claim 1, it is characterised in that:
The halogenated hydrocarbons is selected from methylene chloride, chloroform, carbon tetrachloride or 1, one of 2- dichloroethanes or combinations thereof.
4. a kind of than the preparation method for taking charge of compound shown in his intermediate formula (A) as described in claim 1, it is characterised in that:
The molal volume ratio of (S)-(-)-alpha-amido-gamma-butyrolacton (2) or its salt and halogenated hydrocarbons is 1.0mol/L or less.
5. a kind of than the preparation method for taking charge of compound shown in his intermediate formula (A) as described in claim 1, it is characterised in that:
The adding manner that carbonate solution is added is continuous dropwise addition, and dropping temperature is 20~25 DEG C；Carbonate solution is added dropwise
Afterwards, it is warming up to 33~35 DEG C to be reacted, reaction 0.5h~[2- isopropyl -4- (((N- methyl) amido) first is added later for 24 hours
Base) thiazole (5) or its salt carries out condensation reaction.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008010921A2 (en) * | 2006-07-07 | 2008-01-24 | Gilead Sciences, Inc. | Modulators of pharmacokinetic properties of therapeutics |
| WO2011109470A1 (en) * | 2010-03-05 | 2011-09-09 | Boehringer Ingelheim International Gmbh | Heteroaryl nitrile compounds useful as inhibitors of cathepsin-s |
| CN102659632A (en) * | 2012-04-24 | 2012-09-12 | 江西科技师范学院 | Preparation method of aminonorbornane isocyanate |
| WO2014057498A2 (en) * | 2012-10-08 | 2014-04-17 | Mylan Laboratories Ltd. | Process for the preparation of cobicistat intermediates |
| WO2015057938A1 (en) * | 2013-10-18 | 2015-04-23 | Eisai R&D Management Co., Ltd. | Pyrimidine fgfr4 inhibitors |
| WO2015083066A1 (en) * | 2013-12-03 | 2015-06-11 | Mylan Laboratories Ltd. | Preparation of cobicistat intermediates |
| CN105348157A (en) * | 2015-12-18 | 2016-02-24 | 苏州大学 | Cystamine diisocyanate monomer, cystamine diisocyanate monomer based polymers as well as preparation method and application of cystamine diisocyanate monomer |
-
2016
- 2016-06-13 CN CN201610414991.7A patent/CN105884760B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008010921A2 (en) * | 2006-07-07 | 2008-01-24 | Gilead Sciences, Inc. | Modulators of pharmacokinetic properties of therapeutics |
| WO2011109470A1 (en) * | 2010-03-05 | 2011-09-09 | Boehringer Ingelheim International Gmbh | Heteroaryl nitrile compounds useful as inhibitors of cathepsin-s |
| CN102659632A (en) * | 2012-04-24 | 2012-09-12 | 江西科技师范学院 | Preparation method of aminonorbornane isocyanate |
| WO2014057498A2 (en) * | 2012-10-08 | 2014-04-17 | Mylan Laboratories Ltd. | Process for the preparation of cobicistat intermediates |
| WO2015057938A1 (en) * | 2013-10-18 | 2015-04-23 | Eisai R&D Management Co., Ltd. | Pyrimidine fgfr4 inhibitors |
| WO2015083066A1 (en) * | 2013-12-03 | 2015-06-11 | Mylan Laboratories Ltd. | Preparation of cobicistat intermediates |
| CN105348157A (en) * | 2015-12-18 | 2016-02-24 | 苏州大学 | Cystamine diisocyanate monomer, cystamine diisocyanate monomer based polymers as well as preparation method and application of cystamine diisocyanate monomer |
Non-Patent Citations (1)
| Title |
|---|
| A Safe and and Efficient Method for Preparation of N,N’-Unsymmetrically Disubstituted Ureas Utilizing Triphosgene;Pave1 Majer et al.;《J. Org. Chem.》;19941231;第59卷;第1937-1938页 |
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Effective date of registration: 20200727 Address after: Unit 03, 9 / F, building B1, Xiamen biomedical industrial park, 2050 wengjiao West Road, Haicang District, Xiamen City, Fujian Province Patentee after: Xiamen Weijia Pharmaceutical Co.,Ltd. Address before: Haicang District of Xiamen City, Fujian province 361006 Xinyang Street Weng Kok Road No. 289 Chong Building 717 unit Patentee before: XIAMEN CITY WEI JIA CHEMICAL TECHNOLOGY Co.,Ltd. |
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