CN105968040A - Preparation method of ledipasvir intermediate - Google Patents
Preparation method of ledipasvir intermediate Download PDFInfo
- Publication number
- CN105968040A CN105968040A CN201610514322.7A CN201610514322A CN105968040A CN 105968040 A CN105968040 A CN 105968040A CN 201610514322 A CN201610514322 A CN 201610514322A CN 105968040 A CN105968040 A CN 105968040A
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- formula
- reaction
- add
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
-
- 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
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of a ledipasvir intermediate shown as formula (III). The method is characterized by taking (1R, 3S,4S)-N-t-butyloxycarbonyl-2-azabicyalo[2.2.1] heptane-3-carboxylic acid and o-phenylenediamine as raw materials and synthesizing (1R, 3S,4S)-3-(6-bromine-1H-benzimidazole-2-yl)-2-azabicyalo[2.2.1] heptane-2-carboxylic acid tert-butyl ester by using an anhydride mixing method. The whole route is low in production cost and high in yield; the formed monoamide is easy to purify; the generation and the residual of impurities are reduced; the o-phenylenediamine used as the raw material is cheap and easily-available, is hard to oxidize and discolor and can be stored in bulks; the industrial production is facilitated. The formula (III) is described in the description.
Description
Technical field
The present invention relates to the preparation method of a kind of Lei Dipawei intermediate, belong to field of medicaments.
Background technology
Lei Dipawei (Ledipasvir) is a kind of NS5A protease suppression developed by Gilid Science Co.
Agent.After this compound completes III clinical trial phase, for the Lei Dipawei of therapeutic gene I type hepatitis C
The tablet of the fixed dosage combination of/Suo Feibuwei was included by American Pharmacopeia on February 10th, 2014.
Have the synthesis work to Lei Dipawei such as patent US20130273005, US2013324496 at present
Skill has carried out play-by-play, all refers to structure key intermediate shown below (III):
For the preparation of formula III compound, the method for existing document report is by 4-bromo-1,2-benzene two
Amine and (1R, 3S, 4S)-2-(tertbutyloxycarbonyl)-2-azabicyclo [2.2.1] heptane-3-carboxylic acid exist
It is condensed with 4-bromine o-phenylenediamine under the conditions of EDC.HCl/HOBt or HATU, obtains regional isomer
Mixture, correlated response is as follows:
Although above-mentioned synthesis technique can realize the preparation of key intermediate (III), but there is many defects:
1, condensation reagent cost used is high, and the by-product that condensation reagent reaction generates is difficult to remove, easily at product
The impurity that middle introducing is new；2, above-mentioned reaction has the amide product of two kinds of regional isomerisms to generate, and significantly reduces
Reaction yield, cause the waste of raw material；And, also can generate the impurity of bisamide, this impurity is the most not
Easily remove；3, reaction raw materials 4-bromine o-phenylenediamine is expensive, poor stability, easy oxidation stain,
Can not long term storage, be unfavorable for industrialized production.
For solving the above-mentioned problems in the prior art, need badly a kind of byproduct of reaction of offer generate less,
It is prone to purification and the method preparing Lei Dipawei intermediate easy and simple to handle, that production cost is low.
Summary of the invention
It is an object of the invention to provide the preparation method of a kind of Lei Dipawei intermediate, to solve existing conjunction
Become and technique unavoidably to use expensive reaction raw materials, condensation reagent and reaction purification difficulty
Problem.
The invention provides the preparation method of a kind of Lei Dipawei intermediate (III), comprise the steps:
A, as follows, formula I compound, alkali and acyl chlorides form mixed anhydride in organic solvent, then add
Enter o-phenylenediamine reaction, obtain formula II compound:
B, as follows, formula II compound reacts in organic solvent with bromine source, obtains formula III
Compound:
Further, the acyl chlorides described in step a is pivaloyl chloride, isobutylchloroformate, isobutyl chloroformate
One or more in ester, methylchloroformate, ethyl chloroformate.
Further, in step a, formula I compound is 1:0.9～1:1.1 with the mol ratio of o-phenylenediamine,
It is preferably 1:0.95～1:1.05.
Further, the reaction temperature forming mixed anhydride is-40 DEG C～20 DEG C, is preferably-10 DEG C～10 DEG C.
Further, the organic solvent described in step a be ethyl acetate, isopropyl acetate, butyl acetate,
Diisopropyl ether, methyl tertiary butyl ether(MTBE), dichloromethane, toluene, dimethylbenzene, oxolane, 2-methyl tetrahydrochysene
One or more in furan, acetonitrile, ether, normal hexane.
Further, the alkali described in step a is triethylamine, DIPEA, N, N-dimethyl
Aniline, N-methylmorpholine, pyridine, 2-picoline, 2,6-lutidines, 2,4,6-trimethylpyridine
In one or more.
Further, the organic solvent described in step b be dichloromethane, ethyl acetate, isopropyl acetate,
One in oxolane, 2-methyltetrahydrofuran, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide
Or it is several.
Further, the bromine source described in step b be bromine, DBDMH, N-bromo-succinimide,
One or more in N, N-trimethylaniline three bromide, pyridine three bromide.
Further, in step b, bromo-reaction temperature is-5 DEG C～40 DEG C, is preferably-5 DEG C～20 DEG C.
The invention provides a kind of structure compound as follows (II):
The invention provides the preparation method of a kind of Lei Dipawei intermediate, the method is with (1R, 3S, 4S)-N-
Tertbutyloxycarbonyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid and o-phenylenediamine are raw material, use the side of mixed anhydride
Method, can synthesize (1R, 3S, 4S)-3-(6-bromo-1H-benzimidazolyl-2 radicals-yl)-2-azabicyclo relatively simplely
[2.2.1] heptane-2-carboxylic acid tert-butyl ester (compound III).Synthesis technique of the present invention has the advantage that
1, raw materials used o-phenylenediamine is cheap and easily-available, is difficult to oxidized variable color, can be with mass storage, profit
In industrialized production；
2, reaction avoids the condensation reagent that use is expensive, make production cost significantly reduce；
3, preparation method of the present invention is used can to avoid regional isomer, the generation of bisamide product, aobvious
Write and improve reaction yield；
4, product is prone to purification, effectively reduces the residual of impurity in product.
Obviously, according to the foregoing of the present invention, according to ordinary technical knowledge and the customary means of this area,
Without departing under the present invention above-mentioned basic fundamental thought premise, it is also possible to make other various ways amendment,
Replace or change.
The detailed description of the invention of form by the following examples, remakes the foregoing of the present invention further
Detailed description.But this should not being interpreted as, the scope of the above-mentioned theme of the present invention is only limitted to Examples below.
All technology realized based on foregoing of the present invention belong to the scope of the present invention.
Detailed description of the invention
The raw material, the equipment that use in the specific embodiment of the invention are known product, commercially available by buying
Product obtains.
Synthetic route of the present invention:
Embodiment 1
A) in 500ml there-necked flask, add compound 1 (30.0g, 122.5mmol), add MTBE
(300ml), NMM (14.8g, 146.9mmol, 1.2eq) is added,
Add pivaloyl chloride (14.8g, 122.5mmol, 1eq), during dropping, interior temperature T=0-5 DEG C, keep
T=-5 DEG C-10 DEG C reaction 4h, system is cooled to interior temperature T=-40 DEG C, addition compound 2, be incubated one little
Time, slowly rise again to room temperature reaction 5h, add water cancellation, extracts by ethyl acetate (200ml*2), closes
And organic layer, organic layer washes with water, and anhydrous sodium sulfate is dried, and concentrating under reduced pressure obtains the crude product of compound 3,
The crude product ethyl acetate of 5 times of volumes crystallizes, and obtains compound 3,34g (purity 99.2%, yield 85%).1HNMR(400MHz,CDCl3): δ 8.52 (s, 1H), 7.35 (s, 1H), 7.01 (s, 1H), 6.78-6.75 (m,
2H), 4.15 (s, 1H), 3.92-3.87 (d, J=20.0Hz, 2H), 3.03 (s, 1H), 1.87-1.77 (m, 2H),
1.70-1.68 (m, 2H), 1.65-1.60 (m, 2H), 1.50 (s, 9H), 1.40-1.37 (d, J=12Hz, 1H).
B) in 250ml there-necked flask, add compound 3 (29.0g, 87.6mmol), add DMF
150ml, is down to interior temperature T=-5-0 DEG C, adds NBS (15.6g, 87.6mmol, 1eq), reacts after addition
0.5h, reacts the complete cancellation that adds water, and ethyl acetate (200ml*2) extracts, and merges organic layer, organic facies
Washing with water, concentrating under reduced pressure obtains compound 4.Compound 4 is dissolved in MTBE (300ml), adds second
Acid (26.3g, 438mmol, 5eq), is heated to 55 DEG C of reaction 10h, with the NaOH aqueous solution of 5%
Washing, separatory, organic layer is washed, is concentrated to dryness, and adds 5 times of diisopropyl ether room temperature crystallizations, sucking filtration, concentrates
Obtain compound 5,26.8g (purity 98.8%, two step yields 78%).MS(M-H+):m/z 393.29；1HNMR(400MHz,CDCl3): δ 10.70 (s, 1H), 7.85s, 0.5H), 7.54 (d, J=8.0Hz, 1H),
7.31-7.27 (m, 1.5H), 4.53 (d, J=3.6Hz, 1H), 4.16 (s, 1H), 3.42 (d, J=3.2Hz, 1H),
1.88-1.85(m,1H),1.74-1.70(m,1H),1.59(m,1H),1.57(m,2H),1.52(m,1H),
1.48(s,9H),1.36(s,1H)。
Embodiment 2
A) in 500ml there-necked flask, add compound 1 (30.0g, 122.5mmol), add ethyl acetate
(300ml), add NMM (14.8g, 146.9mmol, 1.2eq), be down to interior temperature T=-10 DEG C--5 DEG C,
Dropping isobutyl chlorocarbonate (16.7g, 122.5mmol, 1eq), temperature control reaction 5h, add compound
2, it is incubated one hour, rises again to room temperature reaction 8h, add water cancellation, with ethyl acetate (200ml*2)
Extraction, merges organic layer, and organic layer washes with water, and concentrating under reduced pressure obtains the crude product of compound 3.
B) in 500ml there-necked flask, add the crude product (40g, 120.8mmol) of compound 3, add DMF
200ml, cryosel bath is down to T=-5 DEG C-5 DEG C, is added NBS (19.4g, 108.7mmol, 0.9eq), add
Reacting 0.5h after entering, react the complete cancellation that adds water, ethyl acetate (200ml*2) extracts, and merges organic
Layer, washing, concentrating under reduced pressure obtains compound 4.Compound 4 is dissolved in ethyl acetate (300ml), adds
Entering acetic acid (36.2g, 600mmol, 5eq), be heated to 70 DEG C of reaction 10h, add water cancellation, organic
Layer washs with the NaOH of 5%, separatory, and organic layer is washed, is concentrated into grease, adds 3 times of diisopropyl ethers
Room temperature crystallizes, and sucking filtration dries to obtain compound 5,29.2g (purity 97.5%, three step yields 60.4%).
MS(M-H+):m/z 393.29；1HNMR(400MHz,CDCl3): δ 10.70 (s, 1H), 7.85s,
0.5H), 7.54 (d, J=8.0Hz, 1H), 7.31-7.27 (m, 1.5H), 4.53 (d, J=3.6Hz, 1H), 4.16 (s,
1H), 3.42 (d, J=3.2Hz, 1H), 1.88-1.85 (m, 1H), 1.74-1.70 (m, 1H), 1.59 (m, 1H),
1.57(m,2H),1.52(m,1H),1.48(s,9H),1.36(s,1H)。
Embodiment 3
A) in 1000ml there-necked flask, add compound 1 (50.0g, 204.1mmol), add acetic acid
Isopropyl ester (400ml), adds triethylamine (24.7g, 245.0mmol, 1.2eq), is down to interior temperature T=-10 DEG C
--5 DEG C, dropping pivaloyl chloride (25.0g, 122.5mmol, 1eq), after dropping completely, T=-5 DEG C-10 DEG C
Reaction 4h, adds 100ml isopropyl acetate solution (23.2g, 214mmol, 1.05eq) of compound 2,
After addition, being incubated one hour, slowly rise again to room temperature reaction 8h, add water cancellation, uses isopropyl acetate
(300ml*2) extraction, merges organic layer, and organic layer 1N HCl/water solution (100ml) washs,
Washing (100ml), organic facies concentrating under reduced pressure obtains the crude product of compound 3, and the crude product of compound 3 adds 5 times
The isopropyl acetate heating for dissolving of quality, is concentrated into 1 times of volume, adds 4 times of volume petroleum ether crystallizations,
Compound 3,54g (purity 99.5%, yield 80.5%).MS(M-H+):m/z 332.4；1HNMR(400MHz,CDCl3): δ 8.52 (s, 1H), 7.35 (s, 1H), 7.01 (s, 1H), 6.78-6.75 (m,
2H), 4.15 (s, 1H), 3.92-3.87 (d, J=20.0Hz, 2H), 3.03 (s, 1H), 1.87-1.77 (m, 2H),
1.70-1.68 (m, 2H), 1.65-1.60 (m, 2H), 1.50 (s, 9H), 1.40-1.37 (d, J=12Hz, 1H).
B) in 500ml there-necked flask, add compound 3 (50.0g, 151.1mmol), add acetic acid different
Propyl ester (150ml), is down to T=0-5 DEG C, adds NBS (26.9g, 151.1mmol, 1eq), after addition
Reaction 0.5h, reacts the complete cancellation that adds water, and isopropyl acetate (200ml*2) extracts, and merges organic layer,
Washing (100ml), concentrating under reduced pressure obtains compound 4.Compound 4 is dissolved in isopropyl acetate (300ml),
Add propanoic acid (755.6mmol, 5eq), be heated to 77 DEG C of reaction 10h, the KOH water of organic layer 5%
Solution washs, separatory, organic layer washing (200ml), is concentrated into grease, adds 4 times of diisopropyl ether room temperature
Crystallization, sucking filtration, dry to obtain compound 5,48.1g (purity 98.3%, two step yields 81%).MS(M-H+):
m/z 393.29；1HNMR(400MHz,CDCl3): δ 10.70 (s, 1H), 7.85s, 0.5H), 7.54 (d,
J=8.0Hz, 1H), 7.31-7.27 (m, 1.5H), 4.53 (d, J=3.6Hz, 1H), 4.16 (s, 1H), 3.42 (d,
J=3.2Hz, 1H), 1.88-1.85 (m, 1H), 1.74-1.70 (m, 1H), 1.59 (m, 1H), 1.57 (m, 2H),
1.52(m,1H),1.48(s,9H),1.36(s,1H)。
Embodiment 4
A) in 1000ml there-necked flask, add compound 1 (50.0g, 204.1mmol), add acetic acid second
Ester (500ml), NMM (25.1g, 245.0mmol, 1.2eq), is down to interior temperature T=-10 DEG C--5 DEG C,
Dropping pivaloyl chloride (25.0g, 122.5mmol, 1eq), insulation reaction 4h after dropping completely, add
Compound 2 (23.2g, 214mmol, 1.05eq), is incubated one hour, rises again to room temperature reaction 8h,
Add water cancellation, extracts by ethyl acetate (300ml*2), merges organic layer, organic layer 1%CuSO4
Aqueous solution (100ml) washs, and washes (100ml), and concentrating under reduced pressure obtains the crude product of compounds Ⅳ, chemical combination
The crude product of thing 3, crude product ethyl acetate: petroleum ether=3:1 mixed solvent making beating, sucking filtration, dry
59.5g (purity 99.3%, yield 88.3%).MS(M-H+):m/z 332.4；1HNMR(400MHz,CDCl3): δ 8.52 (s, 1H), 7.35 (s, 1H), 7.01 (s, 1H), 6.78-6.75 (m,
2H), 4.15 (s, 1H), 3.92-3.87 (d, J=20.0Hz, 2H), 3.03 (s, 1H), 1.87-1.77 (m, 2H),
1.70-1.68 (m, 2H), 1.65-1.60 (m, 2H), 1.50 (s, 9H), 1.40-1.37 (d, J=12Hz, 1H).
B) in 500ml there-necked flask, add compound 3 (50.0g, 151.1mmol), add acetonitrile
(150ml), it is down to T=-10 DEG C--5 DEG C, addition N, N trimethylaniline three bromide (56.7g,
151.1mmol, 1eq).Reaction 0.5h, reacts complete, and add water cancellation, with ethyl acetate (200ml*2)
Extraction, merges organic layer, washes (100ml), and concentrating under reduced pressure obtains compound 4.Compound 4 is dissolved in first
In benzene (300ml), add acetic acid (45.3g, 755.6mmol, 5eq), be heated to 110 DEG C of reactions
3h, organic facies with 5% KOH aqueous solution (100ml) wash, separatory, organic layer washing (100ml),
Being concentrated into grease, add 4 times of diisopropyl ether room temperature crystallizations, sucking filtration, dry to obtain compound 5,47.5g is (pure
Degree 98.9%, two step yields 80%).
MS(M-H+):m/z 393.29；1HNMR(400MHz,CDCl3): δ 10.70 (s, 1H), 7.85 (s,
0.5H), 7.54 (d, J=8.0Hz, 1H), 7.31-7.27 (m, 1.5H), 4.53 (d, J=3.6Hz, 1H), 4.16 (s,
1H), 3.42 (d, J=3.2Hz, 1H), 1.88-1.85 (m, 1H), 1.74-1.70 (m, 1H), 1.59 (m, 1H),
1.57(m,2H),1.52(m,1H),1.48(s,9H),1.36(s,1H)。
Embodiment 5
A) in 1000ml there-necked flask, add compound 1 (50.0g, 204.1mmol), add acetic acid second
Ester (500ml), NMM (25.1g, 245.0mmol, 1.2eq), is down to interior temperature T=-15 DEG C--5 DEG C, drip
Add pivaloyl chloride (25.0g, 122.5mmol, 1eq), insulation reaction 5h after dropping completely, add chemical combination
Thing 2 (23.2g, 214mmol, 1.05eq), is incubated one hour, rises again to room temperature reaction 8h, add water
Cancellation, extracts by ethyl acetate (300ml*2), merges organic layer, and organic layer is with 1N HCl (100ml)
Aqueous solution is washed, and washes (100ml), and concentrating under reduced pressure obtains the crude product of compound 3, and the crude product of compound 3 is used
The MTBE making beating of three times of mass ratioes, sucking filtration, it is dried to obtain 57.5g (purity 98.8%, yield 85.2%).
B) in 500ml there-necked flask, compound 3 (57.5g, 173.7mmol) is added, DMF (200ml),
It is down to T=-15 DEG C--5 DEG C, the DMF (30ml) of dropping DBDMH (35.5g, 124.1mmol, 0.7eq)
Solution.Insulation reaction 0.5h, reacts the complete cancellation that adds water, and ethyl acetate (300ml*2) extracts, and closes
And organic layer, to wash (100ml), concentrating under reduced pressure obtains compound 4.Compound 4 is dissolved in diisopropyl ether (350
Ml), adding formic acid (40.0g, 868.5mmol, 5eq), be heated to 70 DEG C of reaction 6h, organic facies is used
The Na of 10%2CO3(100ml) washing, separatory, organic layer washing (100ml), it is concentrated into grease,
Add 3 times of petroleum ether room temperature crystallizations, sucking filtration, dry to obtain compound 5,55.8g (purity 98.0%, two steps
Yield 82.1%).1HNMR(400MHz,CDCl3): δ 10.70 (s, 1H), 7.85 (s, 0.5H), 7.54 (d,
J=8.0Hz, 1H), 7.31-7.27 (m, 1.5H), 4.53 (d, J=3.6Hz, 1H), 4.16 (s, 1H), 3.42 (d,
J=3.2Hz, 1H), 1.88-1.85 (m, 1H), 1.74-1.70 (m, 1H), 1.59 (m, 1H), 1.57 (m, 2H),
1.52(m,1H),1.48(s,9H),1.36(s,1H)。
Embodiment 6
In 500ml there-necked flask, add compound 3 (50.0g, 151.1mmol), add DMF (150ml),
Cryosel bath is down to T=-10 DEG C-5 DEG C, adds pyridine three bromide (50.0g, 166.2mmol, 1.05eq).
Insulation reaction 0.5h, reacts complete (500ml) cancellation that adds water, and ethyl acetate (200ml*2) extracts,
Merging organic layer, wash (100ml), concentrating under reduced pressure obtains compound 4.Compound 4 is dissolved in MTBE (300
Ml) in, add paratoluenesulfonic acid sodium salt (755.6mmol, 5eq), be heated to 65 DEG C of reaction 10h, organic
(100ml) is washed mutually with the NaOH of 5%, separatory, organic layer washing (100ml), it is concentrated into oily
Thing, adds the crystallization of 3 times of diisopropyl ether room temperature, sucking filtration, dries to obtain compound 5, and 46.4g (purity 98.6%, two
Step yield 77.1%).
Embodiment 7
In 500ml there-necked flask, add compound 3 (50.0g, 151.1mmol), add DCM
(300ml), it is down to T <-5 DEG C, addition N, N trimethylaniline three bromide (56.7g, 151.1mmol,
1eq).Reaction 1h, the cancellation that adds water (100ml), to wash (100ml), concentrating under reduced pressure obtains compound 4.
Compound 4 is dissolved in oxolane (300ml), adds acetic acid (45.3g, 755.6mmol, 5eq),
Being heated to 75 DEG C of reaction 9h, organic facies washs (100ml) with the KOH of 5%, separatory, organic layer water
Wash (100ml), be concentrated into grease, add 4 times of volume diisopropyl ether room temperature crystallizations, sucking filtration, dry to change
Compound 5,43.8g (purity 98.2%, two step yields 74.2%).1HNMR(400MHz,CDCl3): δ
10.70 (s, 1H), 7.85s, 0.5H), 7.54 (d, J=8.0Hz, 1H), 7.31-7.27 (m, 1.5H), 4.53 (d,
J=3.6Hz, 1H), 4.16 (s, 1H), 3.42 (d, J=3.2Hz, 1H), 1.88-1.85 (m, 1H), 1.74-1.70 (m,
1H),1.59(m,1H),1.57(m,2H),1.52(m,1H),1.48(s,9H),1.36(s,1H)。
Under the conditions of being listed below differential responses, the yield of each step and product purity in synthetic route of the present invention:
1, the reactions steps of compound 3 is prepared
Table 1 solvent
| Solvent | Reaction temperature (DEG C) | Yield (%) | Purity (%) |
| Ethyl acetate | -10～-5 | 88.3 | 99.3 |
| Dichloromethane | -10～-5 | 82.3 | 98.7 |
| Methyl tertiary butyl ether(MTBE) | -10～-5 | 85.0 | 99.2 |
| Isopropyl acetate | -10～-5 | 80.5 | 99.5 |
| Oxolane | -10～-5 | 81.8 | 98.8 |
| Diisopropyl ether | -10～-5 | 82.1 | 99.1 |
Table 2 temperature
| Solvent | Reaction temperature (DEG C) | Yield (%) | Purity (%) |
| Ethyl acetate | -40～-30 | 88.2 | 99.2 |
| Ethyl acetate | -30～-20 | 87.7 | 99.3 |
| Ethyl acetate | -20～-10 | 87.2 | 99.2 |
| Ethyl acetate | -10～0 | 85.8 | 99.4 |
| Ethyl acetate | 0～10 | 84.5 | 99.2 |
Table 3 alkali
Table 4 acyl chlorides
| Acyl chlorides | Reaction temperature (DEG C) | Yield (%) | Purity (%) |
| Pivaloyl chloride | -10～-5 | 88.5 | 99.2 |
| Isobutylchloroformate | -10～-5 | 66.2 | 99.3 |
| Isobutyl chlorocarbonate | -10～-5 | 80.3 | 99.0 |
| Methylchloroformate | -10～-5 | 870.5 | 99.2 |
| Ethyl chloroformate | -10～-5 | 72.4 | 99.4 |
2, the reactions steps of compound 4 is prepared by compound 3
Table 5 bromine source
Table 6 solvent
3, the reactions steps of compound 5 is prepared by compound 4
Table 7 lewis acid
| Lewis acid | Solvent | Reaction temperature (DEG C) | Yield (%) |
| Acetic acid | Methyl tertiary butyl ether(MTBE) | 70 | 96.8 |
| Formic acid | Methyl tertiary butyl ether(MTBE) | 70 | 96.5 |
| Propanoic acid | Methyl tertiary butyl ether(MTBE) | 70 | 95.9 |
| Benzoic acid | Methyl tertiary butyl ether(MTBE) | 70 | 96.4 |
| P-methyl benzenesulfonic acid | Methyl tertiary butyl ether(MTBE) | 70 | 96.7 |
| Citric acid | Methyl tertiary butyl ether(MTBE) | 70 | 96.5 |
| Oxalic acid | Methyl tertiary butyl ether(MTBE) | 70 | 96.8 |
Table 8 solvent
| Solvent | Reaction temperature (DEG C) | Lewis acid | Yield (%) |
| Ethyl acetate | 70 | Acetic acid | 96.5 |
| Toluene | 70 | Acetic acid | 95.9 |
| Methyl tertiary butyl ether(MTBE) | 70 | Acetic acid | 96.3 |
| Isopropyl acetate | 70 | Acetic acid | 96.5 |
| Oxolane | 70 | Acetic acid | 95.8 |
| Diisopropyl ether | 70 | Acetic acid | 96.1 |
More than test result indicate that, use preparation method of the present invention to be improved extremely by monoamides product yield
More than 99%, product purity reaches 88%, enormously simplify post-reaction treatment step, reduces production cost.
Visible, synthetic method of the present invention provided for reduction Lei Dipawei production cost, shortening production cycle
A kind of feasible approach, can realize large-scale production, it is simple to commercial introduction is applied.
Claims (10)
1. the preparation method of Yi Zhong Lei Dipawei intermediate (III), is characterized in that: comprise the steps:
A, as follows, formula I compound, alkali and acyl chlorides form mixed anhydride in organic solvent, then add
Enter o-phenylenediamine reaction, obtain formula II compound:
B, as follows, formula II compound reacts in organic solvent with bromine source, obtains formula III
Compound:
2. preparation method as claimed in claim 1, is characterized in that: the acyl chlorides described in step a is special penta
One in acyl chlorides, isobutylchloroformate, isobutyl chlorocarbonate, methylchloroformate, ethyl chloroformate or
Several.
3. preparation method as claimed in claim 1, is characterized in that: formula I compound in step a
It is 1:0.9～1:1.1, preferably 1:0.95～1:1.05 with the mol ratio of o-phenylenediamine.
4. preparation method as claimed in claim 1, is characterized in that: the reaction temperature forming mixed anhydride is
-40 DEG C～20 DEG C, it is preferably-10 DEG C～10 DEG C.
5. preparation method as claimed in claim 1, is characterized in that: the organic solvent described in step a is
Ethyl acetate, isopropyl acetate, butyl acetate, diisopropyl ether, methyl tertiary butyl ether(MTBE), dichloromethane, first
One in benzene, dimethylbenzene, oxolane, 2-methyltetrahydrofuran, acetonitrile, ether, normal hexane or
Several.
6. preparation method as claimed in claim 1, is characterized in that: the alkali described in step a be triethylamine,
N, N-diisopropylethylamine, N, accelerine, N-methylmorpholine, pyridine, 2-picoline, 2,6-
One or more in lutidines, 2,4,6-trimethylpyridine.
7. preparation method as claimed in claim 1, is characterized in that: the organic solvent described in step b is
Dichloromethane, ethyl acetate, isopropyl acetate, oxolane, 2-methyltetrahydrofuran, acetonitrile, two
One or more in first sulfoxide, N,N-dimethylformamide.
8. preparation method as claimed in claim 1, is characterized in that: the bromine source described in step b be bromine,
In DBDMH, N-bromo-succinimide, N, N-trimethylaniline three bromide, pyridine three bromide
One or more.
9. preparation method as claimed in claim 1, is characterized in that: in step b, bromo-reaction temperature is
-5 DEG C～40 DEG C, it is preferably-5 DEG C～20 DEG C.
10. the compound (II) that a structure is as follows:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610514322.7A CN105968040B (en) | 2016-06-29 | 2016-06-29 | A kind of preparation method of Lei Dipawei intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610514322.7A CN105968040B (en) | 2016-06-29 | 2016-06-29 | A kind of preparation method of Lei Dipawei intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105968040A true CN105968040A (en) | 2016-09-28 |
| CN105968040B CN105968040B (en) | 2019-02-05 |
Family
ID=56953600
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610514322.7A Active CN105968040B (en) | 2016-06-29 | 2016-06-29 | A kind of preparation method of Lei Dipawei intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105968040B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107540604A (en) * | 2017-09-19 | 2018-01-05 | 济南大学 | A kind of preparation method of the bromopyridine of 2 amino 5 |
| CN111072592A (en) * | 2019-12-20 | 2020-04-28 | 河北合佳医药科技集团股份有限公司 | High-purity selective preparation and purification method of aminothiazoly loximate dimer |
| CN112851545A (en) * | 2020-07-08 | 2021-05-28 | 日照巴洛特药业有限公司 | Synthetic process of Ledipasvir intermediate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012087596A1 (en) * | 2010-12-20 | 2012-06-28 | Gilead Sciences, Inc. | Combinations for treating hcv |
| CN104244945A (en) * | 2011-09-16 | 2014-12-24 | 吉利德法莫赛特有限责任公司 | Methods for treating hcv |
| CN104520293A (en) * | 2012-06-05 | 2015-04-15 | 吉利德法莫赛特有限责任公司 | Synthesis of antiviral compound |
| CN105399657A (en) * | 2015-10-21 | 2016-03-16 | 海门慧聚药业有限公司 | Preparation of Ledipasvir key intermediate |
-
2016
- 2016-06-29 CN CN201610514322.7A patent/CN105968040B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012087596A1 (en) * | 2010-12-20 | 2012-06-28 | Gilead Sciences, Inc. | Combinations for treating hcv |
| CN104244945A (en) * | 2011-09-16 | 2014-12-24 | 吉利德法莫赛特有限责任公司 | Methods for treating hcv |
| CN104520293A (en) * | 2012-06-05 | 2015-04-15 | 吉利德法莫赛特有限责任公司 | Synthesis of antiviral compound |
| CN105399657A (en) * | 2015-10-21 | 2016-03-16 | 海门慧聚药业有限公司 | Preparation of Ledipasvir key intermediate |
Non-Patent Citations (2)
| Title |
|---|
| JOHN O.LINK, ET AL: "Discovery of Ledipasvir(GS-5885):A Potent, Once-Daily Oral NS5A Inhibitor for the Treatment of Hepatitis C Virus Infection", 《J.MED.CHEM.》 * |
| 赵聿秋,等: "雷迪帕韦及其关键中间体的合成研究", 《上海医药》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107540604A (en) * | 2017-09-19 | 2018-01-05 | 济南大学 | A kind of preparation method of the bromopyridine of 2 amino 5 |
| CN111072592A (en) * | 2019-12-20 | 2020-04-28 | 河北合佳医药科技集团股份有限公司 | High-purity selective preparation and purification method of aminothiazoly loximate dimer |
| CN111072592B (en) * | 2019-12-20 | 2021-07-20 | 河北合佳医药科技集团股份有限公司 | High-purity selective preparation and purification method of aminothiazoly loximate dimer |
| CN112851545A (en) * | 2020-07-08 | 2021-05-28 | 日照巴洛特药业有限公司 | Synthetic process of Ledipasvir intermediate |
| CN112851545B (en) * | 2020-07-08 | 2022-09-20 | 日照巴洛特药业有限公司 | Synthetic process of Ledipasvir intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105968040B (en) | 2019-02-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI710547B (en) | Synthesis of an antiviral compound | |
| EP3712130A1 (en) | Method for synthesis of roxadustat and intermediate compounds thereof | |
| US20180029998A1 (en) | Method for preparing prostacyclin receptor agonist | |
| WO2013014665A1 (en) | Intermediate compounds and process for the preparation of lurasidone and salts thereof | |
| CN105968040A (en) | Preparation method of ledipasvir intermediate | |
| ITMI20101239A1 (en) | PROCESS AND INTERMEDIATE FOR THE PREPARATION OF AN ACTIVE PRINCIPLE | |
| KR100974608B1 (en) | Method of producing 3-o-alkyl-5,6-o-1-methylethylidene-l-ascorbic acid and method of producing 5,6-o-1-methylethylidene-l-ascorbic acid | |
| CN108947919B (en) | Novel preparation method of anti-gout drug Lesinurad and key intermediate thereof | |
| TW201736379A (en) | AD-35 preparation technology | |
| CN108084145B (en) | Ticagrelor intermediate and preparation method thereof | |
| CN106699604A (en) | Sacubitril and preparation method of midbody of sacubitril | |
| CN106977543A (en) | The preparation technology of improved Suo Feibuwei intermediates | |
| CN112939814B (en) | Preparation method of deuterated dacarbazine intermediate | |
| CN102675385A (en) | Preparation method for doxorubicin13-position hydrazone derivative | |
| CN103554224B (en) | A kind of preparation method of VX-960 | |
| CN106749067A (en) | A kind of aryl of pharmaceutical intermediate 2 replaces the synthetic method of tetrazole compound | |
| CN111057052B (en) | Method for preparing minodronic acid intermediate 2- (imidazo [1, 2-alpha ] pyridine-3-yl) acetate compound | |
| CN109678787A (en) | A kind of new HCV virus NS3/4A inhibitor synthetic intermediate and synthetic method | |
| CN101423524B (en) | Diglutamate derivates and application thereof in preparation of pemetrexed | |
| CN110922402B (en) | C-3 iodo-indolizine compound and preparation method thereof | |
| CN116354846B (en) | Synthesis process method of pesticide kresoxim-methyl | |
| JP2003192626A (en) | Method for producing 2-adamantanone | |
| CN103265479B (en) | A kind of synthetic method of the 6 chloromethyl nicotinic acid tert-butyl ester | |
| CN107216302A (en) | A kind of fluorine can draw fixed synthetic method | |
| CN111718334B (en) | Rosuvastatin calcium intermediate compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |