CN107382785B - One seed sand library must bent key intermediate preparation method - Google Patents
One seed sand library must bent key intermediate preparation method Download PDFInfo
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- CN107382785B CN107382785B CN201710675740.9A CN201710675740A CN107382785B CN 107382785 B CN107382785 B CN 107382785B CN 201710675740 A CN201710675740 A CN 201710675740A CN 107382785 B CN107382785 B CN 107382785B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
Abstract
The present invention relates to pharmaceutical technology fields, specifically, being related to a kind of preparation method of new Sha Kubi song key intermediate.Sha Kubi song key intermediate is prepared using method provided by the invention, reaction condition is mild, and it is environmentally protective, and yield is higher than existing preparation method, economical and effective, is suitable for large-scale industrial production.
Description
Technical field
The present invention relates to pharmaceutical technology fields, specifically, be related to a seed sand library must bent key intermediate preparation method.
Background technique
In July, 2015, FDA approval listing Novartis since the dawn of human civilization most soul-stirring cardiotonic agents Sha Kubi it is bent/
Valsartan (Sha Kubi song/Valsartan), trade name Entresto will challenge cardiovascular drugs most successful on the market at present.
Entresto is the ARNI inhibitor class drug of first success of the test.ARNI inhibitor is a kind of angiotensins
Inhibitor, but its effect that endogenous natriuretic peptide (vasodilator) can be enhanced simultaneously.The medicine is a kind of economic benefits and social benefits vasotonia
Plain receptor enkephalinase inhibitor has unique binding mode, is believed to reduce the strain of failure heart.Entresto
Combine the Valsartan (Diovan, common name: Valsartan) and experimental drug AHU-377 of Novartis (Sha Kubi is bent).AHU377 is (husky
Library must be bent) threat can be blocked to be responsible for the mechanism of action of reduce blood pressure 2 kinds of polypeptides, Diovan can then improve vasodilation, stimulate
Body drains sodium and water, and the two plays pharmacological action by reaction forming jointly together.
J.Med.Chem.1995,38,1689-1700. disclose a seed sand library must bent intermediate preparation method, close
It is as follows at route:
The raw material D- tyrosine of this method is unnatural amino acid, and price is costly；Trifluoromethanesulfonic acid is used in the process
Acid anhydride, it is not only expensive, and also activity is very strong, requires production operation very high.
Patent WO2014032627 disclose a seed sand library must bent intermediate preparation method, synthetic route is as follows:
Although this method route is shorter, the relative low price of supplementary material toxic is had using a large amount of in ammonifying process
Evil reagent triphenyl phosphorus, environmental pollution are big；Grignard Reagent activity is higher simultaneously, and operation requires high, mass production difficulty.
Patent CN200780002319.6 disclose a seed sand library must bent intermediate preparation method, synthetic route is as follows:
The biological enzyme fractionation technology that this method is used is high to reaction condition requirement, is not suitable for industrialized production, and biology
The expensive of enzyme, higher cost.
WO2011035569 disclose a seed sand library must bent intermediate preparation method, synthetic route is as follows:
This method route is longer, is just split using traditional method for splitting, and yield is lower, and competitiveness is weak.
In view of the bent good prospect in medicine of Sha Kubi, it is therefore desirable to develop a kind of economic, safety Sha Kubi song intermediate
Preparation method.
Summary of the invention
The purpose of the present invention is to provide a kind of preparation methods of economic, safety Sha Kubi song key intermediate.
The technical proposal adopted by the invention to solve the above technical problems is that: a seed sand library must bent key intermediate preparation
Method includes the following steps:
(1) compound of formula I obtains Formula II compound through reduction；
Wherein, R1For halogen or sulfonate group；R2For C1~6Alkyl, benzyl or H；The C1~6Alkyl includes but is not limited to first
Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group and tert-butyl；The sulfonate group include trifluoromethanesulfonic acid ester group and
P-methyl benzenesulfonic acid ester group etc.；
(2) amino of Formula II compound is protected to obtain formula III compound under alkaline condition through Boc；
(3) formula III compound obtains formula IV compound through coupling；
Preferably, the R1For chlorine, bromine, iodine, p-toluenesulfonyl or trifluoromethanesulfonic acid ester group.
Preferably, the R2For C1~4Alkyl, benzyl or H.
Preferably, the reducing agent that reduction uses in the step (1) includes lithium aluminium hydride reduction, boron hydride and its derivative；
Boron hydride/metal salt system；Boron hydride/ether sulfuric system；Wherein, the boron hydride includes: lithium borohydride, boron hydrogen
Change sodium and potassium borohydride；Metal salt system includes: alkaline-earth halide, lanthanide series metal halide and halogenated transition metal
Object；The hydroboric derivatives include sodium cyanoborohydride, three isopropoxy potassium borohydrides or lithium triethylborohydride etc..
Preferably, the solvent that reduction uses in the step (1) is tetrahydrofuran or methanol.
Preferably, solvent used in the step (2) includes tetrahydrofuran/water, acetonitrile/water, methylene chloride or dioxy
Six rings.
Preferably, alkali used in the step (2) includes sodium carbonate, potassium carbonate, sodium hydroxide or triethylamine.
Preferably, the coupling mode of the step (3) include Suzuki coupling, Negishi coupling, Kumada coupling,
Stille coupling or Hiyama coupling.
Preferably, catalyst used in the step (3) includes: palladium catalyst and Raney nickel；Ligand includes: that phosphorus is matched
Body, nitrogen ligand or carbon ligand.
Preferably, phenyl substrate used in the step (3) includes: phenyl boric acid and its derivative, phenyl zincon, benzene
Base azoviolet, phenyl tin reagent or phenyl silica reagent.
Preferably, solvent used in the step (3) includes ether, tetrahydrofuran, dioxane or toluene.
The present invention also provides the second seed sand library must bent key intermediate preparation method, comprise the following steps:
(1) compound of formula I is protected to obtain Formula II a compound through Boc；
Wherein, R1For R1For halogen or sulfonate group；R2For C1~6Alkyl, benzyl or H；The C1~6Alkyl includes but unlimited
In methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group and tert-butyl；The sulfonate group includes triflate
Base and p-methyl benzenesulfonic acid ester group etc.；
(2) Formula II a compound obtains III compound of formula through reduction；
(3) formula III compound obtains IV compound of formula through coupling
Preferably, solvent used in the step (1) includes tetrahydrofuran/water, acetonitrile/water, methylene chloride or dioxy
Six rings.
Preferably, alkali used in the step (1) includes sodium carbonate, potassium carbonate, sodium hydroxide or triethylamine.
Preferably, the reducing agent that reduction uses in the step (2) includes lithium aluminium hydride reduction, boron hydride and its derivative；
Boron hydride/metal salt system；Boron hydride/ether sulfuric system；Wherein, the boron hydride includes: lithium borohydride, boron hydrogen
Change sodium and potassium borohydride；Metal salt system includes: alkaline-earth halide, lanthanide series metal halide and halogenated transition metal
Object；The hydroboric derivatives include sodium cyanoborohydride, three isopropoxy potassium borohydrides or lithium triethylborohydride.
Preferably, the solvent that reduction uses in the step (2) is tetrahydrofuran or methanol.
Preferably, the coupling mode of the step (3) include Suzuki coupling, Negishi coupling, Kumada coupling,
Stille coupling or Hiyama coupling.
Preferably, catalyst used in the step (3) includes: palladium catalyst and Raney nickel；Ligand includes: that phosphorus is matched
Body, nitrogen ligand or carbon ligand.
Preferably, phenyl substrate used in the step (3) includes: phenyl boric acid and its derivative, phenyl zincon, benzene
Base azoviolet, phenyl tin reagent or phenyl silica reagent.
Preferably, solvent used in the step (3) includes ether, tetrahydrofuran, dioxane or toluene.
The invention has the advantages that the preparation method of Sha Kubi song key intermediate provided by the invention, thirdly step is anti-
Mild condition, environmentally protective is answered, and yield is higher than existing preparation method, economical and effective, is suitable for large-scale industrial production.
Detailed description of the invention
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of compound ii；
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of compound III；
Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of compounds Ⅳ；
Fig. 4 is the hydrogen nuclear magnetic resonance spectrogram of compound IIa.
Specific embodiment
Illustrate technical solution of the present invention below by way of specific embodiment, but the scope of the present invention is not limited thereto.
Embodiment 1: compound of formula I obtains II compound (R of formula through reduction1For I, R2For H)
9.75g sodium borohydride is added in 1L there-necked flask, is added in 300mL tetrahydrofuran, ice salt bath is cooled to 0 DEG C, adds
Enter 30g compound I, stirring is broken up；50mL single port bottle is separately taken, 10mL ether is added, the 7.2mL concentrated sulfuric acid is added dropwise under ice salt bath；0℃
Under, configured ether sulfuric solution is slowly dropped in above-mentioned 1L there-necked flask, drop finishes, and is stirred at room temperature for 24 hours.To reaction solution
Middle addition 10mL methanol, control temperature are no more than 10 DEG C, 300mL 5N NaOH aqueous solution are then added, then organic solvent is steamed
It removes, residue reflux 3h is cooled to room temperature, and 100mL methylene chloride extracts three times, merges organic layer, organic layer saturation chlorination
Sodium washing, anhydrous sodium sulfate is dry, is spin-dried for obtaining white solid, i.e. compound (II) 22.3g, yield 78%.Compound ii
Nmr analysis data are as follows:1H NMR (500MHz, DMSO-d6) δ 7.62 (d, J=7.9Hz, 1H), 7.03 (d, J=7.9Hz,
1H), 3.26 (dd, J=10.4,5.0Hz, 1H), 3.17 (dd, J=10.4,6.3Hz, 1H), 2.82 (p, J=5.8Hz, 1H),
2.64 (dd, J=13.3,5.4Hz, 1H), 2.36 (dd, J=13.3,7.9Hz, 1H), 1.33 (s, 1H) maps are as shown in Figure 1.
Embodiment 2: the amino of II compound of formula is protected to obtain III compound (R of formula through Boc1For I)
10g compound ii is dissolved in 100mL tetrahydrofuran, 50mL water is added and 3.8g sodium carbonate, stirring are broken up.Cooling
To 0~5 DEG C, 8.7g Boc acid anhydrides is added dropwise, drop finishes, warms naturally to room temperature, be stirred overnight.100mL water, 100mL acetic acid is added
Ethyl ester extracts three times, merges organic layer, and organic layer is washed with saturated sodium-chloride, and anhydrous sodium sulfate is dry, is spin-dried for solvent, is added
50mL n-hexane is beaten, and crystallization is stayed overnight at 0~5 DEG C, is filtered, and 40 DEG C of forced air drying 3h obtain white solid, i.e. compound III
12.2g, yield 90%.The nmr analysis data of compound III are as follows:1H NMR (500MHz, DMSO-d6) δ 7.61 (d, J=
7.9Hz, 1H), 7.01 (d, J=8.0Hz, 1H), 6.70-6.36 (m, 1H), 4.69 (s, 1H), 3.72-3.46 (m, 1H),
3.45-3.15 (m, 1H), 2.85-2.68 (m, 1H), 2.58-2.34 (m, 1H), 1.50-0.98 (m, 9H) map such as Fig. 2 institutes
Show.
Embodiment 3: III compound of formula obtains IV compound (R of formula through coupling1For I)
By 4.2g phenyl boric acid, 10g compound III, 0.2g [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride is added
In 100mL tetrahydrofuran, stirring is broken up, and is added configured sodium carbonate liquor (8.4g sodium carbonate is dissolved in 50mL water), heating
To reflux, four hours are reacted.It is spin-dried for organic solvent, 50mL water is added, is extracted 3 times with 100mL ethyl acetate, is merged organic
Layer, organic layer are washed with saturated sodium-chloride, and anhydrous sodium sulfate is dry, and 0.5g active carbon is added, and room temperature decoloration 1h is filtered, 100mL
Ethyl acetate filter wash cake, is spin-dried for, and recrystallizes to obtain white solid, i.e. compound (IV) 8.2g, yield 83% with toluene/n-hexane.
The nmr analysis data of compound (IV) are as follows: 7.63 (d, J=7.5Hz, 2H), 7.56 (d, J=8Hz, 2H), 7.45 (t, J=
7.5Hz, 2H), 7.34 (t, J=7.5Hz, 1H), 7.29 (d, J=8Hz, 2H), 6.60 (d, J=8.5Hz, 1H), 4.70 (t, J
=5Hz, 1H), 3.62 (m, 1H), 3.36-3.40 (m, 1H), 3.28-3.32 (m, 2H), 2.85-2.88 (m, 1H), 2.59-
2.63 (m, 1H), 1.25 (m, 9H) maps are as shown in Figure 3.
Embodiment 4: compound of formula I Boc protects to obtain II a compound (R of formula1For I, R2For methyl)
50g compound I is dissolved in 500mL tetrahydrofuran, 250mL water and 38.8g sodium carbonate is added, is cooled to 0 DEG C, drop
Add Boc acid anhydrides, finish and warm naturally to room temperature, reaction is stirred overnight.End of reaction steams tetrahydrofuran, with 750mL acetic acid second
Ester extraction, merges organic layer, and organic layer is washed with saturated sodium chloride solution, then is removed water with anhydrous sodium sulfate is dry, steams acetic acid
The mashing of 150mL n-hexane is added in ethyl ester, and crystallization is stayed overnight at 0 DEG C to 5 DEG C, obtains 49g white solid, i.e. compound ii a, yield
83%.'H NMR(CDCl3)δ7.61(d,2H),6.86(d,2H),4.98-4.96(m,lH),4.59-4.55(m,lH),3.72
(s, 3H), 3.08 (q, lH), 2.98 (q, lH), 1.41 (s, 9H) maps are as shown in Figure 4.
Embodiment 5: II a compound reduction reaction of formula obtains III compound (R of formula1For I)
20g compound ii a is dissolved in 400mL tetrahydrofuran, 14g zinc chloride is added with stirring, 8g boron hydrogen is then added
Change sodium, has bubble generation, temperature slightly rises.It is warming up to reflux, reacts 4h.600mL water, the extraction of 200ml ethyl acetate is added
Three times, merge organic layer, organic layer is washed with saturated sodium-chloride, and anhydrous sodium sulfate is dry, is spin-dried for organic solvent, and 40mL second is added
Acetoacetic ester and the mashing of 80mL n-hexane, filter, forced air drying obtains 15.6g white solid, i.e. compound III, yield 79%.Chemical combination
The nmr analysis data consistent with Example 2 of object III, map is as shown in Figure 2.
Taking the above-mentioned ideal embodiment according to the present invention as inspiration, through the above description, relevant staff is complete
Various changes and amendments can be carried out without departing from the scope of the technological thought of the present invention' entirely.The technology of this invention
Property range is not limited to the contents of the specification, it is necessary to which the technical scope thereof is determined according to the scope of the claim.
Claims (10)
1. a seed sand library must bent key intermediate preparation method, it is characterised in that include the following steps:
(1) compound of formula I obtains Formula II compound through reduction；
Wherein, R1For halogen or sulfonate group；R2For C1~6Alkyl, benzyl or H；
(2) amino of Formula II compound is protected to obtain formula III compound under alkaline condition through Boc；
(3) formula III compound obtains formula IV compound through coupling；
2. the preparation method of Sha Kubi song key intermediate as described in claim 1, which is characterized in that the R1For chlorine, bromine,
Iodine or sulfonate group, the sulfonate group are trifluoromethanesulfonic acid ester group and p-methyl benzenesulfonic acid ester group.
3. the preparation method of Sha Kubi song key intermediate as described in claim 1, which is characterized in that the R2For C1~4Alkane
Base, benzyl or H.
4. the preparation method of Sha Kubi song key intermediate as described in claim 1, which is characterized in that in the step (1)
Restoring the reducing agent that uses includes lithium aluminium hydride reduction, boron hydride and its derivative, boron hydride/metal salt system, and boron hydride/
Ether sulfuric system；Wherein, the boron hydride includes: lithium borohydride, sodium borohydride and potassium borohydride；The metal salt system
It include: alkaline-earth halide, lanthanide series metal halide and transition metal halide；The hydroboric derivatives include cyano
Sodium borohydride, three isopropoxy potassium borohydrides or lithium triethylborohydride.
5. the preparation method of Sha Kubi song key intermediate as described in claim 1, which is characterized in that in the step (1)
Restoring the solvent used is tetrahydrofuran or methanol.
6. the preparation method of Sha Kubi song key intermediate as described in claim 1, which is characterized in that in the step (2)
Solvent used includes tetrahydrofuran/water, acetonitrile/water, methylene chloride or dioxane；Alkali packet used in the step (2)
Include sodium carbonate, potassium carbonate, sodium hydroxide or triethylamine.
7. the preparation method of Sha Kubi song key intermediate as described in any one of claims 1 to 6, which is characterized in that described
The coupling mode of step (3) includes Suzuki coupling, Negishi coupling, Kumada coupling, Stille coupling or Hiyama even
Connection.
8. the preparation method of Sha Kubi song key intermediate as described in any one of claims 1 to 6, which is characterized in that described
Catalyst used in step (3) includes: palladium catalyst and Raney nickel；Ligand includes: phosphorus ligand, nitrogen ligand or carbon ligand；
Phenyl substrate includes: phenyl boric acid and its derivative, phenyl zincon, phenyl azoviolet, phenyl tin reagent or phenyl silica reagent.
9. the preparation method of Sha Kubi song key intermediate as described in any one of claims 1 to 6, which is characterized in that described
Solvent used in step (3) includes ether, tetrahydrofuran, dioxane or toluene.
10. a seed sand library must bent key intermediate preparation method, comprise the following steps:
(1) compound of formula I is protected to obtain Formula II a compound through Boc；
Wherein, R1For halogen or sulfonate group；R2For C1~6Alkyl, benzyl or H；The C1~6Alkyl include but is not limited to methyl,
Ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group and tert-butyl；The sulfonate group is for trifluoromethanesulfonic acid ester group and to toluene
Sulfonate group；
(2) Formula II a compound obtains III compound of formula through reduction；
(3) formula III compound obtains IV compound of formula through coupling
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012065958A1 (en) * | 2010-11-16 | 2012-05-24 | Novartis Ag | Method of treating contrast-induced nephropathy |
| CN105017082A (en) * | 2015-07-31 | 2015-11-04 | 上海皓元化学科技有限公司 | Preparation method of cardiotonic drug Entresto key intermediate (R)-tert-butyl-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate |
| CN105753741A (en) * | 2016-04-26 | 2016-07-13 | 常州制药厂有限公司 | Method for preparing Sacubitril intermediate of anti-heart-failure medicine |
-
2017
- 2017-08-09 CN CN201710675740.9A patent/CN107382785B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012065958A1 (en) * | 2010-11-16 | 2012-05-24 | Novartis Ag | Method of treating contrast-induced nephropathy |
| CN105017082A (en) * | 2015-07-31 | 2015-11-04 | 上海皓元化学科技有限公司 | Preparation method of cardiotonic drug Entresto key intermediate (R)-tert-butyl-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate |
| CN105753741A (en) * | 2016-04-26 | 2016-07-13 | 常州制药厂有限公司 | Method for preparing Sacubitril intermediate of anti-heart-failure medicine |
Non-Patent Citations (2)
| Title |
|---|
| Dicarboxylic Acid Dipeptide Neutral Endopeptidase Inhibitors;Gary M. Ksander等;《J. Med. Chem.》;19951231;第38卷;1689-1700页 * |
| 沙库必曲合成路线图解;吕训磊等;《中国医药工业杂志》;20161231;第47卷(第11期);1470-1473页 * |
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