CN114516808B - Preparation method of amino-protected benzocyclic ketone compound - Google Patents
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- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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Abstract
The invention discloses a method for preparing amino-protected benzocyclic ketone compounds through a reaction route of a formula A; wherein R is 1 Represents C 1‑6 Alkyl, R 2 Represents F or Cl atoms, R 3 Represents an amino protecting group, X represents Br or I atom, Y represents halogen atom, and n represents an integer of 1 to 4. According to the preparation method of the present invention, amino-protected benzocyclic ketone compounds useful as pharmaceutical intermediates in industrial production can be produced in a simple manner with high yield.
Description
Technical Field
The invention relates to preparation of compounds, in particular to a preparation method of amino-protected benzocyclic ketone compounds serving as medical intermediates. For example, acetamido tetralone compounds useful as intermediates in the preparation of camptothecin derivatives Exatecan.
Background
The compound represented by the following formula IX is Exatecan (DX-8951, an antitumor agent, see Japanese patent application laid-open No. 87746/1994), a synthetic analogue of topoisomerase I inhibitor camptothecin, and is clinically used for treating advanced soft tissue sarcoma, pancreatic cancer, esophageal cancer, gastric cancer, liver cancer and the like. Wherein the compound of formula X is an important intermediate for the total synthesis of Exatecan.
In 1991, JP 3-015812 discloses the use of 2-fluoro-toluene as a starting material to produce a compound of formula X in seven steps. The method has the advantages of high potential safety hazard (low-temperature borane reduction is needed, high-temperature reaction of polyphosphoric acid) and low yield (the yield of the polyphosphoric acid in one step of cyclization is only 25%), and is difficult to separate (the by-product of isomers exists in one step of nitration), thus being not suitable for industrial production.
In 1996, patent WO96/26181 discloses a new synthetic route, which takes 2-fluoro-toluene as raw material to synthesize the compound of formula X through 11 steps. The synthesis method has some defects as follows: multiple Friedel-crafts acylation reactions are carried out in the reaction process; the reduction of the carbonyl group must be carried out in a number of steps (including the formation of alcohols, dehydration, reduction of double bonds, etc.); the reaction steps are longer, and the total yield is only 17 percent.
In 2019, WO2019/044946 discloses a new synthetic route developed by japan first co-company, which uses 2-fluoro-4-nitro-toluene as a raw material, and performs 8 steps of halogenation, reduction, aminoacetylation, heck coupling, reduction and cyclization reaction to obtain the compound of formula X. The side chain is introduced in the route, the Heck coupling reaction is selected to complete, the reaction step is shortened, but the yield is lower in nitration and halogenation, and the total yield of the route is only 14%.
From the above-mentioned published patent, it has been found that the synthesis of aminotetralone compounds has problems such as troublesome synthetic routes, low overall route yields, and the like. Therefore, development of industrially advantageous production methods is required.
Disclosure of Invention
The object of the present invention is to provide a simple process for the preparation of amino-protected benzocyclic ketones in high yields, wherein said compounds are useful as synthetic intermediates for the industrial preparation of camptothecin derivatives (Exatecan).
A preparation method of an amino-protected benzocyclic ketone compound, which has a structure shown in a formula VIII:
wherein R is 1 Represents C 1-6 Alkyl, R 2 Represents F or Cl atoms, R 3 Represents an amino protecting group, X represents Br or I atom, Y represents halogen atom, and n represents an integer of 1 to 4;
the preparation method is characterized in that the preparation process is shown in the following formula, and comprises seven steps of:
a) Carrying out Nigishi coupling on the compound of the formula I to prepare a compound of the formula II;
b) Performing ester hydrolysis on the compound of the formula II to prepare a compound of the formula III;
c) Performing intramolecular Friedel-crafts acylation reaction on the compound shown in the formula III to form a ring to obtain a compound shown in the formula IV;
d) The compound of the formula IV is subjected to monohalogenation on a benzene ring to prepare a compound of the formula V;
e) Performing nitration on the compound of the formula V to prepare a compound of the formula VI;
f) Carrying out hydrogenation reduction on the compound of the formula VI to obtain a compound of the formula VII;
g) Performing amino protection on the compound of formula VII to prepare a compound of formula VIII;
wherein:
the step a specifically comprises the following steps: the compound I and an organic zinc reagent (such as 4-ethoxy-4-oxo-butyl zinc bromide and the like) are subjected to Nigishi coupling reaction, a solvent is preferably selected from anhydrous THF or anhydrous DMF, a common palladium catalyst (triphenylphosphine palladium, palladium acetate and the like) is used as a catalyst, an S-PHOS or X-PHOS is preferably selected as a ligand, the reaction temperature is preferably controlled to be 20-60 ℃, the reaction time is preferably controlled to be 24-36 h, the zinc reagent dosage is preferably controlled to be 1.2-1.5 equivalent, and the catalyst and the ligand dosage are controlled to be 2-10 mol% of the reactant;
the step b specifically comprises the following steps: the compound II is dissolved in a solvent (lower alcohol, tetrahydrofuran and other solvents which are mutually soluble in water), and alkali is added to stir and react. The reaction selects common alkali catalytic hydrolysis (such as sodium hydroxide, potassium hydroxide and the like), the reaction temperature is preferably controlled to be 0-30 ℃, the reaction time is preferably 1-3 h, and the alkali dosage is preferably 1.2-1.6 equivalent;
the step c specifically comprises the following steps: the compound III is subjected to intramolecular Friedel-crafts acylation reaction under the catalysis of acid, the catalyst is preferably protonic acid (such as sulfuric acid, trifluoroacetic acid or polyphosphoric acid, and the like), a dehydrating agent (such as phosphorus pentoxide, trifluoroacetic anhydride, and the like) is preferably added to promote the reaction, the reaction temperature is preferably controlled to be-10-5 ℃, the reaction time is preferably 2-4 h, and the dosage of the dehydrating agent is preferably 2-2.5 equivalents;
the step d specifically comprises the following steps: the compound IV is dissolved in sulfuric acid or anhydrous dichloro, and a brominating reagent (bromosuccinimide, dibromohydantoin and the like) is added in batches for reaction, wherein the reaction temperature is preferably controlled to be 18-35 ℃, the reaction time is preferably 1.5-3 h, and the dosage of the brominating reagent is preferably 1.05-1.25 equivalent;
the step e specifically comprises the following steps: dissolving the compound V in sulfuric acid with the mass fraction of 70-98% of the solvent, adding a nitrifying reagent at a low temperature, stirring and reacting, wherein the nitrifying reagent is common potassium nitrate or nitric acid, the reaction temperature is preferably controlled at-10-30 ℃, the reaction time is preferably 4-8 h, and the molar ratio of the compound I to the nitrifying reagent is 1:2-2.5;
the step f specifically comprises the following steps: the compound VI is reduced by adding hydrogen in a hydrogen atmosphere, the solvent is preferably methanol or tetrahydrofuran, the catalyst is preferably noble metal such as palladium carbon, platinum carbon or Raney nickel, alkali (such as triethylamine, pyridine and other alkali which is easy to form salt with hydrogen halide) is preferably added for the reaction to neutralize the acid generated by the reaction, the reaction temperature is preferably controlled between 15 and 35 ℃, the reaction time is preferably 18 to 24 hours, and the dosage of the alkali is preferably 2.5 to 3.5 equivalents;
the step g specifically comprises the following steps: the compound VII and the amino protecting reagent react, the amino protecting reagent is selected from conventional reagents (for example, an acetylating reagent, a solvent used in common use such as dichloromethane, tetrahydrofuran and the like can be selected as an acetylating reagent, the reaction temperature is preferably controlled to be 15-35 ℃, the reaction time is preferably 1.5-2.5 h, and the mol ratio of the compound VII to the acetylating reagent is 1:2.0-3.0).
The invention has the following advantages when preparing the benzocyclic ketone compound with amino protection: firstly, the introduction of the side chain is realized through a Nigishi coupling reaction, so that the reaction steps are shortened, and compared with the original method, the multi-step reactions such as Friedel-crafts acylation, carbonyl reduction and the like are avoided; secondly, when the intramolecular Friedel-crafts acylation cyclization reaction occurs in the synthetic route, the influence of substituent groups on benzene rings is avoided; finally, the amino is introduced and positioned by introducing a bromine atom, and compared with the reaction of a synthetic route developed by Japanese first third Co-company disclosed in WO2019/044946, the method has the advantages of accurate positioning effect, high atom utilization rate and over 40 percent of total yield through a seven-step synthetic route.
The invention can prepare the amino-protected benzocyclic ketone compound, and the synthesis route has the advantages of easily available raw materials, simple reaction type, convenient post-treatment, short route and high yield, and is a synthesis method suitable for industrial preparation.
Detailed Description
The preparation method of the amino-protected benzocyclic ketone compound is described in more detail in the following examples, which are not intended to limit the invention. In the following examples, R 1 Methyl, R 2 =fluorine atom, R 3 Acetyl, x=bromine atom, y=bromine atom, n=2.
Example 1 preparation of Compound 2
In a 3L volume reaction flask was added anhydrous DMF (1000 mL), 2-bromo-6-fluorotoluene (100.0 g,1.00 eq), palladium acetate (2.3 g,0.02 eq), S-PHOS (8.7 g,0.04 eq) was added after stirring at room temperature for 10min, 4-ethoxy-4-oxobutylzinc bromide (800 mL,1.50 eq) was added after stirring at room temperature for 10min (note that a large amount of heat was evolved upon addition of zinc reagent |), and the reaction was carried out at 30℃for 28 hours after the addition. After the reaction of the raw materials was detected to be complete by GC-MS, the reaction solution was cooled to room temperature, quenched with ammonium chloride solution (50 mL), poured into 10L of water, extracted with ethyl acetate (800 mL x 3), the organic phases combined, washed twice with water, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 135.0g of a reddish brown oily liquid, which was used directly in the next reaction without further purification.
EXAMPLE 2 preparation of Compound 3
The reddish brown liquid (135.0 g) obtained in example 1 was dissolved in 400mL of methanol, and 4M sodium hydroxide solution (200 mL,1.50 eq) was added dropwise under ice-water bath, and the mixture was reacted at room temperature for 16 hours after the addition. After TLC detection of completion of the reaction of the starting material, methanol was distilled off by concentration under reduced pressure, pH was adjusted to 2 with concentrated hydrochloric acid (about 70-75 mL), a large amount of solid was precipitated, filtered and dried to give 93.0g of compound 3 as a pale yellow solid in 90% yield. Melting point: 84.8-85.6 ℃.
1H NMR(400MHz,DMSO)δ12.11(s,1H),7.14(dd,J＝14.2,7.1Hz,1H),6.97(t,J＝7.5Hz,2H),2.61(t,J＝7.7Hz,2H),2.27(t,J＝7.0Hz,2H),2.17(s,3H),1.82–1.64(m,2H)。
EXAMPLE 3 preparation of Compound 4
In a 1L three-necked flask was charged trifluoroacetic acid (250 mL), the temperature was lowered to 0℃and compound 3 (125.0 g,1.00 eq) was added in portions, and trifluoroacetic anhydride (176 mL,2.00 eq) was slowly added dropwise, and the reaction was continued at that temperature for 2.5 hours after the addition. After TLC detection of the completion of the reaction of the raw materials, the reaction solution was slowly dropped into an ice water mixed solution, the pH was adjusted to 7 with 25% w of sodium hydroxide solution, a large amount of solids were precipitated, and filtration was performed, the obtained solids were dissolved with ethyl acetate, washed with water and saturated sodium chloride solution in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 106.0g of a pale yellow solid as compound 4, with a yield of 93.4%.
1H NMR(400MHz,CDCl3)δ7.95(t,J＝7.1Hz,1H),6.98(t,J＝8.8Hz,1H),2.88(t,J＝5.8Hz,2H),2.69–2.56(m,2H),2.22(s,3H),2.16(dt,J＝11.9,6.1Hz,2H)。
EXAMPLE 4 preparation of Compound 5
In a 2L three-necked flask, concentrated sulfuric acid (1L) was added, and compound 4 (100.0 g,1.00 eq) was added in four portions under an ice-water bath, and NBS (110.0 g,1.10 eq) was added in five portions after complete dissolution, and the mixture was allowed to react at room temperature for 2 hours. After the completion of the TLC detection reaction, the reaction solution was slowly dropped into 10L of an ice-water mixture, and a solid was precipitated, stirred for two hours, and filtered. The solid was dissolved with ethyl acetate, washed with saturated sodium carbonate solution, water, saturated sodium chloride solution in this order, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 115g of compound 5 as a pale yellow solid in 80% yield.
1H NMR(400MHz,DMSO)δ7.95(d,J＝7.0Hz,1H),2.90–2.79(m,2H),2.59(t,J＝10.5Hz,2H),2.24(s,3H),2.12–1.98(m,2H)。
EXAMPLE 5 preparation of Compound 6
In a 500mL three-necked flask, concentrated sulfuric acid (300 mL) was added, compound 5 (30.00 g,1.00 eq) was added under an ice-water bath, the temperature was lowered to 0℃after complete dissolution, nitric acid (19.30 mL,2.50 eq) was slowly added dropwise, and the temperature was maintained under stirring after the dropwise addition. After TLC detection of the completion of the reaction of the raw materials, the reaction solution was slowly poured into an ice water mixture to precipitate a solid, and the solid was filtered. Drying, stirring with a mixed solution of PE: ea=10:1 for 2 hours, filtering, and drying to obtain 28g of compound 6 as a bright yellow solid in 81% yield.
1H NMR(400MHz,DMSO)δ2.93(d,J＝4.1Hz,2H),2.66(d,J＝4.6Hz,2H),2.30(s,3H),2.09(d,J＝5.0Hz,2H)。
EXAMPLE 6 preparation of Compound 7
In a 3L flask were charged compound 6 (50.00 g,1.00 eq), methanol (1.5L), triethylamine (68.8 mL,3.00 eq) and palladium on carbon (2.50 g,5 wt%) and reacted at room temperature under a hydrogen atmosphere for 24 hours. After TLC detection of the completion of the reaction of the starting materials, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and was pumped to dryness by a vacuum pump, and was directly used for the next reaction.
EXAMPLE 7 preparation of Compound 8
The product obtained in example 6 was placed in a 1L round bottom flask, anhydrous DCM (320 mL) and pyridine (46.75 mL,3.50 eq) were added, acetyl chloride (3.00 eq,35.45 mL) was slowly added dropwise, the reaction was carried out at room temperature for 2h after the addition was completed, after tlc detection of the completion of the reaction of the starting materials, the reaction solution was washed with dilute hydrochloric acid, sodium bicarbonate solution, water, saturated sodium chloride in this order, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give compound 8 as a pale red solid 31g in 80% yield.
1H NMR(400MHz,CDCl3)δ12.31(s,1H),8.40(d,J＝12.9Hz,1H),2.88(t,J＝6.1Hz,2H),2.66(t,J＝6.4Hz,2H),2.22(s,3H),2.14(d,J＝1.4Hz,3H),2.12–2.05(m,2H)。
Claims (1)
1. A process for preparing a compound of formula VIII:
wherein R is 1 Represents C 1-6 Alkyl, R 2 Represents F or Cl atoms, R 3 Represents an amino protecting group, n represents an integer of 2;
the preparation method comprises the following specific steps:
wherein R is 1 Represents C 1-6 Alkyl, R 2 Represents F or Cl atoms, R 3 Represents an amino protecting group, X represents Br or I atom, Y represents halogen atom, and n represents an integer of 2;
a) Carrying out Nigishi coupling on the compound of the formula I to prepare a compound of the formula II;
b) Performing ester hydrolysis on the compound of the formula II to prepare a compound of the formula III;
c) Performing intramolecular Friedel-crafts acylation reaction on the compound shown in the formula III to form a ring to obtain a compound shown in the formula IV;
d) The compound of the formula IV is subjected to monohalogenation on a benzene ring to prepare a compound of the formula V;
e) Performing nitration on the compound of the formula V to prepare a compound of the formula VI;
f) Carrying out hydrogenation reduction on the compound of the formula VI to obtain a compound of the formula VII;
g) Performing amino protection on the compound of formula VII to prepare a compound of formula VIII;
wherein:
the step a specifically comprises the following steps: carrying out Nigishi coupling reaction on the compound I and an organic zinc reagent, wherein a solvent adopted in the reaction is anhydrous tetrahydrofuran or anhydrous N, N-dimethylformamide, a palladium catalyst is selected as a catalyst, an S-PHOS or an X-PHOS is selected as a ligand, the reaction temperature is controlled at 20-60 ℃, the reaction time is 24-36 h, the dosage of the organic zinc reagent is 1.2-1.5 equivalent, and the dosage of the catalyst and the ligand is controlled at 2-10 mol% of the reactant; wherein the palladium catalyst is triphenylphosphine palladium or palladium acetate;
the step b specifically comprises the following steps: dissolving the compound II in a solvent, adding alkali, and stirring for reaction; the reaction of the step selects alkali catalytic hydrolysis, the reaction temperature is controlled to be 0-30 ℃, the reaction time is 1-3 h, and the dosage of alkali is 1.2-1.6 equivalent; wherein the solvent is lower alcohol or tetrahydrofuran; the alkali is sodium hydroxide or potassium hydroxide;
the step c specifically comprises the following steps: the compound III undergoes intramolecular Friedel-crafts acylation reaction under the catalysis of acid, a proton acid is selected as a catalyst, a dehydrating agent is added into the reaction to promote the reaction, the reaction temperature is controlled to be-10-15 ℃, the reaction time is 2-4 h, and the dosage of the dehydrating agent is 2-2.5 equivalents; wherein the protonic acid is sulfuric acid, trifluoroacetic acid or polyphosphoric acid; the dehydrating agent is phosphorus pentoxide or trifluoroacetic anhydride;
the step d specifically comprises the following steps: the compound IV is dissolved in strong acid or anhydrous solvent, and a brominating reagent is added in batches for reaction, the reaction temperature is controlled at 18-35 ℃, the reaction time is 1.5-3 h, and the dosage of the brominating reagent is 1.05-1.25 equivalent; wherein the strong acid is sulfuric acid or trifluoroacetic acid; the anhydrous solvent is as follows: anhydrous dichloromethane or anhydrous tetrahydrofuran; the brominating reagent is bromosuccinimide or dibromohydantoin;
the step e specifically comprises the following steps: dissolving the compound V in sulfuric acid with the mass fraction of 70-98% of the solvent, adding a nitrifying reagent at a low temperature, stirring and reacting, controlling the reaction temperature to be-10-30 ℃ and the reaction time to be 4-8 h, wherein the molar ratio of the compound I to the nitrifying reagent is 1:2-2.5; wherein the nitrifying reagent is potassium nitrate or nitric acid;
the step f specifically comprises the following steps: adding hydrogen to the compound VI for reduction in a hydrogen atmosphere, wherein a solvent is selected from lower alcohols or tetrahydrofuran, a catalyst is selected from palladium carbon, platinum carbon or Raney nickel, alkali is added to neutralize acid generated by the reaction, the reaction temperature is controlled at 15-35 ℃, the reaction time is 18-24 h, and the dosage of the alkali is 2.5-3.5 equivalents; wherein the base is triethylamine or pyridine;
the step g specifically comprises the following steps: reacting compound VII with an amino protecting agent; wherein the amino protecting reagent is an acetylating reagent, anhydrous dichloromethane or anhydrous tetrahydrofuran is selected as a solvent during acetylating, the reaction temperature is controlled at 15-35 ℃, the reaction time is 1.5-2.5 h, and the mol ratio of the compound VII to the acetylating reagent is 1:2.0-3.0.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0687746A (en) * | 1992-07-16 | 1994-03-29 | Dai Ichi Seiyaku Co Ltd | Antitumor agent |
| CN1175943A (en) * | 1995-02-22 | 1998-03-11 | 第一制药株式会社 | Aminotetralone derivatives and process for producing same |
| CN111065621A (en) * | 2017-08-31 | 2020-04-24 | 第一三共株式会社 | Novel method for preparing antibody-drug conjugates |
| CN111470998A (en) * | 2020-06-28 | 2020-07-31 | 上海皓元生物医药科技有限公司 | Intermediate for synthesizing camptothecin derivative and preparation method and application thereof |
-
2020
- 2020-11-20 CN CN202011309928.XA patent/CN114516808B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0687746A (en) * | 1992-07-16 | 1994-03-29 | Dai Ichi Seiyaku Co Ltd | Antitumor agent |
| CN1175943A (en) * | 1995-02-22 | 1998-03-11 | 第一制药株式会社 | Aminotetralone derivatives and process for producing same |
| CN111065621A (en) * | 2017-08-31 | 2020-04-24 | 第一三共株式会社 | Novel method for preparing antibody-drug conjugates |
| CN111470998A (en) * | 2020-06-28 | 2020-07-31 | 上海皓元生物医药科技有限公司 | Intermediate for synthesizing camptothecin derivative and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| "Synthesis and Antitumor Activity of Ring A- and F-Modified Hexacyclic Camptothecin Analogues";Masamichi Sugimori, etal.;《J. Med. Chem》;第41卷(第13期);2175-2438 * |
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