CN104098499B - The preparation method of 5-benzyloxy-2-(4-benzyloxy phenyl)-3-Methyl-1H-indole - Google Patents

Abstract

The invention discloses the preparation method of 5-benzyloxy-2-(4-benzyloxy phenyl)-3-Methyl-1H-indole. This preparation method comprises the following steps: that (1) is in alcohols solvent, under the effect of alkali, Compound I I and compound III is carried out to condensation reaction; (2) reactant liquor of step (1) is mixed with Bronsted acid, carries out Bischler-Mohlau indoles ring closure reaction. Synthetic route of the present invention is compared with original technology, first step condensation reaction is merged into " one pot " with second step Bischler-Mohlau indoles ring closure reaction and react, easy and simple to handle; Product I directly separates out from reaction dissolvent, has greatly simplified post-reaction treatment process, and purity is high, and reaction yield is high, is suitable for amplifying producing.

Description

The preparation method of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole

technical field

The invention relates to a preparation method of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole.

Background technique

Bazedoxifene, developed by Wyeth, is a new generation of SERM (selective estrogen receptor modulator), which can competitively inhibit the binding of 17β-estradiol to ERα and ERβ, and is used alone for human breast cancer The cell line has no agonist activity. Preclinical tests show that it is superior to raloxifene (second generation SERM) and lasofoxifene (third generation SERM) in improving uterine properties among similar products, and the vasomotor instability model Tests have shown that it has little side effects on the central nervous system, and it is a relatively effective agonist in activating the hepatic lipase promoter, while raloxifene is ineffective. When combined with raloxifene, it can Inhibiting the stimulating effect of raloxifene on the uterus of rodents, it can be seen that the effects of the two on the uterus are different. Preclinical test data show that it has more targeted activity than other SERMs known so far, and it is the "best of its kind" so far. The drug has been launched in the European Union (trade name: Conbriza) and Japan (trade name: Viviant) in 2009. Its primary indication is the treatment and prevention of osteoporosis in postmenopausal women.

The chemical name of bazedoxifene acetate is 1-{4-[2-(cyclohexylimino-1-)ethoxy]benzyl}-2-(4-hydroxyphenyl)-3-methanol Base-1H-indole-5-phenol acetate, its preparation method is as follows:

5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole (I) is a key intermediate in the synthesis of bazedoxifene acetate, and its synthesis mainly has the following three methods :

Route 1 (US5998402):

The route uses 2-bromo-(4-benzyloxyphenyl) acetone (II) and p-benzyloxyaniline hydrochloride (III) as starting materials, DMF as solvent, reflux reaction, and condensation of II and III to obtain 5-Benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole (I). In this reaction, the consumption of p-benzyloxyaniline hydrochloride (III) is 3.5 times (molar ratio) of 2-bromo-(4-benzyloxyphenyl) acetone (II), there is a large amount of p-benzyloxyaniline Oxyaniline hydrochloride (III) remains, which not only brings trouble to post-processing, requires column chromatography purification, but also wastes raw materials, and the yield is low (33%), which is not suitable for industrial production.

Route 2 (US5998402):

This route is based on route 1, also using 2-bromo-(4-benzyloxyphenyl) acetone (II) and p-benzyloxyaniline hydrochloride (III) as starting materials, using DMF as solvent, II Condensation with III gives 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole (I). The difference is that the two-step reactions in this route are combined into a "one-pot" reaction: in the first step, triethylamine is added as a base, and II is condensed with 1.3 times the molar amount of III to obtain the intermediate product 1-(4-benzyloxybenzene Base)-2-[(4-benzyloxyphenyl)amino]acetone (IV), IV was not separated, and the Bischler-Mohlau indole ring closure reaction with 1.5 times molar amount of III was added again to generate product I. Although this route combines the two-step reactions into "one pot", which simplifies the reaction operation, in order to remove excess III and impurities, the post-treatment steps are cumbersome, and the obtained solid crude product needs to be beaten and washed in methanol/ether several times to obtain a relatively pure product. The product I, the yield is lower (55%).

Route 3 (WO2008098527):

This route takes 2-bromo-(4-benzyloxyphenyl) acetone (II) and p-benzyloxyaniline hydrochloride (III) as starting materials (the amount of p-benzyloxyaniline hydrochloride (III) 1.1-1.2 times that of 2-bromo-(4-benzyloxyphenyl) acetone (II), use alcohol (ethanol, isopropanol, etc.) as solvent, and condense to obtain the intermediate 1-(4-benzyloxy Phenyl)-2-[(4-benzyloxyphenyl)amino]acetone (IV), after separating and purifying IV, Bischler-Mohlau indole ring-closing reaction occurs between IV and 0.2 times molar amount of III to obtain product I . The yield of this route is relatively high (the total yield of two steps is 60%-75%), but the intermediate product IV needs to be separated and purified, which increases the reaction operation, and the whole route is not concise enough.

Contents of the invention

The technical problem solved by the present invention is in order to overcome the complex preparation process of the existing 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole, complicated operation and low yield With low defects, a preparation method of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole is provided. The preparation method is simple in operation, low in cost, greatly simplifies the post-reaction treatment process, has high purity and high reaction yield, and is suitable for scale-up production.

The present invention solves the above technical problems through the following technical solutions:

The invention provides a preparation method of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole, which comprises the following steps:

(1) In an alcoholic solvent, under the action of a base, conduct a condensation reaction between compound II and compound III;

(2) Mix the reaction liquid of step (1) with protonic acid, and carry out the Bischler-Mohlau indole ring-closing reaction;

In step (1), the alcohol solvent is preferably one or more of n-butanol, isobutanol, n-propanol, isopropanol and ethanol; more preferably n-butanol, isobutanol One or more of alcohol and n-propanol. The volume mass of the alcohol solvent and compound II is preferably 5-15ml/g.

In step (1), the base is preferably an inorganic base and/or an organic base. Described inorganic base is preferably one or more in potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide; Described organic base is preferably triethylamine One or more of , pyridine, 4-dimethylaminopyridine, morpholine and N,N-diisopropylethylamine. The base is more preferably triethylamine. The molar ratio of the base to compound II is preferably (2:1)-(2.5:1).

In step (1), the molar ratio of compound II to compound III is preferably (1:1)-(1:1.2).

In step (1), the temperature of the condensation reaction is preferably 75-160°C, more preferably 100-130°C. The progress of the condensation reaction can be monitored by conventional means in the art (such as TLC or HPLC). Generally, the end point of the reaction is when the compound II disappears. The condensation reaction time is preferably 2-4 hours.

In the present invention, the reaction solution obtained in step (1) can be directly carried out in step (2) without post-treatment.

In step (2), cooling is preferably performed before mixing the reaction solution in step (1) with the protonic acid. The cooling is preferably natural cooling until the temperature of the reaction liquid in the step (1) is 10-30°C.

In step (2), the protic acid is preferably an inorganic acid and/or an organic acid. Described inorganic acid is preferably one or more in hydrochloric acid, sulfuric acid and phosphoric acid, is more preferably hydrochloric acid; Described organic acid is preferably formic acid, acetic acid, propionic acid, oxalic acid, fumaric acid, One or more of maleic acid, succinic acid, tartaric acid, citric acid, malonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and p-toluenesulfonic acid monohydrate, more preferably p-toluene sulfonic acid. The molar ratio of the protonic acid to compound II is preferably (0.05:1)-(0.3:1).

In step (2), the temperature of the Bischler-Mohlau indole ring closure reaction is preferably 75-160°C, more preferably 100-130°C.

The progress of the Bischler-Mohlau indole ring-closing reaction can be monitored by conventional means in the art (such as TLC or HPLC), and the time of the Bischler-Mohlau indole ring-closing reaction is preferably 5-15 hours.

Wherein, after the completion of the Bischler-Mohlau indole ring-closing reaction, post-treatment can be carried out to further purify compound I. The post-treatment method can be a conventional post-treatment method in the art, preferably including the following steps: suction filtration and drying. When the base is an inorganic base, it is preferably washed with water after suction filtration, and then dried.

On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

The reagents and raw materials used in the present invention are all commercially available.

The positive progress effect of the present invention is: the synthetic route of the present invention compares with prior art, and the first step condensation reaction and the second step Bischler-Mohlau indole ring-closing reaction are merged into "one pot" reaction, easy and simple to operate; Reaction Adding acid into the solution does not need to add the raw material compound III again, which simplifies the operation and saves the cost; the reaction product I is directly precipitated from the reaction solvent, which greatly simplifies the post-reaction treatment process, and has high purity and high reaction yield, which is suitable for scale-up Production.

detailed description

The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples. For the experimental methods that do not specify specific conditions in the following examples, select according to conventional methods and conditions, or according to the product instructions.

Example 1

Synthesis of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole (I)

Add 2-bromo-(4-benzyloxyphenyl) acetone (12.7g, 0.04mol), p-benzyloxyaniline hydrochloride (11.1g, 0.047mol) to n-butanol (120ml), add triethyl Amine (12.2ml) was heated to 118°C and refluxed. After 3 hours, the reaction of 2-bromo-(4-benzyloxyphenyl)acetone was complete; concentrated hydrochloric acid (1.0ml) was added, and the temperature was raised to 118°C to continue the reaction for 7 hours. The reaction liquid was cooled, filtered with suction, and dried to obtain 15.2 g of white solid, HPLC purity: 98%, yield 90.5%.

¹ H-NMR(400MHz,d ⁶ -DMSO)δ(ppm):7.798(brs,1H,-NH-),7.102-7.557(m,14H,Ar-H),7.255(d,1H,J=2.4 Hz,Ar-H),7.174(d,1H,J=4.0Hz,Ar-H),6.978(dd,1H,J=4.0Hz,2.4Hz,Ar-H),5.192(s,2H,-OCH ₂ -),5.153(s,2H,-OCH ₂ -),2.436(s,3H,-CH ₃ )MS(m/z):420(M+1)

Example 2

Synthesis of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole (I)

Add 2-bromo-(4-benzyloxyphenyl) acetone (12.7g, 0.04mol), p-benzyloxyaniline hydrochloride (11.1g, 0.047mol) to isobutanol (120ml), add triethyl Amine (12.2ml), heated to 107°C and refluxed, 2-bromo-(4-benzyloxyphenyl)acetone reacted completely after 3 hours; added p-toluenesulfonic acid monohydrate (1.7g), heated to 107°C The reaction was continued for 14 hours. The reaction solution was cooled, filtered with suction, and dried to obtain 14.4 g of a tan solid, with an HPLC purity of 97% and a yield of 86%.

Example 3

Synthesis of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole (I)

Add 2-bromo-(4-benzyloxyphenyl) acetone (12.7g, 0.04mol), p-benzyloxyaniline hydrochloride (11.1g, 0.047mol) to isopropanol (120ml), add pyridine ( 7.1ml), the temperature was raised to 84°C, and after 4 hours, the reaction of 2-bromo-(4-benzyloxyphenyl)acetone was complete; acetic acid (0.7ml) was added to continue the reaction for 15 hours. The reaction solution was cooled, filtered with suction, and dried to obtain 14.6 g of white solid, HPLC purity: 96%, yield 87%.

Example 4

Synthesis of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole (I)

Add 2-bromo-(4-benzyloxyphenyl)acetone (12.7g, 0.04mol), p-benzyloxyaniline hydrochloride (11.1g, 0.047mol) to n-butanol (120ml), add morpholine (7.7ml), the temperature was raised to 118°C, and after 3 hours, the reaction of 2-bromo-(4-benzyloxyphenyl)acetone was complete; concentrated sulfuric acid (0.6ml) was added, and the reaction was continued for 7 hours. The reaction solution was cooled, filtered with suction, and dried to obtain 14.7 g of white solid, HPLC purity: 98%, yield 88%.

Example 5

Synthesis of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole (I)

Add 2-bromo-(4-benzyloxyphenyl)acetone (12.7g, 0.04mol), p-benzyloxyaniline hydrochloride (11.1g, 0.047mol) to n-butanol (120ml), add sodium carbonate (9.3g), heated to 118°C and refluxed. After 3 hours, the reaction of 2-bromo-(4-benzyloxyphenyl)acetone was complete; concentrated hydrochloric acid (1.0ml) was added, and the temperature was raised to 118°C to continue the reaction for 7 hours. The reaction solution was cooled, filtered with suction, the obtained solid was washed with water (60ml), filtered, and dried to obtain 14.8g of white solid, HPLC purity: 99%, yield 88%.

Claims (10)

1. The preparation method of 1.5-benzyloxy-2-(4-benzyloxy phenyl)-3-Methyl-1H-indole, is characterized in that,It comprises the following steps:

   (1), in alcohols solvent, under the effect of alkali, Compound I I and compound III are carried out to condensationReaction;

   (2) reactant liquor of step (1) is mixed with Bronsted acid, carry out Bischler-Mohlau indoles passRing reaction;
2. 2. preparation method as claimed in claim 1, is characterized in that, in step (1), describedAlcohols solvent is one or more in n-butanol, isobutanol, normal propyl alcohol, isopropyl alcohol and ethanol; DescribedAlcohols solvent be 5～15ml/g with the volume mass ratio of Compound I I.
3. 3. preparation method as claimed in claim 1, is characterized in that, in step (1), describedAlkali is inorganic base and/or organic base, and described inorganic base is potash, sodium carbonate, sodium acid carbonate, carbonic acidOne or more in hydrogen potassium, NaOH and potassium hydroxide, described organic base be triethylamine, pyridine,One or more in 4-dimethylaminopyridine, morpholine and DIPEA.
4. 4. preparation method as claimed in claim 1, is characterized in that, described alkali and Compound I IMol ratio be (2:1)～(2.5:1).
5. 5. preparation method as claimed in claim 1, is characterized in that, in step (1), describedThe mol ratio of Compound I I and compound III is (1:1)～(1:1.2).
6. 6. preparation method as claimed in claim 1, is characterized in that, in step (1), describedThe temperature of condensation reaction is 75～160 DEG C; In step (2), described Bischler-Mohlau indoles closesThe temperature of ring reaction is 75～160 DEG C.
7. 7. preparation method as claimed in claim 6, is characterized in that, in step (1), describedThe temperature of condensation reaction is 100～130 DEG C; In step (2), described Bischler-Mohlau indolesThe temperature of ring closure reaction is 100～130 DEG C.
8. 8. preparation method as claimed in claim 1, is characterized in that, in step (2), will walkSuddenly the reactant liquor of (1) carries out before mixing with Bronsted acid coolingly, and described being cooled to naturally cools to instituteThe temperature of the reactant liquor of the step (1) of stating is 10～30 DEG C.
9. 9. preparation method as claimed in claim 1, is characterized in that, in step (2), describedBronsted acid is inorganic acid and/or organic acid; Described inorganic acid be a kind of in hydrochloric acid, sulfuric acid and phosphoric acid orMultiple; Described organic acid be formic acid, acetic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, butanedioic acid,Tartaric acid, citric acid, malonic acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid and p-methyl benzenesulfonic acid one waterOne or more in compound.
10. 10. preparation method as claimed in claim 1, is characterized in that, described Bronsted acid and chemical combinationThe mol ratio of thing II is (0.05:1)～(0.3:1).