Process for the preparation of biphenyl containing intermediates useful in making angiotensin II receptor antagonists

• US 5,557,002 A
• Filed: 06/06/1995
• Issued: 09/17/1996
• Est. Priority Date: 12/07/1992
• Status: Expired due to Fees

• Current Assignee: Eisai Company Limited (Eisai Medical Research Incorporated)
• Original Assignee: Eisai Chemical Co., Ltd., Eisai Company Limited (Eisai Medical Research Incorporated)
• Inventors: Tsurugi, Tomio, Urawa, Yoshio, Shimizu, Toshikazu, Furukawa, Ken, Yamagishi, Yoji, Ichino, Tomio
• Primary Examiner(s): DENTZ, BERNARD I
• Application Number:
  US08/466,128
• Time in Patent Office: 469 Days
• Field of Search: 558/44, 558/58, 556/442, 560/102, 552/105
• US Class Current: 558/44
• CPC Class Codes: C07C 63/72 Polycyclic acids
• CPC Class Codes: C07C 65/105 polycyclic
• CPC Class Codes: C07C 69/732 of unsaturated hydroxy carboxylic acids
• CPC Class Codes: C07C 69/76 Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07D 213/73 Unsubstituted amino or imino radicals
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 263/10 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 263/12 with radicals containing only hydrogen and carbon atoms
• CPC Class Codes: C07D 263/14 with radicals substituted by oxygen atoms
• CPC Class Codes: C07D 309/12 only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention provides an industrially advantageous process for preparing a 2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative represented by the following formula (II) which is a precursor of an antagonist against an angiotensin II receptor useful as an antihypertensive drug, a biphenyl derivative which is a precursor of the substituent of the pyridine derivative, a process for the preparation thereof, and an intermediate useful for the preparation of the biphenyl derivative: ##STR1## The 2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative can be prepared in a high yield according to the present invention from a 2-amino-5-halogeno-3-nitropyridine derivative through amidation, N-alkylation and reductive cyclization. The halogen atom introduced at the 5-position as a protective group against nitration can be eliminated simultaneously in the step which is conducted thereafter. Thus, this process is industrially advantageous.

Further, the biphenyl derivative of the present invention is excellent in reactivity and purity of the product, thus being an intermediate suitable for the industrial production.

Claims

1. A process for the preparation of a sulfonyloxy-biphenylcarboxylic ester derivative (I) having the formula:

##STR101## wherein R¹ represents a lower alkylsulfonyl group or an arylsulfonyl group; and

R² represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group;

which comprises subjecting a hydroxymethyl-biphenylcarboxylic ester derivative (II) having the formula;

##STR102## wherein R² represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group,

to sulfonylation.

2. The process for the preparation of a sulfonyloxy-biphenylcarboxylic ester derivative (I) having the formula:

##STR103## wherein R¹ represents a lower alkylsulfonyl group or an arylsulfonyl group; and

wherein R² represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group,

which comprises esterifying a hydroxymethyl-biphenylcarboxylic acid derivative (III) having the formula;

##STR104## into a hydroxymethyl-biphenylcarboxylic ester derivative (II) having the formula;

##STR105## wherein R² represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group, and further conducting sulfonylation.

3. A process for the preparation of a sulfonyloxy-biphenylcarboxylic ester derivative (I) having the formula:

##STR106## wherein R¹ represents a lower alkylsulfonyl group or an arylsulfonyl group; and

wherein R² represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group,

which comprises eliminating the protective group of a hydroxymethyl-biphenyloxazoline derivative (IV) having the formula;

##STR107## to form a hydroxymethyl-biphenylcarboxylic acid derivative (III) having the formula;

##STR108## esterifying it into a hydroxymethyl-biphenylcarboxylic ester derivative (II) having the formula;

##STR109## wherein R² represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group,

and further conducting sulfonylation.

4. A process for the preparation of a sulfonyloxy-biphenylcarboxylic ester derivative (I) having the formula:

##STR110## wherein R¹ represents a lower alkylsulfonyl group or an arylsulfonyl group; and

R² represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group;

which comprises eliminating the protective group of an alkoxymethyl-biphenyloxazoline derivative (V) having the formula;

##STR111## wherein R³ represents a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group a thioalkoxyalkyl group, a cycloether group, a trialkylsilyl group, a triarylsilyl group, a lower alkyl group, a vinyl group, an aralkyl group or a triphenylmethyl group,

to form a hydroxymethyl-biphenyloxazoline derivative (IV) having the formula;

##STR112## eliminating the protective group thereof to form a hydroxymethyl-biphenylcarboxylic acid derivative (III) having the formula;

##STR113## esterifying III into a hydroxymethyl-biphenylcarboxylic ester derivative (II) having the formula;

##STR114## wherein R² represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group,

and further conducting a sulfonylation.

5. A process for the preparation of a sulfonyloxy-biphenylcarboxylic ester derivative (I) having the formula:

##STR115## wherein R¹ represents a lower alkylsulfonyl group or an arylsulfonyl group; and

R² represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group;

which comprises coupling a 4-bromobenzyl ether derivative (VI) having the formula;

##STR116## wherein R³ represents a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group a thioalkoxyalkyl group, a cycloether group, a trialkylsilyl group, a triarylsilyl group, a lower alkyl group, a vinyl group, an aralkyl group or a triphenylmethyl group,

with oxazolylanisole through the Grignard reaction to form an alkoxymethyl-biphenyloxazoline derivative (V) having the formula;

##STR117## wherein R³ represents a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group a thioalkoxyalkyl group, a cycloether group, a trialkylsilyl group, a triarylsilyl group, a lower alkyl group, a vinyl group, an aralkyl group or a triphenylmethyl group,

eliminating the protective group thereof to form a hydroxymethyl-biphenyloxazoline derivative (IV) having the formula;

##STR118## eliminating the protective group thereof to form a hydroxymethyl-biphenylcarboxylic acid derivative (III) having the formula;

##STR119## esterifying it into a hydroxymethyl-biphenylcarboxylic ester derivative (II) having the formula;

##STR120## wherein R² represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group,

and further conducting sulfonylation.

6. A process for the preparation of a sulfonyloxy-biphenylcarboxylic ester derivative (I), having the formula:

##STR121## wherein R¹ represents a lower alkylsulfonyl group or an arylsulfonyl group; and

R² represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group;

which comprises protecting 4-bromobenzyl alcohol into a 4-bromobenzyl ether derivative (VI) having the formula;

##STR122## wherein R³ represents a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group a thioalkoxyalkyl group, a cycloether group, a trialkylsilyl group, a triarylsilyl group, a lower alkyl group, a vinyl group, an aralkyl group or a triphenylmethyl group,

coupling VI with oxazolylanisole to form an alkoxymethylbiphenyloxazoline derivative (V) having the formula;

##STR123## wherein R³ represents a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group a thioalkoxyalkyl group, a cycloether group, a trialkylsilyl group, a triarylsilyl group, a lower alkyl group, a vinyl group, an aralkyl group or a triphenylmethyl group,

through the Grignard reaction, eliminating the protective group thereof to form a hydroxymethyl-biphenyloxazoline derivative (IV) having the formula;

##STR124## eliminating the protective group thereof to form a hydroxymethyl-biphenylcarboxylic acid derivative (III) having the formula;

##STR125## esterifying III into a hydroxymethyl-biphenyl-carboxylic ester derivative (II) having the formula;

##STR126## wherein R² represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group

and further conducting sulfonylation.

7. A process for the preparation of a sulfonyloxy-biphenylcarboxylic ester derivative (i) having the formula:

##STR127## wherein R¹ represents a lower alkylsulfonyl group or an arylsulfonyl group; and

R² represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group;

which comprises reducing the carboxy-biphenyloxazoline derivative (VII) having the formula;

##STR128## or an alkoxycarbonyl-biphenyloxazoline derivative (VIII) having the formula;

##STR129## wherein R⁴ represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a trialkylsilyl group, a triarlsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group,

with a metal hydride complex into a hydroxymethylbiphenyloxazoline derivative (IV) having the formula;

##STR130## eliminating the protective group thereof to form a hydroxymethyl-biphenylcarboxylic acid derivative (III) having the formula;

##STR131## esterifying III into a hydroxymethyl-biphenylcarboxylic ester derivative (II) having the formula;

##STR132## wherein R² represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group,

and further conducting sulfonylation.

8. A process for the preparation of a sulfonyloxy-biphenylcarboxylic ester derivative (I) having the formula:

##STR133## wherein R¹ represents a lower alkylsulfonyl group or an arylsulfonyl group; and

R² represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group;

which comprises esterifying a carboxy-biphenyloxazoline derivative (VII) having the formula;

##STR134## with a lower alcohol into an alkoxycarbonyl-biphenyloxazoline derivative (VIII) having the formula;

##STR135## wherein R⁴ represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a trialkylsilyl group, a triarlsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group, with a metal hydride complex into a hydroxymethyl-biphenyloxazoline derivative (IV)

reducing VIII with a metal hydride complex into a hydroxymethyl-biphenyloxazoline derivative (IV) having the formula;

##STR136## eliminating the protective group thereof to form a hydroxymethyl-biphenylcarboxylic acid derivative (III) having the formula;

##STR137## esterifying III into a hydroxymethyl-biphenylcarboxylic ester derivative (II) having the formula;

##STR138## wherein R² represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group,

and conducting sulfonylation.

9. A process for the preparation of a sulfonyloxy-biphenylcarboxylic ester derivative (I) having the formula:

##STR139## wherein R¹ represents a lower alkylsulfonyl group or an arylsulfonyl group; and

R² represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group;

which comprises oxidizing a methyl-biphenyloxazoline derivative (IX) having the formula;

##STR140## with an oxidizing agent into a carboxy-biphenyloxazoline derivative (VII) having the formula;

##STR141## converting VII into a hydroxymethyl-biphenyloxazoline derivative (IV) having the formula;

##STR142## either by esterifying with a lower alcohol to form an alkoxycarbonyl-biphenyloxazoline derivative (VIII) having the formula;

##STR143## wherein R⁴ represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a trialkylsilyl group, a triarlsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group,

and reducing it with a metal hydride complex;

or

by reducing directly with a metal hydride complex, eliminating the protective group to form a hydroxymethyl-biphenylcarboxylic acid derivative (III) having the formula;

##STR144## esterifying III into a hydroxymethyl-biphenylcarboxylic ester derivative (II) having the formula;

##STR145## wherein R² represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group,

and further conducting sulfonylation.

10. A process for the preparation of a halomethyl-biphenylcarboxylic ester derivative (II) having the formula:

##STR146## wherein R¹ represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group,

and X represents a halogen atom,

which comprises subjecting a hydroxymethyl-biphenyl-carboxylic ester derivative (I) having the formula;

##STR147## wherein R¹ is defined above, to halogenation.

19. The process for the preparation of a halomethyl-biphenylcarboxylic ester derivative (II) as set forth in anyone of claims 10 to 18, wherein X is a bromine atom or a chlorine atom.

11. A process for the preparation of a halomethyl-biphenylcarboxylic ester derivative (II) having the formula, ##STR148## wherein R¹ represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group, and X represents a halogen atom,

which comprises esterifying a hydroxymethyl-biphenylcarboxylic acid derivative (III) having the formula:

##STR149## into a hydroxymethyl-biphenylcarboxylic ester derivative (I) having the formula;

##STR150## wherein R¹ represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group,

and further conducting halogenation.

12. A process for the preparation of a halomethyl-biphenylcarboxylic ester derivative (II) having the formula:

##STR151## wherein R¹ represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group, and X represents a halogen atom,

which comprises eliminating the protective group of a hydroxymethyl-biphenyloxazoline derivative (IV) having the formula;

##STR152## into a hydroxymethyl-biphenylcarboxylic acid derivative (III), ##STR153## esterifying III into a hydroxymethyl-biphenylcarboxylic ester derivative (I) having the formula;

##STR154## wherein R¹ represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group, and further conducting halogenation.

13. A process for the preparation of a halomethyl-biphenylcarboxylic ester derivative (II) having the formula, ##STR155## wherein R¹ represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group, and X represents a halogen atom,

which comprises eliminating the protective group of an alkoxymethyl-biphenyloxazoline derivative (V) having the formula:

##STR156## wherein R² represents a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group, a cycloether group, a trialkylsilyl group, a triarylsilyl group, a lower alkyl group, a vinyl group, an aralkyl group or a triphenylmethyl group,

to form a hydroxymethyl-biphenyloxazoline derivative (IV), having the formula, ##STR157## eliminating the protective group thereof to form a hydroxymethyl-biphenylcarboxylic acid derivative (III) having the formula;

##STR158## esterifying III into a hydroxymethyl-biphenylcarboxylic ester derivative (I) having the formula;

##STR159## wherein R¹ represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group

and further conducting halogenation.

14. A process for the preparation of a halomethyl-biphenylcarboxylic ester derivative (II) having the formula, ##STR160## wherein R¹ represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group, and X represents a halogen atom,

which comprises coupling a 4-bromobenzyl ether derivative (VI) having the formula:

##STR161## wherein R² represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group,

with oxazolylanisole to form an alkoxymethyl-biphenyloxazoline derivative (V) having the formula;

##STR162## wherein R² represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group,

through the Grignard reaction, eliminating the protective group thereof to form hydroxymethyl-biphenyloxazoline derivative (IV) having the formula;

##STR163## eliminating the protective group thereof to form a hydroxymethyl-biphenylcarboxylic acid derivative (III) having the formula;

##STR164## esterifying I into a hydroxymethyl-biphenylcarboxylic ester derivative (I), ##STR165## wherein R¹ represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group,

and further conducting halogenation.

15. A process for the preparation of a halomethyl-biphenylcarboxylic ester derivative (II) having the formula, ##STR166## wherein R¹ represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group, and X represents a halogen atom,

which comprises by protecting 4-bromobenzyl alcohol into a 4-bromobenzyl ether derivative (VI) having the formula:

##STR167## wherein R² represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group,

coupling VI with oxazolylanisole to form an alkoxymethylbiphenyloxazoline derivative (V) having the formula;

##STR168## wherein R² represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group,

through the Grignard reaction, eliminating the protective group thereof to form a hydroxymethyl-biphenyloxazoline derivative (IV) having the formula;

##STR169## eliminating the protective group thereof to form a hydroxymethyl-biphenylcarboxylic acid derivative (III) having the formula;

##STR170## esterifying III into a hydroxymethyl-biphenylcarboxylic ester derivative (I) having the formula;

##STR171## wherein R¹ represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group,

and further conducting halogenation.

16. A process for the preparation of a halomethyl-biphenylcarboxylic ester derivative (II) having the formula:

##STR172## wherein R¹ represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group, and X represents a halogen atom,

which comprises reducing a carboxy-biphenyloxazoline derivative (VII) having the formula;

##STR173## or an alkoxycarbonyl-biphenyloxazoline derivative (VIII) having the formula;

##STR174## wherein R³ represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a trialkylsilyl group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkl group, a thioalkoxyalkyl group or a triphenylmethyl group,

with a metal hydride complex into a hydroxymethylbiphenyloxazoline derivative (IV) having the formula;

##STR175## eliminating the protective group thereof to form a hydroxymethyl-biphenylcarboxylic acid derivative (III) having the formula;

##STR176## esterifying III into a hydroxymethyl-biphenylcarboxylic ester derivative (I) having the formula;

##STR177## wherein R¹ represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group,

and further conducting halogenation.

17. A process for the preparation of a halomethyl-biphenylcarboxylic ester derivative (II) having the formula, ##STR178## wherein R¹ represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group, and X represents a halogen atom,

which comprises esterifying a carboxy-biphenyloxazoline derivative (VII) having the formula:

##STR179## wherein R³ represents a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group a thioalkoxyalkyl group, a cycloether group, a trialkylsilyl group, a triarylsilyl group, a lower alkyl group, a vinyl group, an aralkyl group or a triphenylmethyl group,

with a lower alcohol into an alkoxycarbonyl-biphenyloxazoline derivative (VIII) having the formula;

##STR180## wherein R³ represents a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group a thioalkoxyalkyl group, a cycloether group, a trialkylsilyl group, a triarylsilyl group, a lower alkyl group, a vinyl group, an aralkyl group or a triphenylmethyl group,

reducing VIII with a metal hydride complex into a hydroxymethyl-biphenyloxazoline derivative (IV) having the formula;

##STR181## eliminating the protective group thereof to form a hydroxymethyl-biphenylcarboxylic acid derivative (III) having the formula;

##STR182## esterifying III into a hydroxymethyl-biphenylcarboxylic ester derivative (I) having the formula;

##STR183## wherein R¹ represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group,

and conducting halogenation.

18. A process for the preparation of a halomethyl-biphenylcarboxylic ester derivative (II) according to having the formula:

##STR184## wherein R¹ represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group, and X represents a halogen atom,

which comprises oxidizing a methyl-biphenyloxazoline derivative (IX) having the formula;

##STR185## with an oxidizing agent into a carboxy-biphenyloxazoline derivative (VII) according to the formula;

##STR186## obtaining a hydroxymethyl-biphenyloxazoline derivative (IV) having the formula;

##STR187## either by esterifying with a lower alcohol into an alkoxycarbonyl-biphenyloxazoline derivative (VIII) having the formula;

##STR188## wherein R³ represents a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group a thioalkoxyalkyl group, a cycloether group, a trialkylsilyl group, a triarylsilyl group, a lower alkyl group, a vinyl group, an aralkyl group or a triphenylmethyl group, and reducing it with a metal hydride complex, or

by reducing with a metal hydride complex directly, eliminating the protective group thereof to form a hydroxymethyl-biphenylcarboxylic acid derivative (III) having the formula;

##STR189## esterifying III into a hydroxymethyl-biphenylcarboxylic ester derivative (I) having the formula;

##STR190## wherein R¹ represents a lower alkyl group, an aryl group, an aralkyl group, a cycloether group;

a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group,

and conducting halogenation.